Atypical Parkinsonian Disorders PDF

Atypical Parkinsonian Disorders
CURRENT CLINICAL NEUROLOGY

Daniel Tarsy, MD, SERIES EDITOR
Atypical Parkinsonian Disorders: Clinical and Research Aspects, edited by Irene

Litvan, 2005
Psychiatry for Neurologists, edited by Dilip V. Jeste and Joseph H. Friedman, 2005
Status Epilepticus: A Clinical Perspective, edited by Frank W. Drislane, 2005
Thrombolytic Therapy for Acute Stroke, Second Edition, edited by Patrick D.
Lyden, 2005
Parkinsons Disease and Nonmotor Dysfunction, edited by Ronald F. Pfeiffer
and Ivan Bodis-Wollner, 2005
Movement Disorder Emergencies: Diagnosis and Treatment, edited by Steven
J. Frucht and Stanley Fahn, 2005
Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology,
and Clinical Management, edited by Alireza Minagar and J. Steven Alexander, 2005
Neurological and Psychiatric Disorders: From Bench to Bedside, edited by Frank I.
Tarazi and John A. Schetz, 2005
Multiple Sclerosis: Etiology, Diagnosis, and New Treatment Strategies, edited
by Michael J. Olek, 2005
Seizures in Critical Care: A Guide to Diagnosis and Therapeutics, edited by
Panayiotis N. Varelas, 2005
Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management,
edited by Robert H. Paul, Ronald Cohen, Brian R. Ott, Stephen Salloway, 2005
Handbook of Neurocritical Care, edited by Anish Bhardwaj, Marek A. Mirski,
and John A. Ulatowski, 2004
Handbook of Stroke Prevention in Clinical Practice, edited by Karen L. Furie
and Peter J. Kelly, 2004
Clinical Handbook of Insomnia, edited by Hrayr P. Attarian, 2004
Critical Care Neurology and Neurosurgery, edited by Jose I. Suarez, 2004
Alzheimers Disease: A Physicians Guide to Practical Management, edited
by Ralph W. Richter and Brigitte Zoeller Richter, 2004
Field of Vision: A Manual and Atlas of Perimetry, edited by Jason J. S. Barton
and Michael Benatar, 2003
Surgical Treatment of Parkinsons Disease and Other Movement Disorders, edited by
Daniel Tarsy, Jerrold L. Vitek, and Andres M. Lozano, 2003
Myasthenia Gravis and Related Disorders, edited by Henry J. Kaminski, 2003
Seizures: Medical Causes and Management, edited by Norman Delanty, 2002
Clinical Evaluation and Management of Spasticity, edited by David A. Gelber
and Douglas R. Jeffery, 2002
Early Diagnosis of Alzheimer's Disease, edited by Leonard F. M. Scinto and Kirk R.
Daffner, 2000
Sexual and Reproductive Neurorehabilitation, edited by Mindy Aisen, 1997
Atypical
Parkinsonian Disorders
Clinical and Research Aspects
Edited by
Irene Litvan, MD
University of Louisville School of Medicine,
Louisville, KY
Foreword by
Yves Agid, MD, PhD

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Cover illustrations from Fig. 7B in Chapter 4, Neuropathology of Atypical Parkinsonian Disorders, by Ian R. A. Mackenzie;
Fig. 13A in Chapter 19, Corticobasal Degeneration: The Syndrome and the Disease, by Bradley F. Boeve; Fig. 6 in Chapter
24, Role of Electrophysiology in Diagnosis and Research in Atypical Parkinsonian Disorders, by Josep Valls-Sol; and Fig.
5D in Chapter 25, Role of CT and MRI in Diagnosis and Research, by Mario Savoiardo and Marina Grisoli.
Cover design by Patricia F. Cleary
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Library of Congress Cataloging in Publication Data
Atypical Parkinsonian disorders / edited by Irene Litvan.
p. ; cm. -- (Current clinical neurology)
Includes bibliographical references and index.
ISBN 1-58829-331-9 (alk. paper)
1. Parkinson's disease.
[DNLM: 1. Parkinsonian Disorders. WL 359 A8874 2004] I. Litvan, Irene. II. Series.
RC382.A89 2004
616.8'33--dc22
2004008993
Series Editors Introduction
Since the original classic description of Parkinsons disease, there have been swings in concept
from a unitary disease with characteristic clinical features and unique neuropathologic changes to
that of a more variable disorder with multiple etiologies owing to a spectrum of pathological pro-
cesses. Originally, the terms paralysis agitans and Parkinsons disease first used in the 19th century
implied a unitary disease. The concept of parkinsonism as a special disease entity was supported by
the stereotyped features of akinesia, rigidity, tremor, and postural instability. The appearance of pos-
tencephalitic parkinsonism and later the recognition of arteriosclerotic parkinsonism led to the
realization that there must be multiple forms of the disease. Idiopathic Parkinsons disease finally
became anchored by identification of the Lewy body, which provided the necessary objective marker
for what, at least temporarily, quite remarkably came to be called Lewy body disease. However,
the later discovery that parkinsonism and dementia arise from a more diffuse distribution of Lewy
bodies led to the designation of dementia with Lewy bodies, one of the first of the new generation of
atypical parkinsonian disorders to be recognized. Striatonigral degeneration, multiple system atro-
phy, progressive supranuclear palsy, and corticobasal degeneration soon followed and rapidly evolved
from relatively exotic disorders to household words, at least among the rapidly growing community
of movement disorder neurologists. Finally, more recently, even the unitary concept of idiopathic
Parkinsons disease has been shaken by the discovery of multiple genetic types of Parkinsons
disease that may occur with or without Lewy bodies!
Currently, patients are increasingly aware of the possibility of atypical parkinsonism. Many ask
about it at early visits and understand their dismal prognosis and treatment prospects if they should
have one of these disorders. Dr. Irene Litvan has been at the front line for many years in the effort to
make sense of this bewildering array of atypical parkinsonian syndromes. In this volume she has
brought together an impressive group of experts in the field. All aspects of these disorders are
covered by highly knowledgeable and thoughtful investigators. Some of the clinical and scientific
disciplines which are reviewed are clearly more mature than others, but it would be safe to say that
our understanding of these disorders remains very much in its infancy. A particularly unique and very
useful aspect of the book is that each chapter concludes with a section on future directions in
research. As Dr. Litvan states in her preface, an important goal of this book is to enlist new research-
ers to further our knowledge about the cause and treatment of these devastating disorders. Atypical
Parkinsonian Disorders: Clinical and Research Aspects will serve as the comprehensive reference to
current state-of-the-art scientific developments in the field and will hopefully provide a launching
pad for future fundamental discoveries in the pathophysiology and treatment of these currently
hopeless disorders.
Daniel Tarsy, MD
v
Foreword
The term atypical parkinsonian disorders has the unavoidable connotation of neurodegeneration.
Neurodegeneration can be defined as a loss of neurons that is both selective (i.e., several neuronal
systems are affected, but not all), and slow (although faster than similar effects caused by aging).
This definition excludes both sequelae of brain insults and diffuse lesions of the nervous system such
as vascular parkinsonism and encephalopathies (Chapter 23).
Whats in a name? A less depressing definition of parkinsonian disorders (or parkinsonism) might
well be the following: an akinetic-rigid syndrome associated with the selective dysfunction of the
nigrostriatal dopaminergic system. This definition is broad enough to include both typical and atypi-
cal neurodegenerative parkinsonian disorders. Parkinsons disease is what we call a typical par-
kinsonian disorder. Parkinsons disease is characterized by progressive akinesia and rigidity, usually
unilateral at onset, with or without resting tremor, which responds significantly to levodopa treat-
ment or other kinds of dopaminergic replacement therapy. However, the diagnosis of Parkinsons
disease is difficult to establish for several reasons:
1. Akinesia and rigidity are heterogeneous symptoms that can differ from one patient to another.
Plastic rigidity (associated with the classical cogwheel phenomenon and predominant in the extremi-
ties), is different from the diffuse rigidity of the Gegenhalten type (rigidit oppositioniste) observed
in atypical parkinsonian disorders. Akinesia is a general term that is frequently used inappropriately,
and does in fact include several symptoms: akinesia per se, which means delayed initiation of move-
ment (increased reaction time); bradykinesia (slowness of movement); hypokinesia (easily observed
when testing repetitive movements of the extremities); difficulty in performing consecutive or
sequential gestures; and decreased motivation to move, whatever its origin.
2. Parkinsons disease is also difficult to diagnose because in most patients, other symptoms occur
during the course of the disease, including cognitive decline (cortical and/or subcortical dysfunction)
and axial symptoms such as dysarthria, swallowing difficulties, neck rigidity, postural abnormalities,
urinary dysfunction, gait disorders, postural instability (all symptoms that represent a major compo-
nent of atypical parkinsonian disorders), which respond poorly to Levodopa replacement therapy.
3. Before reaching a diagnosis of Parkinsons disease, it is indeed crucial to be sure that the patient
shows a significant response to levodopa treatment (or related therapy) used at adequate doses. What
we mean by significant is either (a) an objective 30% improvement in parkinsonian motor disabil-
ity (as evaluated before and after the administration of Levodopa), or (b) a subjective 30% improve-
ment in motor disability as assessed from the patient interview, either at the start of treatment (i.e.,
What was the percentage improvement in your condition when you received levodopa treatment for
the first time?) or later, during the course of the disease (i.e., What was the percentage improve-
ment in your condition when you took your first dose of levodopa?). A clear-cut response to
levodopa treatment (or dopamine agonists) is a prerequisite for a diagnosis of Parkinsons disease, as
it indirectly reflects the existence of a dysfunction of dopaminergic neurons in the striatum of pa-
tients. A lack of response to levodopa treatment (using adequate doses of levodopa) does not mean
that there is no nigrostriatal deficiency (inherent in the definition of parkinsonism), but rather indi-
cates that the reestablishment of normal brain dopaminergic transmission is not followed by an im-
provement in motor disability owing to the presence of nondopaminergic lesions located downstream
of the output of the basal ganglia.
4. Finally, Parkinsons disease is a heterogeneous disorder that includes several clinical pheno-
types identified in recent years. The term Parkinsons disease should in fact be replaced by
Parkinsons diseases, as several phenotypes of this disorder have been described resulting from
vii
viii Foreword
different mutations within different genes in patients with familial and sporadic forms of the disease.
This suggests that many, if not all, clinical phenotypes of sporadic Parkinsons disease have either a
monogenic cause or at least involve a significant predisposition to develop the illness.
By deduction, atypical parkinsonian disorders can be defined as a mirror image of typical parkin-
sonism, i.e., an akinetic-rigid syndrome that is not improved by the reestablishment of normal dopam-
inergic transmission in the brain. Within the spectrum of diseases that constitute the syndrome of
atypical parkinsonism, akinesia, and rigidity become rapidly severe and characteristically involve the
axis of the body. Shortly after onset other signs become more prominent, leaving parkinsonism in the
background: supranuclear gaze palsy, early falls and frontal lobe symptomatology will suggest pro-
gressive supranuclear palsy (Chapter 18); dysautonomia and cerebellar signs: multiple system atro-
phy (Chapter 20); unilateral apraxia, corticobasal degeneration (Chapters 13 and 19); dementia of the
cortico-subcortical type with early visual hallucinations, Lewy body disease (Chapter 21). Addi-
tional symptoms may help to establish the diagnosis of atypical parkinsonism, including speech dis-
orders (Chapter 14), various behavioral disorders (Chapters 12 and 13), dystonia, pyramidal signs
and pseudo-bulbar palsy. A thorough physical examination (Chapter 10) will either allow a final
diagnosis to be made or will suggest appropriate laboratory tests. Apart from electrophysiological
investigations (Chapter 28), which are mostly interesting in terms of research, three investigations
will provide decisive information as far as the diagnosis is concerned: a careful neuropsychological
examination to evaluate the different cortical (and subcortical) components of cognitive disorders
(Chapters 13, 16, and 24), ocular movement recording (Chapter 17), and neuroimaging, with particu-
lar reference to MRI (Chapter 25) (functional neuroimaging and positron emission tomography are
mainly used for research purposes). Nevertheless, the diagnosis of atypical parkinsonian disorders is
not easy to establish, and proves to be erroneous in about 10% of cases even in the hands of experts
in the field of movement disorders.
The best definition of atypical parkinsonism is probably an anatomo-clinical one, since post-
mortem examination of the brains of patients does not always result in an accurate histological diag-
nosis. There is, indeed, an increasing number of postmortem cases in which histopathology does not
entirely fulfill the diagnostic criteria for these disorders (Chapters 4 and 8), either because the distri-
bution of the lesions is unusual or because atypical histopathological stigmata are associated with the
characteristic hallmarks of the different diseases. Histopathological phenotypes have recently been
identified, based on the presence of various abnormal tau proteins (Chapter 5) or synucleins (Chapter
6). These pathological classifications are of great interest in studying the pathogenesis of the disor-
ders but, unfortunately, are of limited value to the patients and their caregivers. It is hoped that
molecular and cellular research in these fields will help to delineate new clinical and pathological
entities alongside those that have currently been identified in clinical practice.
During the past 5 years, aided by the unrelenting efforts of disease associations and lay groups, an
enormous amount of research has been undertaken with two main aims. One is to find new symptom-
atic treatments. This implies understanding the neuronal substrate underlying each of the many and
complex symptoms characteristic of each disorder, with a special focus on the anatomo-physiologi-
cal organization of the neocortex and basal ganglia. The other is to cure the diseases, i.e., to under-
stand the various mechanisms of nerve cell death that are directly related to the cause (or causes) of
the diseases. The only way to define a disease is, indeed, to define it by its origin, whether the cause
is genetic-monofactorial inheritance or multifactorial predisposition (Chapter 9), whether environ-
mental factors play a predominant or contributive role (Chapter 3), or whether both of these causes
are involved. The progress of research into the pathophysiology and pathogenesis of all these disor-
ders is impressive, when one takes into account their relative recent description (Chapter 2).
An effort needs to be made by our institutions to develop research programs specifically dedicated
to atypical parkinsonian disorders, from molecular and cellular biology to neurophysiology and be-
havioral sciences. The main objective, during the years ahead, must be to discover new drugs to
Foreword ix
improve the symptoms, to limit or stop the process of cell loss, and to repair the affected brain tissues.
Yet, there has been a notable improvement in patient management during the last few years (Chapter
11). Though there is no available curative treatment (does one know of a neurodegenerative disease
that can be cured?), there are numerous symptomatic treatments (Chapter 20) and rehabilitation
approaches (Chapter 30) that will help to reduce disability and improve both the patients well being
and the quality of life for both patients and caregivers. This is perhaps the most important message of
this book, Atypical Parkinsonian Disorders: Clinical and Research Aspects.
Irene Litvan, who has devoted the greater part of her clinical and research activities to these mys-
terious and distressing disorders, is to be applauded for having convinced so many leading experts in
the field to contribute to this promising book.
Yves Agid, MD, PhD
Preface
The atypical parkinsonian disorders, previously known as Parkinson plus syndromes, are char-
acterized by a rapidly evolving parkinsonism that usually has a poor or transient response to dopam-
inergic therapy and often associates with one or more atypical features. These disorders may be
difficult to accurately diagnose, but an early and correct diagnosis is relevant for both patients and
physicians, since it allows for appropriate management and prognosis, which in turn, improves pa-
tients and families quality of life. An accurate diagnosis also allows patients to participate in re-
search and may increase survival.
This book, Atypical Parkinsonian Disorders: Clinical and Research Aspects, the first of its kind,
provides an all-encompassing view of the current status of atypical parkinsonian disorders from both
clinical and research viewpoints. Its goals are threefold: (1) to provide critical, state-of-the-art in-
sight into both the clinical and research aspects of the atypical parkinsonian disorders; (2) to increase
clinicians index of suspicion by providing them with appropriate tools for an accurate diagnosis; and
(3) to enlist new researchers who will further our knowledge on the etiopathogenesis of these devas-
tating disorders and hopefully allow for the identification of new therapeutic paradigms.
The chapters have been written by world-leading experts in their fields, and their efforts have
culminated in a truly unique compilation of what is currently known about the historic aspects, epide-
miology, neuropathology, genetics, neuropsychological, neuropsychiatric, ophthalmologic, neuro-
logic, and radiologic diagnostic evaluations and therapeutic approaches, as well as overall
understanding of atypical parkinsonian disorders. We anticipate that the enclosed DVD, containing
visual and auditory aids, will help clinicians, fellows, residents, students, and neuroscience research-
ers alike to characterize and differentiate the various atypical parkinsonian disorders. Audio seg-
ments will be helpful to characterize and distinguish the diverse speech disturbances found in these
disorders. Current controversies and the role of genetics and neurological and pathological pheno-
types in the nosologic classification of these disorders as well as each chapter authors view on where
research should focus in the future are offered.
Movement disorder specialists, neurologists, neuro-ophthalmologists, neuropathologists, psychia-
trists, neuropsychologists, geriatricians, and physical and occupational therapists alike may find these
pages indispensable. Clinicians, residents, and students may find the chapters on epidemiology, medi-
cal and physical history techniques, neuropsychiatric and neuropsychological testing, praxis,
visuospatial cognition, neuro-ophthalmology, and speech and language assessments invaluable tools
for clinical diagnosis, while the disease-specific videos, tables, and figures may provide them with a
visual handbook for frequent reference. Researchers and fellows will gain further insight into their
own work, which will add to the progression of the knowledge presented in theses pages.
Atypical Parkinsonian Disorders would have not been possible without the hard work and dedica-
tion of friends and colleagues who graciously provided state-of-the-art chapters, excellent figures,
and unique video and audio segments that we believe are crucial tools for learning, teaching, and
research. I want particularly to thank Dr. Daniel Tarsy for encouraging me to edit this exciting book.
I also want to acknowledge the help provided by Theresa Perry and Whitney Rogers in its prepara-
tion, and the support from Michael Gruenthal and the University of Louisville. Finally, I want to
thank patients and caregivers for their time and dedication to our research and for their patience
waiting for a therapeutic paradigm shift. It is hoped that their increasing participation in research and
the knowledge summarized in this book will provide the needed enthusiasm to attract new research-
ers into this field who will further our understanding of these diseases so they can soon be eradicated
from the face of the earth.
xi
Carol Frattali, co-author of Chapter 16 on speech and language, passed away suddenly while this
book was in press. Carol was a superb clinician, valued colleague, and was developing a new pro-
gram of research at the National Institutes of Health when she was taken from us. Carol was not
afraid to begin a new research project, no matter how difficult the challenge. I am sure that attitude
kept her young at heart and permeated all facets of her life. She was inspirational to patients, col-
leagues and friends, and we all surely miss her.
Irene Litvan, MD
Contents
Series Editors Introduction ............................................................................................................. v

Foreword ........................................................................................................................................... vii
Preface ................................................................................................................................................. xi
Contributors ...................................................................................................................................... xv
Companion DVD ............................................................................................................................ xix
1 What is An Atypical Parkinsonian Disorder? ..................................................................... 1
Irene Litvan
2 Historical Issues and Atypical Parkinsonian Disorders ................................................. 11
Christopher G. Goetz
3 Epidemiology of Progressive Supranuclear Palsy
and Multiple System Atrophy ........................................................................................ 23
Adam Zermansky and Yoav Ben-Shlomo
4 Neuropathology of Atypical Parkinsonian Disorders .................................................... 33
Ian R. A. Mackenzie
5 Animal Models of Tauopathies ........................................................................................... 65
Jada Lewis and Michael Hutton
6 Neurodegenerative F-Synucleinopathies .......................................................................... 77
Michel Goedert and Maria Grazia Spillantini
7 Computer Modeling in Basal Ganglia Disorders ............................................................. 95
Jos Luis Contreras-Vidal
8 Atypical Parkinsonian Disorders: Neuropathology and Nosology .................................. 109
Charles Duyckaerts
9 Genetics of Atypical Parkinsonism: Implications for Nosology ...................................... 137
Thomas Gasser
10 Medical History and Physical Examination in Parkinsonian Syndromes:
How to Examine a Parkinsonian Syndrome ..................................................................... 153
Marie Vidailhet, Frdric Bourdain, and Jean-Marc Trocello
11 Role of Neuropsychiatric Assessment in Diagnosis and Research ............................. 161
Dag Aarsland, Uwe Ehrt, and Clive Ballard
12 Added Value of the Neuropsychological Evaluation
for Diagnosis and Research of Atypical Parkinsonian Disorders .......................... 183
Bruno Dubois and Bernard Pillon
13 Role of Praxis in Diagnosis and Assessment .................................................................. 195
Ramn Leiguarda
14 Role of Visuospatial Cognition Assessment in the Diagnosis and Research
of Atypical Parkinsonian Disorders ............................................................................. 211
Paolo Nichelli and Anna Magherini
15 Role of Ocular Motor Assessment in Diagnosis and Research .................................... 233
R. John Leigh and David S. Zee
xiii
xiv Contents
16 Characterizing and Assessing Speech and Language Disturbances .......................... 253

Carol Frattali and Joseph R. Duffy
17 Quality of Life Assessment in Atypical Parkinsonian Disorders ............................... 275
Anette Schrag and Caroline E. Selai
18 Progressive Supranuclear Palsy ........................................................................................ 287
Irene Litvan
19 Corticobasal Degeneration: The Syndrome and the Disease ............................................ 309
Bradley F. Boeve
20 Multiple System Atrophy ................................................................................................... 335
Felix Geser and Gregor K. Wenning
21 Clinical Diagnosis of Dementia With Lewy Bodies ....................................................... 361
David J. Burn, Urs P. Mosimann, and Ian G. McKeith
22 Clinical Diagnosis of Familial Atypical Parkinsonian Disorders ............................... 375
Yoshio Tsuboi, Virgilio H. Evidente, and Zbigniew K. Wszolek
23 Clinical Diagnosis of Vascular Parkinsonism
and Nondegenerative Atypical Parkinsonian Disorders ......................................... 393
Madhavi Thomas and Joseph Jankovic
24 Role of Electrophysiology in Diagnosis and Research
in Atypical Parkinsonian Disorders ............................................................................. 409
Josep Valls-Sol
25 Role of CT and MRI in Diagnosis and Research ............................................................ 431
Mario Savoiardo and Marina Grisoli
26 Role of Functional Magnetic Neuroimaging in Diagnosis and Research .................. 451
Hartwig Roman Siebner and Gnther Deuschl
27 PET and SPECT Imaging in Atypical Parkinsonian Disorders ................................... 459
Alexander Gerhard and David J. Brooks
28 Current and Future Therapeutic Approaches ................................................................ 473
Elmyra V. Encarnacion and Thomas N. Chase
29 Rehabilitation of Patients With Atypical Parkinsonian Disorders ............................. 485
Daniel K. White, Douglas I. Katz, Terry Ellis, Laura Buyan-Dent,
and Marie H. Saint-Hilaire
30 Overview and Future Research ......................................................................................... 497
Andrew Lees
Index ................................................................................................................................................. 503

Contributors
DAG AARSLAND, PhD Centre for Neuro and Geriatric Psychiatric Research, Rogaland Central
Hospital, Stavanger, Norway
YVES AGID, MD, PhD INSERM U-289, Hpital de la Salptriere, Paris, France
CLIVE BALLARD, PhD Wolfson Centre for Age-Related Diseases, Kings College London,
London, UK
YOAV BEN-SHLOMO, MRCP, FFPHM Department of Social Medicine, University of Bristol,
Bristol, UK
BRADLEY F. BOEVE, MD Division of Behavioral Neurology, Department of Neurology, Mayo
Clinic College of Medicine, Rochester, MN
FRDRIC BOURDAIN Department of Neurology, Saint-Antoine Hospital, and U289 Hpital
de la Salptrire, Paris, France
DAVID J. BROOKS, MD, DSC, FRCP MRC Cyclotron Unit Department of Neurology, Faculty
of Medicine, Hammersmith Hospital, Imperial College, London, UK
DAVID J. BURN, MD, FRCP Institute for Aging and Health, Wolfson Research Centre, Regional
Neurosciences Centre, Department of Neurology, Newcastle General Hospital
and University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK
LAURA BUYAN-DENT, MD, PhD Department of Neurology, Boston University School of Medicine,
Boston, MA
THOMAS N. CHASE, MD Experimental Therapeutics Branch, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, MD
JOS LUIS CONTRERAS-VIDAL, PhD Department of Kinesiology and Graduate Program
in Neuroscience and Cognitive Science (NACS), University of Maryland, College Park,
MD
BRUNO DUBOIS, MD Clinique de Neurologie et Neuropsychologie, INSERM U 610, Hpital
de la Salptriere, Paris, France
GNTHER DEUSCHL, MD Department of Neurology, Christian-Albrechts-University, Kiel,
Germany
JOSEPH R. DUFFY, PhD, BC-NCD Department of Neurology, Division of Speech Pathology,
Mayo Clinic and Medical School, Rochester, MN
CHARLES DUYCKAERTS, MD Laboratoire de Neuropathologie Escourolle, Hpital de la
Salptrire, Paris, France
UWE EHRT, MD Centre for Neuro and Geriatric Psychiatric Research, Rogaland Central
Hospital, Stavanger, Norway
TERRY ELLIS, MSPT, NCS Sargent College of Health and Rehabilitation Sciences, Boston
University, Boston, MA
ELMYRA V. ENCARNACION, MD Movement Disorders Section, Neurosciences Department,
Wellspan Health, York, PA
VIRGILIO H. EVIDENTE, MD Department of Neurology, Mayo Clinic, Scottsdale, AZ;
Mayo Medical School, Rochester, MN
CAROL FRATTALI, PhD, BC-NCD Rehabilitation Medicine Department, Speech-Language
Pathology Section, W.G. Magnuson Clinical Center, National Institutes of Health,
Bethesda, MD; Department of Hearing and Speech Sciences, University of Maryland
at College Park, College Park, MD
THOMAS GASSER, MD Department of Neurodegenerative Diseases, Hertie-Institute
for Clinical Brain Research, University of Tbingen, Tbingen, Germany
xv
xvi Contributors
ALEXANDER GERHARD, MD MRC Clinical Sciences Centre and Division of Neuroscience,

Faculty of Medicine, Hammersmith Hospital, Imperial College, London, UK
FELIX GESER, MD Department of Neurology, University Hospital, Innsbruck, Austria
MICHEL GOEDERT, MD, PhD, FRS MRC Laboratory of Molecular Biology, Cambridge, UK
CHRISTOPHER G. GOETZ, MD Departments of Neurological Sciences and Pharmacology, Rush
University/Rush University Medical Center, Chicago, IL
MARINA GRISOLI, MD Department of Neuroradiology, Istituto Nazionale Neurologico
C. Besta, Milan, Italy
MICHAEL HUTTON, PhD Department of Neuroscience, Mayo Clinic Jacksonville,
Jacksonville, FL
JOSEPH JANKOVIC, MD Parkinsons Disease Center and Movement Disorders Clinic, Department
of Neurology, Baylor College of Medicine, Houston, TX
DOUGLAS I. KATZ, MD Healthsouth Braintree Rehabilitation Hospital, Braintree, MA;
Department of Neurology, Boston University School of Medicine, Boston, MA
ANDREW LEES, MD, FRCP Reta Lila Weston Institute of Neurological Studies, Windeyer
Medical Institute, University College London WC1 UK
R. JOHN LEIGH, MD Departments of Neurology, Neurosciences, and Biomedical Engineering,
Veterans Affairs Medical Center and Case Western Reserve University, Cleveland OH;
Department of Neurology, University Hospitals, Cleveland, OH
RAMN LEIGUARDA, MD Professor of Neurology, Ral Correa Institute of Neurological
Research, FLENI, Buenos Aires, Argentina
JADA LEWIS, PhD Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville FL
IRENE LITVAN, MD Raymond Lee Lebby Professor of Parkinson Disease Research, Director,
Movement Disorder Program, Department of Neurology, University of Louisville
School of Medicine, Louisville, KY
IAN R. A. MACKENZIE, MD, FRCPC Department of Pathology and Laboratory Medicine,
University of British Columbia, Vancouver, Canada
ANNA MAGHERINI, MD Clinica Neurologica, Universit di Modena e Reggio Emilia,
Modena, Italy
IAN G. MCKEITH, MD, FRCPSYCH Institute for Aging and Health, Wolfson Research Centre,
Newcastle General Hospital and University of Newcastle-upon-Tyne, Newcastle-
upon-Tyne, UK
URS P. MOSIMANN, MD Institute for Aging and Health, Wolfson Research Centre, Newcastle
General Hospital and University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK
PAOLO NICHELLI, MD Clinica Neurologica, Universit di Modena e Reggio Emilia, Modena,
Italy
BERNARD PILLON, PhD Clinique de Neurologie et Neuropsychologie, INSERM U 610,
Hpital de la Salptriere, Paris, France
MARIE H. SAINT-HILAIRE, MD, FRCAC Healthsouth Braintree Rehabilitation Hospital,
Braintree, MA; Department of Neurology, Boston University School of Medicine,
Boston, MA
MARIO SAVOIARDO, MD Department of Neuroradiology, Istituto Nazionale Neurologico
C. Besta, Milan, Italy
ANETTE SCHRAG, MD, PhD University Department of Clinical Neurosciences, Royal Free
and University College Medical School, London, UK
CAROLINE E. SELAI, PhD, CPSYCHOL Department of Motor Neuroscience and Movement
Disorders, Institute of Neurology, Queen Square, London UK
HARTWIG ROMAN SIEBNER, MD Department of Neurology, Christian-Albrechts-University,
Kiel, Germany
Contributors xvii
MARIA GRAZIA SPILLANTINI, PhD Centre for Brain Repair, Department of Neurology,
University of Cambridge, Cambridge, UK
MADHAVI THOMAS, MD Experimental Therapeutics Branch, National Institutes of Neurologic
Disorders and Stroke, National Institutes of Health, Bethesda, MD
JEAN-MARC TROCELLO Department of Neurology, Saint-Antoine Hospital, and U289
Hpital de la Salptrire, Paris, France
YOSHIO TSUBOI, MD Department of Neurology, Mayo Clinic, Jacksonville, FL; (Currently at)
Fifth Department of Internal Medicine, Fukuoka University School of Medicine,
Fukuoka, Japan
JOSEP VALLS-SOL, MD Unitat dEMG, Servei de Neurologia, Departament de Medicina,
Hospital Clnic, Institut dInvestigacio Biomedica August Pi i Sunyer (IDIBAPS),
Universitat de Barcelona, Barcelona, Spain
MARIE VIDAILHET, MD Department of Neurology, Saint-Antoine hospital, and U289 Hpital
de la Salptrire, Paris, France
GREGOR K. WENNING, MD, PhD Department of Neurology, University Hospital, Innsbruck,
Austria
DANIEL K. WHITE, MSPT Healthsouth Braintree Rehabilitation Hospital, Braintree, MA;
Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA
ZBIGNIEW K. WSZOLEK, MD Department of Neurology, Mayo Clinic, Jacksonville, FL; Mayo
Medical School, Rochester, MN
DAVID S. ZEE, MD Departments of Neurology and Neurosciences, The Johns Hopkins
University School of Medicine, Baltimore, MD
ADAM ZERMANSKY, MBCHB, MRCP Regional Neurosciences Centre, University of Newcastle-
upon-Tyne, Newcastle-upon-Tyne, UK
Companion DVD
To use this DVD-ROM, you will need a computer with a DVD drive. This DVD will not operate
in a CD-ROM drive. To view the PDF files on this DVD-ROM, you will need Adobe Reader. To
view the video clips, you will need an MPEG-1 compatible video player (Windows Media Player,
Quicktime, Real Player, etc.). Most computers and operating systems will play these videos without
further installation or modification.
xix
Classification 1
1
What is an Atypical Parkinsonian Disorder?
Irene Litvan
INTRODUCTION
A parkinsonism is a syndrome defined by akinesia associated with rigidity or rest tremor. The
akinesia can be expressed as motor slowness (bradykinesia) or as a paucity of movement (hypokine-
sia), i.e., difficulty in the initiation of or decreased amplitude of movements such as arm swing or
facial expression. This syndrome is usually the result of a dysfunctional nigrostriatal pallidal path-
way. Impairment of postural reflexes is not included as one of the features of the parkinsonian syn-
drome since abnormal postural reflexes are generally the consequence of dysfunction of other motor
pathways. There are a variety of causes of parkinsonism, but Parkinsons disease (PD) is the most
common (Fig. 1). Although there is extensive literature on PD, this is one of the few books dedicated
to the remaining atypical parkinsonian disorders.To appropriately diagnose PD, one should be aware
of when to suspect that a patient does not have PD and may be suffering from one of these atypical
disorders.
The atypical parkinsonian disorders (previously known as Parkinson plus syndromes) are
characterized by a rapidly evolving parkinsonism that has a poor or transient response to dopaminer-
gic therapy and often associates with one or more atypical features for PD. Some of these features
include early presence of postural instability, early autonomic failure, vertical supranuclear gaze
palsy, pyramidal or cerebellar signs, alien limb syndrome, and apraxia (Table 1; see corresponding
video segments on accompanying DVD). Making the distinction between these two major groups of
disorders is critical for both clinical practice and research because the prognosis and treatment of
patients with an atypical parkinsonian disorder and those with PD differ (14). In the clinical setting,
although patients with PD may have an almost normal life-span if treated appropriately (46), those
with atypical parkinsonian disorders have a shorter survival time and more complications occur at
early stages and are frequently more severe (3,710) (see Table 2 for an example). Moreover, indi-
cated therapies (particularly surgical approaches) differ significantly since some may not be indi-
cated to treat patients with atypical parkinsonian disorders. Until recently, clinicians would lump
all the atypical parkinsonian disorders together and would only distinguish between this group and
PD. However, the need for early identification of the different atypical parkinsonian disorders is
becoming increasingly recognized (11), as their prognosis, complications, and survival differ
(3,7,8,1219).
For research, this distinction is crucial; homogenous groups are a necessity for studies that lead to
firm conclusions. Genetic, analytical, epidemiological, and clinical trials require the inclusion of
accurately diagnosed patients. However, diagnosis of the atypical parkinsonian disorders can be at
times challenging (2025) since these disorders may have similar presentations at early disease stages
From: Current Clinical Neurology: Atypical Parkinsonian Disorders

Edited by: I. Litvan Humana Press Inc., Totowa, NJ
1
2 Litvan
Fig. 1. PSP, progressive supranuclear palsy; CBD, corticobasal degeneration; MSA, multiple system atro-
phy; DLB, dementia with Lewy bodies; FTDP-17, frontotemporal dementia with parkinsonism linked to chro-
mosome 17; SCAs, spinocerebellar atrophy; NBIA, Neurodegeneration With Brain Iron Accumulation,
previously called HallervordenSpatz Syndrome; HIV, human immunodeficiency virus.
Table 1
When Should an Atypical Parkinsonian Disorder be Suspected?
Features suggestive of an atypical parkinsonian disorder
Motor
Rapid disease progression
Early instability and falls
Absent, poor, or not maintained response to levodopa therapy
Myoclonus
Pyramidal signs
Cerebellar signs
Early dysarthria and/or dysphagia
Early dystonia/contractures (unrelated to treatment)
Autonomic Features
Impotence/decreased genital sensitivity in females
Early orthostatic hypotension unrelated to treatment
Early and/or severe urinary disturbances
Oculomotor
Marked slowing of saccades
Difficulty initiating saccades, gaze (oculomotor apraxia)
Supranuclear gaze palsy
Nystagmus
Cognitive and behavioral
Early and severe frontal or cortical dementia
Visual hallucinations not induced by treatment
Ideomotor apraxia
Sensory or visual neglect/cortical disturbances
Classification 3
Table 2
Progression of Various Parkinsonian Disorders
Disorder Sample Median Age Median HY Median HY Median HY Median HY Median survival
Size (N) at Onset II Latencies III Latencies IV Latencies V Latencies After HY V Onset
(yr) (mo) (mo) (mo) (mo) (mo)
PD 18 60 36* 66** 166** 179** 12
CBD 13 64 25 42 55 62 43
DLB 11 65 12 43 45 59 12
MSA 15 56 0 3 56 73 10
PSP 24 65 0 38 56 9
Modified from Muller et al., with permission (17).
*p < 0.05; **p < 0.001 Parkinsons disease (PD) vs atypical parkinsonian disorders (CBD, DLB, MSA, PSP), (Mann
Whitney U Test). PD patients had a significantly longer latency to each Hoehn and Yahr (HY) stage than those with atypical
parkinsonian disorders, confirming the more rapid progression of motor disability in patients with atypical parkinsonian disor-
ders. Most MSA and PSP patients developed postural instability with or without falls significantly earlier than those with CBD
and DLB. Postural instability and falls are the most common initial symptoms in PSP, and almost all PSP patients developed an
HY stage III within 1 yr of motor onset. The majority of MSA (67%), the majority of DLB (55%), and 38% of CBD patients
also reached this stage early.
(i.e., progressive falls, parkinsonism not responsive to dopaminergic therapy). Tell-tale signs may
take 2 to 4 yr after symptom onset to develop, or early features may be either disregarded or misdiag-
nosed by clinicians.
Misdiagnosis of these disorders is frequent, as patients exhibit a variety of symptoms that may
lead them to be initially evaluated by internists or specialists (e.g., ophthalmologists, urologists, neu-
rologists, psychiatrists, neurosurgeons). For example, it is not unusual for a patient with progressive
supranuclear palsy (PSP) to be evaluated by several ophthalmologists (and have their glasses changed
several times) or to have multiple unnecessary studies for evaluating the cause of their falls prior to
being seen by a neurologist. Similarly, patients with corticobasal degeneration (CBD) may present
after unsuccessful carpal tunnel surgery, or those with multiple system atrophy (MSA) may present
only after failed prostate surgery; in both cases these types of surgery can worsen the patients symp-
toms. Diagnostic accuracy would greatly improve, however, if clinicians from different disciplines
would have a broader knowledge of the typical and atypical presentations of these disorders and use
proposed clinical diagnostic criteria (26).
In the absence of biological markers and known pathogenesis, current diagnosis requires the pres-
ence of certain clinical features that allow for clinical diagnosis and eventual pathologic verification.
As a result, diagnostic accuracy requires that both clinical and pathological sets of diagnostic criteria
be valid and reliable (27,28). Neuropathologic diagnostic criteria for most parkinsonian disorders
have been validated and standardized (27,29); the exceptions are those for dementia with Lewy bod-
ies (DLB) and PD with later onset dementia (PDD). Similarly, recently the clinical diagnostic criteria
have undergone the same process of rigorous operationalization and validation for most of these
disorders (26,3035).
Though consensus for the diagnosis of several of these disorders has been put forward (3033),
and validation studies of diagnostic criteria have been performed for most of the atypical parkinso-
nian disorders (36), refinement of the criteria is still needed (36). In practice, clinicians are exposed
to patients who exhibit different parkinsonian disorders, and so validation studies should compare the
accuracy of several sets of criteria with neuropathology. The Scientific Issue Committee of the Move-
ment Disorder Society created a task force to critically review the accuracy of different sets of diag-
nostic criteria for parkinsonian disorders (36). The task force analyzed how well each set of diagnostic
criteria identified all subjects with the disease as having the disease (i.e., sensitivity); identified sub-
4 Litvan
Table 3
Validity of the Clinical Diagnostic Criteria for PSP, MSA, DLB, and VaD
Positive
Sensitivity Specificity Predictive n/n
Disorder Criteria (%) (%) Value (%) Author TOTAL
PSP Blin et al. (47) Litvan et al.
Probable/Possible 21/63 100/85 100/63 (29) 24/83
Blin et al. (47)
Probable/Possible-1st visit 13/34 100/98 100/85 Litvan
Probable/Possible-last visit 55/89 94/74 73/50 (19) 24/105
Clinicians own criteria
First visit 72 93 76 Litvan et al.
Last visit 80 92 76 (19) 24/105
Collins et al. (51) Litvan et al.
Golbe et al. (49)
First visit 49 97 85 Litvan et al.
Last visit 67 94 76 (19) 24/105
Golbe et al. (49) 50 98 92 24/83
Lees (48)
First visit 53 95 77
Last visit 78 87 65 24/105
Litvan
Lees (48) 58 95 82 (29) 24/83
NINDS-SPSP Litvan et al.
NINDS-SPSP Lopez
Probable/Possible 62/75 100/98.5 100/96 (25) 8/40
Queen Square Movement
Disorder neurologists Hughes
diagnosis 84.2 96.8 80 (52)* 20/143
Tolosa et al. (50) Litvan
First visit 56 96.6 75.5 Litvan et al.
MSA Last visit 69 97 80 (21) 16/105
Clinicians prospective
diagnosis in life
First visit 22 92 Oaski et al.
Last visit 100 86 (33) 51/59
Consensus Criteria (55)
Probable/Possible 16/28 100/93
Consensus Criteria (55)
Queen Square movement
disorder neurologists Hughes et al.
diagnosis 88 86 (52)* 34/143
Quinn (54)
Quinn (54)
(continued)
Classification 5
Table 3 (continued)
Validity of the Clinical Diagnostic Criteria for PSP, MSA, DLB, and VaD
Positive
Sensitivity Specificity Predictive n/n
Disorder Criteria (%) (%) Value (%) Author TOTAL
Quinn (54) Litvan et al.

First visit
DLB CERAD 75 50 Mega (56) 4/24
CDLB (30) 75 79 100 Mega (56) 4/24
CDLB (30)
First visit 17.8 75
Last visit 28.6 NR 55.8 Litvan (62) 14/105
CDLB(30) 22 100 100 Holmes (57) 9/80
CDLB(30) 57 90 91 Luis (58) 35/56
CDLB (30) Verghese
CDLB (30)
Probable/Possible 0/34 100/94 NA/55 Lopez (25) 8/40
CDLB (30) McKeith
CDLB (30)
Probable/Possible 100/100 8/0 83/NA Hohl (60) 5/10
CDLB (30) 30.7 100 Lopez (34)* 13/26
First visit 17.8 99 75
Last visit 28.6 99 55.8 Litvan (61) 14/105
First visit 35 99.6 80
VaD Last visit 48 99.6 100 Litvan (62) 10/105
Queen Square movement
disorder neurologists Hughes et al.
diagnosis 25 98.6 33.3 (52)* 3/143
Revised from Litvan et al. (36).
*Prospective studies. Note that all other studies are retrospective. CDLB, consensus criteria for dementia with
Lewy bodies.
jects without the disease as not having the disease (i.e., specificity); and provided reasonable esti-
mates of disease risk (i.e., positive predictive value or PPV). See summary table (Table 3) and refer to
the actual publication (36) and specific disease-related chapters in this book for detailed comments.
Overall, most of these criteria are specific but not very sensitive. It is worth noting that a validation of
pathologic and clinical diagnostic criteria for PD is still needed. Standardization of diagnostic crite-
ria, clinical scales, and identification of outcome measures (37,38) set the stage for conducting
appropriate clinical trials.
CLASSIFICATION OF ATYPICAL PARKINSONIAN DISORDERS

Atypical parkinsonian disorders can be caused by primary or secondary diseases (see Fig. 1). The
primary causes consist of neurodegenerative processes such as PSP, CBD, MSA, DLB, and PDD.
Interestingly, one of the earlier historical cases thought to have the typical features of PSP was recently
found to have a midbrain tumor through autopsy examination. As discussed in Chapter 23, secondary
causes also include drugs, infections, toxins, or vascular disease (21,23,3944).
6 Litvan
Table 4
Classification of Atypical Parkinsonian Disroders
Tauopathies Synucleinopathies
Progressive supranuclear palsy Parkinsons disease
Corticobasal degeneration Multiple system atrophy
Lytico-bodig disease Dementia with Lewy bodies
West-French Indies parkinsonian disorder Parkinson disease and dementia
Frontotemporal dementias with parkinsonism Neurodegeneration with brain iron
linked to chromosome 17 accumulation
An alternative classification (mostly helpful for research and future therapeutic approaches rather
than for clinical use) considers the type of aggregated proteins in the brain lesions and classifies these
disorders as tauopathies and synucleinopathies (Table 4; see also Chapters 4 and 8). Commonalities
in clinical, biological, or genetic findings question the nosological classification of some of these
disorders; for further information the reader is referred to Chapters 8 and 9.
PSP and DLB/PDD are the most frequent neurodegenerative primary cause of an atypical parkin-
sonian disorders (31,4547). A good history and physical examination will rule out drug-induced
atypical parkinsonian disorders and supports the diagnosis of these specific disorders (Chapter 10).
Each disorder is specifically covered in Chapters 1823. The role of ancillary and laboratory tools to
assist in the diagnosis of these disorders is discussed in Chapters 1116 and 2427. Ancillary tests
(e.g., neuroradiologic or cerebrospinal studies) also help with the diagnosis of disorders caused by
vascular diseases, tumors, or infection (e.g., Whipples disease, CreutzfeldtJakob disease, human
immunodeficiency virus). Specific therapeutic and rehabilitation approaches for all of these disor-
ders are provided in each disease chapter and an overview of future biologic and rehabilitation ap-
proaches is provided in Chapters 28 and 29.
It is our expectation that this book will continue to improve the accuracy of the diagnosis of these
disorders by raising awareness of their different presentations and by increasing diagnosticians
index of suspicion. An early and accurate diagnosis will allow better management of these patients
and increase research potential.
There has been a tremendous increase in our knowledge concerning the proteins that characterize
and aggregate in the brain in each of these disorders. Moreover, animal models are now available to
help test potential new therapies (see Chapters 5 and 6). Hence, in addition to serving as a reference
source, it is hoped that this book will stimulate new investigators to join us in the search for answers
to the multiple questions raised throughout the book and in the battle against these disorders. It is
anticipated that a better understanding of these diseases, their nosology, and etiopathogenesis (see
Chapters 39) will lead to better management, quality of life (see Chapter 17), and treatment for
patients who suffer them. We anticipate that the eradication of these devastating diseases from the
face of the earth will occur in not such a remote future.
LEGEND TO VIDEOTAPE
Postural Instability: Video segment shows a patient with a history of falls and an impaired postural
reflex with the backward pull test. The patient would have fallen, unless aided by the examiner. The
gait is stable but slightly wide-based.
Supranuclear gaze palsy: This patient shows a severe limitation in the range of ocular motor move-
ments observed, which affects more upward than downward voluntary and pursuit gaze. As observed,
the oculocephalic reflex is preserved when the the dolls head maneuver is performed.
Slowing of vertical saccades: Patient shows markedly slow vertical saccades and relatively pre-
served horizontal saccades.
Classification 7
Ocular motor apraxia: The patient shows difficulty initiating the voluntary gaze and saccades but
exhibits a preserved pursuit and optokinetic nystagmus. Once the saccades are initiated their speed is
normal.
Corticosensory deficits: This patient shows right sensory neglect and agraphesthesia. These later-
alized cognitive features in conjunction with the progressive development of a right ideomotor
apraxia, dystonia, and stimulus sensitive myoclonus led to the diagnosis of corticobasal degeneration
(corticobasal syndrome).
Limb kinetic apraxia: The performance of this patient does not improve with imitation. Move-
ments are coarse and do not represent the intended action.
Blepharospasm: Difficulty opening the eyes because of inhibition of eyelid opening, which is
followed by blepharospasm.
REFERENCES
1. Litvan I. Parkinsonian features: when are they Parkinson disease? JAMA 1998;280:16541655.
2. Wenning GK, Ebersbach G, Verny M, et al. Progression of falls in postmortem-confirmed parkinsonian disorders. Mov
Disord 1999;14:947950.
3. Muller J, Wenning GK, Verny M, et al. Progression of dysarthria and dysphagia in postmortem-confirmed parkinso-
nian disorders. Arch Neurol 2001;58:259264.
4. Elbaz A, Bower JH, Peterson BJ, et al. Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol
2003;60:9196.
5. Mortality in DATATOP: a multicenter trial in early Parkinsons disease. Parkinson Study Group. Ann Neurol
1998;43:318325.
6. Scigliano G, Musicco M, Soliveri P, et al. Mortality associated with early and late levodopa therapy initiation in
Parkinsons disease. Neurology 1990;40:265269.
7. Wenning GK, Ben-Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinicopathological study of 35 cases of multiple
system atrophy. J Neurol Neurosurg Psychiatry 1995;58:160166.
8. Wenning GK, Litvan I, Jankovic J, et al. Natural history and survival of 14 patients with corticobasal degeneration
confirmed at postmortem examination. J Neurol Neurosurg Psychiatry 1998;64:184189.
9. Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system
atrophy: a meta-analysis. Neurology 1997;48:3843893.
10. Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supra-
nuclear palsy: A clinical cohort study. Neurology 2003;60:910916.
11. Siderowf A, Quinn NP. Progressive supranuclear palsy: setting the scene for therapeutic trials. Neurology
2003;60:892893.
12. Litvan I, Mangone CA, McKee A, et al. Natural history of progressive supranuclear palsy (SteeleRichardson
Olszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiatry
1996;60:6156120.
13. Maher ER, Lees AJ. The clinical features and natural history of the SteeleRichardsonOlszewski syndrome (progres-
sive supranuclear palsy). Neurology 1986;36:10051008.
14. Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese
patients. Brain 2002;125:10701083.
15. Wenning GK, Geser F, Stampfer-Kountchev M, Tison F. Multiple system atrophy: an update. Mov Disord
2003;18(Suppl 6):S34S42.
16. Wenning GK, Braune S. Multiple system atrophy: pathophysiology and management. CNS Drugs 2001;15:839852.
17. Muller J, Wenning GK, Jellinger K, McKee A, Poewe W, Litvan I. Progression of Hoehn and Yahr stages in Parkinso-
nian disorders: a clinicopathologic study. Neurology 2000;55:888891.
18. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple
system atrophy. An analysis of 100 cases. Brain 1994;117(Pt 4):835845.
19. Golbe LI. The epidemiology of PSP. J Neural Transm Suppl 1994;42:263273.
20. Litvan I, Agid Y, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy
(SteeleRichardsonOlszewski syndrome). Neurology 1996;46:922930.
21. Litvan I, Agid Y, Goetz C, et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic
study. Neurology 1997;48:119125.
22. Litvan I, Goetz CG, Jankovic J, et al. What is the accuracy of the clinical diagnosis of multiple system atrophy? A
clinicopathologic study. Arch Neurol 1997;54:937944.
8 Litvan
23. Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degenera-
tion. Neurology 1999;53:795800.
24. Wenning GK, Ben-Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn NP. What clinical features are most useful to distin-
guish definite multiple system atrophy from Parkinsons disease? J Neurol Neurosurg Psychiatry 2000;68:434440.
25. Bhatia KP, Lee MS, Rinne JO, et al. Corticobasal degeneration look-alikes. Adv Neurol 2000;82:169182.
26. Lopez OL, Litvan I, Catt KE, et al. Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative
dementias. Neurology 1999;53:12921299.
27. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary NINDS neuropathologic criteria for
progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 1996;55:97105.
28. Litvan I. Methodological and research issues in the evaluation of biological diagnostic markers for Alzheimers dis-
ease. Neurobiol Aging 1998;19:121123.
29. Dickson DW, Bergeron C, Chin SS, et al. Office of Rare Diseases neuropathologic criteria for corticobasal degenera-
tion. J Neuropathol Exp Neurol 2002;61:935946.
30. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele
RichardsonOlszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:19.
31. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia
with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:11131124.
32. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis
and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999;53:902905.
33. Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. American Auto-
nomic Society and American Academy of Neurology. Clin Auton Res 1998;8:359362.
34. Osaki Y, Wenning GK, Daniel SE, et al. Do published criteria improve clinical diagnostic accuracy in multiple system
atrophy? Neurology 2002;59:14861491.
35. Lopez OL, Becker JT, Kaufer DI, et al. Research evaluation and prospective diagnosis of dementia with Lewy bodies.
Arch Neurol 2002;59:4346.
36. Litvan I, Bhatia KP, Burn DJ, et al. SIC Task Force appraisal of clinical diagnostic criteria for parkinsonian disorders.
Mov Disord 2003;18:467486.
37. Goetz CG, Leurgans S, Lang AE, Litvan I. Progression of gait, speech and swallowing deficits in progressive supra-
nuclear palsy. Neurology 2003;60:917922.
38. Tison F, Yekhlef F, Balestre E, et al. Application of the International Cooperative Ataxia Scale rating in multiple
system atrophy. Mov Disord 2002;17:12481254.
39. Averbuch-Heller L, Paulson GW, Daroff RB, Leigh RJ. Whipples disease mimicking progressive supranuclear palsy:
the diagnostic value of eye movement recording. J Neurol Neurosurg Psychiatry 1999;66:532535.
40. Siderowf AD, Galetta SL, Hurtig HI, Liu GT. Posey, Spiller and progressive supranuclear palsy: an incorrect attribu-
tion. Mov Disord 1998;13:170174.
41. Berger JR, Arendt G. HIV dementia: the role of the basal ganglia and dopaminergic systems. J Psychopharmacol
2000;14:214221.
42. Mirsattari SM, Power C, Nath A. Parkinsonism with HIV infection. Mov Disord 1998;13:684689.
43. Wojcieszek J, Lang AE, Jankovic J, Greene P, Deck J. What is it? Case 1, 1994: rapidly progressive aphasia, apraxia,
dementia, myoclonus, and parkinsonism. Mov Disord 1994;9:358366.
44. Amarenco P, Roullet E, Hannoun L, Marteau R. Progressive supranuclear palsy as the sole manifestation of systemic
Whipples disease treated with pefloxacine. J Neurol Neurosurg Psychiatry 1991;54:11211122.
45. Nath U, Ben-Shlomo Y, Thomson RG, et al. The prevalence of progressive supranuclear palsy (SteeleRichardson
Olszewski syndrome) in the UK. Brain 2001;124:14381449.
46. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple
system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49:12841288.
47. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County,
Minnesota, 1976-1990. Neurology 1999;52:12141220.
48. Blin J, Baron JC, Dubois B, et al. Positron emission tomography study in progressive supranuclear palsy. Brain
hypometabolic pattern and clinicometabolic correlations. Arch Neurol 1990;47:747752.
49. Lees A. The SteeleRichardsonOlszewski sydrome (progressive supranuclear palsy). In: Marsden CD, Fahn S, eds.
Movement Disorders 2. London: Butterworths, 1987;272287.
50. Golbe LI. Progressive supranuclear palsy. In: Jankovic J, Tolosa E, eds. Parkinsons Disease and Movement Disorders.
Baltimore: Williams & Wilkins, 1993;145161.
51. Tolosa E, Valldeoriola F, Marti MJ. Clinical diagnosis and diagnostic criteria of progressive supranuclear palsy (Steele
RichardsonOlszewski syndrome). J Neural Transm Suppl 1994;42:1531.
52. Collins SJ, Ahlskog JE, Parisi JE, Maraganore DM. Progressive supranuclear palsy: neuropathologically based diag-
nostic clinical criteria. J Neurol Neurosurg Psychiatry 1995;58:167173.
53. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist
movement disorder service. Brain 2002;125:861870.
Classification 9
54. Litvan I, Booth V, Wenning GK, et al. Retrospective application of a set of clinical diagnostic criteria for the diagnosis
of multiple system atrophy. J Neural Transm 1998;105:217227.
55. Quinn N. Multiple system atrophy. In: Marsden CD, Fahn S, eds. Movement Disorders 3. London: Butterworths,
1994:262281.
56. Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci
1999;163:9498.
57. Mega MS, Masterman DL, Benson DF, et al. Dementia with Lewy bodies: reliability and validity of clinical and patho-
logic criteria. Neurology 1996;47:14031409.
58. Ballard C, Holmes C, McKeith I, et al. Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and
neuropathological comparative study with Alzheimers disease. Am J Psychiatry 1999;156:10391045.
59. Duara R, Barker W, Luis CA. Frontotemporal dementia and Alzheimers disease: differential diagnosis. Dement Geriatr
Cogn Disord 1999;10:3742.
60. Verghese J, Crystal HA, Dickson DW, Lipton RB. Validity of clinical criteria for the diagnosis of dementia with Lewy
bodies. Neurology 1999;53:19741982.
61. Hohl U, Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. Diagnostic accuracy of dementia with Lewy bodies. Arch
Neurol 2000;57:347351.
62. Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease,
and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol 1998;55:969978.
63. Litvan I, Agid Y, Goetz C, et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathological
64. McKeith IG, Ballard CG, Perry RH, et al. Prospective validation of consensus criteria for the diagnosis of dementia
with Lewy bodies. Neurology 2005;54:10501058.
Historical Issues 11
2
Historical Issues and Atypical Parkinsonian Disorders
Christopher G. Goetz
Studying archetypes is a fundamental task in nosography. Duchenne de Boulogne practiced it instinc-

tively, and many others have done it before and after him: It is indispensable, and the only way to
extract a specific pathological state from the chaos of imprecision. The history of medicine, which is
long and grand, shows this truth well. But once the archetype is established, the second nosographic
operation begins: dissect the archetype and analyze its parts. One must, in other words, learn how to
recognize the imperfect cases, the formes frustes, or examples where only one feature occurs in
isolation. Using this second method, the physician will see the archetypal illness in an entirely new
light. Ones scope enlarges, and the illness becomes much more important in the doctors daily
practice. To the patients benefit, the doctor becomes attentive and sensitive to recognizing a dis-
ease, even when it is in its earliest developmental stages (1).
INTRODUCTION
As shown in the above quotation from Jean-Martin Charcots teaching of the late 19th century, the
concept of atypical Parkinsonian disorders and formes frustes of the classic disease emerged in
parallel with the definition of Parkinsons disease itself. In 1817, James Parkinson, a London general
practitioner, described resting tremor and gait impairment in the small sample of subjects whose
symptoms would later be coalesced into a disorder that would bear his name (2). Nearly 50 yr later,
Charcot returned to this early description and used his large patient population to study Parkinsons
disease in full detail. With access to thousands of elderly patients who lived in the sprawling hospital-
city of the Hpital de la Salptrire in central Paris, Charcot studied the evolution of signs from very
early disease through the most advanced stages (3,4). Charcot used specialized recording equipment
to distinguish the rest tremor of typical Parkinsons disease from the tremors typical of multiple
sclerosis and other conditions where posture- or action-induced exacerbation occurred (5). He was
particularly adept in distinguishing bradykinesia as a cardinal feature of the illness and separating it
from weakness. These studies led him to discourage the original designation of paralysis agitans,
because patients did not develop clinically significant loss of muscle power until very late. Charcot
further emphasized the distinctive elements of rigidity and delineated its distinction from spasticity
or other forms of hypertonicity. Finally, he succinctly described the stance and gait of the subject
with Parkinsons disease:
His head bends forward, he takes a few steps and they become quicker and quicker to the point that
he can even bump into the wall and hurt himself. If I pull on his trousers from behind, he will
retropulse in the same distinctive way (4).

11
12 Goetz
Charcots celebrated teaching courses and publications established these four featuresrest
tremor, bradykinesia, rigidity, and postural reflex impairment in balance and stanceas the cardinal
features of typical Parkinsons disease. Charcot complemented these studies with documentation of
trophic and arthritic features of the illness, with further studies of pain and autonomic nervous system
alterations, and with pharmacological observations (3). At the same time, however, as indicated in
the introductory quotation of this chapter, he emphasized the importance of recognizing cases that he
termed variants or formes frustes, cases that were similar to and yet distinct from the classic, arche-
typal form of the disease. These cases were termed atypical Parkinsons disease, at a time when the
pathological substrate of Parkinsons disease itself remained unknown. As a historical introduction
to the conditions that are the primary focus of this book and today collectively termed atypical par-
kinsonian disorders, these historical cases provide source material for the early study of conditions
later to be separated from Parkinsons disease and defined in the mid- and late-20th century as pro-
gressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration.
EARLY CONCEPTS OF ATYPICAL PARKINSONS DISEASE

Nineteenth-century neurologists recognized three basic categories of parkinsonism that were suit-
ably different from typical Parkinsons disease to merit designation: cases without typical tremor,
those with atypical postures (extension rather than flexion), and those with marked asymmetry in the
form of seeming hemiplegia. Within these categories, modern neurologists will find characteristics
that typify progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration,
though these latter diagnoses were not defined specifically until clinical-pathological studies distin-
guished them as distinct from Parkinsons disease itself. Each of these clinical categories is described
from the perspective of 19th-century neurology and then followed by a specific discussion of the
history of progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration.
Parkinsonism Without Prominent Rest Tremor

Early neurologists recognized resting tremor as the most distinctive feature of typical Parkinsons
disease, and placed patients who had unusual, intermittent tremor patterns or no tremor into the
clinical category termed Parkinsons disease without tremor (3,4). Some of these cases actually
had tremor, but the movements were mild in severity or intermittent and primarily induced with
emotion or action (3). It is possible that myoclonus, a feature frequently seen in corticobasal degen-
eration, and mild action tremor that can be seen in multiple system atrophy would have been catego-
rized as one of these intermittent tremors. Myoclonus was appreciated in the 19th century, especially
by Germanic and Austrian researchers (6,7), but not specifically designated as an aspect of atypical
Parkinsons disease. Charcot studied tremor extensively and drew attention to its typical features in
Parkinsons disease. He conducted his tremor examination with patients at rest and during activity. In
addition to clinical observation, he used tremor oscillometers (Fig. 1) and small portable lamps that
he attached to the shaking extremities in order to record the trajectory movements on light-sensitive
paper (8). To accentuate an appreciation of very mild tremor, he attached feathers or other light-
weight objects to the shaking body part to magnify the oscillations. He held strongly that titubation
was not part of typical Parkinsons disease, but lip and tongue tremors could occur. Because parkin-
sonian cases without tremor were still considered as variants of the primary disease, Charcot advo-
cated the use of the term Parkinsons disease, rather than paralysis agitans, as coined by Parkinson
himself (3,4).
Parkinsonism With Atypical Postures

Charcot studied muscle tone extensively and established that most Parkinsons disease subjects
showed a flexed posture with the shoulders hunched forward, neck bent down toward the chest, and
the arms held in partial flexion at rest. In contrast, he found a small number of parkinsonian patients
Fig. 1. Tremor recording machine used by Charcot to separate cases of typical rest tremor from those with
postural tremor and action-induced tremor. Early studies focused on the differentiation by tremor type of mul-
tiple sclerosis and Parkinsons disease, but this apparatus was later used to study the various formes frustes of
Parkinsons disease as well. In the insert, tremor recordings are shown for resting posture (AB) and action (BC)
in patients with different tremor patterns. From Dictionnaire Encyclopdique des Sciences Mdicales, 1883.
who were bradykinetic, unstable in their stance and gait, and yet showed a very different posture.
These subjects, collectively termed Parkinsons disease with extended posture, were of particular
interest to Charcot, and he recognized several features of these cases that distinguished them from the
archetypal cases of Parkinsons disease. These cases are further discussed later in the subheading on
Progressive Supranuclear Palsy and shared several additional features of this diagnosis including the
distinctive facial expression, swallowing difficulties, and frequent falls (Fig. 2).
Hemiplegic Parkinsons Disease

Early neurologists considered Parkinsons disease to be a bilateral condition, but often commented
on the mild asymmetry of tremor, especially in the early years of disease. Within the context of this
asymmetric but bilateral archetype, they distinguished another form of Parkinsons disease that was
highly asymmetric with prominent disability in the involved upper extremity beyond that expected
with bradykinesia alone (3). Collectively termed hemiplegic Parkinsons disease, these cases form a
large series in the French neurological literature of the late 19th century and include cases of abrupt
strokelike onset as well as slowly progressive disability (9) (Fig. 3). They are discussed in the section
on corticobasal degeneration, because they clinically fit best into this designation among the group of
atypical parkinsonian disorders. Because infectious disease (abscess and hemorrhagic strokes espe-
cially from military tuberculosis) were frequent disorders in the 19th century, some of these cases
may not have related to primary neurodegeneration. Furthermore, autopsy reports were not system-
atically recorded, so that analysis of cases as corticobasal degeneration remains only suggestive.
14 Goetz
Fig. 2. Drawing by J-M Charcot comparing two patients: (left) typical Parkinsons disease with flexed pos-
ture and (right) another patient with an atypical variant of extended posture (4).
Fig. 3. Photograph from an article by Dutil (17) showing asymmetric parkinsonism suggestive of corticobasal
degeneration but with an extended trunk and neck posture with gaze impairment suggestive of progressive
supranuclear palsy.
HISTORICAL DESCRIPTIONS OF ATYPICAL PARKINSONIAN

DISORDERS
Progressive Supranuclear Palsy
In 1963, Steele, Richardson, and Olszewski presented a report at the American Neurological As-
sociation of a new syndrome typified by parkinsonism, marked vertical gaze paresis, dementia, and
axial rigidity (10,11). Though they felt they were describing a new syndrome, they referred col-
leagues to similar cases from the recent past (1214) (Fig. 4). H. Houston Merritt opened the discus-
sion, commenting that he had not seen similar cases, that the involved areas all related to cell
populations of similar phylogenetic age, and that dementia was of particular interest. F. McNaughton
acclaimed: I believe that the authors have described a clear-cut neurological syndrome and to judge
from the pathological studies, it may, in fact, represent a new disease entity. D. Denny-Brown was
less sure and ascribed the cases to variants of Jakobs spastic pseudosclerosis (10).
Prior to these 20th-century descriptions, several cases of Parkinsons disease with extended pos-
ture can be identified with characteristics suggestive of progressive supranuclear palsy. Charcot
presented a man, named Bachre, to his students on several occasions (see Fig. 2). Commenting on
June 12, 1888, Charcot mentioned that Bachre did not have marked tremor and emphasized the issue
of extension posture:
There is something else unusual here worth noting. Look how he stands. I present him in profile so
you can see the inclination of the head and trunk, well described by Parkinson. All this is typical.
What is atypical, however, is that Bachres forearms and legs are extended, making the extremities
like rigid bars, whereas in the ordinary case, the same body parts are partly flexed. One can say then
that in the typical case of Parkinsons disease, flexion is the predominant feature, whereas here,
extension predominates and accounts fro this unusual presentation. The difference is even more
evident when the patient walks (3).
In addition to extended posture, this patient had particular facial bradykinesia and contracted fore-
head muscles (15). Charcot commented that the patient had the perpetual look of surprise because the
eyes remained widely opened and the forehead continually wrinkled (Fig. 5). In a modern setting,
Jankovic has detailed similar facial morphology in Parkinsonism-plus patients, specifically those
with progressive supranuclear palsy (16). The extended truncal posture of this patient would be com-
patible with the posture of progressive supranuclear palsy, although Charcot did not comment on
specific supranuclear eye movement abnormalities. Another Salptrire patient with Parkinsons
disease in extension was described by Dutil in 1889 and eye movement abnormalities are men-
tioned, although a supranuclear lesion is not documented clinically (17,18) (see Fig. 3). This case
also had highly asymmetric rigidity of the extremities, a feature more reminiscent of corticobasal
degeneration than progressive supranuclear palsy (see next subheading). In this case, the extended
neck posture was graphically emphasized:
The face is masked, the forehead wrinkled, the eyebrows raised, the eyes immobile. This facies,
associated with the extended posture of the head and trunk, gives the patient a singularly majestic air
(17,18).
With clinical features reminiscent of both progressive supranuclear palsy and corticobasal degenera-
tion, this patient was mentioned in several articles from the Salptrire school, although no autopsy was
apparently performed.
In their studies of tremor and Parkinsons disease, Charcot and contemporary colleagues described
several other cases of parkinsonian patients who never suffered with either prominent resting or
postural tremor. Although the descriptive details are often cursory, several of these cases may well
represent cases of progressive supranuclear palsy. Bourneville published two cases in 1876 (19), and
later French students chose this subclass of patients for special clinical emphasis (20). In his thesis on
16 Goetz
Fig. 4. Photograph from 1951 article by Chavany (12) showing a patient with extended posture suggestive of
progressive supranuclear palsy prior to the definitive description by Steele and colleagues in 1964.
atypical forms of parkinsonism, Compin specifically noted that parkinsonian cases without tremor
showed especially marked rigidity and often fall (20). His first case history documented several addi-
tional features typical of the group of parkinsonism-plus syndromes, including early age of onset
(age 45), prominent gait and balance difficulty within the first years of illness, and other midline
dysfunction such as marked and early speech impairment.
Historical research on early medical diagnoses has occasionally benefited from nonmedical sources,
especially literary descriptions. Because movement disorders are particularly visual in their character,
it is reasonable to search the writings of celebrated authors known for their picturesque descriptive
Fig. 5. Four pictures drawn by Charcot of a patient with likely progressive supranuclear palsy. The top two
sketches emphasize the superior orbicularis contracture of the forehead, whereas the lower sketches capture the
activation of the palpebral portion of the orbicularis (muscle of reflection, left) and the combined activation of
the frontalis superior portion of the orbicularis and platysma, giving a frightened expression (right) (4).
writings. In this context, Larner proposed that Charles Dickens captured the essential features of
progressive supranuclear palsy in his description of a character in The Lazy Tour of Two Idle Appren-
tices (21). Dickens wrote:
A chilled, slow, earthy, fixed old man. A cadaverous man of measured speech. An old man who
seemed as unable to wink, as if his eyelids had been nailed to his forehead. An old man whose
eyestwo spots of firehad no more motion than if they had been connected with the back of his
skull by screws driven through it and riveted and bolted outside, among his grey hair. He had come
in and shut the door, and he now sat down. He did not bend himself to sit, as other people do, but
seemed to sink bold upright, as if in water until the chair stopped him (22).
For the medical reader with a knowledge of progressive supranuclear palsy, this description pro-
vides images compatible with the medical diagnosis. On the other hand, the passage falls short of the
more convincing descriptions of sleep apnea in the Pickwick Papers or torticollis in Little Dorrit.
18 Goetz
Corticobasal Degeneration
The clinical and pathological hallmarks of corticobasal degeneration were delineated in 1968 by
Rebeiz (23). Asymmetric parkinsonism in the context of a progressive dyspraxia, unilateral dystonia,
and cortical sensory impairment are the major clinical findings found in association with
corticodentatonigral degeneration with neuronal achromasia. In addition to the Dutil report cited
earlier (see Fig. 3), a thesis by Bchet (24), dated 1892, documents a patient (case VIII) with possible
corticobasal degeneration. The patients hallmarks were progressive tremor and contracture of the
right upper extremity. Gradually, the trunk and neck developed extreme rigidity as well. The remark-
able posture of the right upper extremity dominated the atypical picture:
The right upper extremity is held along side the body, extended and stiff, the elbow held straight, the
wrist flexed, the hand pronated and held in front of the thigh. The hand is markedly contorted . . . the
fingers completely flexed, especially the last three digits to the point that the finger nails sometimes
leave impressions on the palm. The flexion of the index finger is less marked and the adducted
thumb is held over the palmer surface of the middle finger. This contracture of the flexor muscles,
however is only one of appearance, for the examiner can (with a some effort, admittedly) extend the
hand and fingers completely, and afterwards, they can hold this position briefly (24).
Further discussing the functional impairment of the involved right upper extremity and the asym-
metry of the case, he continued:
Spontaneous movements of the upper extremity are practically impossible, very limited and
extremely slow. The upper left extremity is only mildly flexed and the hand has no notable defor-
mity (24).
No photographs or medical drawings accompanied the report.
Nearly 30 yr later, in 1925, J. Lhermitte reported a case to the French Neurological Society that
may also represent an early case of the same diagnosis (25,26). A carpenter retired at age 67 because
of progressive right-hand clumsiness. At age 72, he could no longer walk independently and ambu-
lated with a wide-based, shuffling gait with the right arm flexed. In addition, his right arm moved
involuntarily like a foreign body. In spite of normal primary sensation, he could not recognize
objects placed in his right hand. The patient did not have an autopsy (Fig. 6).
With the advent of cognitive neurology as a subspecialization of neurology, historical research
efforts related to corticobasal degeneration have focused on descriptions of cases with signs of corti-
cal dysfunction rather than motor. The clinical disorder of the celebrated composer, Maurice Ravel,
has been retrospectively diagnosed as corticobasal degeneration, focal dementia, and progressive
aphasia without dementia (27,28). These analyses provide interesting reading, but, because the medi-
cal information is incomplete and no autopsy material has been identified, they do not substantially
advance historical understanding of corticobasal degeneration.
Multiple System Atrophy

This diagnosis is particularly difficult to study historically, because the variety of symptoms and
different phenotypes have been labeled with a wide vocabulary and nosology. In 1865, Sanders intro-
duced the term dystaxia or pseudo-paralysis agitans to describe a patient with severe action tremor
and gait impairment without sensory loss (29). Dejerine and Thomas described olivopontocerebellar
atrophy in 1900 and emphasized varying mixtures of parkinsonian, cerebellar, and autonomic dys-
function (30). Critchley and Greenfield reviewed cases from the early 20th century, citing such names
as Pierre Marie, Murri, Lhermitte, and Wilson, commenting on the changing terminology and noso-
graphic confusion related to this disorder (31). In 1925, Ley reported the same type of presentation as
Dejerine and Thomas in a 50-yr-old man, and at autopsy, he noted not only olivopontocerebellar lesions,
but also atrophic substantia nigra (32,33).
Fig. 6. Photograph from 1925 article by Lhermitte (25) and studied by Ballan and Tisson (26), showing a
patient with possible corticobasal degeneration. The picture captures his unusual posturing of the right arm and
hand with marked dyspraxia.
In 1960, Shy and Drager described two patients with orthostatic hypotension and parkinsonism or
pyramidal/cerebellar features, who showed highly distinctive autopsy features including vacuolation
of the autonomic ganglia, shrunken, hyperchromatic cells in the intermediolateral column, and degen-
erative changes in the pons, substantia nigra, hypothalamus, locus ceruleus, and Purkinje layer of the
cerebellum (34). Striatonigral degeneration became widely known after Adams, van Bogaert, and
van der Eecken published their series in 1961 (35). The conditions were consolidated in the seminal
article by Graham and Oppenheimer (36).
Early reports of multiple system atrophy of the striatonigral phenotype were written by Lewys
student, Fleischhacker, in 1924 and Scherer in 1933, both analyzed by Wenning and colleagues (37
39). Of these five subjects, three had severe parkinsonism and two had more prominent cerebellar
features. All had neuropathological evidence of putaminal and pallidal degeneration as well as depig-
mentation and degeneration of the small cells of the substantia nigra. Those with cerebellar features
had additional olivopontocerebellar lesions. Fleischhackers case had been clinically diagnosed dur-
ing life as paralysis agitans, but the author argued that both clinically and pathologically, the findings
were atypical for Parkinsons disease. Clinically, he emphasized the atypical tremor (coarse and
20 Goetz
postural rather than resting), an early age of disease onset, and prominent rigidity. Berciano considers
that Scherers contribution was essential in establishing the striatal-nigral lesions that underlie par-
kinsonism in this phenotype. With his report, he definitively established that parkinsonism in
olivopontocerebellar atrophies related to additional degenerative changes outside this system (33).
FUTURE PERSPECTIVES
The study of early texts that describe Parkinsons disease and other forms of parkinsonism remains
vital as the search for causes of these illnesses intensifies. Epidemiological and neurotoxicological
research that will be reviewed in this text has focused increasingly on the putative role of environ-
mental factors to parkinsonian syndromes, and many current industrial exposures did not exist in
prior eras. It may not be by chance that the first medical description of Parkinsons disease emerged
from the center of international industrialization in the midst of the Industrial Revolution. The iden-
tification of atypical parkinsonian disorders naturally followed the identification of the archetype of
Parkinsons disease, but establishing exactly when such cases came to medical attention has not been
precisely defined. In this light, readers of early medicine, literature, and other disciplines offer an
important resource for research efforts in the 21st century. As readers examine the evidence for
genetic and environmental causes of the atypical parkinsonian disorders discussed in this book, a
vigilance to literature, artworks, and early medical descriptions will complement these data and may
further the understanding of these collective entities.
REFERENCES
1. Charcot J-M. (March 20, 1888) Leons du Mardi: Policlinique la Salptrire. Paris: Bureaux du Progrs Mdical,
18871888.
2. Parkinson J. The Shaking Palsy. London: Whittingham & Rowland, 1817.
3. Charcot J-M. De la paralysie agitante, Leon 5. In: Oeuvres Compltes, vol 1. Paris: Bureaux du Progrs Mdical,
1892:155189 [In English: On paralysis agitans. In: Lectures on Diseases of the Nervous System, Sierson, G, trans.
Philadelphia:HC Lea, 1879:105127.
4. Charcot J-M. (Leon 21: June 12, 1888) Leons du Mardi: Policlinique la Salptrire. Paris:Bureaux du Progrs
Mdical, 1888.
5. Goetz CG, Bonduelle M, Gelfand T. Charcot: Constructing Neurology. New York: Oxford University Press, 1995.
6. Friedreich N. Neuropathologische Beobachtung beim Paramyoklonus mutiplex. Virchow Arch Path Anat 1881;
86:421434.
7. Unverricht H. Die Myoclonie. Leipsig:Franz Deuticke, 1891.
8. Goetz CG. Visual art in the neurological career of Jean-Martin Charcot. Arch Neurol 1991;48:421425.
9. Marie P. Hmiplgie chez les parkinsoniens. In: Brouardel P, Gilbert JP, eds. Trait de Mdecine et de Thrapeutique.
Masson, 1911.
10. Transactions of the American Neurological Association. St. Paul MN: American Neurological Association, 1963.
11. Steele J, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the
brain stem, basal ganglia and cerebellum with verticle gaze and pseudobulbar palsy, nuchal dystonia and dementia.
Arch Neurol 1964;10:333359.
12. Chavany JA, van Bogaert L, Godlewski S. Sur un syndrome de rigidit, prdominance axiale avec perturbation des
automatismes oculo-palpbraux dorigine encphalopatique. Presse Md 1951;50:958962.
13. Brusa A. Dgnrescence plurisystmatise du nvraxe, de charactre sporadique. Rev Neurol 1961;104:412429
14. Steele JC. Historical notes. J Neural Transm 1994(Suppl);42:314.
15. Goetz CG. Charcot, the Clinician: The Tuesday Lessons. New York: Raven, 1987.
16. Jankovic J. Progressive supranuclear palsy. Neurol Clin 1984;2:473486.
17. Dutil A. Sur un cas de paralysie agitante forme hemiplgique avec attitude anormale de la tte et du tronc (extension).
Nouv Icon Salptrire 1889;2:165169.
18. Goetz CG. Visual art in the neurological career of Jean-Martin Charcot. Arch Neurol 1991;48:421425.
19. Bourneville D-M. Deux cas de la maladie de Parkinson sans tremblement. Prog Md Sept. 17, 1876, Paris.
20. Compin P. Etude clinique des formes anormales de la maladie de Parkinson (Thse de Mdecine). Lyon: FA Rey, 1902.
21. Larner AJ. Did Charles Dickens described progressive supranuclear palsy in 1857? Mov Disorders 2002;17:832833.
22. Dickens C. The lazy tour of two idle apprentices. Household Words 1857;3:4446, 4:6672; 5:7289.
23. Rebeiz JL, Kolodny EW, Richardson EP. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol
1968;18:2033.
24. Bchet A. Etude clinique des formes de la maladie de Parkinson (Thse de Mdecine). Paris: Bureaux du Progrs
Mdical, 1892.
25. Lhermitte J, Lvy G, Kyriaco N. Les perturbations de la representation spatial chez les apraxiques. Rev Neurolog
(Paris) 1925;2:586600.
26. Ballan G, Tison F. A historical case of probable corticobasal degeneration? Mov Disord 1997;12:10731074
27. Baeck E. Was Maurice Ravels illness a corticobasal degeneration? Clin Neurol and Neurosurg 1996;98:5761.
28. Cytowic RE. Aphasia in Maurice Ravel. Bull Los Angeles Neurol Soc 1976;41:109114.
29. Sanders WR. Case of an unusual form of nervous disease, dystaxia or pseudo-paralysis agitans. Edinburgh Med J
1865;10:987997.
30. Dejerine J, Thomas AA. Latrophie olivo-ponto-crbelleuse. Nouv Icon Saleptrire 1900;13:330370.
31. Critchley M, Greenfield JG. Olivo-ponto-cerebellar atrophy. Brain 1948;61:343364.
32. Ley R. Forme atypique datrophie olivo-ponto-crbelleuse. J Belge Neurol Psychiatr 1925;25:92108.
33. Berciano J, Combarros O, Polo JM. An early description of striatonigral degeneration. J Neurol 1999;246:462466.
34. Shy SM, Drager GA. A neurological syndrome associated with orthostatic hypotension. Arch Neurol 1963;2:511517.
35. Adams RD, van Bogaert L, Vander Eecken H. Striato-nigral degeneration. J Neuropath Exper Neurol 1964;23:584608.
36. Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.
J Neurol Neurosurg Psychiat 1969;32:2834.
37. Fleischhacker H. Afamilire chronisch-progressive Erkankung des mitteren Lebensalters vom Pseudosklerosetyp. Z ges
Neurol Psyschiat 1924;91:122
38. Scherer HJ. Extrapyramidale Storungen bei der Olivopontocerebellarer Atrophie. Ein Beitrag zum Problem des lokalen
vorzeitigen Alterns. Zbl ges Neurol Psychiat 1933;145:406419.
39. Wenning GK, Jellinger KJ, Quinn NP, Werner HP. An early report of striatonigral degeneration. Mov Disord
2000;15(1):159162.
Epidemiology of PSP and MSA 23
3
Epidemiology of Progessive Supranuclear Palsy
and Multiple System Atrophy
Adam Zermansky and Yoav Ben-Shlomo
INTRODUCTION
Epidemiology seeks to prevent disease by identifying risk factors, be they genetic and/or environ-
mental, that are of etiological relevance through the use of descriptive studies, natural experiments,
and very occasionally randomized trials. In addition, clinical epidemiology can examine the utility of
diagnostic tests, determine predictors of disease prognosis, and test whether therapies can modify
disease progression. This chapter will focus on descriptive studies that have either measured disease
frequency (prevalence or incidence) or estimated the risk associated with environmental exposures.
We have chosen to focus solely on progressive supranuclear palsy (PSP) and multiple system atrophy
(MSA) as there is hardly any data for other atypical parkinsonian disorders such as corticobasal
degeneration or dementia with Lewy bodies. For any uncommon disease, undertaking epidemiologi-
cal studies presents several major challenges: case identification, representativeness of cases, and
obtaining adequate sample sizes. For both PSP and MSA, there are additional problems as both these
conditions can be difficult to diagnose. As there are no adequate tests that are both highly sensitive and
specific, the gold standard remains the diagnostic expertise of a movement disorders specialist (1).
THE PREVALENCE AND INCIDENCE OF PSP AND MSA

Measuring the prevalence and incidence of disease serves several important functions. First, each
measure enables health planners to estimate the number of existing cases (prevalence) and new cases
(incidence) that one would expect to find in a community and hence provide the appropriate health
staff required for their care. Second, by comparing age-standardized rates in different populations or
over different time periods, one may observe differences, which if not artifactual or merely because
of chance, that provide etiological clues and enable the formulation of hypotheses concerning risk
factors. Marked changes over time, unless a result of increased disease awareness and hence a greater
likelihood of diagnosis, strongly suggest an environmental factor or a genetic environmental interac-
tion. Geographical variations are more complex as they may reflect differences in health services,
variations in disease survival if only comparing prevalence rates, methodological differences in study
design and/or diagnostic criteria, chance variations, or genuine population differences in genetic and/
or environmental factors.
Current consensus diagnostic criteria for PSP and MSA were only published in 1996 and 1999
respectively (2,3). Prevalence studies prior to these dates relied upon heterogeneous groups of pub-
lished criteria and some used none (or did not state which were used) at all. This makes any interpre-

23
24 Zermansky and Ben-Shlomo
tation of data from such studies even more complex as these different criteria would have had differ-
ing sensitivities and specificities (4). Even the current consensus criteria, which at least enable a
more standardized approach, have yet to be tested in large-scale representative prognostic cohorts
with postmortem-validated diagnoses so their true diagnostic utility remains to be elucidated.
Despite these difficulties, such studies provide the empirical basis for suggesting or testing ideas
concerning causal agents.
Prevalence of PSP and MSA

Measures of the prevalence of PSP vary from 0.97 to 6.54 per 100,000 (eight studies) and for
MSA from 2.29 to 39.3 per 100,000 (five studies) (Table 1). A study from Sicily (8) reported one of
the highest rates of 28.6 per 100,000 but this was for unspecified parkinsonism, so this category may
have included cases other than MSA and PSP. The results presented in Table 1 are simple crude
rates for the whole population rather than age-standardized rates. Though some studies do report
such standardized rates, each study generally uses a different standard population and some studies
fail to present age-specific rates making it impossible to restandardize the rates to a single popula-
tion. The purpose of standardization is to remove any confounding effect owing to the age structure
of the population. As all the studies except one from Libya (7) have been undertaken in a developed
world population, it is likely that such confounding is not too large. In fact, differences between the
crude and standardized rates are often small. For example, the crude rate for the New Jersey study is
1.38 per 100,000 and after standardization this increases to 1.39 per 100,000 (6). In the London
study, the crude PSP rate of 4.9 per 100,000 increased to 6.4 per 100,000 (14). However, the inci-
dence rate from Benghazi, Libya, is misleadingly small as a large proportion of this population will be
under 55 yr of age and standardizing this rate to a European population will certainly increase this rate
by a large degree.
Despite the various different diagnostic criteria, the rates for PSP and MSA across all studies are
not too dissimilar. One obvious observation is that studies with very large populations, e.g., New
Jersey (6) or United Kingdom (15), produce lower prevalence estimates whereas very small popula-
tions produce high rates. The effect of varying population size and hence intensity of case finding is
most elegantly demonstrated by the Russian Doll Method method employed by Nath and col-
leagues (15). This general pattern is also well noted with prevalence studies for multiple sclerosis
(16). This is unsurprising because, although large populations give precise estimates, they are likely
to be biased downward as it is easier to miss a proportion of cases. On the other hand, smaller popu-
lations will enable much more thorough case ascertainment and hence less biased but imprecise esti-
mates. The highest prevalence rate (39.3 per 100,000) was observed in a study from rural Bavaria
(10). However being based on only three cases in a very small population, its lower 95% confidence
interval is still 8.1 per 100,000, which will overlap with most of the other estimates. Almost all the
studies except that from Nath and colleagues (15) estimate rates based on 11 or fewer cases, which
demonstrates the problem with studying rare neurological disorders.
Some studies have specifically aimed to detect cases of PSP and/or MSA whereas others have
been generic prevalence studies for parkinsonism. Interestingly, there is little difference between the
estimates for these different studies. Perhaps more surprising is that studies that have screened a
whole population (9,10) did not find higher rates than those using existing medical records or other
databases. It is well recognized in the Parkinsons disease (PD) literature that a proportion of PD
cases will be detected de novo by the screening procedure, though this varies across European centers
(17). It is possible that this clinical iceberg phenomenon is less important for PSP and MSA because
their symptoms and disease progression make them less likely to be undetected. However, studies
aimed at parkinsonism may underestimate rates of MSA since cases with predominantly cerebellar
features may be undetected. Similarly, excluding patients who became demented before the onset of
parkinsonism (14) will assist in the exclusion of dementia with Lewy bodies, in which a supranuclear
gaze palsy may occur, but may also exclude cases of PSP.
Table 1
Prevalence Studies of PSP and MSA
PSP Prevalence MSA Prevalence

Lead Author Year of Generic (G) Population Size Case Diagnostic per 100,000 per 100,000
(Ref. No.) Publication or Specific (S) Location (Total Estimated) Ascertainment Criteria (No. of Cases) (No. of Cases)
Golbe (6) 1988 S New Jersey, USA 799,022 Neurologists, Clinical diagnosis 1.38* (11)
PD support group, aimed at specificity
nursing homes
Morgante (8) 1992 G 3 areas in Sicily 24,496 Two-phase screening Vaidated screening tool 28.6 (7)
but no specific criteria unspecified
for PSP, MSA parkinsonism
so covers both
Epidemiology of PSP and MSA
MSA and PSP

as well as other
conditions
de Rijk (9) 1995 G Suburb of Rotterdam 6969 ( 55 yr) Two phase screening Clinical diagnosis 2.87* (1) 5.74* (2)
Netherlands (34,845)* assuming
20% = 55
Trenkwalder (10) 1995 G Rural villages in 1190 (7628) Two phase screening Quinn criteria for MSA 39.3 (3)
Bavaria, Germany
Wermuth (12) 1997 G Faroe Islands 43,709 Neurologists, GPs, Clinical diagnosis 4.58 (2) 2.29 (1)
nursing homes,
pharmacies
Chio (13) 1998 G Cosatto, Italy 61,830 Neurologists, GPs, Clinical diagnosis 3.23 (2) 4.85 (3)
hospital records,
pharmacies
Schrag (14) 1999 S London, UK 121,608 GP records Quinn criteria for MSA 4.93 (6) 3.29 (4)
& NINDS criteria for
PSP
Nath (15) 2001 S United Kingdom 59,236,500 Neurologist (BNSU),
PSP support group NINDS criteria for PSP 0.97 (577)
Nath (15) 2001 S North of England
Region, UK 2,589,240 Neurologists, care of NINDS criteria for PSP 3.09 (80)
the elderly consultants,
hospital records &
databases
Nath (15) 2001 S Newcastle-upon-
Tyne, UK 259,998 GP records NINDS criteria for PSP 6.54 (17)
25
*Estimated from paper

The study by Schrag and colleagues (14) had an additional important feature in that all subjects
that were categorized as unclassifiable parkinsonism, were reevaluated at 1 yr for signs of PSP or
MSA. This approach is clearly helpful, as some patients who look like PSP or MSA may not fulfill
diagnostic criteria at the time of screening but with further follow-up will develop these features.
Incidence of PSP and MSA

There are even fewer estimates of incidence and two of these are based in almost the same popu-
lation (5,11) (Table 2). The relatively low rate from the first paper from Rochester, Minnesota (5),
may have reflected less recognition for PSP than in the later study (11). The estimates by Schrag and
colleagues (14) are remarkably similar to that by Bower and colleagues (11), though the former are
only indirect estimates based on prevalence data and dividing this by the median survival. This was
probably a fortuitous coincidence but further studies are required to confirm these rates.
Implications From Prevalence and Incidence Data

Despite rather limited data, there are no clear signs that there are widespread geographical differ-
ences in PSP and MSA, however there are almost no data from developing countries and one cannot
exclude that in other populations or ethnic groups there may be higher rates. Atypical parkinsonism
has been reported with greater frequency in the Caribbean (18) and among South Asians and African
Caribbeans (19) in the United Kingdom, though these latter observations remain controversial. Little
obvious differences exist across Europe, as has been noted for PD (17), or North America, yet more
higher-quality studies are required especially to estimate incidence rates.
RISK FACTORS FOR PSP AND MSA

The epidemiology of PD has been greatly aided by two natural experiments that generated impor-
tant hypotheses regarding its etiology. The first was the encephalitis lethargica epidemic, which sug-
gested a role for an infective agent (20). The second was the strange occurrence of MPTP-induced
parkinsonism (21), which suggested the role of a neurotoxic agent and led to studies examining the
role of pesticides because of its similarity with paraquat (22). The relevance of these models for the
etiology of PSP and/or MSA is far more questionable. However, in the absence of any other clues,
most researchers have simply used risk factors that have been suggested to be important for PD, e.g.,
smoking behavior, head injury, pesticides, well water, etc., and tested them out in PSP and MSA as
essentially a hypothesis-generating exercise.
Risk Factors for PSP

One possible natural experiment has been the study of an atypical form of parkinsonism in
Guadeloupe, clinically indistinguishable from PSP, which was prompted by the discovery that an
unexpectedly high proportion of parkinsonian patients were unresponsive to levodopa (23). Based
upon the hypothesis that some of the herbal tea and tropical fruits consumed in Guadeloupe contain
benzyltetrahydoisoquinolones, which are known to be neurotoxic, a case-control study was under-
taken (see Table 3). During a 1-yr period, they compared herbal tea and tropical fruit consumption
among 87 parkinsonism patients referred to the sole neurological center in Guadeloupe (22 had IPD
[idiopathic Parkinsons disease], 31 PSP, 30 could not be classified, and 4 had atypical parkinsonism
with motor neurone disease) with 65 hospital inpatients with non-neurodegenerative diseases. They
demonstrated a higher consumption of herbal teas and tropical fruits in PSP patients and atypical
parkinsonism. This was associated with a fourfold increased risk for both groups compared to con-
trols. Although the confidence intervals for the odds ratios are wide and approach unity, further
evidence supporting a causal role for these agents comes from the observation that two of the PSP
patients and four of the atypical cases improved significantly after stopping their consumption of
these substances, one patient being able to return to work. It remains unclear whether these atypical
Table 2
Incidence Studies of PSP and MSA
PSP Incidence MSA Incidence
Lead Author Year of Generic (G) Population Case Diagnostic per 100,000 per 100,000
Epidemiology of PSP and MSA
(Ref. No.) Publication or Specific (S) Location Size Ascertainment Criteria (No. of Cases) (No. of Cases)
Rajput (5) 1984 G Rochester, USA 53,885* Hospital medical Clinical diagnosis 0.29* (2) 0.71* (5)
records
Radhakrishnan (7) 1988 G Benghazi, Libya 519,000 Polyclinics, hospitals,
rehab centers, and
neurology dept. Clinical diagnosis 0.29 (6)
Bower (11) 1997 S Olmsted County,
USA 94,965 Hospital medical MSA consensus 1.12 (16) 0.63 (9)
records 1996 & Collins
1995
Schrag (14) 1999 S London, UK 121,608 GP records Quinn criteria
for MSA &NINDS
criteria for PSP 1.41** 0.46**
*Estimated from paper.
**Indirect estimates based on prevalence and median survival.
27
28
Table 3
Case control studies of PSP and MSA
Lead Author Year of Results - Odds
(Ref. No.) Publication Design Location Cases Controls Ratios (95% CI)
PSP
Davis (24) 1988 Case-control study New Jersey, USA 50 cases from 100 hospital controls Finished high school 3.1,
neurologists and finished college 2.9,
tertiary center rural residence 2.4
Golbe (25) 1996 Case-control study New Jersey, USA 75 cases from tertiary 75 neurology outpatients At least 12 years education
center (91 unmatched) excluding neurodegenrative 0.35 (0.12 to 0.96); no dif-
diseases (106 unmatched) ference by rurality
Caparros-Lefebvre (23) 1999 Case-control study French West Indies 31 PSP and 30 atypical 65 hospital controls Fruit or herbal tea 4.35,
parkinsonism from (1.25 to 15.2) for PSP,
neurology dept. 4.27, (1.22 to 14.9), for
atypical parkinsonism
Vanacore (26) 2000 Case-control study Mainly Italy but also 55 cases from tertiary 134 relatives of patients Smoking OR 0.91 (0.42
Austria and Germany centers with non-neurological 1.98); no dose-response
controls
MSA
Nee (27) 1991 Case-control study USA 60 cases from NINDS, 60 controls from spouses, College education 0.39
newsletters, or private friends, and volunteers (0.160.90); significant
doctors associations with metal dust
and fumes 14.8, pesticides
5.8, plastic monomers and
addditives 5.3
Vanacore (26) 2000 Case-control study Mainly Italy but also 75 cases from tertiary 134 relatives of patients Smoking 0.56 (0.291.06);
Austria and Germany centers with non-neurological dose-response effect
controls
Zermansky and Ben-Shlomo
cases represent PSP or not. Only one patient in their study had a neuropathological examination,
which showed changes seen in amyotrophic lateral sclerosis (ALS). It is not clear whether this was
one of the PSP, PSP and ALS, or unclassifiable patients. Circumstantial evidence that the PSP-like
syndrome may be PSP comes from a neuropathological study of five PSP patients from Guadeloupe,
all of whom consumed large amounts of either tropical fruits or herbal teas. All these cases had
neuropathologically confirmed PSP, with four-repeat tau deposition.
Although this study provides a model for the role of dietary factors or a neurotoxin, the specific
dietary components are fairly unique to this population and can provide clues to other substances
only by analogy. Two case-control studies in New Jersey, conducted by the same research group 8 yr
apart tried to identify a wide range of possible factors. The first (24), in 1988, compared 50 PSP
patients (Golbe diagnostic criteria) in a tertiary-referral center with 100 age- and sex-matched inpa-
tients with non-neurological disorders. It examined 85 potential factors including educational attain-
ment, family history, and toxin exposures. In an attempt to improve the quality of information and
possibly reduce recall bias between control and patient groups, questionnaires were administered to
surrogate respondents only (the patients spouse or offspring or sibling). This may have led to reduc-
ing any true association as relatives may not have been aware of all occupational exposures resulting
in nondifferential misclassification toward the null. The only significant finding was that PSP patients
were more likely to have completed high school, completed 4 yr at college, and live in an area with a
population of less than 10,000 as an adult. It is unsurprising that out of 85 hypothesis tests, 34 tests
were significant by chance at the 5% level (type I error). These findings could also be explained, as
discussed in the paper, by selection bias; patients identified from tertiary referral centers are more
likely to have a higher educational level and come from a wider catchment area than inpatients with
acute medical problems from the local community. These findings failed to replicate in the follow-up
study in 1996 (25). On this occasion, to avoid selection bias, non-neurodegenerative controls were
drawn from the same pool of neurology outpatient referrals as the patients. Using a self-completed
postal questionnaire, the study examined factors that neared statistical significance in the previous
study. Now, PSP patients were less likely to have completed 12 yr at school, but no other factors were
significant. The authors hypothesized that this may be a proxy for either lower nutritional status,
somehow leading to a propensity to develop PSP, or possibly exposure to an unknown neurotoxin in
early life. However, it is unclear how representative was the sample of controls. Given the severity of
PSP, it is likely that all cases will eventually be referred for a neurological opinion, though not
always to a tertiary specialist center. However, other neurological conditions, e.g., headaches, sci-
atica, etc., may be referred to a wide variety of other clinicians. Those reaching a tertiary center may
be biased toward a higher educational level.
Since smoking shows a negative association with Parkinsons disease, Vanacore and colleagues
examined this factor among PSP patients (26). The study recruited 55 PSP and 134 control subjects.
The control subjects were healthy relatives of patients with non-neurodegenerative diseases. Any
further information about control selection was not given nor were the response rates reported. Since
smokers are likely to be overrepresented in any randomly selected patient cohort, there is the possi-
bility that controls were more likely to be relatives of patients who smoked. This bias would tend to
show an inverse association with PSP but in fact there was little evidence of any association, though
the wide 95% confidence intervals mean it is not possible to exclude even a halving of risk as seen
with PD.
Risk Factors for MSA

Only two case-control studies have been reported for MSA. The first examined family history and
specific occupational exposures. This noted significant odds ratios for organic solvents (2.4), metal-
lic dusts (14.8), pesticides (5.8), and plastic monomers and additives (5.3) (27). Anecdotal case reports
have also suggested pesticides (28), heavy metals (28), and organic solvents (28,29).
Logistic regression analysis uncovered an increased risk of MSA with a positive family history of
any neurological disease. No response rates were reported for cases and controls and the use of
spouse, friends, and volunteer controls may have introduced substantial selection bias. In particular,
as more male cases were ascertained, the use of female spouses will artifactually increase the risk of
any occupationally related exposure found in male jobs. The increased odds ratio of having a family
history of neurological disorders may have been spurious, since only 33 of the 60 MSA subjects
family members participated, and attempts to recruit MSA-subject family members were made only
if the MSA patients thought their relatives would be interested.
Vanacore and colleagues in the same study mentioned earlier did find an inverse association
between smoking and MSA. Although the odds rations for smoking were not significant at the 5%
level, they did observe a doseresponse effect with decreasing odds as the number of pack-years
increased. This may have been biased, owing to the control selection, however their results for PD are
consistent with other studies suggesting that this may not have been a real problem.
Implications From Case-Control Studies of PSP and MSA

Summarizing the current published data, it appears that there is no evidence identifying any clear
environmental risk factor for PSP, other than tropical fruit and herbal tea consumption for the PSP-
like disorder in Guadeloupe. Evidence for environmental factors in MSA is mainly anecdotal, although
the study by Nee and colleagues implicates various nonspecific occupational exposures. This does not,
however, exclude the possibility of the role for an environmental factor in the etiology of either
disorder. Furthermore, none of these studies recruited more than 100 cases. This means they are
limited in statistical power with a high likelihood of a type II error, accepting the null hypothesis
when the alternative hypothesis is true. Even with a study recruiting 100 cases and 200 controls, at a
5% level of significance and 90% power, one could only detect an odds ratio of 2.3 for a common
exposure with 50% prevalence in the control group. For a rarer exposure with only 10% prevalence,
this further deteriorates to an odds ratio of 3.0.
CONCLUSIONS
Remarkably little good-quality evidence exists on the epidemiology of PSP and MSA. Basic
descriptive data on the variations of both diseases in time, place, and person are sparse. There is at
this stage little evidence of widespread geographical variations, but many areas of the world have yet
to report prevalence and incidence rates. Other than the possible rare exposure of benzyl-
tetrahydoisoquinolones, we have little to go on for specific environmental clues. Positive findings
with occupational exposures may reflect publication bias and negative studies may simply be under-
powered to detect modest increased risks. Single centers are unlikely to be able to undertake suffi-
ciently large and powerful studies so future research must either use a multicenter approach or use
standardized methods to enable future meta-analysis of results. The challenges of undertaking high-
quality epidemiology of PSP and MSA are likely to remain well into the 21st century.
FUTURE DIRECTIONS
The future direction for PSP and MSA epidemiology will depend on various factors. Firstly, clini-
cal anecdotes or natural experiments as occurred with MPTP and parkinsonism, will generate new
hypotheses. Whilst many of these will be red herrings, true etiological insights can be gained by
methodological sound exploration of such reports. Secondly, new developments in laboratory-based
research may highlight etiological factors that have an analogous lifestyle exposure. This in turn can
be tested using either questionnaires or, better still, with some plausible biomarker. Finally, well
undertaken large case control studies will be necessary to refute or support plausible hypotheses.
REFERENCES
movement disorder service. Brain 2002;125:861870
2. Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci
1999;163(1):9498.
RichardsonOlszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47(1):19.
4. Litvan I, Bhatia KV, Burn DJ, et al. Movement Disorders Society Scientific Issues Committee report: SIC Task Force
appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18(5):467486.
5. Rajput AH, Offord KP, Beard M, Kurland LT. Epidemiology of parkinsonism: incidence, classification and mortality.
Ann Neurol 1984;16:278282.
6. Golbe LI, Davis PH, Schoenberg, et al. Prevalence and Natural History of Progressive Supranuclear Palsy. Neurology
1988;38:10311034.
7. Radhakrishnan K, Thacker AK, Maloo JC, et al Descriptive epidemiology of some rare neurological diseases in
Benghazi, Libya. Neuroepidemiology 1988;7(3):159164.
8. Morgante L, Rocca WA, Di Rosa AE, et al. Prevalence of Parkinsons disease and other types of Parkinsonism: a door-
to-door survey in three Sicillian municipalities. Neurology 1992;42:19011907.
9. de Rijk MC, Breteler MMB, Graveland GA, et al. Prevalence of Parkinsons disease in the elderly: the Rotterdam
Study. Neurology, 1995;45(12):21432146.
10. Trenkwalder C, Schwarz J, Gebhard J, et al. Starnberg trial on epidemiology of Parkinsonism and hypertension in the
elderly. Prevalence of Parkinsons disease and related disorders assessed by a door-to-door survey of inhabitants older
than 65 years. Arch Neurol 1995;52(10):10171022.
11. Bower JH, Maranganore DM, McDonnell SK, Rocca W. Incidence of progressive supranuclear palsy and multiple
system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49(5):12841288.
12. Wermuth, L, Joensen P, Bunger N, Jeune B. High prevalence of Parkinsons disease in the Faroe Islands. Neurology
1997;49(2):426432.
13. Chio A, Magnani C, Schiffer D. Prevalence of Parkinsons disease in Northwestern Italy: comparison of tracer method-
ology and clinical ascertainment of cases. Mov Disord 1998;13(3):400405.
14. Schrag A., Ben-Shlomo Y, Quinn NP. Prevalence of progressive supranuclear palsy and multiple system atrophy: a
cross-sectional study. Lancet 1999;354:17711775.
15. Nath U, Ben-Shlomo Y, Thomson RG, et al. The Prevalence of progressive supranuclear palsy (SteeleRichardson
Olszewski syndrome) in the UK. Brain 2001;124:14381449.
16. Matthews WB, Compston A, Allen IV, Martyn CN. McAlpines Mmultiple sclerosis, 2 ed. Edinburgh: Churchill
Livingstone, 1990.
17. de Rijk MC, Tzourio C, Breteler MM, et al. Prevalence of parkinsonism and Parkinsons disease in Europe: the
EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinsons
disease. J Neurol Neurosurg Psychiatry 1997;62:1015.
18. Steele JC, Caparros-Lefebvre D, Lees AJ, Sacks OW. Progressive supranuclear palsy and its relation to pacific foci of
the parkinsonism-dementia complex and Guadeloupean parkinsonism. Parkinsonism Relat Disord 2003;9:3954.
19. Chaudhuri KR, Hu MT, Brooks DJ. Atypical parkinsonism in Afro-Caribbean and Indian origin immigrants to the UK.
Mov Disord 2000;15(1):1823.
20. Duvoisin RC, Yahr MD, Schweitzer MD, Merritt HH. Parkinsonism before and since the epidemic of Encephalitis
Lethargic. Arch Neurol 1963;9:232236.
21. Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog
synthesis. Science 1983;219:970980.
22. Sanchez-Ramos JR, Hefti F, Weiner WJ. Paraquat and Parkinsons disease. Neurology 1987;37:728.
23. Caparros-Lefebvre D, Elbaz A, and the Caribbean Parkinsonism Study Group. Possible relation of atypical parkin-
sonism in the French West Indies with consumption of tropical plants: a case-control study. Lancet 1999;354:281286.
24. Davis PH, Golbe LI, Duvoisin RC, Schoenberg BS. Risk factors for progressive supranuclear palsy. Neurology
1988;38(10):15461552.
25. Golbe LI, Rubin RS, Cody RP et al. Follow-up study of risk factors in progressive supranuclear palsy. Neurology
1996;47(1):14854.
26. Nee LE, Gomez MR, Dambrosia J, Bale S, Eldridge R, Polinsky RJ. Environmental-occupational risk factors and
familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991;1(1):913.
27. Vanacore, N., et al., Smoking habits in multiple system atrophy and progressive supranuclear palsy. European Study
Group on Atypical Parkinsonisms. Neurology 2000;54(1):114119.
28. Hanna PA, Jankovic J, Kirkpatrick JB. Multiple system atrophy: the putative causative role of environmental toxins.
Arch Neurol 1999;56(1):9094.
29. McCrank E. PSP risk factors. Neurology 1990; 40:1637.
Neuropathology of Atypical Parkinsonian Disorders 33
4
Neuropathology of Atypical Parkinsonian Disorders
Ian R. A. Mackenzie
INTRODUCTION
Although the clinical syndrome of parkinsonism (rigidity, bradykinesia, and tremor) is most often
owing to idiopathic Parkinsons disease (PD), it may also be associated with a variety of other under-
lying pathologies (Table 1) (13). Each of these other pathological conditions tends to have a charac-
teristic clinical phenotype, however atypical cases are increasingly recognized (48). Moreover, some
patients with PD have additional clinical features such as dementia, autonomic dysfunction, or gas-
trointestinal dysmotility (913). As a result, the accurate diagnosis of a patient with parkinsonism,
and especially those with atypical or additional clinical features, ultimately depends on neuropatho-
logical examination. This chapter will review the pathological changes that characterize those condi-
tions that may present with or have parkinsonism as a major feature, either in isolation or combined
with other clinical manifestations. Although the focus of this text and chapter are the atypical causes
of parkinsonism, a description of the pathological features of typical PD is included for comparison.
Most of the conditions that cause parkinsonism have damage of the striatonigral system as the
common anatomicopathological substrate. Some have additional neuropathology, which is more dis-
ease specific, such as the presence of characteristic cellular inclusions in many of the idiopathic
neurodegenerative disorders (Table 2). Others, such as many toxic and metabolic conditions, show
only nonspecific chronic degeneration with neuronal loss and reactive gliosis. In this chapter, greater
discussion will be devoted to those disease entities that more commonly cause parkinsonism and
have distinctive pathology, whereas conditions that rarely cause parkinsonism and those with non-
specific pathology will receive less attention.
IDIOPATHIC PARKINSONS DISEASE

Although there is some controversy as to the most appropriate use of the term (14), Parkinsons
disease is most often used to denote idiopathic parkinsonism associated with the pathological finding
of neuronal loss and Lewy bodies in the substantia nigra.
External examination of the brain is generally unremarkable, although PD patients who develop
dementia may have mild to moderate cerebral atrophy. On cut sections, there is usually loss of pig-
ment from the substantia nigra and locus ceruleus (Fig. 1A). The caudate, putamen, globus pallidus,
thalamus, and other brainstem structures appear normal.
The histopathological hallmark of PD is the loss of dopaminergic neurons from the substantia
nigra associated with the presence of intraneuronal inclusions called Lewy bodies (LBs). Cell loss in
the substantia nigra occurs in a region-specific manner, with the lateral ventral tier of the pars com-
pacta being most affected (15). It is estimated that at least 50% of the nigral neurons must degenerate

33
34 Mackenzie
Table 1
Causes of Parkinsonism
1. Neurodegenerative disease:
synucleinopathies
Lewy body disorders
- idiopathic Parkinsons disease
- dementia with Lewy bodies
multiple system atrophy
HallervordenSpatz syndrome
tauopathies
corticobasal degeneration
progressive supranuclear palsy
FTDP-17
parkinsonism/dementia complex of Guam
other:
Alzheimers disease
motor neuron disease and frontotemporal dementia with MND-type inclusions
Huntingtons disease
spinocerebellar ataxia
2. Infectious disease:
postencephalitic parkinsonism
HIV
other (bacteria, viruses, parasites, fungi)
3. Vascular disease
4. Trauma
5. Toxins:
MPTP
others
6. Dugs:
neuroleptics (phenothiazines)
7. Metabolic disease:
Wilsons disease
aceruloplasminemia
8. Space-occupying lesions
9. Hydrocephalus
Note: It has recently become popular to classify some neurodegenerative diseases based on the
protein abnormality (molecular pathology) that is believed to be central to the pathogenesis. This
interpretation is often supported by genetic analysis of familial cases. Although this type of classifi-
cation may help to organize discussion of the comparative pathology and biochemistry between
conditions, it may be an oversimplification, which will require revision in the future. For instance, it
is increasingly recognized that many of the tauopathies often have some accumulation of F-synuclein
and vice versa.
to produce symptoms and, at autopsy, most cases show more than 80% reduction (15). Significant
neuronal loss also occurs in the locus ceruleus, dorsal motor nucleus of the vagus, raphe nuclei, and
nucleus basalis. LBs may be found in all of these locations as well as numerous other subcortical
structures. Neurodegeneration is accompanied by reactive changes including astrogliosis and micro-
glial cell activation. In pigmented nuclei, neuromelanin is released from dying neurons and may lie
free within the neuropil or be taken up by macrophages.
In 1912, Frederich H. Lewy first described intraneuronal inclusions in the substantia innominata
and dorsal motor nucleus of the vagus, in patients with paralysis agitans (16). Seven years later,
Tretiakoff recognized similar inclusions in the substantia nigra and called them corps de Lewy (17).
Since then, LBs have been considered the pathological hallmark of idiopathic PD and most
Table 2
Comparative Neuropathology of Major Causes of Parkinsonism
Disease Most Diagnostic Pathology Other Characteristic Pathology
idiopathic Parkinsons subcortical LBsa cortical LBsa
disease pale bodiesa
Lewy neuritesa
dementia with Lewy bodies cortical LBsa subcortical LBsa
Lewy neuritesa
multiple system atrophy glial cytoplasmic inclusionsa glial intranuclear inclusionsa
neuronal cytoplasmic
and intranuclear inclusionsa
corticobasal degeneration achromatic neurons cortical neuronal cytoplasmic inclusionsb
astrocytic plaquesb corticobasal bodiesb
threadsb thorn-shaped astrocytesb
coiled bodiesb
progressive supranuclear subcortical NFTsb cortical NFTsb
palsy tufted astrocytesb thorn-shaped astrocytesb
coiled bodiesb
threadsb
grumose degeneration
FTDP-17T various neuronal cytoplasmic achromatic neurons
inclusionsb
various glial cytoplasmic
inclusionsb
ALS/parkinsonism/
dementia complex of Guam cortical and subcortical NFTsb glial cytoplasmic inclusionsb
Alzheimers disease cortical SPs
cortical NFTsb subcortical SPs ( subcortical NFTsb
postencephalitic parkinsonism cortical and subcortical NFTsb glial cytoplasmic inclusionsb
vascular parkinsonism cerebral infarcts
posttraumatic parkinsonism NFTsb
SPs
LB, Lewy body; NFT, neurofibrillary tangle
aF-synuclein immunoreactive
btau-immunoreactive
neuropathologists are reluctant to make the diagnosis in their absence. Classical LBs are spherical
intracytoplasmic neuronal inclusions, measuring 830 m in diameter, with an eosinophilic hyaline
core and a pale-staining peripheral halo (Fig. 1B). They occasionally have a more complex, multilobar
shape and more than one LBs may occur in a single cell. Following neuronal death, LBs may remain
as an extracellular deposit in the neuropil. Ultrastructurally they are composed of radially arranged 7-
to 20-nm filaments associated with granular electron-dense material.
An additional finding in most cases of PD is the presence of pale bodies: ill-defined rounded areas
of granular pale-staining eosinophilic material that also occur in pigmented neurons of the substantia
nigra and locus ceruleus (Fig. 1C). Although they are distinguished from LBs histologically, their
similar immunocytochemical profile suggests they likely represent precursors to LBs (18,19).
LBs are difficult to isolate and purify and so most of our understanding of their chemical compo-
sition is based on immunohistochemical studies. Until recently, the two main components were
36 Mackenzie
Fig. 1. Idiopathic Parkinsons disease (PD). (A) Gross photograph of the midbrain showing loss of pigmen-
tation of the substantia nigra in PD compared with normal control (C). (B) Classical Lewy body in pigmented
neuron of the substantia nigra (H&E stain). (C) Pale bodies in pigmented neurons of the substantia nigra (H&E
stain). (D) Filamentous cytoplasmic inclusion in glial cell (Gallyas silver stain).
thought to be neurofilament proteins and ubiquitin, although many other protein and non-proteina-
ceous elements are also recognized (2022). The biochemistry of LBs was clarified following the
discovery of mutations in the gene for F-synuclein in some families with autosomal dominant PD
(23). F-Synuclein is a presynaptic nerve terminal protein and immunohistochemistry of normal brain
tissue shows punctate staining around neuronal perikarya. Direct involvement of F-synuclein in the
pathogenesis of all LB disorders (sporadic as well as familial PD and dementia with LB) is supported
by immunohistochemical studies confirming F-synuclein as a major component of both brainstem
and cortical LB, as well as pale bodies and Lewy-related neurites (19,24). In addition to these neu-
ronal pathologies, recent reports have described the presence of argyrophilic, F-synuclein-positive
cytoplasmic inclusions in both astrocytes and oligodendrocytes in PD (Fig. 1D) (25,26). The consis-
tency and significance of this glial pathology awaits clarification.
DEMENTIA WITH LEWY BODIES

Although it has long been recognized that a significant proportion of PD patients develop demen-
tia (12), the pathological substrate for this cognitive dysfunction remained uncertain. In 1961, Okazaki
reported finding LBs in the cerebral cortex of two patients with PD and atypical dementia (27).
Although subsequent cases of diffuse Lewy body disease (DLBD) were published, the condition was
initially considered rare. In the late 1980s, with greater awareness of cortical LBs and the develop-
ment of more sensitive staining methods, several groups reported finding cortical LBs in 1525% of
elderly demented patients, both with and without parkinsonism (28,29). It has recently been proposed
that dementia associated with Lewy bodies (DLB) represents a recognizable clinicopathological syn-
drome that may be distinguishable during life from other causes of dementia (30). The proposed
diagnostic criteria are purely clinical however, and recommendations as to how to quantitate LBs are
only designed to assess the hypothesis that dementia is more likely to occur when LBs are numerous
and widespread (i.e., DLB = DLBD) (30). Although numerous cortical LBs are most characteristic of
DLB, smaller numbers are found in most (if not all) patients with idiopathic PD, even in the absence
of dementia (31). As a result, the clinical and pathological relationship between PD and DLB and the
appropriate terminology remains an ongoing source of controversy.
Some cases of DLB show microvacuolation of the superficial neocortex, particularly in the tem-
poral lobe. Cortical LBs occur primarily in small and medium-size pyramidal neurons of the deeper
cortical layers and are most abundant in the transentorhinal and cingulate cortex, less numerous in
neocortex, and generally spare the hippocampus. They tend to be less well defined and are more
difficult to recognize than classical brainstem LBs, using conventional staining methods (Fig. 2A). It
is largely the advent of more sensitive immunohistochemical methods of detection (especially for
ubiquitin and F-synuclein) that has allowed the extent of cortical LB pathology to be fully appreci-
ated (Fig. 2B).
A distinctive neuritic degeneration was first reported in cases of DLB (32) but has subsequently
been found in many cases of PD, as well (33). These abnormally swollen neuronal processes are not
seen using hematoxylin and eosin (H&E) or conventional silver stains but are well demonstrated
using ubiquitin and F-synuclein immunohistochemistry (Fig. 2C) (19). Often referred to as Lewy
neurites, they are most concentrated in the CA2/3 region of the hippocampus but are also found in the
amygdala, nucleus basalis, and various brainstem nuclei. In addition to accumulating in neuronal cell
bodies and processes, F-synuclein-positive glial inclusions have also been reported in DLB (25,34).
Most, but not all, cases of DLB have some degree of Alzheimers disease (AD)-like pathology
(28,35). Senile plaques (SPs) are the most common finding with the majority being of the diffuse
type. When neuritic plaques are present, most contain only tau-negative, ubiquitin-positive neurites.
Neurofibrillary tangles (NFTs) and neuropil threads, containing paired helical filaments, may be
found in the limbic structures and mesial temporal lobe but are uncommon in the neocortex. This
pattern of pathology may be sufficient to fulfil pathological criteria for AD that are based on SP
numbers (such as CERAD) (36) but not those that stress the importance of NFTs (such as Braak
staging) (37). This overlap between DLB and AD pathology, combined with the lack of universally
accepted pathological diagnostic criteria for either disorder, has resulted in confusion over the rela-
tionship between the conditions and the appropriate terminology. It also raises questions as to the
pathological substrate for dementia in DLB patients. Although some studies have shown a correla-
tion between the numbers of cortical LBs and cognitive dysfunction (3841), others have not (29).
This suggests that coexisting AD pathology, Lewy neurites, and/or degeneration of specific neuronal
populations could all contribute to dementia, possibly in an additive fashion (42,43).
THE SPECTRUM OF LB DISORDERS

There is striking clinical and pathological overlap between PD and DLB. Up to one-third of patients
with a clinical diagnosis of PD will develop dementia (9,12,42) and most (but not all) patients with
DLB display some degree of parkinsonism (30). LBs are the defining histopathological feature of
both conditions. In PD, LBs are most numerous in subcortical nuclei and it is the associated loss of
dopaminergic neurons that is largely responsible for the characteristic extrapyramidal features. How-
ever, small numbers of cortical LBs may be found in virtually all cases of PD, even in the absence of
dementia (31). In DLB, cortical LBs are usually more numerous and some studies have shown a
38 Mackenzie
Fig. 2. Dementia with Lewy bodies. (A) Cortical Lewy body (LB) (H&E stain). (B) Three neurons in deep
layers of neocortex containing LBs (F-synuclein immunohistochemistry). (C) Lewy neurites in CA2 region of
hippocampus (ubiquitin immunohistochemistry).
correlation between their number and the degree of dementia (3841). Even in the absence of parkin-
sonism, however, the vast majority of DLB cases display some brainstem LB. Recognition of this
overlap has led to the concept of a spectrum of LB disorders with different clinical features, depend-
ing on the severity and anatomic distribution of LB involvement (4446). Other less common clinical
manifestations may be associated with involvement of other neuroanatomic regions, autonomic dys-
function with involvement of sympathetic ganglia, dysphagia when the dorsal motor nucleus of the
vagus is damaged, and gastrointestinal dysmotility with LBs in enteric plexi (10,11). Each condition
may occur in isolation or in various combinations. Although this concept is attractive, at least one
recent study failed to demonstrate the degree of clinical-anatomic correlation predicted (38).
FAMILIAL PARKINSONS DISEASE

At the time this manuscript was being prepared, at least 11 different genetic loci had been linked to
familial PD, including mutations in four specific genes (47,48). The pattern of inheritance includes
both autosomal dominant and recessive and the clinical phenotypes vary from typical PD to families
with juvenile or early onset and others with atypical clinical features. For most of these, information
about the pathological findings is not yet available. Families with autosomal dominant PD and muta-
tion of the gene for F-synuclein have changes similar to sporadic PD, with nigral degeneration and
LBs (23). Cases of autosomal recessive, juvenile-onset PD and parkin mutations have neuronal loss
in the substantia nigra and locus ceruleus, but only one report has described finding LBs (49). A
single family has been identified with a mutation in the gene for ubiquitin C-terminal hydrolase L1
(UCH-L1) (50). No pathological information is available from this family but mice with intronic
deletion of this gene develop axonal degeneration (51).
MULTIPLE SYSTEM ATROPHY

Although the term multiple system atrophy (MSA) has been used rather indiscriminately in the
past, recent advances in our understanding of the genetic, biochemical, and pathological basis of a
number of neurodegenerative diseases has resulted in some reclassification and refinement of the
definition. On the basis of a common pathological substrate, the diagnosis of MSA is currently
restricted to include cases formerly designated as striatonigral degeneration (SND),
olivopontocerebellar atrophy (OPCA), and some (but not all) cases of ShyDrager syndrome. Because
of the high degree of clinical and pathological overlap between these conditions, a recent Consensus
Conference recommended using the terms MSA-P for cases with prominent parkinsonism and MSA-
C for those with mainly cerebellar features (52). A review of 100 cases of the clinical course of MSA
found that almost all eventually developed parkinsonism and autonomic dysfunction whereas cer-
ebellar features occurred in less than half (53).
Several excellent reviews of the neuropathology of MSA have recently been published (54,55).
Macroscopically, there is atrophy of specific cortical and subcortical regions, which reflects the ana-
tomic distribution of degenerative change. In cases previously designated as SND (most probably
corresponding to MSA-P), there tends to be severe atrophy and discoloration of the putamen and loss
of pigmentation of the substantia nigra and locus ceruleus (Fig. 3A), whereas in OPCA (MSA-C) the
cerebellum, middle cerebellar peduncles, and basis pontis are most affected (Fig. 3B).
Microscopically, the involved gray matter structures show neuronal loss and reactive gliosis
whereas associated white matter tracts demonstrate loss of myelin. The degree and pattern of degen-
eration vary from case to case but the putamen, substantia nigra, locus ceruleus, inferior olives, pon-
tine nuclei, Purkinje cell layer, and intermediolateral columns are most often affected in some
combination (56). Nerve biopsy may show a reduction in the number of unmyelinated fibres (57).
The specific histopathological changes that characterize MSA, and which are now considered
mandatory for the diagnosis (58), were first described in a series of articles by Papp and Lantos (59
61). The most characteristic change is the presence of small flame or sickle-shaped structures in the
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Fig. 3. Multiple system atrophy. (A) Gross photographs of a case of striatonigral degeneration showing
atrophy and discoloration of the putamen (arrows) and loss of pigmentation of the substantia nigra (inset).
(B) Gross photograph showing atrophy of the pons in a case of olivopontocerebellar atrophy (OPCA) compared
with normal control (C). (C,D) Numerous glial cytoplasmic inclusions (GCIs) in oligodendrocytes (Gallyas
silver stain). (E) GCIs immunoreactive for F-synuclein.
cytoplasm of oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). They are difficult
to detect in routine H&E-stained sections but are well demonstrated with a variety of silver stains,
particularly the Gallyas method (Fig. 3C,D). Although GCIs show variable immunoreactivity for a
variety of proteins including tau, ubiquitin, tubulins, and B-crystallin (59,6264), they are most
strongly immunoreactive for F-synuclein (Fig. 3E) (65,66). The ultrastructural composition includes
tubules and straight and twisted filaments associated with granular material (59,60,6265). GCIs
tend to be widely distributed throughout the brain, beyond the areas showing obvious degeneration.
They are found in motor cortex, putamen, globus pallidus, subthalamic nucleus, pontine nuclei, vari-
ous cranial nerve nuclei, and several white matter tracts in the cerebrum, brainstem, and spinal cord.
In addition to GCI, argyrophilic, ubiquitin-, and F-synuclein immunoreactive fibrillar or filamentous
inclusions are also found in the cytoplasm of neurons and the nuclei of both neurons and glia in MSA
(60,63,67). These other types of inclusions tend to be less numerous and have a more restricted
anatomical distribution, found primarily in the putamen and basis pontis, and their presence is not
required for diagnosis.
CORTICOBASAL DEGENERATION
This clinicopathological entity was first described under the name corticodentonigral degenera-
tion with neuronal achromasia (68) and early reports stressed the characteristic movement abnor-
malities, which often include akinetic rigidity (69). More recently, however, a number of postmortem
studies have found abnormalities of higher mental function, such as language disturbance and demen-
tia, to be a common and sometimes predominant feature in patients with corticobasal degeneration
(CBD) pathology (6,8,7074).
Cortical atrophy is often focal and asymmetric with parasagittal, peri-Rolandic, or peri-Sylvian
regions most often involved (Fig. 4A). Macroscopic degeneration of subcortical structures is variable
with depigmentation of the substantia nigra being most consistent. Microscopically, degenerative
changes are more widespread but the severity and anatomical distribution vary between cases. In
addition to neuronal loss and gliosis, the affected cortical regions may show superficial laminar or
transcortical microvacuolation. Of subcortical structures, the substantia nigra tends to be the most
severely and consistently affected whereas involvement of globus pallidus, striatum, subthalamic,
thalamic nuclei, and brainstem regions is more variable.
The original description identified numerous swollen achromatic neurons (ANs) as the character-
istic histopathological feature of CBD (68). ANs are most numerous in limbic cortex and amygdala
in CBD, however this finding is not disease specific (75,76). Of greater diagnostic significance is the
presence of neocortical ANs, which are most common in layers III, V, and VI of posterior frontal and
parietal lobes. They may also be present in small numbers in subcortical regions. ANs resemble cells
undergoing central chromatolysis; the perikaryon is swollen and often rounded, the Nissl substance is
inconspicuous, and the nucleus is often in an eccentric position (Fig. 4B). They occasionally show
cytoplasmic vacuolation. Although easy to recognize with standard H&E stain, ANs are best demon-
strated by their strong cytoplasmic immunoreactivity for phosphorylated neurofilament and FB-crys-
tallin (Fig. 4C) (75,77). Argyrophilia, tau-, and ubiquitin-immunoreactivity are more variable (72,78).
The other change visible with H&E stain is the presence of ill-defined faintly basophilic filamen-
tous cytoplasmic inclusions in surviving neurons of the substantia nigra and some other subcortical
structures (Fig. 4D). These were originally termed corticobasal bodies (79) but appear to have the
same immunophenotype and ultrastructure as the NFTs found in broader distribution in progressive
supranuclear palsy (PSP) (80,81).
The major recent advance in understanding the pathology of CBD has been the demonstration of
widespread accumulation of abnormal phosphorylated tau protein in both glia and neurons (72,80,82
84). Tau is a microtubule-associated protein (MAP) whose primary function is to promote the assem-
bly and stabilization of microtubules. It is constitutively expressed and is normally found in axons
42 Mackenzie
Fig. 4. Corticobasal degeneration. (A) Gross photograph showing mild peri-Rolandic cortical atrophy.
(B) Achromatic neuron (AN) in neocortex (H&E stain). (C) AN showing cytoplasmic immunoreactivity for
phosphorylated neurofilament. (D) Corticobasal body in pigmented neuron of substantia nigra (H&E stain).
(E,F) Neuronal inclusions in neocortex. Diffuse cytoplasmic immunoreactivity for phosphorylated tau (E) and
argyrophilic neurofibrillary tangle (F) (Gallyas silver stain). (GJ) Glial inclusions. (G) Astrocytic plaque (tau
immunohistochemistry). (H) Thorn-shaped astrocyte (Gallyas silver stain). (I) Coiled bodies in oligodendro-
cytes (Gallyas silver stain). (J) Thread-like processes in cerebral white matter (tau-immunohistochemistry).
and mature neurons. Most of the tau-positive inclusions of CBD are also well demonstrated with
silver stains such as Gallyas method but tend to react poorly with antibodies against ubiquitin pro-
tein. Neurons in the cerebral cortex may show diffuse granular cytoplasmic staining or contain denser
inclusions, resembling either Picks bodies or small NFTs (Fig. 4E,F) (72,80,85). Filamentous or
fibrillar cytoplasmic inclusions are also found in some subcortical neurons, especially in the substan-
tia nigra, where they correspond to the corticobasal bodies (80,81).
Several types of tau-immunoreactive, argyrophilic inclusions are found in the cytoplasm of glial
cells. The most specific is the astrocytic plaque, which consists of a circular arrangement of short cell
processes in the cortical or subcortical gray matter (Fig. 4G) (72,82,83,86,87). Although vaguely
resembling the neuritic plaques of AD, these structures are not associated with extracellular amyloid
and double-immunolabeling has confirmed they represent tau accumulation in the most distal portion
of astrocytic processes (72). More numerous but less disease specific are thorn-shaped astrocytes
and coiled bodies (83,88,89). Thorn-shaped astrocytes result from the accumulation of tau in the cell
body and most proximal portion of astrocytic processes, producing short, sharp processes (Fig. 4H).
44 Mackenzie
These are seen in cortical and subcortical gray matter and white matter. Coiled bodies occur in oli-
godendrocytes and appear as delicate bundles of fibrils that wrap around the nucleus and extend
into the proximal cell process (Fig. 4I). They are located primarily in the subcortical white matter.
One of the most striking changes in CBD is the presence of numerous tau-immunoreactive, silver-
positive threadlike processes in affected gray and white matter (Fig. 4J) (72,80,82,83,85,90). In con-
trast with the neuropil threads of AD, which are exclusively neuronal in origin, the threads of CBD
are primarily glial (72,90). Although similar threads are found in some other conditions such as PSP,
their extreme number in CBD is diagnostically helpful.
PROGRESSIVE SUPRANUCLEAR PALSY

In the original description of this disease entity, patients with supranuclear ophthalmoplegia,
pseudobulbar palsy, dysarthria, rigidity, and mild cognitive deficits were found to have abundant
NFTs in subcortical nuclei (91). The clinical phenotype is now recognized to be much more variable
and includes both pure parkinsonism and frontotemporal dementia with no movement abnormality
(1,2,4,5,71).
The macroscopic changes are quite variable. The cerebral cortex often appears normal but may
show significant frontotemporal atrophy that may be quite circumscribed (Fig. 5A). The midbrain
and pontine tegmentum are often atrophic whereas the globus pallidus is the most commonly affected
part of the basal ganglia (Fig. 5B). Microscopic degeneration with neuronal loss and gliosis also
tends to be more widespread and severe in PSP than CBD, with substantia nigra, locus ceruleus,
globus pallidus, subthalamic nucleus, midbrain tegmentum, cerebellar dentate nucleus, and pontine
nuclei usually involved.
As with CBD, the histopathology of PSP is characterized by the abnormal accumulation of tau
protein, in both neurons and glia, which can be demonstrated with immunohistochemistry or silver
methods such as Gallyas (82,83,86,88,90,92). The most characteristic feature is widespread NFT
formation (Fig. 5C) (91). Current diagnostic criteria require the presence of numerous NFTs in at
least three of the following sites: pallidum, subthalamic nucleus, substantia nigra, or pons, and at
least some tangles in three of striatum, oculomotor nucleus, medulla, or dentate (93,94). The tangles
in these subcortical regions often have a rounded or globose shape (Fig. 5D) and ultrastructural stud-
ies show they are composed predominantly of 1220 nm straight filaments. NFTs may also be found
in cerebral cortex where their morphology more closely resemble those seen in AD, being flame-
shaped and composed of paired helical filaments (9597). Although the number and distribution of
cortical NFTs in PSP is usually more restricted than in AD, some studies have shown a correlation
with cognitive dysfunction (98). ANs (more characteristic of CBD) may be found in some cases of
PSP but tend to be limited to limbic cortex (76).
Several types of argyrophilic, tau-positive glial inclusions occur consistently in PSP. Many of
these, such as thorn-shaped astrocytes, coiled bodies, and threadlike lesions, are nonspecific, also
being seen in other tauopathies such as CBD and Picks disease (82,83,8890). The most diagnostic
glial pathology in PSP is the presence of tufted astrocytes, which are most numerous in striatum but
that are also found in other subcortical regions and frontal cortex (86,88). Although immunoreactive
for tau, the morphology is best appreciated with Gallyas silver method, which shows the filamentous
inclusion material surrounding the astrocyte nucleus and extending into a complex collection of long
delicate processes, producing a shrublike appearance (Fig. 5E). This is different from thorn-shaped
astrocytes where the inclusion material is restricted to more proximal processes (Fig. 4G) and astro-
cytic plaques in which only the most distal parts of processes are involved (Fig. 4F).
Finally, a unique pathology, which may be seen in the cerebellar dentate nucleus in PSP, is grumose
degeneration in which granular eosinophilic material surrounds neurons, some of which are achro-
matic (Fig. 5F). Ultrastructural studies have shown the granular material to be degenerating axon
terminals of Purkinje cells (99).
Fig. 5. Progressive supranuclear palsy. Gross photographs showing (A) lobar frontal atrophy and (B) atrophy
and discoloration of basal ganglia. (C) Multiple neurofibrillary tangles (NFTs) and pretangles in midbrain (tau-
immunohistochemistry). (D) Globose NFT (H&E stain). (E) Tufted-astrocyte (Gallyas silver stain). (F) Grumose
degeneration (arrows) of neurons in cerebellar dentate nucleus (H&E stain).
46 Mackenzie
FTDP-17T
The term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was
recommended at a consensus conference in 1997 to denote a growing number of families recognized,
in which frontotemporal dementia (FTD), behavioral disturbances, language abnormalities, and/or
parkinsonism are inherited in an autosomal dominant fashion and genetic analysis shows linkage to
chromosome 17 (100). The following year, a number of reports were published, describing mutations
in the tau gene in some of these families (101104). It is now common for a T to be added to the end
of the acronym to distinguish these cases from other chromosome 17-linked FTD in which the tau
gene is normal and there is no tau accumulation in the brain (105,106). At the present time, more than
80 FTDP-17T kindreds have been identified, with more than 30 different tau mutations (107). The
types of genetic abnormality include missense, deletion, and silent transition mutations in the coding
region of the tau gene and intronic mutations near the splice site of the intron following exon 10
(108). Sufficient material is just now becoming available to allow for detailed examination of how
different genetic abnormalities correlate with the clinical and pathological phenotypes (108,109).
FTDP-17T shows significant heterogeneity in both the clinical manifestations and the underlying
neuropathology (100,108110). In some families, FTD predominates and parkinsonism is variable,
mild, or of late onset, whereas other pedigrees have parkinsonism as the major feature. A limited
amount of postmortem information is available on FTDP-17T families. Most cases show frontotem-
poral atrophy with varying degeneration of subcortical nuclei and tracts (100,110). Loss of pigmen-
tation of the substantia nigra is common. The histopathology of all cases described to date is
characterized by the accumulation of abnormal hyperphosphorylated tau in neurons and/or glial cells
(108,110). Neuronal changes may include ballooned neurons, pretangles, NFTs, Picks-like bodies,
and/or neuropil threads. A variety of tau-positive inclusions may be seen in both astrocytes and oligo-
dendrocytes. In some cases, the pattern of pathology closely resembles one of the sporadic tauopathies
such as AD (111), CBD (112,113), PSP (114), or Picks disease (115,116), whereas others show
some novel combination of findings (117). Although a detailed description of each of the different
patterns of pathology in FTDP-17T is not possible in this review, two specific conditions are worth
mentioning because of the prominence of parkinsonism and availability of detailed neuropathology.
Parkinsonism is the dominant feature of several families with the N279K mutation in the alterna-
tively spliced exon 10; this includes the American kindred designated as having pallido-ponto-nigral
degeneration (PPND), for which there is detailed pathological information (118). Most patients show
mild frontotemporal atrophy with grossly obvious degeneration of the globus pallidus and substantia
nigra. The histopathologic and immunohistochemical findings include ballooned neocortical neurons
and tau-positive subcortical threadlike structures, globose NFTs (corticobasal bodies), and oligoden-
droglial inclusions resembling coiled bodies. Astrocytic inclusions are uncommon and tufted astro-
cytes and astrocytic plaques are not a feature. Although these findings most closely resemble sporadic
CBD, the anatomic distribution is more similar to that seen in PSP.
Parkinsonism is also a major feature in the Irish-American kindred with disinhibition-dementia-
parkinsonism-amyotrophy-complex (DDPAC). This was the first family to be linked to chromosome
17 and has subsequently been show to be owing to an intronic mutation of the exon 10 5' slice site
(119). There is gross atrophy of temporal lobes, prefrontal cortex, cingulum, basal ganglia, and sub-
stantia nigra (120). Affected cortical regions show gliosis, occasional ballooned neurons, and tau-
positive NFTs and spheroids. The hippocampus is relatively spared. Subcortical regions affected
include the amygdala, substantia nigra, globus pallidus, striatum, midbrain tegmentum, and hypo-
thalamus. In these areas, neuronal loss and gliosis are accompanied by small numbers of ballooned
neurons, argyrophilic neuronal inclusions, and spheroids. Some neuronal inclusions resembled AD-
type NFTs and are immunoreactive for tau whereas other have a more spiculated appearance and are
positive for neurofilament and ubiquitin but are tau negative. Argyrophilic, tau-positive tanglelike
inclusions are also present in oligodendrocytes in various white matter tracts.
ALS/PARKINSONISM DEMENTIA COMPLEX OF GUAM

A high incidence of neurodegenerative disease is found within the Chamorro population of the
Western Pacific island of Guam, and includes parkinsonism, dementia, and amyotrophic lateral scle-
rosis (ALS), each of which may occur in isolation but are more commonly combined (121). The
cause is unknown but a toxic or viral etiology has been postulated (122124). The histopathology is
dominated by the presence of numerous NFTs (125,126), with similar immunohistochemical, bio-
chemical, and ultrastructural features as those seen in AD (127,128), but usually in the absence of SP
(Fig. 6A,B). The anatomical distribution of NFTs is different from AD (129) and more similar to that
seen in PSP and postencephalitic parkinsonism (PEP) (130,131). Chronic degenerative changes includ-
ing neuronal loss and gliosis are found in regions where NFTs are numerous, including the frontotem-
poral neocortex, hippocampus, entorhinal cortex, nucleus basalis, basal ganglia, thalamus,
subthalamus, substantia nigra, locus ceruleus, and periaqueductal gray (125,126,129). Glial pathol-
ogy has recently been described and includes argyrophilic, tau-positive coiled bodies in oligodendro-
glia and granular inclusions in astrocytes (132). There tends to be large numbers of Hirano bodies
and abundant granulovacuolar degeneration in the hippocampus (133). Cases with clinical features of
ALS have pathologic changes in the pyramidal motor system, similar to sporadic ALS (134).
OTHER NEURODEGENERATIVE CONDITIONS

Many other common idiopathic neurodegenerative conditions have parkinsonism as an inconsis-
tent or minor clinical feature. Extrapyramidal symptoms are very common in AD and may take the
form of true parkinsonism (135137). Many patients with a clinical diagnosis of AD and parkin-
sonism are found to have coexisting LB pathology at autopsy, either restricted to subcortical struc-
tures or also involving the cerebral cortex (35,136,138). The correct terminology for these cases is
uncertain, because of the lack of universally accepted neuropathological diagnostic criteria for both
AD and DLB (see subheading Dementia with Lewy Bodies). Interpretation is further complicated by
recent reports of LBs as a common incidental finding in AD patients, even in the absence of extrapy-
ramidal features (139). However, parkinsonism also occurs in some AD patients who have only SP
and NFT pathology (136,138,140). SPs are a consistent finding in the striatum and are occasionally
seen in the substantia nigra in AD, however most are the diffuse type of SP, which lack amyloid and
are thought not to be injurious to neurons (137,141,142). Numerous NFTs in the substantia nigra is
also a consistent feature of AD (137,141143). Whereas some studies have reported loss of pig-
mented neurons in the nigra in AD (143), others have found the difference not to be significantly
different from age-matched controls (141). It is not clear which, if any, of these changes is the sub-
strate for parkinsonism in AD. Though several studies have found that extrapyramidal features in AD
correlate with pathology in the substantia nigra (and not the striatum), there is disagreement as to
whether the association is a result of neuronal loss or the number of NFTs (140,144).
Motor neuron disease (MND) may be complicated by dementia and/or akinetic-rigidity (145). In
addition to the characteristic changes in the pyramidal motor system, cases of MND with dementia
have a unique pathology in the extramotor cortex; ubiquitin-immunoreactive neuronal cytoplasmic
inclusions and dystrophic neurites ae present in the neocortex and the hippocampal dentate granule
layer (146). Degeneration of various subcortical structures, including substantia nigra and basal gan-
glia, is well recognized in MND (145). Recently, several studies have described various types of
ubiquitin-positive neuronal inclusions and dystrophic neurites in a wide range of these subcortical
locations (Fig. 7A,B) (147149). Although detailed clinicopathological correlation is still lacking,
we have recently reported that MND-dementia patients with extrapyramidal features have a greater
burden of ubiquitin pathology in the substantia nigra and striatum (Fig. 6) (150).
Although the movement abnormality in most cases of Huntingtons disease (HD) is chorea, juve-
nile or early-onset cases may have akinetic-rigidity. The most characteristic pathological feature of
HD is severe atrophy of the caudate nucleus and putamen, with neuronal loss and gliosis (Fig. 8A).
48 Mackenzie
Fig. 6. ALS/parkinsonism/dementia complex of Guam. (A,B) Numerous neurofibrillary tangles in CA1

region of hippocampus (A, tau-immunohistochemistry) and temporal neocortex (B, Bielschowsky silver
stain). Photographs courtesy of C. Schwab.
Fig. 7. Case of motor neuron disease with dementia and parkinsonism. (A) Dystrophic neurites and neuronal
cytoplasmic inclusions (arrow) in striatum (ubiquitin-immunohistochemistry). (B) Filamentous skeinlike cyto-
plasmic inclusion in substantia nigra neuron (ubiquitin-immunohistochemistry).
The globus pallidus, thalamus, and cerebral cortex may also be affected and loss of pigmented neu-
rons has been reported in the substantia nigra (151). A recent finding in HD is the presence of intra-
nuclear neuronal inclusions and dystrophic neurites that are immunoreactive for huntingtin, ubiquitin,
and polyglutamine repeats, in the striatum, allocotex, and neocortex (Fig. 8B) (152,153).
Parkinsonism may be a presenting or prominent feature in some types of autosomal dominant
spinocerebellar ataxia (SCA) (154), particularly those caused by trinucleotide repeat expansions.
Degenerative changes are most severe in the cerebellum and its connections but are also found in the
substantia nigra and basal ganglia (155,156). Many of these conditions have neuronal intranuclear
inclusions that are immunoreactive for ubiquitin, polygutamine repeats, and/or the disease-specific
mutant protein (157,158).
HallervordenSpatz disease (HSD), recently renamed neurodegenertion with brain iron accumu-
lation type I (NBIA-1), is a rare neurodegenerative disorder in which various abnormalities of move-
ment are associated with cognitive decline. Some cases are familial, usually with an autosomal
50 Mackenzie
Fig. 8. Huntingtons disease. (A) Gross photograph showing severe atrophy of caudate nuclei (arrows).
(B) Intranuclear neuronal inclusions (ubiquitin-immunohistochemistry).
recessive inheritance pattern. Extrapyramidal features are more often a presenting feature in adult-
onset cases (159). The neuropathology is characterized by axonal dystrophy (spheroids) and the
intra- and extracellular accumulation of iron in the globus pallidus, substantia nigra, and other
locations (Fig. 9A,B). It has been recognized for some time that some cases of HSD have LBs (160).
Recent reports of F-synuclein immunoreactivity in LBs, axonal spheroids, and neuronal and glial
inclusions (161163) has resulted in HSD being classified as a synucleinopathy, along with more
classical LB disorders (PD and DLB).
Fig. 9. HallervordenSpatz disease. (A) Iron deposition (black) and numerous axonal spheroids in globus
pallidus (H&E stain). (B) Numerous axonal spheroids in globus pallidus (H&E stain).
POSTENCEPHALITIC PARKINSONISM
Following the pandemic of encephalitis lethargica (von Economos disease), in the early part of
the 20th century, a large proportion of individuals who survived the acute encephalitic phase devel-
oped parkinsonism, after a latency of several years or decades. PEP was therefore common in the
1940s and 1950s but is now rarely encountered. Although a viral etiology (possibly influenza A) has
long been suspected, this remains to be proven (164,165).
Most detailed accounts of the neuropathology of PEP were published several decades ago
(166,167). There may be mild cerebral atrophy and the substantia nigra and locus ceruleus show loss
52 Mackenzie
of pigmentation (Fig. 10A). There is severe chronic degeneration of substantia nigra with neuronal
loss and gliosis. The histopathology is characterized by the presence of numerous NFTs (Fig. 10B).
The tangles may be either flame-shaped or globose (164) and have the same immunohistochemical
and ultrastructural features as those seen in AD (168,169). NFTs are most numerous in the substantia
nigra, locus ceruleus, hippocampus, and nucleus basalis, but are also found in many other cortical
and subcortical regions (130). This distribution is different from that seen in AD (170) and more
similar to other causes of parkinsonism with numerous NFTs, such as PSP and parkinsonism-demen-
tia complex of Guam (94,130,131). Tau-positive glial inclusions include tufted astrocytes, thorn-
shaped astrocytes, and astrocytic plaques (164,171,172).
VASCULAR PARKINSONISM
Patients with cerebrovascular disease may develop features of parkinsonism (173175) and a small
but significant fraction of those with a clinical diagnosis of idiopathic PD will turn out to have vascu-
lar lesions demonstrated by neuroimaging or at autopsy (2,176). This vascular pseudoparkinsonism
is most often seen in patients with cerebral arteriolosclerosis and multiple small lacunar infarcts
affecting the basal ganglia or deep cerebral white matter (173177) but has also been reported with
isolated lesions of the substantia nigra (178,179).
POSTTRAUMATIC PARKINSONISM
Parkinsomism immediately following a single episode of acute head injury is rare (180) but has
been reported with direct penetrating lesions of the midbrain (181) and with subdural hematoma
(182). Epidemiologic studies have shown a history of remote head trauma to be a risk factor for PD,
however the mechanism is unclear (183184). Repeated head injury may result in a syndrome that
includes psychiatric symptoms, memory loss, and/or parkinsonism (dementia pugilistica, punch-
drunk syndrome). This most often occurs in professional and amateur boxers, with the onset of symp-
toms occurring several years after the end of their athletic career. Pathological studies have shown
loss of pigmented neurons in the substantia nigra and the presence of widespread AD-like pathology,
with numerous tau-immunoreactive NFTs and amyloid G (AG) containing SPs (185,186). A direct
link between these pathological changes and preceding trauma is supported by studies showing AG
deposits in the brains of individuals dying a few weeks following severe head injury (187) and evi-
dence that both AG and phosphorylated tau accumulate following brain injury in experimental ani-
mals (188,189). Anatomical-pathologic correlation for movement disorder in some of these patients
is supported by in vivo neuroimaging, showing damage or dysfunction of the nigrostriatal system
(190192).
MPTP INTOXICATION
Some intravenous drug addicts who use a synthetic heroin-like drug (meperidine) develop chronic
parkinsonism as a result of contamination by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
(193). MPTP is metabolized in the brain to 1-methyl-4-phenylpyridinium (MPP+) (194) and is selec-
tively transported into dopaminergic cells, which it kills by inhibiting mitochondrial function (195).
Human postmortem studies reveal severe depletion of pigmented neurons in the substantia nigra
without LBs (196). The presence of active gliosis and microglial activity has been interpreted as
indicating ongoing neurodegeneration, years after the initial exposure. MPTP-induced parkinsonism
in experimental nonhuman primates has become a valuable model for studying idiopathic PD (197).
In addition to nerve cell degeneration in both the substantia nigra and the locus ceruleus, these ani-
mals develop eosinophilic neuronal inclusions that show both similarities and differences compared
with LBs in human disease (198).
Fig. 10. Postencephalitic parkinsonism (PEP). (A) Gross photograph showing atrophy of the midbrain with
degeneration of the substantia nigra in PEP compared with normal control (C). (B) Globose neurofibrillary
tangle (H&E stain).
54 Mackenzie
WILSONS DISEASE
Wilsons disease is an autosomal recessively inherited disorder of copper metabolism in which the
metal deposits in a number of organs including brain. Neurologic findings vary but often include
extrapyramidal features. The neuropathology also varies depending on the rate of disease progres-
sion. There is degeneration of the basal ganglia, which may appear shrunken or even cavitated and
often has a brown discoloration (Fig. 11A). The putamen tends to be more severely affected than the
caudate, globus pallidus, and substantia nigra. Other areas that may be involved include the pons,
thalamus, cerebellum, and subcortical white matter. There is neuronal loss, extensive fibrillary glio-
sis, and macrophages containing lipid and hemosiderin pigment. There may be visible accumulation
of copper around capillaries. A number of more disease-specific cellular changes may be present.
Alzheimer type II astrocytes are commonly seen in cases of chronic hepatic failure with neurological
dysfunction and are numerous in most cases of Wilsons disease. They have swollen pale nuclei with
little chromatin, prominent nucleoli, and sometimes contain small dots of glycogen (Fig. 11B). Large
multinucleate Alzheimer type I cells are rare and not seen in every case (199). Most disease specific
is the presence of cells with small nuclei, abundant granular or foamy cytoplasm, and no obvious
processes (200). These Opalski cells are of uncertain origin, possible derived from astrocytes,
macrophages, or degenerating neurons (Fig. 11C). They are most numerous in the thalamus, globus
pallidus, and substantia nigra and rare in the striatum.
CONCLUSION
Parkinsonism may be associated with a wide range of underlying pathologies, in which the com-
mon feature is damage to the striatonigral system. In addition to the diseases discussed, virtually any
pathological process that affects the striatonigral system has the potential to produce parkinsonism;
these include various toxins (201206), infections (207212), mass lesions (213), and other condi-
tions. As a result, neuropathological examination is essential for accurate diagnosis in an individual
with clinical parkinsonism.
FUTURE RESEARCH
It was the recognition of a unique pattern of histopathology that originally allowed most of the
conditions described in this chapter to be designated as specific disease entities. Over the past few
decades, greater understanding of the biochemical and genetic basis of these conditions has helped to
clarify the disease pathogenesis and has shed light on the relationship between diseases (e.g.,
tauopathies, synucleinopathies, etc.). Although it is anticipated that future advances will occur pri-
marily in the field of molecular genetics, the role of tissue pathology should not be overlooked.
Defining the cellular localization and anatomical distribution of abnormal protein accumulations in
postmortem tissue will continue to illuminate mechanisms of disease and help to confirm the rel-
evance of new molecular findings. It will be the combination of genetic, biochemical, and histo-
pathological research, matched with appropriate clinical correlative studies, that will further our
understanding of these fascinating conditions.
MAJOR POINTS
Parkinsonism may be associated with a variety of underlying pathologies.
Most of the conditions that cause parkinsonism have damage of the striatonigral system as the
anatomicopathological substrate.
The most common causes of parkinsonism are neurodegenerative diseases, each of which has a
defining pattern of neuropathology, often characterized by the abnormal accumulation of protein in
the form of a cellular inclusion.
For many of these conditions, recent molecular genetic findings have helped to define disease
pathogenesis and have clarified the relationship between disease entities.
Fig. 11. Wilsons disease. (A) Gross photograph showing cystic degeneration of putamen. (B) Alzheimer
type II astrocytes with swollen pale nuclei (H&E stain). (C) Opalski cell (H&E stain).
56 Mackenzie
REFERENCES
1. Hughes AJ, Daniel SE, Ben-Shlomo Y, et al. The accuracy of diagnosis of parkinsonism syndromes in a specialist
movement disorder service. Brain 2002;125:861870.
2. Hughes AJ, Daniel SE, Kilford L, Lees AG. Accuracy of clinical diagnosis of idiopathic Parkinsons disease: a clinico-
pathological study of 100 cases. J Neurol Neurosurg Psych 1992;55:181184.
3. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis of parkinsonisma prospective study. Can J Neurol
Sci 1991;18:275278.
4. Daniel SE, Bruin VMS, Lees AJ. The clinical and pathological spectrum of SteeleRichardsonOlszewski syndrome
(progressive supranuclear palsy): a reappraisal. Brain 1995;118:759770.
5. Gearing M, Olson DA, Watts RL, Mirra SS. Progressive supranuclear palsy: neuropathologic and clinical heterogene-
ity. Neurology 1994;44:10151024.
clinicopathological study. Arch Neurol 1997;54:937944.
8. Schneider JA, Watts RL, Gearing M, Brewer RP, Mirra SS. Corticobasal degeneration: neuropathological and clinical
heterogeneity. Neurology 1997;48:959969.
9. Aarsland D, Landberg E, Larsen JP, Cummings J. Frequency of dementia in Parkinsons disease. Arch Neurol
1996;53:538542.
10. Edwards LL, Quigley EM, Harned RD, Hofman R, Pfeiffer RF. Characterization of swallowing and defecation in
Parkinsons disease. Am J Gastroenterol 1994;89:1525.
11. Edwards LL, Quigley EM, Pfeiffer RF. Gastrointestinal dysfunction in Parkinsons disease: frequency and pathophysi-
ology. Neurology 1992;32:726732.
12. Mayeux R, Stern Y, Rosenstein, et al. An estimate of the prevalence of dementia in idiopathic Parkinsons disease.
Arch Neurol 1988;45:260262.
13. Olanow CW. Tatton WG. Etiology and pathogenesis of Parkinsons disease. Ann Rev Neurosci 1999;22:123144.
14. Calne DB. Parkinsons disease is not one disease. Parkinsonism Rel Dis 2000;17:37.
15. Fearnley JM, Lees AJ. Ageing and Parkinsons disease: substantia nigra regional selectivity. Brain 1991;114:22832301.
16. Lewy FH. Paralysis agitans. Pathologische anatomie. In: Lewandowsky M, eds. Handbuch der Neurologie. New York:
Springer, 1912: 920933.
17. Tretiakoff MC. Contribution a letude de lanatomie pathologique de Locus Niger de Soemmerling. Paris: Universite
de Paris, 1919.
18. Dale GE, Probst A, Luthert P, Martin J, Anderton BH, Leigh PN. Relationship between Lewy bodies and pale bodies in
Parkinsons disease. Acta Neuropathol 1992;83:525529,
19. Irizarry MC, Growdon W, Gomez-Isla T, et al. Nigral and cortical Lewy bodies and dystrophic nigral neurites in
Parkinsons disease and cortical Lewy body disease contain F-synuclein immunoreactivity. J Neuropathol Exp Neurol
1998;57:334337.
20. Bancher C, Lassmann H, Budka H, et al. An antigenic profile of Lewy bodies: immunocytochemical indication for
protein phosphorylation and ubiquitination. J Neuropathol Exp Neurol 1989;48:8193.
21. Goldman J, Yen SH, Chui F, et al. Lewy bodies in Parkinsons disease contain neurofilament antigens. Science
1983;221:4.
22. Kuzuhara S, Mori H, Izumiyama N, Yoshirmura M, Ihara Y. Lewy bodies are ubiquitinated. A light and electron
microscopic immunocytochemical study. Acta Neuropathol 1988;75:345353.
23. Polymeropoulos MHC, Leroy E, Ide SE, et al. Mutation in the alpha-synuclein gene identified in families with
Parkinsons disease. Science 1997;276:20452047.
24. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature
1997;388:839840.
25. Arai T, Ueda K, Ikeda K, et al. Argyrophilic glial inclusions in the midbrain of patients with Parkinsons disease and
diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein. Neurosci Lett 1999;259:8386.
26. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H. NACP/alpha-synuclein-positive filamentous inclu-
sions in astrocytes and oligodendrocytes of Parkinsons disease brains. Acta Neuropathol 2000;99:1420.
27. Okazaki H, Lipkin LS, Aronson SM. Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with pro-
gressive dementia and quadraparesis in flexion. J Neuropathol Exp Neurol 1961;20:237244.
28. Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimers disease: a clinical and pathological
entity. Neurology 1990;40:18.
29. Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK. Senile dementia of Lewy body type: a clinically and pathologi-
cally distinct form of Lewy body dementia in the elderly. J Neurol Sci 1990;95:119139.
30. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathological diagnosis of dementia
with Lewy bodies (DLB): report of the consortium on DLB International Workshop. Neurology 1996;47:11131124.
31. Hughes AJ, Daniel SE, Blankson S, et al. A clinicopathological study of 100 cases of Parkinsons disease. Arch Neurol
1993;50:140148.
32. Dickson DW, Ruan D, Crystal H, et al. Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD)
from Alzheimers disease. Neurology 1991;41:14021409.
33. De Vos RA, Jansen EN, Stam FC, et al. Lewy body disease: clinicopathological correlations in 18 consecutive cases of
Parkinsons disease with and without dementia. Clin Neurol Neurosurg 1995;97:1322.
34. Piao YS, Wakabayashi K, Hayashi S, yoshimoto M, Takahashi H. Aggregation of F-synuclein/NACP in the neuronal
and glial cells in diffuse Lewy body disease: a survey of six patients. Clin Neuropathol 2000;19:163169.
35. Hansen LA, Masliah E, Galasko D, Terry RD. Plaque-only Alzheimer disease is usually the Lewy body variant and vice
versa. J Neuropathol Exp Neurol 1993;52:648654.
36. Mirra SS, Heyman A, McKeel D, et al. The consortium to establish a registry for Alzheimers disease (CERAD). Part
II. Standardisation of the neuropathologic assessment for Alzheimers disease. Neurology 1991; 41:479486.
37. Braak H, Braak E. Neuropathological staging of Alzheimer related changes. Acta Neuropathol 1991;82:239259.
38. Gomez-Tortosa E, Newell K, Irizarry MC, Albert M, Growdon JH, Hyman BT. Clinical and quantitative pathologic
correlates of dementia with Lewy bodies. Neurology 1999;53:12841291.
39. Lennox G, Lowe J, Landon M, Bryne EJ, Mayer RJ, Godwin-Austen RB. Diffuse Lewy body disease: correlative
neuropathology using anti-ubiquitin immunohistochemistry. J Neurol Neurosurg Psychiatry 1989;52:12361247.
40. Mattila PM, Roytta M, Torikka H, Dickson DW, Rinne JO. Cortical Lewy bodies and Alzheimer-type changes in
patients with Parkinsons disease. Acta Neuropathol 1998;95:576582.
41. Samuel W, Galasko D, Masliah E, Hansen LA. Neocortical Lewy body counts correlate with dementia in Lewy body
variant of Alzheimers disease. J Neuropathol Exp Neurol 1996;55:4452.
42. Jellinger KA. Morphological substrates of dementia in parkinsonism. A critical update. J Nerual Trans (Suppl)
1997;51:5782.
43. Samuel W, Alford M, Hofstetter R, Hansen L. Dementia with Lewy bodies versus pure Alzheimer disease: differences in
cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 1997;56:499508.
44. Ince PG, Perry EK, Morris CM. Dementia with Lewy bodies. A distinct non-Alzheimer dementia syndrome. Brain
Pathol 1998;8:299324.
45. Kosaka K, Iseki E. Diffuse Lewy body disease within the spectrum of Lewy body disease. In: Perry R, McKeith I, Perry
E, eds. Dementia with Lewy Bodies. New York: Cambridge University Press, 1996:238247.
46. Kosaka K, Tsuchiya K, Yoshimura M. Lewy body disease with and without dementia: a clinicopathological study of 35
cases. Clin Neuropathol 1989;7;299305.
47. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset
parkinsonism. Science 2003;299:256259.
48. Mouradian MM. Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology 2002;58:179185.
49. Farrer M, Chan P, Chen R, et al. Lewy bodies and parkinsonism in families with parkin mutation. Ann Neurol
2001;50:293300.
50. Wintermeyer P, Kruger R, Kuhn W, et al. Mutation analysis and association studies of the UCHL1 gene in German
Parkinsons disease patients. Neuroreport 2000;11:20792082.
51. Saigoh K, Wang YL, Suh JG, et al. Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in
gad mice. Nat Genet 1999;23:4751.
1999;163:9498.
53. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SF, Quinn NP. Clinical features and natural history of multiple
system atrophy. An analysis of 100 cases. Brain 1994;117:835845.
54. Lantos PL. The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol
1998;57:10991111.
55. Dickson DW, Lin WL, Liw WK, yen SH. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol
1999.9:721732.
56. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically
proven cases. Mov Disord 1997;12:133147.
57. Kanada T, Tsukagoshi H, Oda M, et al. Changes of unmyelinated nerve fibres in sural nerve in amyotrophic lateral
sclerosis, Parkinsons disease, and multiple system atrophy. Acta Neuropathol 1996;91:145154.
58. Lantos PL. Neuropathological diagnostic criteria of multiple system atrophy: a review. In Cruz-Sanchez FF, Ravid R,
Cuzner ML, eds. Neuropathological Diagnostic Criteria for Brain Banking, Amsterdam: IOS Press, 1995:116121.
59. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy
(striatonigral degeneration, olivopontocerebellar atrophy and ShyDrager syndrome). J Neurol Sci 1989;94:79100.
60. Papp MI, Lantos PL. Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in
multiple system atrophy. J Neurol Sci 1992;107:172182.
61. Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to
clinical symptomatology. Brain 1994;117:235243.
58 Mackenzie
62. Abe H, Yagishita S, Amano N, et al. Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immu-
nocytochemical and ultrastructural study. Acta Neuropathol 1992 84:273277.
63. Arima K, Murayama S, Mukoyama M, Inose T. Immunocytochemical and ultrastructural studies of neuronal and oligo-
dendroglial cytoplasmic inclusions in multiple system atrophy. 1. Neuronal cytoplasmic inclusions. Acta Neuropathol
1992;83:453460.
64. Murayama S, Arima K, Nakazato Y, Satoh J, Oda M, Inose T. Immunocytochemical and ultrastructural studies of
neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. 2. Oligodendroglial cytoplasmic
inclusions. Acta Neuropathol 1992;84:3238.
65. Spillantini MG, Crowther RA, Jakes R, Cairus NJ, Lantos PL, Goedert M. Filamentous F-synuclein inclusions link
multiple system atrophy with Parkinsons disease and dementia with Lewy Bodies. Neurosci Lett 1998;251:205208.
66. Wakabayashi K, Yoshimoto M, Tsuji S, takahashi H. F-synuclein immunoreactivity in glial cytoplasmic inclusions in
multiple system atrophy. Neruosci Lett 1998;249:180182.
67. Kato S, Nakamura H. Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with
olivopontocerebellar atrophy: immunohistochemical and ultrastructural studies. Acta Neuropathol 1990;79:584594.
68. Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentonigral degeneration with neuronal achromasia. Arch Neurol
1968;18:2033.
69. Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration. A clinical study of 36 cases. Brain
1994;117:11831196.
70. Arima K, Uesugi H, Fujita I, et al. Corticonigral degeneration with neuronal achromasia presenting with primary pro-
gressive aphasia: ultrastructural and immunocytochemical studies. J Neurol Sci 1994;127:186197.
71. Bergeron C, Davis A, Lang AE. Corticobasal ganglionic degeneration and progressive supranuclear palsy presenting
with cognitive decline. Brain Pathol 1998;8:355365.
72. Feany MB, Dickson DW. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol
1995;146:13881396.
73. Kertesz A, Hudson L, Mackezie IRA, et al. The pathology and nosology of primary progressive aphasia. Neurology
1994;44:20652072.
74. Kertesz A, Martinez-Lage P, Davidson W, Munoz DG. The corticobasal degeneration syndrome overlaps progressive
aphasia and frontotemporal dementia. Neurology 2000;55:13681375.
75. Dickson DW, Yen SH, Suzuki KI, Davies P, Garcia JH, Hiraqno A. Ballooned neurons in select neurodegenerative
diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol 1986;71:216223.
76. Mackenzie IRA, Hudson LP. Achromatic neurons in the cortex of progressive supranuclear palsy. Acta Neuropathol
1995;90:615619.
77. Lowe J, Errington DR, Lennox G, et al. Ballooned neurons in several neurodegenerative diseases and stroke contain
alpha B crystallin. Neruopathol Appl Neurobiol 1992;18:515516.
78. Smith TW, Lippa CF, de Girolami U. Immunocytochemical study of ballooned neurons in cortical degeneration with
neuronal achromasia. Clin Neuropathol 1992;11:2835.
79. Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112:11711192.
80. Mori H, Nishimura M, Namba Y, Oda M. Corticobasal degeneration: a disease with widespread appearance of abnormal
tau and neurofibrillary tangles and its relation to progressive supranuclear palsy. Acta Neuropathol 1994;88:113121.
81. Paulus W, Selim M. Corticonigral degeneration with neuronal achromasia and basal neurofibrillary tangles. Acta
Neuropathol 1990;81:8994.
82. Feany MB, Dickson DW. Neurodegenerative disorders with extensive tau pathology: a comparative study and review.
Ann Neurol 1996;40:139148.
83. Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Picks disease and
corticobasal degeneration. J Neuropathol Exp Neurol 1996;55:5367.
84. Wakabayashi K, Oyamagi K, Makifuchi T, et al. Corticobasal degeneration: etiopathological significance of the
cytoskeletal alterations. Acta Neuropathol 1994;87:545553.
85. Dickson DW, Bergeron C, Chin WW, et al. Office of rare diseases. Neuropathologic criteria for corticobasal degenera-
tion. J Neuropathol Exp Neurol 2002; 61:935946.
86. Komori T, Arai N, Oda M, et al. Astrocytic plaques and tufts of abnormal fibres do not coexist in corticobasal degenera-
tion and progressive supranuclear palsy. Acta Neuropathol 1998;96:401408.
87. Mattice LA, Wu E, Aronson M, Dickson D. A new type of neuritic plaque without amyloid in corticonigral degenera-
tion with neuronal achromasia. J Neuropathol Exp Neurol 1991;50:310.
88. Chin SSM, Goldman JE. Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol1996;55:499508.
89. Ikeda K, Akiyama H, Kondo H, et al. Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibril-
lary tangles. Acta Neuropathol 1995;90:620625.
90. Ikeda K, Akiyama H, Haga C, Kondo H, Arima K, Oda T. Argyrophilic thread-like structure in corticobasal degenera-
tion and supranuclear palsy. Neurosci Lett 1994;174:157159.
91. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol 1964;10:333359.
92. Dickson DW. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol
1999;246(Suppl 2):II6I15.
93. Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic criteria for SteeleRichardsonOlszewski
syndrome (progressive supranuclear palsy). Neurology 1994;44:20152019.
94. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary NINDS neuropathologic criteria for
progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 1996;55:97105.
95. Braak H, Jellinger K, Braak E, et al. Allocortical neurofibrillary changes in progressive supranuclear palsy. Acta
Neuropathol 1992;84:478483.
96. Hauw JJ, Verny M, Delaere P, Cervera P, He Y, Duyckaerts C. Constant neurofibrillary changes in the neocortex in
progressive supranuclear palsy. Basic differences with Alzheimers disease and aging. Neurosci Lett 1990;119:182186.
97. Hof PR, Delacourte A, Bouras C. Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: a
quantitative analysis of six cases. Acta Neruoapathol 1992;84:4551.
98. Bigio EH, Brown DF, White CL. Progressive supranuclear palsy with dementia: cortical pathology. J Neuroapthol Exp
Neurol 1999;58:359364.
99. Arai N. Grumose degeneration of the dentate nucleus. A light and electron microscopic study in progressive supra-
nuclear palsy and dentatorubropallidoluysial atrophy. J Neurol Sci 1989;90:131145.
100. Foster NL, Wilhelmsen K, Sima AA, Jones MZ, DAmato CJ, Gilman S. Frontotemporal dementia and parkinsonism
linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 1997;41:706715.
101. Clark LN, Poorkaj P, Wszolek Z, et al. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral
degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci USA 1998;95:
1310313107.
102. Dumanchin C, Camuzat A, Campion D, et al. Segregation of a missense mutation in the microtubule-associated protein
tau gene with familial frontotemporal dementia and parkinsonism. Hum Mol Genet 1998;7:18251829.
103. Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5' splice-site mutations in tau with the inherited
dementia FTDP-17. Nature 1998;393:702705.
104. Spillantini MG, Murrell JR, Goedert M, et al. Mutation in the tau gene in a familial multiple system tauopathy with
presenile dementia. Proc Natl Acad Sci USA 1998;95:77377741.
105. Kertesz A, Kawarai T, Rogaeva E, et al. Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclu-
sions. Neurology 2000;54:818827,
106. Rosso SM, Kamphorst W, de Graaf B, et al. Familial frontotemporal dementia with ubiquitin-positive inclusions is
linked to chromosome 17q21-22. Brain 124;19481957.
107. Ghetti B, Hutton ML, Wszolek ZK. Frontotemporal dementia and parkinsonism linked to chromosome 17 associated
with tau gene mutations (FTDP-17T). In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of Dementia
and Movement Disorders. Los Angeles: ISN Neuropath Press, 2003:86102.
108. Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurbiol Aging 2001;22:89107.
109. van Swieten JC, Stevens M, Rosso SM, et al. Phenotypic variation in hereditary frontotemporal dementia with tau
mutations. Ann Neurol 1999;46:617626.
110. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and parkinsonism linked to chromosome 17; a new group
of tauopathies. Brain Pathol 1998;8:386402.
111. Sumi SM, Bird TD, Nochlin D, raskind MA. Familial presenile dementia with psychosis associated with corticoal
neurofibrillary tangles and degeneration of the amygdala. Neurology 1992;42:120127.
112. Mirra SS, Murrell JR, Gearing M, et al. Tau pathology in a family with dementia and P301L mutation in tau. J Neuropathol
Exp Neurol 1999;58:335345.
113. Spillantini MG, Yoshida H, Rizzini C, et al. A novel tau mutation (N296N) in familial dementia with swollen achro-
matic neurons and corticobasal inclusion bodies. Ann Neurol 2000;48:939943.
114. Stanford PM, Halliday GM, Brooks WS, et al. Progressive supranuclear palsy pathology caused by a novel silent
mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. Brain
2000;123:880893.
115. Murrell Jr, Spillantini MG, Zolo P, et al. Tau gene mutation G389R causes a tauopathy with abundant pick body-like
inclusions and axonal deposits. J Neuropathol Expo Neurol 1999;58:12071226.
116. Rizzini C, Goedert M, Hodges JR, et al. Tau gene mutation K257T causes a tauopathy similar to Picks disease. J
Neuropathol Exp Neurol 2000;59:9901001.
117. Spillantini MG, Goedert M, Crowther RA, Smith MJ, Jakes R, Hills R. Familial multiple system tauopathy: a new
neurodegenerative disease of the brain with tau neurofibrillary pathology. Proc Natl Acad Sci USA 1997;95:41134118.
118. Reed LA, Schmidt ML, Wszolek ZK, et al. The neuropathology of a chromosome 17-linked autosomal dominant par-
kinsonism and dementia (pallido-ponto-nigral degeneration). J Neuropathol Exp Neurol 1998;57:588601.
119. Wilhelmsen KC, Lynch T, Pavlou E, et al. Localization of disinhibition-parkinsonism-amyotrophy complex to 17q21-
22. Am J Hum Genet 1994;55:11591165.
60 Mackenzie
120. Sima AA, Defendini R, Keohane C, et al. The neuropathology of chromosome 17linked dementia. Annals of Neurol-
ogy 1996;39:734743.
121. Hirano A, Kurland LT, Krooth RS, lessell S. Parkinsonism-dementia complex, an endemic disease on the island of
Guam. I. Clinical features. Brain 1961;84:642661.
122. Gibbs CJ, Gajdusek DC. An update on long-term in vivo and in vitro studies designed to identify a virus as the cause of
amyotrophic lateral sclerosis, parkinsonism dementia and Parkinsons disease. Adv Neurol 1982;36:343353.
123. Hudson AJ, Rice GP. Similarities of guamanian ALS/PD to post-encephalitic parkinsonism/ALS: possible viral cause.
Can J Neurol Sci 1990;17:427433.
124. Spencer PS, Nunn PB, Hugon J, et al. Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant
excitant neurotoxin. Science 1987;237:517522.
125. Hirano A, Malamjud N, Kurland LT. Parkinsonism-dementia complex, an endemic disease on the island of Guam. II.
Pathological features. Brain 1961;84:662679.
126. Malamud N, Hirano A, Kurland LT. Pathoanatomic changes in amyotrophic lateral sclerosis on Guam. Neurology
1961;5:401414.
127. Buee-Scherrer V, Buee L, Hof PR, et al. Neurofibrillary degeneration in amyotrophic lateral sclerosis/parkinsonism-
dementia complex of Guam. Immunochemical characterization of tau proteins. Am J Pathol 1995;146:924932,
128. Shankar SK, Yanagihara R, Garruto RM, Grundke-Iqbal I, Kosik KS, Gajdusek DC. Immunocytochemical character-
ization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-complex of Guam. Ann Neurol
1989;25:146151.
129. Hof PR, Nimchinsky EA, Buee-Scherrer V, et al. Amyotrophic lateral sclerosis/parkinsonism dementia-complex from
Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability and comparison with
related neurodegenerative disorders. Acta Neuropathol 1994;88:397404.
130. Geddes JF, Hughes AJ, Lees AJ, Daniel SE. Pathological overlap in cases of parkinsonism associated with neurofibril-
lary tangles. A study of recent cases of postencephalitic parkinsonism and comparison with progressive supranuclear
palsy and Guamanian parkinsonism-dementia complex. Brain 1993;116:281302.
131. Hudson AJ. Amyotrophic lateral sclerosis/parkinsonism/dementia: clinico-pathological correlations relevant to Gua-
manian ALS/PD. Can J Neurol Sci 1991;19:458461.
132. Oyanagi K, Makifuchi T, Ohtoh T, Chen KM, Gajdusek DC, Chase TN. Distinct pathological features of the Gallyas-
and tau-positive glia in the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. J Neuropathol
Exp Neurol 1997;56:308316.
133. Hirano A, Dembitzer HM, Kurland.LT. The fine structure of some intraganglionic alterations. Neurofibrillary tangles,
granulovacuolar bodies and rod-like structures as seen in Guam amyotrophic lateral sclerosis and parkinsonism-
dementia complex. J Neuropathol Exp Neurol 1968;27:167182.
134. Oyanagi K, Makifuchi T, Ohtoh T, et al. Amyotrophic lateral sclerosis of Guam: the nature of the neuropathological
findings. Acta Neuropathol 1994;88:405412.
135. Merello M, Sabe L, Teson A, et al. Extrapyramidalism in Alzheimers disease: prevalence, psychiatric and neuropsy-
chological correlates. J Neurol Neurosurg Psychiatry 1994;57:15031509.
136. Morris JC, Drazner M, Fulling K, Grant EA, Goldring J. Clinical and pathological aspects of parkinsonism in
Alzheimers disease. A role for extranigral factors? Arch Neurol 1989;46:651657.
137. Tsolaki M, Kokarida K, Iakovidou V, et al. Extrapyramidal symptoms and signs in Alzheimers disease: prevalence and
correlation with the first symptom. Am J Alz Dis 2001;16:268278.
138. Hulette C, Mirra S, Wilkinson W, et al. The consortium to establish a registry for Alzheimers disease (CERAD). Part
IX. A prospective cliniconeuropathologic study of Parkinsons features in Alzheimers disease. Neurology
1995;45:19911995.
139. Stern Y, Jacobs D, Goldman J, et al. An investigation of clinical correlates of Lewy bodies in autopsy-proven
Alzheimers disease. Arch Neurol 2001;58:460465.
140. Lui Y, Stern Y, Chun MR, Jacobs DM, Yan P, Goldman JR. Pathological correlates of extrapyramidal signs in
Alzheimers disease. Ann Neurol 1997;41:368374.
141. Love S, Wilcock GK, Matthews SM. No correlation between nigral degeneration and striatal plaques in Alzheimers
disease. Acta Neuropathol 1996;91:432436.
142. Uchihara T, Kondo H, Ikeda K, et al. Alzheimer-type pathology in melanin-bleached sections of substantia nigra. J
Neurol 1995;242:485489.
143. Uchihara T, Kondo H, Kosaka K, Tsukagoshi H. Selective loss of nigral neurons in Alzheimers disease: a morphomet-
ric study. Acta Neuropathol 1992;83:271276.
144. Kazee AM, Cox C, Richfield EK. Substantia nigra lesions in Alzheimers disease and normal aging. Alz Dis Assoc
Disord 1995;9:6167.
145. Hudson AJ. Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological dis-
orders: a review. Brain 1981;104:217247.
146. Okamoto K, Murakami N, Kusaka H, et al. Ubiquitin-positive intraneuronal inclusions in the extramotor cortices of
presenile dementia patients with motor neuron disease. J Neurol 1992;239:426430.
147. Kawashima T, Kikuchi H, Takita M, et al. Skein-like inclusions in the neostriatum from a case of amyotrophic lateral
sclerosis with dementia. Acta Neuropathol 1998;96:541545.
148. Su M, Yoshida Y, Ishiguro H, et al. Nigral degeneration in a case of amyotrophic lateral sclerosis: evidence of Lewy-
like and skein-like inclusions in the pigmented neurons. Clin Neuropathol 1999;18:293300.
149. Wakabayashi K, Piao YS, Hayashi S, et al. Ubiquitinated neuronal inclusions in the neostriatum in patients with amyo-
trophic lateral sclerosis with and without dementiaa study of 60 patients 31 to 87 years of age. Clin Neuropathol
2001;20:4752.
150. Mackenzie IR, Feldman H. Extrapyramidal features in patients with motor neuron disease and dementia; a clinico-
pathological correlative study. Acta Neuropathol 2004;107:336340.
151. Oyanagi K, Takeda S, Takahashi H, Ohama E, Ikuta F. A quantitative investigation of the substantia nigra in
Huntingtons disease. Ann Neurol 1989;26:1319.
152. DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic
neurites in brain. Science 1997;227:19901993.
153. Maat-Schieman MLC, Dorsman JC, Smoor MA, et al. Distribution of inclusions in neuronal nuclei and dystrophic
neurites in Huntington Disease brain. J Neuropathol Exp Neurol 1999;58:129137.
154. Harding A. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of
eleven families including descendants of the Drew family of Walworth. Brain 1982;105:128.
155. Estrada R, Galarraga J, Orozco G, Nodarse A, Auburger G. Spinocerebellar ataxia 2 (SCA2): morphometric analyses in
11 autopsies. Acta Neuropathol 1999;97:306310.
156. Martin JJ, van Regemorter N, Krols L, et al. On an autosomal dominant form of retinal-cerebellar degeneration: an
autopsy study of five patients in one family. Acta Neuropathol 1994;88:277286.
157. Fujigasaki H, Uchihara T, Koyano S, et al. Ataxin-3 is translocated into the nucleus for the formation of intranuclear
inclusions in normal and Macado-Joseph disease brains. Exp Neurol 2000;165:248256.
158. Koyano S, Uchihara T, Fujigasaki H, Nakamura A, Yagishita S, Iwabuchi K. Neuronal intanuclear inclusions in spinoc-
erebellar ataxia type 2: triple-labelling immunofluorescent study. Neuro Sci Lett 1999;273:117120.
159. Jankovic J, Kirkpatrick JB, Blomquist KA, et al. Late-onset Hallervorden-Spatz disease presenting as familial parkin-
sonism. Neurology 1985;35:227234.
160. Antoine JC, Tommasi M, Chalumeau A. HallervordenSpatz disease with Lewy bodies. Rev Neurol Paris
1985;141:806809.
161. Arawaka S, Saito Y, Murayama S, Mori H. Lewy body in neurodegeneration with brain iron accumulation type I is
immunoreactive for alpha-synuclein. Neurology 1998;51:887889.
162. Galvin JE, Giasson B, Hurtig HI, lee V, Trojanowski JQ. Neurodegeneration with brain iron accumulation, type 1 is
characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol 2000;157:361368.
163. Wakabayashi K, Yoshimoto M, Fikushima T, et al. Widespread occurrence of alpha-synuclein/NACP-immunoreactive
neuronal inclusions in juvenile and adult-onset Hallervorden-Spatz disease with Lewy bodies. Neuropathol Exp Neurol
1999;25:363368.
164. McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute
encephalitis lethargica cases or in postencephalitic Parkinson cases. J Neuropathol Exp Neurol 2001;60:696704.
165. Reid AH, McCall S, Henry JM, Taubenberger JK. Experimenting on the past: the enigma of von Economos encepha-
litis lethargica. J Neuropathol Exp Neurol 2001;663670.
166. Hallervorden J. Anatomische untersuchungen zur pathologenese des postencephaliticshen Parkinsonismus. Dtsch Z
Nervenheilkunde 1935;136:6877.
167. Torvik A, Meen D. Distribution of the brainstem lesions in postencephalitic parkinsonism. Acta Neurol Scand
1966;42:415425.
168. Buee-Scherrer V, Buee L, Leveugle B, et al. Pathological tau proteins in postencephalitic parkinsonism: comparison
with Alzheimers disease and other neurodegenerative disorders. Ann Neurol 1997;42:924932.
169. Ishii T, Nakamura Y. Distribution and ultrastructure of Alzheimers neurofibrillary tangles in postencephalitic parkin-
sonism of Economo type. Acta Neuropathol 1981;55:5962.
170. Hof PR, Charpiot A, Delacourte A, Purohit D, Perl DP, Bouras C. Distribution of neurofibrillary tangles and senile
plaques in the cerebral cortex in postencephalitic parkinsonism. Neurosci Lett 1992;139:1014.
171. Haraguchi T, Ishizu H, Terada S, et al. An autopsy case of postencephalitic parkinsonism of von Economo type: some
new observations concerning neurofibrillary tangles and astrocytic tangles. Neuropathology 2000;20:143148.
172. Ikeda K, Akiyama H, Kondo H, Ikeda K. Anti-tau-positive glial fibrillary tangles in the brain of postencephalitic
parkinsonism of Economo type. Neurosci Lett 1993;162:176178.
173. Reider-Groswasser I, Bornstein NM, Korczyn AD. Parkinsonism in patients with lacunar infarcts of the basal ganglia.
Eur Neurol 1996;36:248249.
174. Tomonaga M, Yamanouchi H, Tohgi H, Kameyama M. Clinicopathologic study of progressive subcortical vascular
encephalopathy (Binswanger type) in the elderly. J Am Geriatr Soc 1982;30:524529.
175. Van Zagten M, Lodder J, Kessels F. Gait disorder and parkinsonian signs in patients with stroke related to small deep
infarcts and white matter lesions. Mov Disord 1998;13:8995.
62 Mackenzie
176. Chang CM, Yu YL, Ng HK, et al. Vascular pseudoparkinsonism. Acta Neurol Sci 1992;86;588592.
177. Murrow RW. Schweiger GD, Kepes et al. Parkinsonism due to basal ganglia lacunar state: clinicopathologic correla-
tion. Neurology 1990:40:897900.
178. De Reuck J, Sieben G, de Coster W, et al. Parkinsonism in patients with cerebral infarcts. Clin Neurol Neurosurg
1980;82:177218.
179. Hunter R, Smith J, Thomson T, et al. Hemiparkinsonism with infarction of the ipsilateral substantia nigra. Neuropathol
Appl Neurobiol 1978;4:297301.
180. Krauss JK, Jankovic J. Head injury and posttraumatic movement disorders. Neurosurgery 2002;50:927940.
181. Rondot P, Bathien N, De Recondo J, et al. Dystonia-parkinsonism syndrome from a bullet injury in the midbrain. J
Neurol Neurosurg Psychiatry 1994;57:658.
182. Wiest RG, Burgunder JM, Krauss JK. Chronic subdural haematomas and Parkinsonian syndromes. Acta Neurochir
1999;141:753758.
183. Taylor CA, Saint-Hilaire MH, Cupples LA, et al. Environmental, medical and family history risk factors for Parkinsons
disease: a New England-based case control study. Am J Med Genet 1999;88:742749.
184. Tsai CH, Lo SK, See LC, et al. Environmental risk factors of young onset Parkinsons disease: a case-control study.
Clin Neurol Neurosurg 2002;104:328333.
185. Clinton J, Ambler MW, Roberts GW. Post-traumatic Alzheimers disease: preponderance of a single plaque type.
Neuropathol Appl Neurobiol 1991;17:6974.
186. Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG. Re-examination of ex-boxers brains using immunohis-
tochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol 1991;82:280285.
187. Roberts GW, Gentleman SM, Lynch A, Graham DI. GA4-amyloid protein deposition in the brain after head injury.
Lancet 1991;338:14221423.
188. Hoshino S, Tamaoka A, Takahashi M, et al. Emergence of immunoreactivities for phosphorylated tau and amyloid-beta
protein in chronic stage of fluid percussion in rat brain. Neuroreport 1998;9:18791893.
189. Smith DH, Chen XH, Nonaka M, et al. Accumulation of amyloid G and tau and the formation of neurofilament inclu-
sions following diffuse brain injury in the pig. J Neuropathol Exp Neurol 1999;58:982992.
190. Bhatt M, Desai J, Mankodi A, Elias M, Wadia N. Posttraumatic akinetic-rigid syndrome resembling Parkinsons dis-
ease: a report on three patients. Mov Disord 2000;15:313317.
191. Nayernouri T. Posttraumatic parkinsonism. Surg Neurol 1985;24:263264.
192. Turjanski N, Lees AJ, Brooks DJ. Dopaminergic function in patients with posttraumatic parkinsonism: an 18F-dopa
PET study. Neurology 1997;49:183189.
193. Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analogue
194. Langston JW, Irwin I, Langston EB, et al. 1-methyl-4-phenylpyridinium (MPP+): identification of a metabolite of
MPTP, a toxin selective to the substantia nigra. Neurosci Lett 1984;48:8792.
195. Singer TP, Ramsay RR. Mechanism of the neurotoxicity of MPTP. An update. FEBS Lett 1990;274:18.
196. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. Evidence of active nerve cell degeneration in the
substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol
1999;46:598605.
197. Tetrud JW, Langston JW. MPTP-induced parkinsonism as a model for Parkinsons disease. Acta Neurol Scand
1989;126:3540.
198. Forno LS, DeLanney LE, Irwin I, Langston JW. Similarities and differences between MPTP-induced parkinsonism and
Parkinsons disease. Neuropathologic considerations. Adv Neurol 1993;60:600608.
199. Lapham LW. Cytologic and cytochemical studies of neuroglia. I. A study of the problem of amitosis in reactive astro-
cytes. Am J Pathol 1962;41:121.
200. Opalski A. Uber eine besondere Art von Gliazellen bei der Wilson-Pseudosklerosegruppe. Z Ges Neurol Psychiat
1930;124:420425.
201. Huang CC, Chu NS, Lu CS, et al. Chronic manganese intoxication. Arch Neurol 1989;46:11041106.
202. Klawans HL, Stein RW, Tanner CM, Goetz CG. A pure parkinsonian syndrome following acute carbon monoxide
intoxication. Arch Neurol 1983;39:302304.
203. McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical and pathological study. Ann Neurol 1980;8:161167.
204. Okuda B, Iwamoto Y, Tachibana H, et al. Parkinsonism after acute cadmium poisoning. Clin Neurol Neurosurg
1997;99:263265.
205. Peters HA, Levine RL, Matthew CG, Chapman LJ. Extrapyramidal and other neurologic manifestations associated with
carbon disulfide fumigant exposure. Arch Neurol 1998;45:537540.
206. Uitti RJ, Rajput AH, Ashenhurst EM, Rozdilsky B. Cyanide-induced parkinsonism: a clinicopathologic report. Neurol-
ogy 1985;35:921925.
207. Kim JS, Choi IS, Lee MC. Reversible parkinsonism and dystonia following probable mycoplasma pneumoniae infec-
tion. Mov Disord 1995;10:510512.
208. Mirsattari SM, Power C, Nath A. Parkinsonism with HIV infection. Mov Disord 2000;15:10321033.
209. Murakami T, Nakajima M, Nakamura T, et al. Parkinsonian symptoms as an initial manifestation in a Japanese patient
with acquired immunodeficiency syndrome and Toxoplasma infection. Intern Med 2000;39:10061007.
210. Viader F, Poncelet AM, Chapon F, et al. Neurologic forms of Lyme disease. Rev Neurol 1989;145:362368.
211. Wszolek Z, Monsour H, Smith P, et al. Cryptococcal meningoencephalitis with parkinsonian features. Mov Disord
1988;3:271273.
212. Yazaki M, Yamazaki M, Urasawa N, et al. Successful treatment with alpha-interferon of a patient with chronic measles
infection of the brain and parkinsonism. Eur Neurol 2000;44:184186.
213. Lhermitte F, Agid Y, Serdaru M, Guimaraes J. Parkinson syndrome, frontal tumor and L-dopa. Rev Neurol
1984;140:138139.
Animal Models of Tauopathies 65
5
Animal Models of Tauopathies
Jada Lewis and Michael Hutton
INTRODUCTION
The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to
chromosome 17 (FTDP-17) (14) has demonstrated that tau dysfunction can result in
neurodegeneration and has allowed researchers to generate transgenic models of the human
tauopathies (5) (see Table 1 for summary). Transgenic models permit studies on the mechanisms of
formation of filamentous tau lesions in neurons and glia as well as their role in neurodegeneration.
They also serve as models to develop treatments for tauopathies.
The tau gene is subject to alternative splicing of three exons, which generates six tau isoforms
(6,7) (Fig. 1). Additional heterogeneity is derived from posttranslational modifications of tau. Two
exons in the amino half of the molecule (exon 2 and exon 3) and one exon in the microtubule-binding
domain (exon 10) are alternatively spliced (8). Exon 2 is included (1N) or excluded (0N), whereas
exon 3 is always coexpressed with exon 2 (2N). Exon 10 contains a conserved repeat domain that is
also present in exons 9, 11, and 12. Inclusion of exon 10 generates tau with 4 repeats (4R), whereas
exclusion generates tau with 3 repeats (3R). The various splice combinations of tau are thus abbrevi-
ated as follows: 0N3R, 0N4R, 1N3R, 1N4R, 2N3R, and 2N4R. Adult brain has all six isoforms,
whereas fetal tau is composed of 3R tau (9).
MICE EXPRESSING TRANSGENES THAT ALTER TAU KINASE

OR PHOSPHATASE ACTIVITY
The filamentous tau lesions observed in human neurodegenerative disease invariably contain tau
that is hyperphosphorylated at specific residues (10). As a result, there has been much speculation
about the role of abnormal tau phosphorylation in the development of neurofibrillary pathology in
Alzheimers disease (AD) and the tauopathies. To examine this question, several groups have gener-
ated mice that overexpress transgenes designed to upregulate tau phosphorylation.
Transgenic mice were generated using a tetracycline-regulated system for conditional gene expres-
sion to express glycogen synthase 3 G (GSK3G) in adult animals thus avoiding possible deleterious
effects of expression during development (11). Strong somatodendritic immunostaining of
hyperphosphorylated tau was detected in cortex and hippocampus, but no thioflavin-S fluorescence
was detected. Western blotting with the phospho-tau antibodies (e.g., PHF-1 and AD2) in cortex,
striatum, hippocampus, and cerebellum revealed increased levels of tau phosphorylation in the hip-
pocampus. Increased TUNEL staining and astrogliosis further suggested that increased GSK3G activity
was initiating neurodegenerative changes in the mice; however, these changes occurred in the absence

65
66
Table 1
Summary of Tau Transgenic Mouse Models
Reference Promoter Isoform Mutation Mouse Strain Tau Immunoreactivity Observed
19,20 mouse prion 0N3R Wild-type B6/D2 12E8, AT8, AT270, PHF1, PHF6, T3P
23 2F Ta1-tubulin (0N,1N,2N)3R Wild-type B6/SJL AT8, AT270, PHF1, PHF6, T3P
21 PAC (tau) (0N,1N,2N)3R > (0N,1N,2N)4R Wild-type B6/D2/SW MC-1
22 PAC (tau)/murine tau KO (0N,1N,2N)3R > (0N,1N,2N)4R Wild-type B6/D2/SW CP13, MC-1, PHF1
16 mouse thy-1 2N4R Wild-type B6/D2 AT8, AT180, PHF1
17 mouse thy-1 2N4R Wild-type FVB/N ALZ50, AT8, AT180, AT270, MC1, PHF1
24 mouse prion 0N4R P301L B6/D2/SW ALZ50, AT8, AT100, AT180, CP3, CP9, CP13, MC1, PHF1
31 mouse thy-1 2N4R P301L B6/D2 AD199, AT8, AT180, MC1, TG3
41 mouse thy-1 0N4R P301S B6/CBA 12E8, ALZ50, AT8, AT100, AT180, AP422, CP3, PG5,
PHF1
40 mouse prion-tTA/ tetOp-tau 2N4R G272V B6/D2 12E8, AD2, AT8,TG3
37,38 PDGFG 2N4R V337M B6/SJL ALZ50, AT8, PS199
39 CamKII 2N4R R406W B6/SJL ALZ50, AT180, PS199, PS404
36 mouse thy-1 2N4R G272V, P301L, R406W B6/CBA AT8, AT180
Lewis and Hutton
Fig. 1. Tau Isoforms. A. The tau gene is encoded on chromosome 17q21. Alternatively spliced exons 2, 3,
and 10 are shown above the constitutive exons. Exons 4A, 6, and 8 are generally excluded from human tau
mRNA. Most tau transcripts include the intron between exons 13 and 14. B. Exons 2, 3, and 10 (shaded boxes)
are alternatively spliced to yield six tau isoforms (3R0N, 3R1N, 3R2N, 4R0N, 4R1N, 4R2N). The microtubules
binding domains (black boxes) are encoded by exons 912.
of neurofibrillary pathology (11). In a separate study, Ahlijanian and coworkers (12) overexpressed
p25, a calpain cleavage product of p35, the endogenous regulator of another potential tau kinase,
cdk5 (13). P25 lacks the regulatory region of p35 and thus causes constitutive activation of cdk5. P25
production has been suggested to underlie tau hyperphosphorylation in AD (13). Mice expressing
p25 developed hyperphosphorylated tau and silver-positive inclusions that also had neurofilament
immunoreactivity, but again neurofibrillary pathology was not observed (12). Bian and colleagues
(14) recently generated another transgenic mouse line, which overexpressed p25 in neurons. Despite
the elevated cdk5 activity observed in these animals, axonal degeneration resulted in the absence of
neurofibrillary tau pathology.
Kins and colleagues (15) addressed the role of tau hyperphosphorylation by generating mice that
expressed a dominant negative mutant of the catalytic subunit of protein phosphatase 2A transgene in
neurons. Abnormal tau phosphorylation (AT8 immunoreactivity) was observed in Purkinje cells of
these transgenic mice. Ubiquitin immunoreactivity colocalized with the AT8 immunopositive aggre-
gates; however, neurofibrillary lesions were not identified.
Transgenesis that resulted in altered tau kinase or phosphatase activity has produced some of the
initial features of the tau pathology seen in human disease; however, the absence of neurofibrillary
pathology or pronounced cell loss suggests that these enzymes may not initiate mature tau pathology.
These models have now been bred with various tau transgenic models to further define the role that
altered kinase or phosphatase activity has in the presence of early and late tau pathology.
TRANSGENIC MICE EXPRESSING WILD-TYPE TAU TRANSGENES

Two tau transgenic models have been reported that overexpress the longest isoform of wild-type
4R tau (2N4R). These mice expressed the transgene up to 10-fold over the level of endogenous tau
and displayed somatodendritic localization of tau in neurons reminiscent of the pre-tangle state
68 Lewis and Hutton
observed in human tauopathies including AD (16,17). The 2N4R animals also showed motor distur-
bances in tasks involving balancing on a rod and clinging from an inverted grid. This observation was
consistent with the presence of prominent axonopathy characterized by swollen axons with
neurofilament, tubulin, mitochondria, and vesicles in the brains and spinal cords of these mice. Dys-
trophic neurites that stained with antibodies recognizing hyperphosphorylated and conformational
tau epitopes (e.g., Alz50) were also identified. Astrogliosis, demonstrated by glial fibrillary acidic
protein (GFAP) immunoreactivity, was also observed in the cortex and spinal cord. Wild-type 4R tau
transgenic mice did not, however, develop filamentous tau inclusions characteristic of neurofibrillary
tangles (NFTs) and neuronal loss was not observed.
To examine the role of tau hyperphosphorylation in disease pathogenesis, 2N4R wild-type tau
animals were crossed with mice overexpressing GSK3G, a possible tau protein kinase (18). These
mice displayed a twofold increase in GSK3G activity and tau phosphorylation that surprisingly did
not lead to NFTs, but instead resulted in rescue of axonopathy and motor deficits observed in the
wild-type tau 2N4R transgenic mice. This observation indicates that tau hyperphosphorylation does
not inevitably result in abnormal tau aggregation, although clearly GSK3G and tau
hyperphosphorylation could still play a role in the pathogenesis of tauopathies.
The adult mouse brain predominantly expresses 4R tau isoforms. Therefore, Ishihara and co-
workers generated transgenic mice that overexpress the shortest tau isoform (0N3R) to test the hy-
pothesis that absence of 3R tau inhibits the development of neurofibrillary pathology (19). Five- to
10-fold overexpression of the 0N3R wild-type transgene resulted in axonal spheroids in the spinal
cord from 1 mo of age that were immunopositive for multiple phospho-dependent tau antibodies.
The spheroids also stained for neurofilament. The spinal cord inclusions in the 3R mice were argy-
rophilic with the Gallyas stain, but negative for thioflavin S. Binding of thioflavin S and other
congophilic dyes to the neurofibrillary pathology in AD and other tauopathies is consistent with
the presence of tau filaments with a G-sheet structure. It was therefore interesting that after 2 yr of
age, occasional (12 NFTs per mouse brain section) NFTs were observed in the hippocampus of
these mice. These inclusions consisted of straight tau filaments of 10- to 20-nm diameter that did not
stain with neurofilament antibodies. Additionally, insoluble tau accumulated in the brains and spi-
nal cords of these tau mice with age. Because the NFTs were sparse and required up to 2 yr to
develop, it has been suggested that these mice represent a model of normal aging (20). It will be
interesting to determine whether modifying factors can be identified that accelerate the development
of neurofibrillary pathology in these mice.
Duff and coworkers (21) created mice that expressed a P1-derived artificial chromosome (PAC)
transgene containing the entire human tau gene to drive expression of all six human tau isoforms.
Despite the almost fourfold overexpression of transgenic tau, robust tau pathology and behavioral
changes were absent. These mice produce all six human tau isoforms with a 3.7-fold increase in total
tau levels. Interestingly, in the mouse brain, splicing of the human genomic tau transgene is altered to
favor the production of exon 10-negative mRNA and 3R tau. In these mice neuronal processes and
synaptic terminals were positive for human tau. With the exception of immunoreactivity with certain
conformation-specific tau antibodies (e.g., MC-1), these mice lacked evidence of abnormal tau pathol-
ogy or behavioral changes up to 8 mo of age. It is uncertain why these mice, despite relatively high tau
expression levels, develop little overt pathology; however, subsequent breeding of these mice onto a
background lacking endogenous tau suggests that the presence of the mouse tau, which is largely 4R,
may have inhibited the development of robust pathology.
Andorfer et al. subsequently bred the wild-type genomic tau mice to mice lacking the endogenous
murine tau (22). At early ages, the axons of these animals (Htau) are immunopositive for phospho-tau
(CP13); however, this pathologic tau redistributes into the cells bodies with age, similarly to that
observed in human tauopathies. Significantly, neurons in the hippocampus and cortex of Htau mice
stained with PHF-1, MC1, and CP13. Similarly to the parental genomic tau line, these Htau preferen-
tially produce 3R human tau isoforms. Sarkosyl-insoluble tau accumulated as early as 2 mo of age
and was immunopositive for phosphotau epitopes as well as an antibody for 3R tau. Soluble, but not
insoluble, tau fractions from these Htau mice stained with 4R tau antibody. Ultrastructural analysis
showed remarkable similarity between human AD and the Htau isolated filaments. The extent to
which the tauopathy matures in these animals is still somewhat unclear. Staining with Thioflavin S,
Congo Red, and a variety of silver stains may be able to clarify the stage to which the animals progress.
Also, there are currently no published reports of neurodegeneration or behavior deficits in associa-
tion with the tau pathology in these mice. Despite this, these mice are currently the most impressive
model employing wild-type tau to mimic human tauopathy and will be useful in testing therapeutic
strategies. Additionally, these mice may prove valuable in determining the role of 3R and 4R tau in
human tauopathies.
Higuchi and coworkers generated transgenic mice using the T1 F-tubulin promoter to obtain 3R
tau expression (23), but instead of a cDNA with 0N3R tau, they used a minigene construct that
permitted expression of three human tau isoforms (0N3R, 1N3R, and 2N3R). Hyperphosphoryated
tau accumulated in glia and insoluble tau, extracted in formic acid, accumulated in spinal cord and
cerebellum by 12 mo. At 24 mo of age the glial inclusions were argyrophilic and immunoelectron
microscopy showed tau immunoreactive fibrils within oligodendrocyte inclusions. There was also an
age-related decrease in oligodendrocytes in spinal cord.
TRANSGENIC MICE EXPRESSING FTDP-17-ASSOCIATED P301L MUTANT

TAU TRANSGENES
Overexpression of wild-type tau transgenes has had only limited success in modeling the pathol-
ogy observed in the human tauopathies. As a result, several groups have generated mice that express
human tau containing FTDP-17-associated mutations in an attempt to accelerate the development of
neurofibrillary inclusions and other tau-related pathology.
Lewis and coworkers (24) reported a tau (P301L) transgenic mouse that expresses at about one- to
twofold above endogenous levels the shortest 4R tau isoform (0N4R) with the P301L mutation in
exon 10. Hemizygous and homozygous animals developed motor and behavioral deficits, as shown
in the accompanying video, initially presenting with hind-limb dysfunction starting at 7 and 4.5 mo,
respectively. Dystonic posturing and immobility developed within 12 mo of the initial symptoms.
Additional features of the phenotype included docility, reduced weight, decreased vocalization, and
eye irritations.
The P301L tau mice developed NFTs composed of 15- to 20-nm diameter straight and wavy tau
filaments that were concentrated in the spinal cord, brainstem, and basal telencephalon. Occasional
NFTs (one to two per section) were observed in the cortex and hippocampus. Pretangles had a much
wider brain distribution. The NFTs contained hyperphosphorylated tau, were congophilic, and were
positive with silver stains. Additionally, NFTs were negative for neurofilament and some were posi-
tive for ubiquitin. In addition to NFT, argyrophilic oligodendroglial inclusions were also detected in
the spinal cord, and the glial inclusions were composed of tau-immunoreactive fibrils with electron
microscopy (25). Tau-immunoreactive astrocytes were also detected, but they did not have
argyrophilia and ultrastructural studies showed dispersed tau fibrils (25). Consistent with the neuro-
pathology, the mice accumulated hyperphosphorylated tau that was insoluble after sarkosyl extrac-
tion of brain tissue including a prominent hyperphosphorylated 64kD species that comigrated with
pathologic tau from FTDP-17 and AD patients (24,26). Associated with the neurofibrillary pathol-
ogy, the P301L animals demonstrated almost 50% neuronal loss in the spinal cord (neuronal counts
in other brain regions were not reported), which likely explains much of the motor dysfunction in
these mice.
Subsequent studies with these animals have evaluated the interaction of tau with APP/AG and the
kinases GSK3 and cdk5. Breeding of these P301L mice with a transgenic model for amyloid deposi-
tion (Tg2576) (27) resulted in enhanced neurofibrillary tau pathology in the limbic system and olfac-
70 Lewis and Hutton
tory cortex of double transgenic animals (TAPP), supporting an interaction between amyloid precur-
sor protein (APP) or amyloid G (AG) and tau pathology in human AD (28). Additionally, neurons
containing tangle, but not pretangle, pathology from the P301L mice showed the abnormal accumu-
lation of tyrosine-phosphorylated GSK3 (29). Consistent with the enhanced neurofibrillary pathol-
ogy, TAPP mice contained larger numbers of neurons that were immunopositive for this abnormal
GSK3 sequestration. Noble and colleagues (30) investigated the interaction of tau with cdk5 by breed-
ing mice that overexpressed the constitutive activator of cdk5 (p25) (12) onto the P301L tau back-
ground. In these double transgenic mice, increased cdk5 activity, either alone or in conjunction with
GSK3, increased tau hyperphosphorylation and enhanced the degree of tau neurofibrillary pathology.
The evidence that GSK3 and cdk5 may play a role in the tauopathy in these mice suggests that
therapeutics aimed at reducing kinase activity may be beneficial in human tauopathies.
A second P301L tau transgenic mouse expressing the longest 4R tau isoform (2N4R) under the
mouse Thy-1 promoter was described by Gtz and coworkers (31). Pretangles and some thioflavin-S-
positive neurofibrillary-like structures were identified in the cortex, brainstem, and spinal cord of 8-mo-
old P301L animals. Tau filaments with straight and twisted ribbon morphologies were observed in
brain extracts. Additionally, astrocytosis and neuronal apoptosis, as demonstrated with terminal
deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL), accompanied the tau
pathology. Direct injection of AG42 fibrils into the brains of this P301L model resulted in a signifi-
cant enhancement (5X) in the degree of neurofibrillary tau pathology in the amygdala (32). These
results demonstrated that AG42 can accelerate tau pathology in this mouse model, supporting the role
of AG peptide in the development of tauopathy in humans.
Recently, Oddo et al. generated a mouse model expressing both a P301L tau transgene and an APP
transgene with the Swedish mutation on a gene-targeted mutant presenilin 1 (M146V) background
(33). These animals deposit extracellular AG in the cortex and hippocampus followed by the develop-
ment of tau pathology, initially in the CA1. This is a model of both tau and amyloid pathology in
regions directly relevant to AD; however, most interesting is the initial pathological appearance of
intraneuronal AG in this model. This accumulation of intracellular AG appeared to be responsible for
the synaptic dysfunction and long-term potentiation deficits reported in this model. Ultrastructural
analysis of the tau pathology and sarkosyl-insoluble tau analysis have not been published in these
mice; therefore, the filamentous nature of the tau pathology has not been fully defined. Additionally,
the impact of both intracellular and extracellular amyloid as well as the tau pathology on the behav-
ioral features of these mice should prove interesting.
To determine if F-synuclein could promote the fibrillization of tau, Giasson and colleagues gener-
ated single transgenic lines expressing mutant (A53T) F-synuclein protein or mutant (P301L) tau
protein under the direction of the murine 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter (34).
Mice expressing just one of the two transgenes failed to develop synuclein or tau inclusions; how-
ever, bigenic tau/synuclein mice developed inclusions for both proteins at 12 mo of age that were
positive for thioflavin S. Data from these bigenic mice suggests that F-synuclein and tau may inter-
act, resulting in fibrillization, and therefore promote the hypothesis that future therapeutic strategies
for synucleinopathies may also prove effective for tauopathies.
Models expressing the P301L human tau protein have been utilized in three novel ways to support
the role of amyloid in the development of human AD. Additionally, results from one P301L model
suggests that tau and synuclein pathology may be linked, supporting a role for tau in Parkinsons
disease (PD). It is possible that the inclusion of the P301L mutation in these mice, which has not been
identified in human AD or PD, may complicate these results; however, attempts to reproduce these
findings using wild-type tau may be unsuccessful given the abbreviated life-span of the model organ-
ism. Nonetheless, the pathology of many of these P301L models at the cellular level closely recapitu-
lates the tau pathological features of human AD and other tauopathies.
TRANSGENIC MICE EXPRESSING OTHER FTDP-17-ASSOCIATED

MUTANT TAU TRANSGENES
Similar to Christi and colleagues approach to modeling accelerated amyloid pathology in
transgenic mice (35), Lim and coworkers generated transgenic mice expressing 4R2N human tau
containing three different FTDP-17 mutations under the mouse Thy-1 promoter (36). These mice
were termed VLW because of inclusion of the G272V, P301L, and R406W mutations in the transgenic
tau. Dystrophic neurites and hyperphosphorylated tau were detected in cortex and hippocampus. The
lesions resembled pretangles in their lack of immunoreactivity with phospho-tau antibodies that rec-
ognize NFTs (phosphoserine 396/404). Electron microscopy revealed tau immunoreactive filamen-
tous structures 2- to 8-nm in diameter that were negative for neurofilament. Presence of tau-positive
filaments was confirmed with ultrastructural analysis of sarkosyl-insoluble tau; however,
immunogold labeling with phosphoepitopes of tau filaments was not reported in situ or in extracts.
Increased lysosomal bodies were identified in the VLW animals, particularly in the neurons that were
immunopositive for tau, as early as 1 mo of age.
Tanemura and coworkers (37,38) generated transgenic mice expressing V337M in 2N4R tau under
the PDGFG promoter. The construct contained myc and FLAG epitope tags at the amino- and carboxyl-
terminal ends. Hippocampal neurons from 14-mo transgenic mice displayed myc and phospho-tau
immunoreactivity, which was lacking in nontransgenic littermates. The immunoreactive neurons were
irregularly shaped and darkly stained with a variety of staining methods, and ultrastructural studies
showed organelles, lipofuscin pigment, and cytoskeletal elements, but no definitive evidence of NFTs.
Using a similar strategy, Tatebayashi and coworkers (39) generated transgenic mice expressing
R406W mutation under the calcium calmodulin kinase-II promoter, again with myc and FLAG tags
on amino and carboxyl terminal ends. Mutant tau was expressed from 7- to 18-fold over endogenous
tau, and mutant tau was detected predominantly in forebrain neurons. In animals more than 18 mo of
age there was abnormal tau immunoreactivity in neurons, and some of the neurons had argyrophilia
or weak Congo red birefringence. Ultrastructural studies showed cytoplasmic bundles of thin fila-
ments that were different from thicker tubular fibrils that characterize human tauopathies. Transgenic
animals also showed impairment in tests for contextual and cued fear conditioning.
Gtz and coworkers generated transgenic mice with tetracycline-inducible expression of G272V
tau under the mouse prion promotor (40). The expression was above endogenous levels and
expressed in both neurons and glia. By 6 mo of age thioflavin-S-positive oligodendroglial inclu-
sions were detected in the spinal cord. The oligodendroglial inclusions were not argyrophilic with
Gallyas stain, but at the electron microscopic level contained tubulofilamentous aggregates, with
individual fibrils measuring 1720 nm in width. Neurons formed tau-positive pretangles, but were
not filamentous lesions and there was only a small amount of insoluble tau in formic acid extractable
fractions.
Most recently, Allen and colleagues (41) utilized the mouse thy-1 promoter to drive expression of
0N4R human tau with the P301S mutation at approximately twofold the endogenous levels. Homozy-
gous and hemizygous P301S mice developed paraparesis at approx 6 and 12 mo of age, respectively.
Insoluble, hyperphosphorylated tau accumulated in the brains and spinal cords of the P301S animals
that showed identical mobility to aggregated tau from human patients. Abnormally phosphorylated
tau largely accumulated in nerve cells of the brainstem and spinal cords of the P301S animals with
reduced immunoreactivity in the regions of the forebrain. Argyrophilic, thioflavin S neurons were
also reported in the regions of concentrated tau pathology. Ultrastructurally, the lesions predomi-
nantly consisted of half-twisted ribbons that almost exclusively stained for human tau and lacked
murine tau. Apoptosis did not appear to cause the neuronal loss (49%) that was reported in the ventral
horn of the P301S mice. Interestingly, these mice shared many characteristics with the P301L 0N4R
mice generated by Lewis et al. (24) including the development of frequent eye irritations.
72 Lewis and Hutton
OTHER ANIMAL MODELS OF TAU DYSFUNCTION

In addition to the range of mouse models now available, there have been attempts to use
nonmammalian systems to model the tau dysfunction observed in human tauopathies. Although often
ignored by many mouse-based researchers, these systems have proven useful in modeling some
aspects of the disease while providing relatively simple screening systems for potential therapeu-
tics before trials in mammals.
One such system is a lamprey model for tau dysfunction developed by Hall and colleagues (42).
By expressing wild-type human tau in the large anterior bulbar cells (ABCs) of the lamprey, Hall et al.
(42) succeeded in producing a fish model of tau dysfunction. Tau within these ABCs became
hyperphosphorylated and filamentous, and the neurons degenerated, resulting in a lamprey tauopathy
that can be staged similarly to human tauopathies. The ease of therapeutic trials using this lamprey
system allows the model to be a valuable link between cellular models and the in vivo mammalian
models detailed earlier. Hall et al. (43) has recently utilized this system to screen a novel proprietary
compound aimed at blocking tau filament formation. Limitations of this model system include differ-
ences of central nervous system and the inability to perform cognitive and motor tests that accom-
pany the tauopathies that occur in complex organisms.
Kraemer et al. recently generated a Caenorhabditis elegans model of tau pathology (44). Expres-
sion of tau with either the P301L or V377M mutation resulted in worms with locomotor deficits,
accumulation of insoluble tau protein, and increased tau phosphorylation. Axonal degeneration and
neuronal loss were also reported in this mold. The simplicity of this model makes it an attractive
system with which to screen potential therapeutic compounds before trials in mammals.
A Drosophila model of tauopathy expressing the human tau containing the R406W mutation also
mimicked many aspects of tauopathy without the development of NFTs (45). Aged flies showed
progressive neurodegeneration, accumulation of abnormally phosphorylated tau, but lacked the large
neurofibrillary accumulations of tau that characterize human tauopathies. This model system sug-
gested that mature tau pathology may not be necessary to result in the neurodegenerative process.
Additionally, this model has now been used to examine the gene expression changes that occur as the
result of tau-related neurodegeneration (46). Evidence of these expression changes such as those in
lysosomal and cellular stress response genes in the Drosophila model will now allow us to more
closely investigate similar changes in both mouse models and human tauopathies.
CONCLUSION
A range of different in vivo model systems is now available that can be used to investigate both the
development and progression of tauopathies (see Table 2 for future directions). These models mimic
many of the basic cellular changes that accompany development of tauopathy. Additionally, some of
the models share clinical features and distribution of tau pathology that could be compared to human
4R tauopathies such as progressive supranuclear palsy (PSP). PSP is a rare parkinsonian movement
disorder that is associated with early postural instability and supranuclear vertical gaze palsy (47).
The brains of PSP patients display neurofibrillary tangles that are primarily localized to the basal
ganglia, diencephalon, and the brainstem (48,49). Brainstem regions that are usually affected in PSP
included the locus ceruleus, pontine nuclei, and pontine tegmentum. Additionally, the cerebellar den-
tate nuclei and spinal cord are frequently affected in PSP patients (48,49). The distribution of the
neurofibrillary tau pathology in the JNPL3 mice overlaps many of the same regions affected in PSP,
including the pontine nucleus, the dentate nucleus, and the spinal cord. 0N4R P301S mice (41) also
showed a similar distribution of pathology. Additionally, the reduced vocalization and progressive
Table 2
Future Directions in Animal Modeling of Tauopathies
Determine gene expression changes that accompany tauopathies.
Isolate loci or specific alleles that modify the progression of tauopathy
based on comparison of different mouse models and different strains and
based on simple models of tauopathy.
Develop and utilize inducible mouse models of tauopathy to determine
at which stages tauopathies are targets for therapeutic efforts.
Design, develop,a nd screen therapeutic strategies using the current and
future transgenic tau models.
Utilize current models to understand the interaction of tau with other
disease-related processes.
Understand how and at which stage tau leads to neurodegeneration.
movement disorder, including rigidity, observed in the JNPL3 model is similar to that observed in
PSP patients. In addition, the selective distribution of 4R tau in both neurons and glia is a feature
observed in both PSP and these mouse models.
The neuronal response to tauopathy, including of gene expression and protein (level and modifica-
tion) changes, can now be investigated at various pathological stages in these models and compared
with observations from end-stage human tissue. Additionally, multiple disease modifiers may now
be identified in the more simple systems such as in the fly or worm, which may lead to a greater
understanding of the mechanisms that result in tau-induced neurodegeneration and perhaps identify
additional therapeutic targets. It is important however to recognize the limitations of these simple
genetic animal models and follow-up studies in mouse models will be required to verify the rel-
evance of the findings in these systems.
The development of multiple animal models of tauopathy has also enabled the field to investigate
the relationship between tau dysfunction and other proteins previously implicated in
neurodegenerative disease including AG, F-synuclein, and various tau kinases/phosphatases. Given
the similarities between the various protein aggregation disorders, these interactions may provide
essential clues for understanding the basic process of tau-associated neurodegeneration and for devel-
oping therapeutic strategies (Fig. 2).
Comparisons of various tau transgenic mice on different mouse strain backgrounds should further
our understanding of how genetic or environmental factors modify the progression of tauopathy.
Novel inducible models of tauopathy should also help determine which aspects of the disease process
are reversible and which stages are associated with functional deficits. Overall the rapid development
of animal models of tauopathy in the last 4 yr will inevitably accelerate progress in understanding the
pathogenesis of tauopathy and should also identify potential therapeutic approaches that can be used
to treat these diseases in human patients.
74 Lewis and Hutton
Fig. 2. Tau therapeutic targets. Therapeutic targets may be aimed at different stages of tau dysfunction.
Kinase inhibitors could be tested to prevent hyperphosphorylation of tau and dissociation from microtubules
(mt). Compounds that prevent or dissociate the polymerization of tau into lesions might also be effective thera-
pies. Additionally, it may be possible to target therapies to decrease the stabilization of tau lesions or to increase
the turnover of abnormal tau. Finally, neuroprotective agents may be effective in maintaining or recovering
functional neurons.
REFERENCES
1. DSouza, I, Poorkaj P, Hong M, et al. Missense and silent tau gene mutations cause frontotemporal dementia with
parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl
Acad Sci USA 1999;96:55985603.
2. Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice site mutations in tau with the inherited
3. Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann
Neurol 1998;43:815825.
4. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple
system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:77377741.
5. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and parkinsonism linked to chromosome 17: a new group
of tauopathies. Brain Pathol 1998;8:387402.
6. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA. Cloning and sequencing of the cDNA encoding an
isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein
mRNAs in human brain. EMBO J 1989;8:393399.
7. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated
protein tau: sequences and localization in neurofibrillary tangles of Alzheimers disease. Neuron 1989;3:519526.
8. Lee G, Neve RL, Kosik KS. The microtubule binding domain of tau protein. Neuron 1989;2:16251624.
9. Kosik KS, Orecchio LD, Bakalis S, Neve RL. Developmentally regulated expression of specific tau sequences. Neuron
1989;2:13891397.
10. Spillantini MG, Goedert M. Tau protein pathology in neurodegenerative diseases. Trends Neurosci 1998;21:428433.
11. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran M, Hen R, Avila J. Decreased nuclear F-catenin, tau hyperphos-
phorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 2001;20:2739.
12. Ahlijanian MK, Barrezueta NX, Williams RD, et al. Hyperphosphorylated tau and neurofilament and cytoskeletal dis-
ruptions in mice overexpressing human p25, an activator of Cdk5. Proc Natl Acad Sci USA 2000;97:29102915.
13. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5
activity and promotes neurodegeneration. Nature 1999;402:615622.
14. Bian F, Nath R, Sobocinski G, et al. Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in
p25-transgenic mice. J Comp Neurol 2002;446:257266.
15. Kins S, Crameri A, Evans DRH, Hemmings BA, Nitsch R, Gotz J. Reduced PP2A activity induces tau
hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem 2001;276:3819338200.
16. Probst A, Gtz J, Wiederhold KH, et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau
protein. Acta Neuropathol 2000;99:469481.
17. Spittaels K, Van den Haute C, Van Dorpe J, et al. Prominent axonopathy in the brain and spinal cord of transgenic mice
overexpressing four-repeat human tau protein. Am J Pathol 1999;155:21532165.
18. Spittaels K, Van den Haute C, Van Dorpe J, et al. Glycogen synthase kinase-3G phosphorylates protein tau and rescues the
axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 2000;275:4134041349.
19. Ishihara T, Hong M, Zhang B, et al. Age-dependent emergence and progression of a tauopathy in transgenic mice
overexpressing the shortest human tau isoform. Neuron 19999;24:751762.
20. Ishihara T, Zhang B, Higuchi M, Yoshiyama Y, Trojanowski JQ, Lee VM. Age-dependent induction of congophilic
neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 2001;158:555562.
21. Duff K, Knight H, Refolo LM, et al. Characterization of pathology in transgenic mice over-expressing human genomic
and cDNA tau transgenes. Neurobiol Dis 2000;7:8798.
22. Andorfer C, Kress Y, de Silva R, et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human
tau isoforms. J Neurochem 2003;86:582590.
23. Higuchi M, Ishihara T, Zhang B, et al. Transgenic mouse model of tauopathies with glial pathology and nervous system
degeneration. Neuron 2002;35:433446.
24. Lewis J, McGowan E, Rockwood J, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in
mice expressing mutant (P301L) tau protein. Nat Genet 2000;25:402-405.
25. Lin W-L, Lewis J, Yen S-H, Hutton M, Dickson DW. Filamentous tau in oligodendrocytes and astrocytes of transgenic
mice expressing the human tau isoform with the P301L mutation. Am J Pathol 2003;162:213218.
26. Sahara N, Lewis J, DeTure M, et al. Assembly of tau in transgenic animals expressing P301L tau: alterations of phos-
phorylation and solubility. J Neurochem 2002;83:14981508.
27. Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic
mice. Science 1996;274:99102.
28. Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau
and APP. Science 2001;293:14871491.
29. Ishizawa T, Sahara N, Ishiguro K, et al. Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and
granulovacular degeneration in transgenic mice. Am J Pathol 2003;163:10571067.
30. Noble W, Olm V, Takata K, et al. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron
2003;38:555565.
31. Gtz J, Chen F, Barmettler R, Nitsch RM. Tau filament formation in transgenic mice expressing P301L tau. J Biol
Chem 2001;276:529534.
32. Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by
Abeta fibrils. Science 2001;293:14911495.
33. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimers Disease with plaques and tangles:
intracellular Ab and synaptic dysfunction. Neuron 2003; 39:409421.
34. Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science
2003;300:636640.
35. Chrishti MA, Yang DS, Janus C, et al. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing
a double mutant form of amyloid precursor protein 695. J Biol Chem 2001;276:2156221570.
36. Lim F, Hernandez F, Lucas JJ, Gomez-Ramos P, Moran MA, Avila J. FTDP-17 Mutations in tau transgenic mice
provoke lysosomal abnormalities and tau filaments in forebrain. Mol Cell Neurosci 2001;18:702714.
37. Tanemura K, Akagi T, Murayama M, et al. Formation of filamentous tau aggregates in transgenic mice expressing
V337M human tau. Neurobiol Disease 2001;8:10361045.
38. Tanemura K, Murayama M, Akagi T, et al. Neurodegeneration with tau accumulation in a transgenic mouse expressing
V337M human tau. J Neurosci 2002;22:133141.
39. Tatebayashi Y, Miyasaka T, Chui D-H, et al. Tau filament formation and associative memory deficit in aged mice
expressing mutant (R406W) human tau. Proc Natl Acad Sci USA 2002;99:1389613901.
40. Gtz J, Tolnay M, Barmettler R, Chen F, Probst A, Nitsch RM. Oligodendroglial tau filament formation in transgenic
mice expressing G272V tau. Eur J Neurosci 2001;13:21312140.
41. Allen B, Ingram E, Takao M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice
expressing human P301S tau protein. J Neurosci 2002;22:93409351.
76 Lewis and Hutton
42. Hall GF, Lee VM, Lee G, Yao J. Staging of neurofibrillary degeneration caused by human tau overexpression in a
unique cellular model of human tauopathy. Am J Pathol 2001;158:235246.
43. Hall GF, Lee S, Yao J. Neurofibrillary degeneration can be arrested in an in vivo cellular model of human tauopathy by
application of a compound which inhibits tau filament formation in vitro. J Mol Neurosci 2002;19:253260.
44. Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg G. Neurodegeneration and defective
neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci USA 2003;100:99809985.
45. Whitmann CW, Wszolek MF, Shulman JM, et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary
tangles. Science 2001;293:711714.
46. Scherzer CR, Jensen RV, Gullans SR, Feany MB. Gene expression changes presage neurodegeneration in a Drosophila
model of Parkinsons disease. Hum Mol Genet 2003;12:24572466.
47. Litvan I, Hutton M. Clinical and genetic aspects of progressive supranuclear palsy. J Geriatr Psychiatry Neurol
1998;11:107114.
1999;246(Suppl 2):II/6II/15.
49. Ishizawa K, Dickson DW. Microglial activation parellels system degeneration in progression supranuclear palsy and
Neurodegenerative F-Synucleinopathies 77
6
Neurodegenerative F-Synucleinopathies
Michel Goedert and Maria Grazia Spillantini
INTRODUCTION
Parkinsons disease (PD) is the most common movement disorder (1). Neuropathologically, it is
defined by nerve cell loss in the substantia nigra and the presence there of Lewy bodies and Lewy
neurites. Nerve cell loss and Lewy body pathology are also found in a number of other brain regions,
such as the dorsal motor nucleus of the vagus, the nucleus basalis of Meynert, and some autonomic
ganglia. Lewy bodies and Lewy neurites also constitute the defining neuropathological characteris-
tics of dementia with Lewy bodies (DLB), a common late-life dementia that exists in a pure form or
overlaps with the neuropathological characteristics of Alzheimers disease (AD) (2). Unlike PD,
DLB is characterized by large numbers of Lewy bodies in cortical brain areas. Ultrastructurally,
Lewy bodies and Lewy neurites consist of abnormal filamentous material. Despite the fact that the
Lewy body was first described in 1912 (3), its molecular composition remained unknown until 1997.
The two developments that imparted a new direction to research on the aetiology and pathogenesis
of PD and DLB were the twin discoveries that a missense mutation in the F-synuclein gene is a rare
genetic cause of PD (4) and that F-synuclein is the main component of Lewy bodies and Lewy neurites
in idiopathic PD, DLB, and several other diseases (5). Subsequently, the filamentous glial and neu-
ronal inclusions of multiple system atrophy (MSA) were also found to be made of F-synuclein, reveal-
ing an unexpected molecular link with Lewy body diseases (68). These findings have placed the
dysfunction of F-synuclein at the center of PD and several atypical parkinsonian disorders (Table 1).
THE SYNUCLEIN FAMILY

Synucleins are abundant brain proteins whose physiological functions are only poorly understood.
The human synuclein family consists of three membersF-synuclein, G-synuclein, and L-synuclein
which range from 127 to 140 amino acids in length and are 5562% identical in sequence, with a
similar domain organization (Fig. 1) (911). The amino-terminal half of each protein is taken up by
imperfect 11-amino acid repeats that bear the consensus sequence KTKEGV. Individual repeats are
separated by an interrepeat region of five to eight amino acids. The repeats are followed by a hydro-
phobic intermediate region and a negatively charged carboxy-terminal domain; F- and G-synuclein
have identical carboxy-termini. By immunohistochemistry, F- and G-synuclein are concentrated in
nerve terminals, with little staining of somata and dendrites. Ultrastructurally, they are found in close
proximity to synaptic vesicles (12). In contrast, L-synuclein is present throughout nerve cells in many
brain regions. In rat, F-synuclein is most abundant throughout telencephalon and diencephalon, with
lower levels in more caudal regions (13). G-Synuclein is distributed fairly evenly throughout the
central nervous system, whereas L-synuclein is most abundant in midbrain, pons, and spinal cord,

77
78 Goedert and Spillantini
Table 1
F-Synuclein diseases
Lewy body diseases
Idiopathic Parkinsons disease
Dementia with Lewy bodies
Pure autonomic failure
Lewy body dysphagia
Inherited Lewy body diseases
Multiple system atrophy
Olivopontocerebellar atrophy
Striatonigral degeneration
ShyDrager syndrome
Fig. 1. Sequence comparison of human F-synuclein (F Syn), G-synuclein (G Syn), and L-synuclein (L Syn).
Amino acid identities between at least two of the three sequences are indicated by black bars. As a result of a
common polymorphism, residue 110 of L-synuclein is either E or G.
with much lower levels in forebrain areas. At the level of neurotransmitter systems, F-synuclein is
particularly abundant in central catecholaminergic regions, G-synuclein in somatic cholinergic neu-
rons, whereas L-synuclein is present in both catecholaminergic and cholinergic systems.
Synucleins are natively unfolded proteins with little ordered secondary structure that have only
been identified in vertebrates (14). Experimental studies have shown that F-synuclein can bind to
lipid membranes through its amino-terminal repeats, indicating that it may be a lipid-binding protein
(15,16). It adopts structures rich in F-helical character upon binding to synthetic lipid membranes
containing acidic phospholipids. This conformation is taken up by amino acids 198 and consists
of two F-helical regions (residues 142 and 4598) that are interrupted by a break of two amino
acids (residues 43 and 44) (17,18). Residues 99140 are unstructured. In cell lines and primary neu-
rons treated with high fatty acid concentrations, F-synuclein was found to accumulate on phospholipid
monolayers surrounding triglyceride-rich droplets (19). G-Synuclein bound in a similar way, but L-
synuclein failed to bind to lipid droplets and remained cytosolic. Accordingly, F-synuclein has been
shown to bind fatty acids in vitro, albeit with a lower affinity than physiological fatty acid-binding
proteins (20,21). Both F- and G-synucleins have been shown to inhibit phospholipase D2 (22). This
isoform of phospholipase D localizes to the plasma membrane, where it might be involved in signal-
induced cytoskeletal regulation and endocytosis. It is therefore possible that F- and G-synucleins
regulate vesicular transport processes.
Little is known about posttranslational modifications of synucleins in the brain. In transfected
cells, F-synuclein is constitutively phosphorylated at residues 87 and 129, with residue 129 being the
predominant site (23). However, in normal brain, only a small fraction of F-synuclein is phosphory-
lated at S129 (24). Casein kinase-1 and casein kinase-2 phosphorylate S129 of F-synuclein in vitro,
as do several G protein-coupled receptor kinases (2325). Phosphorylation at S129 has been reported
to result in a reduced ability of F-synuclein to interact with phospholipids and phospholipase D2 in
one study, whereas another study found no effect of phosphorylation on lipid binding (25,26). F-Synuclein
contains four tyrosine residues, three of which are located in the carboxy-terminal region. Tyrosine
kinases of the Src family phosphorylate Y125 in vitro and in transfected cells (27,28). The same
site also becomes phosphorylated following exposure of cells to osmotic stress (29), suggesting that
tyrosine phosphorylation of F-synuclein may be regulated. However, it remains to be seen whether
synucleins are phosphorylated on tyrosines in brain. Like some other natively unfolded proteins,
F-synuclein can be degraded by the proteasome in the absence of polyubiquitination (30).
Inactivation of the F-synuclein gene by homologous recombination does not lead to a neurologi-
cal phenotype, with the mice being largely normal (3135). So, a loss of function of F-synuclein is
unlikely to account for its role in neurodegeneration. Analysis of mice lacking L-synuclein has simi-
larly failed to reveal any gross abnormalities (34). Mice lacking G-synuclein have not yet been re-
ported. Ultimately, mice lacking all three synucleins may be needed for an understanding of the
physiological functions of these abundant brain proteins. One study has reported that targeted disrup-
tion of the F-synuclein gene confers specific resistance of dopamine neurons to the toxic effects of 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (35). The resistance to neurodegeneration
appeared to be mediated through the inability of MPTP to inhibit the complex I activity of the mito-
chondrial respiratory chain. A second study on two additional lines of mice without F-synuclein has
reported partial resistance to MPTP in one line and normal sensitivity to the toxin in the other (36). It
thus appears that F-synuclein is not obligatorily coupled to sensitivity to MPTP, but that it can influ-
ence MPTP toxicity on some genetic backgrounds.
LEWY BODY DISEASES

The PARK1 Locus
In 1990, Golbe, Duvoisin, and (contursi kindred) colleagues described an autosomal-dominantly
inherited form of PD in an Italian-American family (37). It was the first familial form of disease in
which Lewy bodies had been shown to be present. Subsequently, several more families with autopsy-
confirmed Lewy body disease were identified. In 1996, Polymeropoulos and colleagues mapped the
genetic defect responsible for disease in the Contursi kindred to chromosome 4q21-23 (PARK1)
(38). One year later, they reported a missense mutation (A53T) in the F-synuclein gene as the cause
of familial PD in this kindred and several PD families of Greek origin (Fig. 2) (4). A founder effect
probably accounts for the relatively frequent occurrence of the A53T mutation in southern Italy
and Greece. In 1998, a second mutation (A30P) in the F-synuclein gene was identified in a German
pedigree with early-onset PD (Fig. 2) (39). In 2003, the genetic defect responsible for a familial form
of PD dementia in a large family (the Iowa kindred; see ref. 40) was shown to be a triplication of a
1.62.0 Mb region on the long arm of chromosome 4 (41). One of an estimated 17 genes located in
this region is the F-synuclein gene. These findings thus suggest that that the simple overproduction
of wild-type F-synuclein may be sufficient to cause PD dementia. Moreover, polymorphic varia-
tions in the 5' noncoding region of the F-synuclein gene have been found to be associated with
idiopathic PD in some, but not all, studies (4245). They probably influence the level of F-synuclein
expression (46).
Fig. 2. Mutations in the F-synuclein gene in familial Parkinsons disease. (A) Schematic diagram of human
F-synuclein. The seven repeats with the consensus sequence KTKEGV are shown as black bars. The two known
missense mutations are indicated. Triplication of a region on chromosome 4 that comprises the F-synuclein gene
causes familial PD dementia. Therefore, it appears likely that the overexpression of wild-type F-synuclein can
also cause disease (B) Repeats in human F-synuclein. Residues 787 of the 140-residue protein are shown. Amino
acid identities between at least five of the seven repeats are indicated by black bars. The A to P mutation at
residue 30 between repeats two and three and the A to T mutation at residue 53 between repeats four and five
are shown.
F-Synuclein and Sporadic Lewy Body Diseases

Shortly after the identification of the genetic defect responsible for PD in the Contursi kindred,
Lewy bodies and Lewy neurites in the substantia nigra from patients with sporadic PD were shown to
be strongly immunoreactive for F-synuclein (Fig. 3) (5). Subsequently, Lewy bodies and isolated
Lewy body filaments from PD brain were found to be decorated by antibodies directed against
F-synuclein (47,48). In addition to PD, Lewy bodies and Lewy neurites also constitute the defin-
ing neuropathological characteristics of DLB. Unlike PD, DLB is characterized by large numbers of
Lewy bodies and Lewy neurites in cortical brain areas. But like PD, DLB is also characterized by
Lewy body pathology in the substantia nigra, and the Lewy bodies and neurites associated with DLB
are strongly immunoreactive for F-synuclein (Fig. 4) (5). Filaments from Lewy bodies in DLB are
decorated by F-synuclein antibodies, and their morphology closely resembles that of filaments
extracted from the substantia nigra of PD brains (49,50).
The F-synuclein filaments associated with PD and DLB are unbranched, with a length of 200
600 nm and a width of 510 nm. Full-length F-synuclein is present, with its amino- and carboxy-
termini being exposed on the filament surface. Protease digestion and site-directed spin labeling
studies have shown that the core of the F-synuclein filaments extends over a stretch of about 70
amino acids, from residues 34101 (51,52). This sequence overlaps almost entirely with the lipid-
binding region of F-synuclein. Biochemically, the presence of F-synuclein inclusions has been found
to correlate with the accumulation of F-synuclein. Of the three human synucleins, only F-synuclein
is associated with the filamentous inclusions of Lewy body diseases. Using specific antibodies, G- and
L-synucleins are absent from these inclusions (5,50).
Fig. 3. Substantia nigra from patients with Parkinsons disease immunostained for F-synuclein. (A) Two
pigmented nerve cells, each containing an F-synuclein-positive Lewy body. Lewy neurites (small arrows) are
also immunopositive. Scale bar, 20 m. (B) Pigmented nerve cell with two F-synuclein-positive Lewy bodies.
Scale bar 8 m. (C) F-Synuclein-positive extracellular Lewy body. Scale bar, 4 m.
Prior to this work, ubiquitin staining had been the preferred immunohistochemical marker of Lewy
body pathology (53). By double-labeling immunohistochemistry, the number of F-synuclein-posi-
tive structures was greater than that stained for ubiquitin, suggesting that the ubiquitination of F-synuclein
occurs after its assembly into filaments (50,54,55). In DLB brain, F-synuclein is mostly mono- or
diubiquitinated (5456). Phosphorylation and nitration are two additional posttranslational modifica-
tions of filamentous F-synuclein. Phosphorylation at S129 has been documented in Lewy bodies and
Lewy neurites by mass spectrometry and phosphorylation-dependent antibodies (24). It has been
suggested that phosphorylation of F-synuclein at S129 may trigger filament assembly. However, it
remains to be determined whether it occurs before or after filament assembly in human brain. Nitra-
tion of tyrosine residues in proteins is the result of the action of oxygen, nitric oxide, and their prod-
ucts, such as peroxynitrite. Nitration of filamentous F-synuclein was found using antibodies specific
for nitrated tyrosine residues (57). As for ubiquitin, staining for nitrotyrosine was less extensive than
staining for F-synuclein, suggesting that nitration of F-synuclein occurs after its assembly into
filaments.
Fig. 4. Brain tissue from patients with dementia with Lewy bodies immunostained for F-synuclein.
(A,B) F-Synuclein-positive Lewy bodies and Lewy neurites in substantia nigra stained with antibodies
recognizing the amino-terminal (A) or the carboxy-terminal (B) region of F-synuclein. Scale bar, 100 m (in
B, for A,B). (C,D) F-Synuclein-positive Lewy neurites in serial sections of hippocampus stained with antibodies
recognizing the amino-terminal (C) or the carboxy-terminal (D) region of F-synuclein. Scale bar, 80 m (in D, for
C,D). (E), F-Synuclein-positive intraneuritic Lewy body in a Lewy neurite in substantia nigra. Scale bar, 40 m.
Lewy body pathology is also the defining feature of several other, rarer diseases. Cases in which
F-synuclein immunoreactivity has been examined have shown its presence. Thus, pure autonomic
failure is characterized by F-synuclein-positive Lewy body pathology in sympathetic ganglia (58,59).
Incidental Lewy body disease describes the presence of small numbers of Lewy bodies and Lewy
neurites in the absence of clinical symptoms. It is observed in 510% of the general population over
the age of 60, and is believed to represent a preclinical form of Lewy body disease (60,61). In cases
with incidental Lewy body disease, the first pathological F-synuclein-immunoreactive structures do
not form in dopaminergic nerve cells of the substantia nigra, but in non-catecholaminergic neurons of
the dorsal glossopharyngeus-vagus complex, projection neurons of the reticular zone, and in the
locus coeruleus, raphe nuclei, and the olfactory system (62). Incidental Lewy body disease may be at
one end of the spectrum of Lewy body diseases, with DLB at the other end and PD somewhere in
between. The Lewy body pathology that is sometimes associated with other neurodegenerative dis-
eases, such as Alzheimers disease, the parkinsonism-dementia complex of Guam, and
neurodegeneration with brain iron accumulation type I has also been shown to be immunoreactive for
F-synuclein (7,63,64). However, it is not an invariant feature of these diseases. Nevertheless, under-
standing why F-synuclein pathology develops in a proportion of cases in these apparently unrelated
conditions may shed light on the mechanisms operating in the diseases defined by the presence of
Lewy body pathology.
F-Synuclein and Inherited Lewy Body Diseases

The discovery that F-synuclein is the major component of Lewy bodies and Lewy neurites in
idiopathic PD raised the question of the neuropathological picture in cases of familial PD with mutations
in the F-synuclein gene. Widespread Lewy bodies and Lewy neurites immunoreactive for F-synuclein
were described in the brainstem pigmented nuclei, hippocampus, and temporal cortex in two indi-
viduals from an Australian family of Greek origin with the A53T mutation (65). Lewy neurites ac-
counted for much of the pathology, underscoring their relevance for the neurodegenerative process.
As in other Lewy body diseases, the F-synuclein pathology was neuronal. However, it was much
more widespread than in idiopathic PD. Similarly extensive deposits of F-synuclein have been found
in a case of the Contursi kindred (66). In addition, substantial tau pathology was reported in this case,
suggesting that a missense mutation in the F-synuclein gene can somehow also lead to tau deposition.
This is in line with recent studies that have reported that tau staining is frequently associated with
Lewy bodies and that F-synuclein assemblies can induce tau filament formation in vitro (67,68).
Work so far has been on cases with the A53T mutation. Nothing is known about the neuropathology
in cases of familial PD with the A30P mutation in F-synuclein.
In the Iowa kindred with a triplication of the region of chromosome 4 that encompasses the F-synuclein
gene, abundant and widespread F-synuclein-immunoreactive Lewy bodies and Lewy neurites have been
described (69). The pathological picture resembled that of DLB. In addition, F-synuclein-positive
glial inclusions were also present, suggesting that overproduction of wild-type F-synuclein may be a
mechanism leading to the formation of glial cytoplasmic inclusions.
A genetic locus (PARK3) that is linked to autosomal-dominantly inherited PD has been mapped to
chromosome 2p13 (70). Although the underlying genetic defect is not yet known, neuropathological
analysis has shown the presence of F-synuclein-immunoreactive Lewy bodies and Lewy neurites,
with a distribution resembling PD (71). It appears likely that the defective PARK3 gene product
functions in the pathway that leads from soluble to filamentous F-synuclein.
Subsequent to the identification of the A53T mutation in the F-synuclein gene, a missense muta-
tion (I93M) in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene was reported in a patient
with familial PD (PARK5) (72). UCHL1 is an abundant neuron-specific deubiquitinating enzyme.
This mutation resulted in a partial loss of the catalytic activity of the thiol protease, which could, in
principle, lead to protein aggregation. However, no information is available about neuropathology in
this family, and the presence of Lewy body pathology with the accumulation of F-synuclein remains
a possibility. In 1998, mutations in the gene parkin (PARK2) were identified as the genetic cause of
a form of autosomal-recessive juvenile parkinsonism (AR-JP) (73). These mutations constitute a
common cause of parkinsonism, especially when the age of onset is relatively early in life. Parkin
functions as a ubiquitin ligase, and the known mutations are believed to lead to a loss of its function
(74). It is possible that one or more proteins accumulate as a result, and that this causes nerve cell
degeneration. Parkin has been reported to be present in Lewy bodies and to ubiquitinate a minor,
O-glycosylated form of F-synuclein (7577). However, with one exception, mutations in parkin
have, so far, not been found to lead to the development of Lewy body pathology (7880). Further-
more, a more rigorous study using well-characterized anti-parkin antibodies failed to confirm
colocalization with F-synuclein (81). In 2002, mutations in the gene DJ-1 were found to cause
another form of AR-JP (PARK7), presumably through a loss of function mechanism (21). The physi-
ological function of DJ-1 remains to be identified. To date, there is no information about the neuro-
pathological features of cases with mutations in DJ-1. DJ-1-immunoreactivity does not colocalize
with Lewy bodies or Lewy neurites (83). It will be interesting to see whether there are links between
the mechanisms that lead to Lewy body diseases and AR-JP, or whether they constitute distinct
disease entities.

After the discovery of F-synuclein in the filamentous lesions of Lewy body diseases, multiple
system atrophy (MSA) was also shown to be characterized by filamentous F-synuclein deposits (Fig. 5)
(68). Lewy body pathology is not generally observed in MSA. Instead, glial cytoplasmic inclusions,
Fig. 5. Brain tissue from patients with multiple system atrophy immunostained for F-synuclein. (AD)
F-Synuclein-immunoreactive oligodendrocytes and nerve cells in white matter of pons (A,B,D) and cer-
ebellum (C) identified with antibodies recognizing the amino-terminal (A,C) or the carboxy-terminal (B,D) region
of F-synuclein. (E,F) F-Synuclein-immunoreactive oligodendrocytes and nerve cells in gray matter of pons (E)
and frontal cortex (F) identified with antibodies recognizing the amino-terminal (E) or the carboxy-terminal (F)
region of F-synuclein. Arrows identify representative examples of each of the characteristic lesions stained for
F-synuclein: cytoplasmic oligodendroglial inclusions (A,F), cytoplasmic nerve cell inclusions (B), nuclear oli-
godendroglial inclusion (C), neuropil threads (D), and nuclear nerve cell inclusion (E). Scale bars, 33 m (in E);
50 m (in F, for AD,F).
which consist of filamentous aggregates, are the defining neuropathological feature of MSA (84).
They are found mostly in the cytoplasm and, to a lesser extent, in the nucleus of oligodendrocytes.
Inclusions are also observed in the cytoplasm and nucleus of some nerve cells, and in neuropil threads.
The principal brain regions affected are the substantia nigra, striatum, locus coeruleus, pontine nu-
clei, inferior olives, cerebellum, and spinal cord. Typically, nerve cell loss and gliosis are observed.
The formation of glial cytoplasmic inclusions might be the primary lesion that will eventually com-
promise nerve cell function and viability. Nerve cell loss and clinical symptoms of MSA in the pres-
ence of only glial cytoplasmic inclusions have been described (85).
Glial cytoplasmic inclusions are strongly immunoreactive for F-synuclein, and filaments isolated
from the brains of patients with MSA are labeled by F-synuclein antibodies (68). No staining is
obtained with antibodies specific for G- or L-synuclein. As in DLB, assembled F-synuclein is nitrated
and phosphorylated at S129, and the number of F-synuclein-positive structures exceeds that stained
by anti-ubiquitin antibodies, indicating again that the accumulation of F-synuclein precedes
ubiquitination. The filament morphologies and their staining characteristics were found to be similar
to those of filaments extracted from the brains of patients with PD and DLB (8). Two distinct mor-
phologies were observed. Some filaments showed a distinctly twisted appearance, alternating in width
between 5 and 18 nm, with a period of 7090 nm. The other class of filaments had a more uniform
width of approx 10 nm. The formation of inclusions was shown to correlate with decreased solubility
of F-synuclein. However, the reduction in solubility was less marked than in PD and DLB (86).
This work has revealed an unexpected molecular link between MSA and Lewy body diseases. The
main difference is that in MSA most of the F-synuclein pathology is found in glial cells, whereas in
Lewy body diseases most of the pathology is present in nerve cells.
SYNTHETIC F-SYNUCLEIN FILAMENTS

Recombinant F-synuclein assembles into filaments that share many of the morphological and
ultrastructural characteristics of filaments present in humans (Fig. 6) (8789). Assembly is a nucle-
ation-dependent process and occurs through the repeats in the amino-terminal half (90,91). The
carboxy-terminal region, in contrast, inhibits assembly (87,92,93). It has been reported that the struc-
tural transformation involves a partially folded intermediate (94). The A53T mutation increases the
rate of filament assembly, indicating that this might be its primary effect (88,89,92,95). The effect of
the A30P mutation on the assembly of F-synuclein is less clear. One study reported an increase in
filament assembly (95), another study found no change (92), and a third found an inhibitory effect on
assembly (96). The third study showed that the A30P monomer was consumed at a similar rate to
wild-type F-synuclein, leading to the suggestion that oligomeric, nonfibrillar F-synuclein species
might be detrimental to nerve cells. The A30P mutation has also been shown to produce reduced
binding of F-synuclein to rat brain vesicles in vitro (16,97), indicating that this might lead to its
accumulation over time, resulting in filament assembly. Consistent with this, it has been shown that
the F-helical conformation that is induced and stabilized by the interaction between F-synuclein and
acidic phospholipids prevents its assembly into filaments (98). Thus, lipid binding and self-assembly
of F-synuclein appear to be mutually exclusive.
The assembly of F-synuclein is accompanied by the transition from random coil to a G-pleated
sheet (92,99). By electron diffraction, F-synuclein filaments have been found to show a conforma-
tion characteristic of amyloid fibers. Under the conditions of these experiments, G- and L-synuclein
failed to assemble into filaments, and remained in a random coil conformation (92,100). This behav-
ior is consistent with their absence from the filamentous lesions of the F-synuclein diseases. When
incubated together with F-synuclein, G- and L-synuclein markedly inhibit the fibrillation of F-synuclein,
suggesting that they could indirectly influence the pathogenesis of Lewy body diseases and MSA
(101103).
The sequence requirements for the assembly of F-synuclein are only incompletely understood.
One difference between F- and G-synuclein is the presence of a stretch of 11 amino acids (residues
7383) in F-synuclein that is missing from G-synuclein. It has been suggested that this sequence is both
necessary and sufficient for the assembly of F-synuclein and that its absence explains why G-synuclein
does not form filaments (101,104). A similar sequence is present in L-synuclein, but it differs at four
positions from residues 7383 of F-synuclein. Other studies have suggested that residues 7184
(105), 6876 (106), or 6674 (107) of F-synuclein are essential for its ability to form filaments.
Many studies have identified factors that influence the rate and/or extent of F-synuclein assembly
in vitro. Methionine-oxidized and nitrated F-synucleins were found to be poor at assembling into
Fig. 6. Filaments extracted from the brains of patients with dementia with Lewy bodies (DLB) and multiple
system atrophy (MSA) or assembled from bacterially expressed human F-synuclein (SYN) were decorated by
an anti-F-synuclein antibody. The gold particles conjugated to the second antibody appear as black dots. Scale
bar, 100 nm.
filaments compared with the unmodified proteins (108,109). For the nitrated protein, stable oligo-
meric intermediates formed that were reminiscent of protofibrils. A similar inhibition of the protofibril
to fibril conversion of F-synuclein has been reported for a number of catecholamines, including
oxidized dopamine (110). This has led to the suggestion that nonvesicular, cytoplasmic dopamine
may be harmful by sustaining the accumulation of potentially toxic protofibrils. Factors that have
been reported to accelerate the fibrillation of F-synuclein include cytochrome C (111), some pesti-
cides (112), several di- and trivalent metal ions (113), sulphated glycosaminoglycans (114),
polyamines (115), and oxidized glutathione (116).
The aforementioned substances were used largely because they had previously been implicated in
the pathogenesis of PD. These findings in vitro are consistent with many of these hypotheses. How-
ever, the true relevance of these factors for the transition from soluble to filamentous F-synuclein in
nerve cells in the brain remains to be established.
ANIMAL MODELS
Transgenic Mice
Experimental animal models of F-synucleinopathies are being produced by a number of laborato-
ries (Table 2). They are essential for studying disease pathogenesis and for identifying ways to inter-
fere with the disease process. Several transgenic mouse lines that express wild-type or mutant human
Table 2
Animal Models of F-Synucleinopathies
Toxin Model Genetic Models
Rotenone Worm Fly Mouse Rat Marmoset
Dopaminergic + + + + +
Nerve cell loss
Filamentous + + + u u
F-Synuclein inclusions
Motor deficits + + + u u
Complex I + u u u u u
Inhibition
The rotenone model is in the rat. The genetic models in worm, fly, and mouse are based on the transgenic
expression of human F-synuclein (wild-type and mutant), whereas the rat and marmoset models are based
on viral vector-mediated transfer of human F-synuclein (wild-type and mutant). u = unknown.
F-synuclein in nerve cells have been described. One study has reported on the effects of F-synuclein
overexpression in glial cells. In all published studies, mice developed numerous F-synuclein-immu-
noreactive cell bodies and processes.
The first study to be published described the expression of wild-type human F-synuclein driven by
the human platelet-derived growth factor-G promoter (117). The mice developed cytoplasmic and
nuclear intraneuronal inclusions in neocortex, hippocampus, olfactory bulb, and substantia nigra.
These inclusions were F-synuclein-immunoreactive, with some being ubiquitin-positive as well. By
electron microscopy, they consisted of amorphous, nonfilamentous material. The mice showed a
reduction in dopaminergic nerve terminals in the striatum and signs of impaired motor function, but
they failed to exhibit nerve cell loss in the substantia nigra. Two studies have reported the expression
of wild-type and A53T or A30P mutant human F-synuclein driven by the murine Thy-1 promoter. In
one study (118), mice expressing wild-type or A53T mutant F-synuclein developed an early-onset
motor impairment that was associated with axonal degeneration in the ventral roots and signs of
muscle atrophy. Some F-synuclein inclusions were argyrophilic and ubiquitin-immunoreactive, but
they lacked the filaments characteristic of the human diseases. In the second study (119,120), mice
expressing A30P mutant F-synuclein developed a neurodegenerative phenotype consisting of the
accumulation of protease-resistant human F-synuclein phosphorylated at S129. Occasional inclu-
sions were also ubiquitin-positive. By electron microscopy, filamentous structures were observed,
although they were not shown to be made of F-synuclein. The transgenic mice showed a progressive
deterioration of motor function. It remains to be seen whether the accumulation of mutant F-synuclein
was accompanied by nerve cell loss.
Three studies have described the expression of wild-type and A53T or A30P mutant human
F-synuclein under the control of the murine prion protein promoter (121123). A severe movement
disorder was observed that was accompanied by the accumulation of F-synuclein in nerve cells and
their processes. One study documented the presence of abundant F-synuclein filaments in brain and
spinal cord of mice transgenic for A53T F-synuclein (121). The formation of filamentous inclusions
closely correlated with the appearance of clinical symptoms, suggesting a possible cause-and-effect
relationship. A minority of inclusions was ubiquitin-immunoreactive. Signs of Wallerian degenera-
tion were much in evidence in ventral roots, but nerve cell numbers in the ventral horn of the spinal
cord were unchanged. A major difference with PD was the absence of significant pathology in dopam-
inergic nerve cells of the substantia nigra. In mice, these neurons appear to be relatively resistant to
the effects of F-synuclein expression. This is further supported by reports showing that the expres-
sion of wild-type and mutant human F-synuclein under the control of the tyrosine hydroxylase pro-
moter did not lead to the formation of inclusions or neurodegeneration (124,125).
Mouse lines transgenic for wild-type human F-synuclein under the control of a proteolipid protein
promoter were generated to give high levels of expression in oligodendroglia (126). Expression of
human F-synuclein phosphorylated at S129 was obtained, but there was no sign of argyrophilic glial
cytoplasmic inclusions or abnormal filaments. Behavioral changes were also not observed.
Transgenic Flies and Worms

One of the first reports describing the overexpression of F-synuclein made use of Drosophila
melanogaster, an organism without synucleins (127). Expression of wild-type and A30P or A53T
mutant human F-synuclein in nerve cells of D. melanogaster resulted in the formation of filamentous
Lewy bodylike inclusions and an age-dependent loss of some dopaminergic nerve cells (Table 2).
The inclusions were F-synuclein- and ubiquitin-immunoreactive. An age-dependent locomotor de-
fect was observed that could be reversed by the administration of L-DOPA or several dopamine
agonists, underscoring the validity of this model for PD (128). Overexpression of wild-type and
A53T mutant human F-synuclein in nerve cells of Caenorhabditis elegans resulted in a loss of dopam-
inergic nerve cells and motor deficits, in the apparent absence of filamentous F-synuclein inclusions
(Table 2) (129).
Disease models in D. melanogaster and C. elegans offer some advantages over mouse models, in
particular with regard to the speed and relative ease with which genetic modifiers of disease pheno-
type can be discovered and pharmacological modifiers can be screened. Coexpression of human heat-
shock protein 70 alleviated the toxicity of F-synuclein in transgenic flies (130). Conversely, a
reduction in the fly chaperone system exacerbated nerve cell loss. Increasing chaperone activity
through the administration of geldanamycin delayed neurodegeneration in transgenic flies (131). It
thus appears that chaperones can modulate the neurotoxicity resulting from the overexpression of
human F-synuclein.
Viral Vector-Mediated Gene Transfer

Viral vector-mediated gene transfer differs from standard transgenic approaches by being tar-
geted to a defined region of the central nervous system and by being inducible at any point during
the life of the animal. Recombinant adeno-associated virus and recombinant lentivirus vector sys-
tems have been used to express wild-type and mutant F-synuclein in the substantia nigra of rat and
marmoset (Table 2).
In the rat, expression of F-synuclein was maximal 23 wk after virus injection (132134). At 810 wk,
numerous swollen, dystrophic axons and dendrites were observed in conjunction with F-synuclein inclu-
sions. Nerve cell bodies contained Lewy bodylike inclusions and substantial nerve cell loss (30
80%) was present in the substantia nigra. The inclusions were F-synuclein-positive and
ubiquitin-negative, but it remains to be determined whether they were also filamentous. Behavior-
ally, about a quarter of animals were impaired in spontaneous and drug-induced motor behaviors.
Similar findings were reported for wild-type and A30P or A53T mutant human F-synuclein. One
study has reported that degeneration of transduced nigral cells was seen upon expression of human,
but not rat, F-synuclein (134). In the marmoset, dopaminergic nerve cells of the substantia nigra
were transduced with high efficiency and human F-synuclein was expressed (135). Similar to the
rat, F-synuclein-positive inclusions were observed, together with a loss of 4075% of tyrosine
hydroxylase-positive neurons. Overexpression of disease-causing gene products by using recom-
binant viral vectors constitutes a promising way forward for modeling human neurodegenerative
diseases in a number of species, including primates.
Rotenone Neurotoxicity
A model of F-synuclein pathology has been developed in the rat by using the chronic administra-
tion of the pesticide rotenone, a high-affinity inhibitor of complex I, one of the five enzyme com-
plexes of the inner mitochondrial membrane involved in oxidative phosphorylation (136,137). The
rats developed a progressive degeneration of nigrostriatal neurons and Lewy body-like inclusions
that were immunoreactive for F-synuclein and ubiquitin (Table 2). Behaviorally, they showed
bradykinesia, postural instability, and some evidence of resting tremor. Using this regime of rotenone
administration, the inhibition of complex I was only partial, indicating that a bioenergetic defect with
ATP (adenosine 5'-triphosphate) depletion was probably not involved. Instead, oxidative damage
might have contributed to this condition, as partial inhibition of complex I by rotenone is known to
stimulate the production of reactive oxygen species. It would therefore seem that oxidative stress can
lead to the assembly of F-synuclein into filaments. Although it remains to be seen how robust a
model rotenone administration is, it appears clear that it can lead to the degeneration of nigrostriatal
dopaminergic nerve cells in association with F-synuclein-positive inclusions. This has so far not
been achieved following the administration of either 6-hydroxydopamine or MPTP, the two most
widely used toxin models of PD. It has been reported that the systemic administration of rotenone
leads to the specific degeneration of dopaminergic nerve cells in the substantia nigra. However, a
subsequent study has described additional nerve cell loss in the striatum (138), raising the question of
how valid a model rotenone intoxication is for PD.
CONCLUSION
The relevance of F-synuclein for the neurodegenerative process in Lewy body diseases and MSA
is now well established. The development of experimental models of F-synucleinopathies has opened
the way to the identification of the detailed mechanisms by which the formation of inclusions causes
disease. These model systems have also made it possible to identify disease modifiers (enhancers and
suppressors) that may well lead to the development of the first mechanism-based therapies for these
diseases. At a conceptual level, it will be important to understand whether F-synuclein has a role to
play in disorders, such as the autosomal-recessive juvenile forms of parkinsonism caused by muta-
tions in the parkin and DJ-1 genes, or whether there are entirely separate mechanisms by which the
dopaminergic nerve cells of the substantia nigra degenerate in PD and in inherited disorders with
parkinsonism.
BOX 1: MAJOR RESEARCH ISSUES

The new work has established that a neurodegenerative pathway leading from soluble to
insoluble, filamentous F-synuclein is central to Lewy body diseases and multiple system atro-
phy. The study of familial forms of diseases with filamentous F-synuclein inclusions has re-
vealed that missense mutations in the F-synuclein gene or overexpression of wild-type protein
are sufficient to cause neurodegeneration. It appears likely that these genetic defects induce the
assembly of F-synuclein into filaments. What causes assembly of F-synuclein in the much
more common cases of sporadic disease remains to be discovered. In normal brain, the bio-
physically driven propensity of F-synuclein to undergo ordered self-assembly is probably coun-
terbalanced by a number of factors, including the ability of cells to dispose of the protein prior
to assembly. Other factors may include the binding of F-synuclein to lipid membranes and its
interactions with G- and L-synucleins. Identification of the detailed mechanisms at work con-
stitutes an important area for future research. In particular, we need to know more about the
factors that regulate the production of F-synuclein and the mechanisms that ensure its degrada-
tion. We need to understand what the toxic F-synuclein species are and how they exert their
effects. It appears probable that all familial forms of Lewy body disease are caused by genetic
defects that act at the level of the neurodegenerative F-synuclein pathway. It remains to be seen
whether they are mechanistically linked to familial forms of parkinsonism that lead to nerve
cell loss in the substantia nigra, without formation of Lewy body pathology. The availability of
ever better animal models of the F-synucleinopathies opens the way to the identification of
genetic and pharmacological modifiers (enhancers and suppressors) of the disease process.
This will be essential for a better understanding of the pathogenesis of Lewy body diseases and
multiple system atrophy and for the discovery of novel therapeutic avenues.
REFERENCES
1. Jellinger KA, Mizuno Y. Parkinsons disease. In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of
Dementia and Movement Disorders. Basel: ISN Neuropath Press, 2003: 159187.
2. Ince PG, McKeith IG. Dementia with Lewy bodies. In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of
Dementia and Movement Disorders. Basel: ISN Neuropath Press, 2003:188199.
3. Lewy F. Paralysis agitans. In: Lewandowski M, Abelsdorff G, eds. Handbuch der Neurologie. Berlin: Springer Verlag,
1912: 920933.
4. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the F-synuclein gene identified in families with Parkinsons
disease. Science 1997;276:20452047.
5. Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M. F-Synuclein in Lewy bodies. Nature
1997;388:839840.
6. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. F-Synuclein immunoreactivity in glial cytoplasmic inclusions in
multiple system atrophy. Neurosci Lett 1998;249:180182.
7. Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system
atrophy brains contain insoluble F-synuclein. Ann Neurol 1998;44:415422.
8. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous F-synuclein inclusions link
multiple system atrophy with Parkinsons disease and dementia with Lewy bodies. Neurosci Lett 1998;251:205208.
9. Ueda K, Fukushima H, Masliah E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid
in Alzheimer disease. Proc Natl Acad Sci USA 1993;90:1128211286.
10. Jakes R, Spillantini MG, Goedert M. Identification of two distinct synucleins from human brain. FEBS Lett
1994;345:2732.
11. Ji H, Liu YE, Jia T, et al. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequenc-
ing. Cancer Res 1997;57:759764.
12. Clayton DF, George JM. Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res
1999;58:120129.
13. Li JY, Jensen PH, Dahlstrm A. Differential localization of F-, G- and L-synucleins in the rat CNS. Neuroscience
2002;113:463478.
14. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT. NACP, a protein implicated in Alzheimers disease and
learning, is natively unfolded. Biochemistry 1996;35:1370913715.
15. Davidson WS, Jonas A, Clayton DF, George, JM. Stabilization of F-synuclein secondary structure upon binding to
synthetic membranes. J Biol Chem 1998;273:94439449.
16. Jensen PH, Nielsen MH, Jakes R, Dotti CG, Goedert M. Binding of F-synuclein to rat brain vesicles is abolished by
familial Parkinsons disease mutation. J Biol Chem 1998;273:2629226294.
17. Chandra S, Cheng X, Rizo J, Jahn R, Sdhof TC. A broken F-helix in folded F-synuclein. J Biol Chem 2003;278:
1531315318.
18. Bussell R, Eliezer D. A structural and functional role for 11-mer repeats in F-synuclein and other exchangeable lipid
binding proteins. J Mol Biol 2003;329:763778.
19. Cole NB, Murphy DD, Grider T, Rueter S, Brasaemle D, Nussbaum RL. Lipid droplet binding and oligomerization
properties of the Parkinsons disease protein F-synuclein. J Biol Chem 2002;277:63446352.
20. Sharon R, Goldberg MS, Bar-Joseph I, Betensky RA, Shen J, Selkoe DJ. F-Synuclein occurs in lipid-rich high molecu-
lar weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc Natl Acad Sci
USA 2002;98:91109115.
21. Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of
F-synuclein is regulated by fatty acids and enhanced in Parkinsons disease. Neuron 2003;37:583595.
22. Jenco RM, Rawlingson A, Daniels B, Morris AJ. Regulation of phospholipase D2: selective inhibition of mammalian
phospholipase D isoenzymes by F- and G-synucleins. Biochemistry 1998;37:49014909.
23. Okochi M, Walter J, Koyama A, et al. Constitutive phosphorylation of the Parkinsons diseaseassociated F-synuclein.
J Biol Chem 2000;275:390397.
24. Fujiwara H, Hasegawa M, Dohmae N, et al. F-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell
Biol 2002;4:160164.
25. Pronin AN, Morris AJ, Surguchov A, Benovic JL. Synucleins are a novel class of substrates for G proteincoupled
receptor kinases. J Biol Chem 2000;275:2651526522.
26. Ahn BH, Rhim H, Kim SY, et al. F-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-
induced phospholipase D activation in human embryonic kidney-293 cells. J Biol Chem 2002;277:1233412342.
27. Nakamura T, Yamashita H, Takahashi T, Nakamura S. Activated Fyn phosphorylates F-synuclein at tyrosine residue
125. Biochem Biophys Res Commun 2001;280:10851092.
28. Ellis CE, Schwartzberg PL, Grider TL, Fink DW, Nussbaum RL. F-Synuclein is phosphorylated by members of the Src
family of protein tyrosine kinases. J Biol Chem 2001;276:38793884.
29. Nakamura T, Yamshita H, Nagano Y, et al. Activation of Pyk2/RAFTK induces tyrosine phosphorylation of F-synuclein
via Src-family kinases. FEBS Lett 2002;521:190194.
30. Tofaris GK, Layfield R, Spillantini MG. F-Synuclein metabolism and aggregation is linked to ubiquitin-independent
degradation by the proteasome. FEBS Lett 2001;509:2226.
31. Abeliovich A, Schmitz Y, Farinas I, et al. Mice lacking F-synuclein display functional deficits in the nigrostriatal
dopamine system. Neuron 2000;25:239252.
32. Cabin DE, Shimazu K, Murphy D, et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to
prolonged repetitive stimulation in mice lacking F-synuclein. J Neurosci 2002;22:87978807.
33. Specht CG, Schoepfer R. Deletion of the F-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci
2001;2:11.
34. Ninkina N, Papachroni K, Robertson DC, et al. Neurons expressing the highest levels of L-synuclein are unaffected by
targeted inactivation of the gene. Mol Cell Biol 2003;23:82338245.
35. Dauer W, Kholodilov N, Vila M, et al. Resistance of F-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc
Natl Acad Sci USA 2002;99:1425414259.
36. Schlter OM, Fornai F, Alessandri MG, et al. Role of F-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-
induced parkinsonism in mice. Neuroscience 2003;118:9851002.
37. Golbe LI, Di Iorio G, Sanges G, et al. Clinical genetic analysis of Parkinsons disease in the Contursi kindred. Ann
Neurol 1990;27:276282.
38. Polymeropoulos MH, Higgins JJ, Golbe LI, et al. Mapping of a gene for Parkinsons disease to chromosome 4q21-q23.
Science 1996;274:11971199.
39. Krger T, Kuhn W, Mller T, et al. Ala30Pro mutation in the gene encoding F-synuclein in Parkinsons disease. Nature
Genet 1998;18:106108.
40. Muenter MD, Forno LS, Hornykiewicz O, et al. Hereditary form of Parkinsonism-dementia. Ann Neurol 1998;43:768781.
41. Singleton AB, Farrer M, Johnson J, et al. F-Synuclein locus triplication causes Parkinsons disease. Science
2003;302:841.
42. Krger R, Vieira-Saecker AMM, Kuhn W, et al. Increased susceptibility to sporadic Parkinsons disease by a certain
combined F-synuclein/apolipoprotein E genotype. Ann Neurol 1998;45:611617.
43. Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T. Polymorphism of NACP-Rep1 in Parkinsons
disease: an etiologic link with essential tremor? Neurology 2000;54:11951198.
44. Khan N, Graham E, Dixon P, et al. Parkinsons disease is not associated with the combined F-synuclein/apolipoprotein
E susceptibility genotype. Ann Neurol 2001;49:665668.
45. Farrer M, Maraganore DM, Lockhart P, et al. F-Synuclein gene haplotypes are associated with Parkinsons disease.
Hum Mol Genet 2001;10:18471851.
46. Chiba-Falek O, Nussbaum RL. Effect of allelic variation at the NACP-Rep1 repeat upstream of the F-synuclein gene
(SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 2001;10:31013109.
47. Arima K, Ueda K, Sunohara N, et al. Immunoelectron microscopic demonstration of NACP/F-synuclein epitopes on
the filamentous component of Lewy bodies in Parkinsons disease and in dementia with Lewy bodies. Brain Res
1998;808:93100.
48. Crowther RA, Daniel SE, Goedert M. Characterisation of isolated F-synuclein filaments from substantia nigra of
Parkinsons disease brain. Neurosci Lett 2000;292:128130.
49. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. F-Synuclein in filamentous inclusions of Lewy
bodies from Parkinsons disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 1998;95:64696473.
50. Baba M, Nakajo S, Tu PS, et al. Aggregation of F-synuclein in Lewy bodies of sporadic Parkinsons disease and
dementia with Lewy bodies. Am J Pathol 1998;152:879884.
51. Miake H, Mizusawa H, Iwatsubo T, Hasegawa M. Biochemical characterization of the core structure of F-synuclein
filaments. J Biol Chem 2002;277:1921319219.
52. Der-Sarkissian A, Jao CC, Chen J, Langen R. Structural organization of F-synuclein fibrils studied by site-directed spin
labeling. J Biol Chem 2003;278:3753037535.
53. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y. Lewy bodies are ubiquitinated: a light and electron micro-
scopic immunocytochemical study. Acta Neuropathol 1988;75:345353.
54. Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VMY. Ubiquitination of F-synuclein is not required for
formation of pathological inclusions in F-synucleinopathies. Am J Pathol 2003;163:91100.
55. Tofaris GK, Razzaq A, Ghetti B, Lilley K, Spillantini MG. Ubiquitination of F-synuclein in Lewy bodies is a patho-
logical event not associated with impairment of proteasome function. J Biol Chem 2003;278:4440544411.
56. Hasegawa M, Fujiwara H, Nonaka T, et al. Phosphorylated F-synuclein is ubiquitinated in F-synucleinopathy lesions.
J Biol Chem 2002;277:4907149076.
57. Giasson BI, Duda JE, Murray IV, et al. Oxidative damage linked to neurodegeneration by selective F-synuclein nitra-
tion in synucleinopathy lesions. Science 2000;290:985989.
58. Arai K, Kato N, Kashiwado K, Hattori T. Pure autonomic failure in association with human F-synucleinopathy. Neurosci
Lett 2000;296:171173.
59. Kaufmann H, Hague K, Perl D. Accumulation of alpha-synuclein in autonomic nerves in pure autonomic failure. Neu-
rology 2001;56: 980981.
60. Perry RH, Irving D, Tomlinson BE. Lewy body prevalence in the aging brain: relationship to neuropsychiatric disor-
ders, Alzheimer-type pathology and catecholaminergic nuclei. J Neurol Sci 1990;100:223233.
61. Saito Y, Kawashima A, Ruberu NN, et al. Accumulation of phosphorylated F-synuclein in aging human brain. J Neuropathol
Exp Neurol 2003;62:644654.
62. Del Tredici K, Rb U, De Vos RAI, Bohl JRE, Braak H. Where does Parkinson disease pathology begin in the brain?
J Neuropathol Exp Neurol 2002;61:413426.
63. Lippa CF, Fujiwara H, Mann DM, et al. Lewy bodies contain altered F-synuclein in brains of many familial Alzheimers
disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 1998;153:13651370.
64. Yamazaki M, Arai Y, Baba M, et al. F-Synuclein inclusions in amygdala in the brains of patients with the parkin-
sonism-dementia complex of Guam. J Neuropathol Exp Neurol 2000;59:585591.
65. Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA. Clinical and pathological features of a parkinsonian
syndrome in a family with an Ala53Thr F-synuclein mutation. Ann Neurol 2001;49:313319.
66. Duda JE, Giasson BI, Mahon ME, et al. Concurrence of F-synuclein and tau brain pathology in the Contursi kindred.
Acta Neuropathol 2002;104:711.
67. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. Colocalization of tau and alpha-synuclein epitopes in Lewy
bodies. J Neuropathol Exp Neurol 2003;62:389397.
68. Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science
2003;300:636640.
69. Gwinn-Hardy K, Mehta ND, Farrer M, et al. Distinctive neuropathology revealed by F-synuclein antibodies in heredi-
tary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 2000;99:663672.
70. Gasser T, Mller-Myhsok B, Wszolek ZK, et al. A susceptiibility locus for Parkinsons disease maps to chromosome
2p13. Nature Genet 1998;18:262265.
71. Wszolek ZK, Gwinn-Hardy K, Wszolek EK, et al. Neuropathology of two members of a German-American kindred
(Family C) with late onset parkinsonism. Acta Neuropathol 2002;103:344350.
72. Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinsons disease. Nature 1998;395:451452.
73. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.
Nature 1998;392:605608.
74. Shimura H, Hattori N, Kubo S, et al. Familial Parkinsons disease gene product, parkin, is a ubiquitin-protein ligase.
Nature Genet 2000;25:302305.
75. Choi P, Golts N, Snyder H, et al. Co-association of parkin and alpha-synuclein. Neuroreport 2001;12:28392843.
76. Schlossmacher MG, Frosch MP, Gai WP, et al. Parkin localizes to the Lewy bodies of Parkinson disease and dementia
with Lewy bodies. Am J Pathol 2002;160:16551667.
77. Shimura H, Schlossmacher MG, Hattori N, et al. Ubiquitination of a new form of alpha-synuclein by parkin from
human brain: implications for Parkinsons disease. Science 2001;293:263269.
78. Takahashi H, Ohama E, Suzuki S, et al. Familial juvenile parkinsonism: clinical and pathologic study in a family.
Neurology 1994;44:437441.
79. Mori H, Kondo T, Yokochi M, et al. Pathologic and biochemical studies of juvenile parkinsonism linked to chromo-
some 6q. Neurology 1998;51:890892.
80. Farrer M, Chan P, Chen R, et al. Lewy bodies and parkinsonism in families with parkin mutations. Neurology
2001;50:293300.
81. Pawlyk AC, Giasson BI, Sampathu DM, et al. Novel monoclonal antibodies demonstrate biochemical variation of brain
parkin with age. J Biol Chem 2003;278:48,12048,128.
82. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset
parkinsonism. Science 2003;299:256259.
83. Takao M, Ghetti B, Yoshida H, et al. Early-onset dementia with Lewy bodies. Brain Pathol 2004;14:137147.
84. Lantos PL, Quinn N. Multiple system atrophy. In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of
Dementia and Movement Disorders. Basel: ISN Neuropath Press, 2003: 203214.
85. Wenning GK, Quinn N, Magalhaes M, Mathias C, Daniel SE. Minimal change multiple system atrophy. Mov Disord
1994;9:161166.
86. Campbell BC, McLean CA, Culvenor JG, et al. The solubility of alpha-synuclein in multiple system atrophy differs
from that of dementia with Lewy bodies and Parkinsons disease. J Neurochem 2001;76:8796.
87. Crowther RA, Jakes R, Spillantini MG, Goedert M. Synthetic filaments assembled from C-terminally truncated F-
synuclein. FEBS Lett 1998;436:309312.
88. Conway KA, Harper DJ, Lansbury PT. Accelerated in vitro fibril formation by a mutant F-synuclein linked to early-
onset Parkinsons disease. Nature Med 1998;4:13181320.
89. El-Agnaf IMA, Jakes R, Curran MD, Wallace A. Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical
and morphological properties of F-synuclein implicated in Parkinsons disease. FEBS Lett 1998;440:6770.
90. Giasson BI, Uryu K, Trojanowski JQ, Lee VMY. Mutant and wild-type human F-synuclein assemble into elongated
filaments with distinct morphologies in vitro. J Biol Chem 1999;274:76197622.
91. Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL. F-Synuclein fibrillogenesis is nucleation-depen-
dent. J Biol Chem 1999;274:1950919512.
92. Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA. Fiber diffraction of synthetic alpha-synuclein filaments
shows amyloid-like cross-beta conformation. Proc Natl Acad Sci USA 2000;97:48974902.
93. Murray IVJ, Giasson BI, Quinn SM, et al. Role of F-synuclein carboxy-terminus on fibril formation in vitro. Biochem-
istry 2003;42:85308540.
94. Uversky VN, Li J, Fink AL. Evidence for a partially folded intermediate in F-synuclein fibril formation. J Biol Chem
2001;276:1073710744.
95. Narhi L, Wood SJ, Steavenson S, et al. Both familial Parkinsons disease mutations accelerate F-synuclein aggrega-
tion. J Biol Chem 1999;274:98439846.
96. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT. Acceleration of oligomerization, not
fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinsons disease: implica-
tions for pathogenesis and therapy. Proc Natl Acad Sci USA 2000;97:571576.
97. Jo E, Fuller N, Rand PR, St George-Hyslop P, Fraser PE. Defective membrane interactions of familial Parkinsons
disease mutant A30P F-synuclein. J Mol Biol 2002;315:799807.
98. Zhu M, Fink AL. Lipid binding inhibits F-synuclein filament formation. J Biol Chem 2003;278:1687316877.
99. Conway KA, Harper JD, Lansbury PT. Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to
Parkinsons disease are typical amyloid. Biochemistry 2000;39:25522563.
100. Biere AL, Wood SJ, Wypych J, et al. Parkinsons disease-associated F-synuclein is more fibrillogenic than G- and L-
synuclein and cannot cross-seed its homologs. J Biol Chem 2000;275:3457434579.
101. Hashimoto M, Rockenstein E, Mante, Mallory M, Masliah E. G-Synuclein inhibits F-synuclein aggregation: a possible
role as an antiparkinsonian factor. Neuron 2001;32:213223.
102. Uversky VN, Li J, Souillac P, et al. Biophysical properties of the synucleins and their propensities to fibrillate: inhibi-
tion of F-synuclein assembly by G- and L-synucleins. J Biol Chem 2002;277:1197011978.
103. Park JY, Lansbury PT. G-Synuclein inhibits formation of F-synuclein protofibrils: a possible therapeutic strategy against
Parkinsons disease. Biochemistry 2003;42:36963700.
104. Kahle PJ, Neumann M, Ozmen L, et al. Selective insolubility of F-synuclein in human Lewy body diseases is recapitu-
lated in a transgenic mouse model. Am J Pathol 2001;159:22152225.
105. Giasson BI, Murray IVJ, Trojanowski JQ, Lee VMY. A hydrophobic stretch of 12 amino acid residues in the middle of
F-synuclein is essential for filament assembly. J Biol Chem 2001;276:23802386.
106. Bodles AM, Guthrie DJS, Greer B, Irvine GB. Identification of the region of non-AG component (NAC) of Alzheimers
disease amyloid responsible for its aggregation and toxicity. J Neurochem 2001;78:384395.
107. Du HN, Tang L, Luo XY, et al. A peptide motif consisting of glycine, alanine, and valine is required for the fibrillation
and cytotoxicity of human F-synuclein. Biochemistry 2003;42:88708878.
108. Uversky VN, Yamin G, Souillac PO, Goers J, Glaser CB, Fink AL. Methionine oxidation inhibits fibrillation of human
F-synuclein in vitro. FEBS Lett 2002;517:239244.
109. Yamin G, Uversky VN, Fink AL. Nitration inhibits fibrillation of human F-synuclein in vitro by formation of soluble
oligomers. FEBS Lett 2003;542:147152.
110. Conway KA, Rochet JC, Bieganski RM, Lansbury PT. Kinetic stabilization of the F-synuclein protofibril by a dopam-
ine-F-synuclein adduct. Science 2001;294:13461349.
111. Hashimoto M, Takeda A, Hsu LJ, Takenouchi T, Masliah E. Role of cytochrome C as a stimulator of F-synuclein
aggregation in Lewy body disease. J Biol Chem 1999;274:2884928852.
112. Uversky VN, Li J, Fink AL. Pesticides directly accelerate the rate of F-synuclein fibril formation: a possible factor in
Parkinsons disease. FEBS Lett 2001;500:105108.
113. Uversky VN, Li J, Fink AL. Metal-triggered structural transformations, aggregation and fibril formation of human F-
synuclein. A possible molecular link between Parkinsons disease and heravy metal exposure. J Biol Chem
2001;276:4428444296.
114. Cohlberg JA, Li J, Uversky VN, Fink AL. Heparin and other glycosaminoglycans stimulate the formation of amyloid
fibrils from F-synuclein in vitro. J Biol Chem 2002;41:15021511.
115. Antony T, Hoyer W, Cherny D, Heim G, Jovin TM, Subramaniam V. Cellular polyamines promote the aggregation of
F-synuclein. J Biol Chem 2003;278:32353240.
116. Paik SR, Lee D, Cho HJ, Lee EN, Chang CS. Oxidized glutathione stimulated the amyloid formation of F-synuclein.
FEBS Lett 2003;537:6367.
117. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in F-synuclein mice:
implications for neurodegenerative disorders. Science 2000;287:12651269.
118. Van der Putten H, Wiederhold KH, Probst A, et al. Neuropathology in mice expressing human F-synuclein. J Neurosci
2000;20:60216029.
119. Kahle PJ, Neumann N, Ozmen L, et al. Subcellular localization of wild-type and Parkinsons diseaseassociated mutant
F-synuclein in human and transgenic mouse brain. J Neurosci 2000;20:63656373.
120. Neumann M, Kahle PJ, Giasson BI, et al. Misfolded proteinase Kresistant hyperphosphorylated F-synuclein in aged
transgenic mice with locomotor deterioration and in human F-synucleinopathies. J Clin Invest 2002;110:14291439.
121. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VMY. Neuronal F-synucleinopathy with severe
movement disorder in mice expressing A53T human F-synuclein. Neuron 2002;34:521533.
122. Lee MK, Stirling W, Xu Yet al. Human F-synuclein-harboring familial Parkinsons diseaselinked Ala53 to Thr muta-
tion causes neurodegenerative disease with F-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA
2002;99:89688973
123. Gomez-Isla T, Irizarry MC, Mariash A, et al. Motor dysfunction and gliosis with preserved dopaminergic markers in
human F-synuclein A30P transgenic mice. Neurobiol Aging 2003;24:245258.
124. Matsuoka Y, Vila M, Lincoln S, et al. Lack of nigral pathology in transgenic mice expressing human F-synuclein
driven by the tyrosine hydroxylase promoter. Neurobiol Dis 2001;8:535539.
125. Richfield EK, Thiruchelvam MJ, Cory-Schlechta DA, et al. Behavioral and neurochemical effects of wild-type and
mutated human F-synuclein in transgenic mice. Exp Neurol 2002;175:3548.
126. Kahle PJ, Neumann M, Ozmen L, et al. Hyperphosphorylation and insolubility of F-synuclein in transgenic mouse
oligodendrocytes. EMBO Rep 2002;3:583588.
127. Feany MB, Bender WW. A Drosophila model of Parkinsons disease. Nature 2000;404:394398.
128. Pendleton RG, Parvez F, Sayed M, Hillman R. Effects of pharmacological agents upon a transgenic model of
Parkinsons disease in Drosophila melanogaster. J Pharmacol Exp Ther 2002;300:9196.
129. Lakso M, Vartiainen S, Moilanen AM, et al. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans
overexpressing human F-synuclein. J Neurochem 2003;86:165172.
130. Auluck PK, Chan E, Trojanowski JQ, Lee VMY, Bonini NM. Chaperone suppression of F-synuclein toxicity in a
Drosophila model for Parkinsons disease. Science 2002;295:865868.
131. Auluck PK, Bonini NM. Pharmacologic prevention of Parkinsons disease in Drosophila. Nature Med 2002;8:11851186.
132. Klein RL, King MA, Hamby ME, Meyer EM. Dopaminergic cell loss induced by human A30P F-synuclein gene trans-
fer to the rat substantia nigra. Hum Gene Ther 2002;13:605612.
133. Kirik D, Rosenblad C, Burger C, et al. Parkinson-like neurodegeneration induced by targeted overexpression of F-synuclein
in the nigrostriatal system. J Neurosci 2002;22:27802791.
134. Lo Bianco C, Ridet JL, Schneider BL, Dglon N, Aebischer P. F-Synucleinopathy and selective dopaminergic neuron
loss in a rat lentiviral-based model of Parkinsons disease. Proc Natl Acad Sci USA 2002;99:1081310818.
135. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjrklund A. Nigrostriatal F-synucleinopathy induced by
viral vectormediated overexpression of human F-synuclein: a new primate model of Parkinsons disease. Proc Natl
Acad Sci USA 2003;100:28842889.
136. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide expo-
sure reproduces features of Parkinsons disease. Nature Neurosci 2000;3:13011306.
137. Sherer TB, Kim JH, Betarbet R, Greenamyre JT. Subcutaneous rotenone exposure causes highly selective dopaminer-
gic degeneration and F-synuclein aggregation. Exp Neurol 2003;179:916.
138. Hglinger GU, Fger J, Prigent A, et al. Chronic systemic complex I inhibition induces a hypokinetic multisystem
degeneration in rats. J Neurochem 2003;84:491502.
Computer Models of Atypical Parkinsonism 95
7
Computer Modeling in Basal Ganglia Disorders
Jos Luis Contreras-Vidal
1. INTRODUCTION
The last two decades have witnessed an increasing interest in the use of computational modeling
and mathematical analysis as tools to unravel the complex neural mechanisms and computational
algorithms underlying the function of the basal ganglia and related structures under normal and neu-
rological conditions (13). Computational modeling of basal ganglia disorders has until recently
been focused on Parkinsons disease (PD), and to a smaller scale, Huntingtons disease (HD) (46).
However, with the advent of large-scale neural network models of frontal, parietal, basal ganglia, and
cerebellar network dynamics (79), it is now possible to use these models as a window to study
neurological disorders that involve more distributed pathology such as in atypical parkinsonian dis-
orders (APDs). Importantly, computational models may also be used for bridging data across scales
to reduce the gap between electrophysiology and human brain imaging (10), to integrate data in all
areas of neurobiology and across modalities (11), and to guide the design of novel experiments and
intervention programs (e.g., optimization of pharmacotherapy in PD) (12).
This chapter aims to present the paradigm of computational modeling as applied to the study of
PD and APDs so that it can be understood for those approaching it for the first time. Therefore,
mathematical details are kept to a minimum; however, references to detailed mathematical treat-
ments are given. The brain, in its intact state, is a very complex dynamical system both structurally
and functionally, and many questions remain unanswered. However, theoretical and computational
neuroscience approaches may prove to be a very valuable tool for the neuroscientist and the neurolo-
gist in understanding how the brain works in health and disease.
The Modeling Paradigm

Computational models of brain and neurological disorders vary widely in the focus and scale of
the modeling, their degrees of simulated biological realism, and the mathematical approach used
(13). A combination of top-down and bottom-up approaches to computational modeling in neu-
roscience is depicted in Fig. 1, which shows the series of steps that need to be taken to study brain
disorders computationally. One first has to measure the behavioral operating characteristics (BOCs),
such as movement kinematics, average firing rates of homogenous cell populations, or neurotrans-
mitter levels under intact conditions. The next step is to construct a mathematical model based on the
behavioral, anatomical, neurophysiological, and pharmacological data concerned with the produc-
tion of the BOCs. The specified model should be capable of reproducing the measured behavior. The
modeled output is compared with the initial BOCs, leading to model refinement and further computer
simulations until a reasonable match between the measured and the modeled BOC can be achieved.

95
96 Contreras-Vidal
Fig. 1. The paradigm of neural network modeling.
Although models are usually developed to demonstrate the biological plausibility of a particular
preexisting hypothesis, or to show how computational algorithms may be implemented in neural
networks, the same models can be used to generate and test new ideas by analyzing the emergent
properties of the modelmodel properties that cannot be explained by the operation or the wiring of
individual model components alone. Moreover, by lesioning the intact structural components of the
model, manipulating its dynamic mechanisms, or altering its inputs, it is possible to characterize the
neuropathology of the disease and the associated changes in the behavior. It is then also possible to
test the effect of surgical or pharmacological interventions to counteract the effects of lesions or
disease (2,12). Thus, computational modeling of neurological disorders involves a succession of
modeling cycles to first account for neural mechanisms underlying the normative data, followed by
the characterization and simulation of diseased mechanisms and abnormal behavior.
Modeling PD and APDs

Although a comprehensive review of the literature on modeling of basal ganglia function in health
and disease is not possible because of space limitations, the reader is referred to the reviews of Beiser
et al. (1), Ruppin et al. (2), and Gillies and Arbuthnott (3) for a detailed account. These efforts have
focused on explaining the roles of the basal ganglia in procedural learning (1417), action selection
(1820), serial order (2123), and movement planning and control (2427). Unfortunately, although
these models have provided insights on the abnormal mechanisms underlying PD, few efforts have
been put forward on modeling APDs. Thus, one goal of this chapter is to describe how existing
models of cortical, basal ganglia, and cerebellar dynamics can be used to model and simulate APDs.
In the next section, we briefly review the neuropathology in APDs. The reader is referred to Chapters 1,
4, 8, and 1820 of this book for detailed reviews and discussion of the underlying neuropathology.
Neuropathology of the APDs

It is widely recognized that the differential diagnosis of APDs presents some difficult problems.
First, clinical diagnostic criteria are often suboptimal or partially validated (28); and second, the
usefulness of routine brain-imaging techniques, such as magnetic resonance imaging (MRI), is still
debatable because of issues such as specificity, sensitivity, variations in technical parameters, and the
experience of radiologists and neurologists (29). Nevertheless, modern MRI methodologies are use-
ful to differentiate PD from APDs, as brain MRI in PD is grossly normal. Moreover, MRI studies
suggest specific regional brain markers associated with the underlying pathology in APDs, such as
multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degenera-
tion (CBD). Importantly, as these data can be used as a starting point for modeling purposes (Fig. 1),
we briefly summarize the MRI findings.
Multiple system atrophy of the parkinsonian type (MSA-P) appears to be characterized by
putaminal atrophy, T2-hypointensity, and slit-like marginal hyperintensity (2932), whereas MSA
of the cerebellar type (MSA-C) usually is accompanied by atrophy of the lower brainstem, pons,
middle cerebellar peduncles, and vermis, as well as signal abnormalities in the pontine and the middle
cerebellar peduncles (30,31,33,34). Mild-to-moderate cortical atrophy is also common to both MSA-
P and MSA-C (29,35).
PSP is usually characterized by widespread cell loss and gliosis in the globus pallidus, subtha-
lamic nucleus, red nucleus, substantia nigra, dentate nucleus, and brainstem, and often cortical atro-
phy and lateral ventricle dilatation (29). These patients also show decreased 18F-flurodopa in both
anterior and posterior putamen and caudate nucleus, and an anteriorposterior hypometabolic gradi-
ent (36). On the other hand, CBD may be differentiated by the presence of asymmetric frontoparietal
and midbrain atrophy (29).
Interestingly, cortical atrophy in APDs, particularly in cases involving damage of frontoparietal
networks, is consistent with reports of ideomotor apraxia, which can also be seen in PD patients when
their pathology is coincident with cortical atrophy (3639). In particular, patients with PD and PSP,
who showed ideomotor apraxia, had the greatest deficits in movement accuracy, spatial and temporal
coupling, and multijoint coordination (38). However, as has been noted elsewhere, it remains to be
seen if the kinematic deficits observed in this patients are characteristic of apraxia or are caused by
elementary motor deficits (40). Given the pathological heterogeneity seen in patients with APDs, and
even in PD, it seems that computer modeling would be a useful tool to study how damage to fronto-
parietal networks and their interaction with a dysfunctional basal ganglia and/or cerebellar systems
may increase the kinematic abnormalities beyond some threshold that would result in the genesis of
limb apraxia.
MODELING STUDIES
In this section we present two examples of computational models of basal ganglia disorders. The
first example presents a model formulated as a control problem to investigate akinesia and bradyki-
nesia in PD, whereas the second example, formulated as a large-scale, dynamic neural network model
involving frontoparietal, basal ganglia, and cerebellar networks, investigates the effects of PD and
PSP on limb apraxia.
Modeling Hypokinetic Disorders in PD

Contreras-Vidal and Stelmach proposed a neural network model of the sensorimotor cortico-
striato-pallido-thalamo-cortical system to explain some movement deficits (the BOCs in the mod-
eling cycle) seen in PD patients (24). This model, originally specified as a set of nonlinear differential
equations, proposed the concept of basal ganglia gating of thalamo-cortical pathways involved in
movement preparation (or priming), movement initiation and execution, and movement termination
(Fig. 2A). In this model, three routes for cortical control of the basal ganglia output exist: activation
of the direct pathway opens the gate by disinhibition of the thalamic neurons (route 1), whereas
activation of both a slower indirect (through GPe, route 2) pathway and a faster direct cortical (route 3)
pathway closes the gate through inhibition of thalamo-cortical neurons.
98 Contreras-Vidal
Fig. 2. (A) Three pathways for control of pallidal output by cortical areas. B) Block diagram of the cortico-
basal ganglia-thalamo-cortical network of Contreras-Vidal and Stelmach (24). The basal ganglia output (GPi)
gates activity at the ventro-lateral thalamus (VLo), thus modulating cortico-cortical communication in the vec-
tor integration model that progressively moves the endeffector (PPV) to the target location (TPV). The basal
ganglia gating allows priming and controls the speed of change from limb present position (PPV) to target
position (TPV). Filled circles imply inhibitory connections, whereas arrows imply excitatory connections.
In this theoretical framework, activation of pathway 1 would result in activation of thalamo-corti-

cal motor circuits leading to initiation and modulation of movement, whereas activation of pathway 2
would lead to breaking of ongoing movement. Activation of pathway 3 would facilitate rapid move-
ment switching, or prevent the release of movement. The model postulated a role of the pallidal
output for generating an analog gating signal (at the thalamus) that modulated a (hypothesized) cor-
tical system that vectorially computed the difference between a target position vector and the present
limb position vector, the so-called Vector-Integration-To-Endpoint (VITE) model (Fig. 2B) (41).
In this computational model, the basal ganglia output had the role of gating the onset, timing, and
the rate of change of the difference vector (DV), therefore controlling movement parameters such
as movement initiation, speed, and size. Moreover, the proposed basal ganglia gating function
allows three control modes: preparation for action or priming (gate is closed), initiation of action
(gate starts to open), and termination of action (gate starts to close). Simulations of this model dem-
onstrated a single mechanism for akinesia, bradykinesia, and hypometria, and a correlation between
degree of striatal dopamine depletion and the severity of the PD signs.
In the terminology of control theory, it can been shown that the sensorimotor cortico-basal ganglia
network of Contreras-Vidal and Stelmach (24) can be approximated as a proportional + derivative
controller (Equation 1) with time-varying position (Gp; Equation 2) and velocity (Gv; Equation 3)
gains. The system described by the second-order differential equation (1) represents the motion of
the endpoint (P) toward the target (T) under the initial position and velocity conditions P = P0 and
dP0/dt = 0, respectively.
2
d
P = Gv d P G p P T
2
(1)
dt dt
G p = FG 0 t
(2)
1+t
Gv = 1 + t 2 F (3)
1+t
where F represents an integration rate and G0 is a scaling constant and t is the time in sec. The
system given by Equations 13 is based on the experimentally testable assumption that pallidal sig-
nals modulate the ventro-lateral thalamus (VLo) such that the pattern of thalamic output has a sigmoi-
dal shape or is gradually increasing as a function of time as in Equation 4. This assumption implies
that either a compact set of pallidal neurons progressively decrease their firing rate as a function of
time before movement onset, therefore gradually disinhibiting the motor thalamus, or an increasing
number of (inhibitory) pallidal cells, controlling the prime movers, are depressed as the movement
unfolds.
VL o = G 0 t (4)
1+t
Figure 3 shows the mean cumulative distributions of onsets (decreases and increases) for GPi neu-
rons prior to movement onset obtained from a set of neurophysiological studies published between
1978 and 1998 (Table 1) in which information about the timing of internal globus pallidus (GPi)
neurons was available. The plot shows a gradual buildup or decrease of the mean cumulative distribu-
tion of neurons whose activations were either enhanced or depressed prior to movement onset. Overall,
increases in GPi activity were predominant (48% and 26% for increases and decreases, respectively). It
is likely that the small percentage of GPi depressions prior to movement onset reflects the focused
activation of prime mover muscles required to produce an arm movement. Interestingly, the mean
cumulative distribution shows an increasing number of GPi neurons that are depressed, which supports
the foregoing models assumption.
Computer simulations of the set of equations (14) show that smaller-than-normal position and
velocity gains can lead to bradykinesia (Fig. 4). Therefore, it is hypothesized that a function of basal
ganglia networks is to compute these time-varying position and velocity gains. Low gains would
prevent appropriate opening of the pallidal gate leading to poor activation of thalamo-cortical path-
ways involved in movement, whereas high gains may lead to excess or unstable movement. Interest-
ingly, Suri and colleagues also used a dynamical linear model to model basal ganglia function and
their simulations suggested that low gains in the direct and indirect pathways resulted in PD motor
deficits (26).
In addition, reduced movement amplitudes may be caused by premature resetting of these gains
that prevent movement completion. Indeed, we have shown that smaller-than-normal (in duration
and size) pallido-thalamic signals produced by dopamine depletion in the basal ganglia can repro-
duce micrographic handwriting (12).
Modeling Abnormal Kinematics During Pointing Movement and Errors in Praxis

in PD and APDs
To study the kinematic aspects of movement in basal ganglia disorders, we have performed com-
puter simulations of the finger-to-nose task and a bread-slicing gestural task; the latter task is used
commonly in testing for ideomotor apraxia (38). These two tasks require the integration and transfor-
mation of sensory information into motor commands for movement, and therefore successful task
completion depends on accurate spatial and temporal organization of movement.
100 Contreras-Vidal
Fig. 3. Mean cumulative (SE) distributions of activations and depressions of GPi activity obtained from set
of studies in Table 1.
Table 1
Cumulative Distribution of Onsets for GPi Cells
Initial Timing of Discharge (%) Prior to:
150 ms 100 ms 50 ms 0 ms EMG cells
Ref Location #
42a C (m. N) 7 0 27 0 40 7 53 13 20 0 15
43b NAc 2 2 7 7 35
44d DL EP 22 14 45 29 48 31 53 34 37 24 114
45 NA 38 26 11 14 36
46e VL 10f 4 29 12 2 1 41
47g VL (m. 2) 19 3 81 14 84 15 37 7 68
48h DL EP 57 16 57 16 63 18 66 19 NA NA 28
49i DL/VL 17 17 25 53 62 91 NA NA 18
Mean % 10.8 3.8 21.9 8.6 32.4 15.6 48.1 26.3 14.3 6.63
Total 355
, increase;, decrease; C, centered; DL, dorsolateral; EMG, onset of first muscle activity in prime
movers; EP, entopenduncular nucleus (GPi-like structure in felines); GPi, internal globus pallidus; m., mon-
key; NA, data not available; VL, ventrolateral. All times with respect to movement onset, except EMG data.
Notes: a biphasic stimulation trains (from Fig. 8), b EMG recordings were made at separate times from the
single-cell recordings; c recording was done from full extent of GP and percentages of discharges were
divided equally in increases and decreases; d estimated from Fig. 9 (61%: , 39%: ); e for VisStep task
(71% [29%] GPi increased [decreased] their discharge overall); f estimated from Fig. 5, by counting num-
ber of samples during time interval and dividing by the maximum number of conditions (four); g data
estimated from Fig. 6C (85%: , 15%: ); h estimated from Fig. 4 (assumes uniform distributions of 78%
activations in EP); i data estimated from Fig. 3B.
Fig. 4. Simulations of normal (thick lines) and Parkinsons disease (thin lines) movement control. Joint
position (ramp trajectories) and velocity (bell-shaped trajectories) for three different position and velocity gain
settings are shown (F = 10; G0 = 10; normal: Gp = Gv = 1.0; PD1: Gp = Gv = 0.6; PD2: Gp = Gv = 0.2).
Reducing the gain resulted in slower movement (bradykinesia).
Figure 5 depicts a schematic diagram of frontal, parietal, basal ganglia, and cerebellar networks
postulated to be engaged in the learning and updating of sensorimotor transformations for reaching to
visual or proprioceptive targets. The model is based on an extension of the computational models of
Bullock et al. (9) and Burnod et al. (8), and recent imaging and behavioral experiments (5053) that
suggest distinct roles for fronto-parietal, basal ganglia, and cerebellar networks. In the model, visual
and/or proprioceptive signals about target location and end-effector position are used to code an
internal representation for target (T) and arm (Eff), presumably in posterior parietal cortex (PPC).
These internal representations are compared to compute a spatial difference vector (DVs) as in the
cortical vector integration model depicted in Fig. 2B. The DVs outflow must be transformed into
a joint rotation vector (DVm) in order to guide the end-effector to the target. This spatial direction-to-
joint rotation transformation is an inverse kinematic transformation and computationally, it can be
learned through certain amount of simultaneous exposure to patterned proprioceptive and visual
stimulation under conditions of self-produced movementreferred to as motor babbling (8,9).
The cortical network just described is complemented by two subcortical networks connected in
two distinct, parallel, lateral loops, namely, a frontostriatal network and a parieto-cerebellar system.
The former provides a learned bias term that rotates the frame of reference for movement, whereas
the latter provides a correction term that is added to the direction vector whenever the actual direction
of movement deviates from the desired one. The frontostriatal network is modeled as an adaptive
search element that performs search and action selection using reinforcement learning (15). This
system uses an explicit error (dopamine) signal to drive the selection and the reinforcement/punish-
ment mechanisms used for learning new procedural skills. It searches and evaluates candidate
visuomotor actions that would lead to acquisition of a spatial target. The cerebellar component is
modeled as an adaptive error-correcting module that continuously provides a compensatory signal to
drive the visuomotor error (provided by the climbing fibers) to zero (7).
102 Contreras-Vidal
Fig. 5. Diagram of hypothesized networks involved in sensorimotor transformation for reaching. See text for
description.
Simulating the Finger-to-Nose Test in Control, PD, and APD

The model summarized in the previous discussion was implemented in Matlab Simulink (follow-
ing the mathematical equations in refs. 8 and 9) to investigate the effects of PD and APDs in the
spatial and temporal characteristics of repetitive pointing movement to the nose (a kinesthetic target).
Figure 6 depicts the movement trajectories and the joint angles for a simulated arm with three joints
(shoulder, elbow, wrist). The simulation assumed horizontal movements at the nose level, and there-
fore the paths are shown as two-dimensional plots. As expected, in the virtual control subject, the
finger-to-nose trajectories were slightly curved and showed high spatial and temporal accuracy. The
joint excursions reflected the repetitive nature of the task with most of the movement performed by
elbow flexion/extension followed by the shoulder and to a lesser degree by the wrist.
To simulate PD, the gain of the basal ganglia gating signal was decreased by 30% with respect to
that in the intact system. In addition, Gaussian noise (N(0,1)*30) was added to the internal represen-
tation of the hand to account for kinesthetic deficits reported in PD patients (degradation of the
kinesthetic representation of the spatial location of the nose would have had the same effect) (54).
Computer simulations of the PD network showed decreased movement smoothness and increased
spatial and temporal movement variability. Moreover, the joint rotations were slower and progres-
sively decreased in amplitude. Thus, the simulation is consistent with reports of deficits in the pro-
duction of multiarticulated repetitive movement in PD.
Following the observations of cortical atrophy in frontal and parietal areas in APD summarized in
subheading Neuropathology of the APDs, we modeled this disease in two steps: First, we added noise
(uniform distribution between 0 and 1.5) to the adaptive synaptic weights of the frontoparietal net-
work in the intact (control) system; second, we pruned the synaptic weights by randomly setting
50% of the weights to zero; and third, the gain of the basal ganglia gating signal was reduced to 50%
of the control value. Simulation of the APD network model showed that the movement trajectories
Fig. 6. Simulations of the finger-to-nose test in normal, PD, and APD models. Movement trajectories and
joint angles are shown. See videoclip for real-time simulation.
were severely affected. The virtual subject showed misreaching to the nose and produced movement
paths that varied widely in space. This was reflected in the joint excursions, which were character-
ized by noisy and asymmetrical flexion and extension ranges, as well as some periods of joint immo-
bility. Thus, simulation of APD had the largest effect on the spatial and temporal aspects of movement
coordination.
104 Contreras-Vidal
Simulating the Bread-Slicing Gesture in Control, PD, and APD

Recent clinical studies suggest that apraxia may be explained in terms of damage to a fronto-
parietal network involved in reaching and prehension (38). According to Rothi, ideomotor apraxia is
characterized by impairment in the timing, sequencing, and spatial organization of gestural move-
ments (55). Studies involving patients with PD and APDs, including PSP and CBD, indicate that
combined involvement of basal ganglia and cortical networks may underlie the presence of apraxia in
these patients (37,38). Moreover, in a group of studies by Leiguarda and colleagues, they found that
patients with PD, PSP, and CBD, who tested positive for apraxia in the clinical test, showed larger
kinematic abnormalities than those patients who do not show apraxia on clinical examination. How-
ever, as discussed initially by Roy, it is still a matter of debate whether these kinematic abnormalities
are a result of an apraxia-like impairment or to basic motor control deficits (40). For example, do the
basic motor control deficits seen in these clinical populations explain the abnormal kinematic deficits
seen in patients with ideomotor apraxia?
In the computer simulations that follow we focus on production errors, which are associated with
deficits in the programming and execution of gestural movements, like the bread-slicing task. Simu-
lations of higher-order content errors would require modeling of frontal areas related to ideational or
conceptual processing, which are not included in the current model. In the model simulations, it is
assumed that the planning and control components are disturbed because of the pathology in fronto-
parietal networks.
Figure 7 shows the performance in the bread slicing task in a normal virtual subject (Control),
and after simulated PD and APD. Both diseases were simulated as in subheading Modeling
Hypokinetic Disorders in PD. In the control simulation the slicing gesture, depicted as a continuous
dark line, reflected a tight, curvilinear trajectory, which was primarily a result of the repetitive, peri-
odic, shoulder rotations. Elbow and wrist joint angles also showed sustained, periodic patterns albeit
of smaller amplitude. Simulation of the parkinsonian network resulted in reduced spatial and tempo-
ral accuracy of the slicing movement. This was accompanied by slower and asymmetrical joint oscil-
lations that were maximal for the shoulder joint, but considerably reduced for the wrist joint. In fact,
as the slicing gesture was generated, the wrist joint was progressively rotated from ~18 to ~38 (see
geometry of the arm in top panel of Fig. 7). Simulation of PSP resulted in large production errors as
evidenced by distorted spatial trajectories, some of which left the spatial area for the simulated bread
surface. The profiles of the joint angles also resemble those reported in recent studies (see e.g., Fig. 5
in ref. 38). For example, the angular changes of virtual patients with PD and APDs are smaller,
irregular, and distorted compared to the simulated control subject.
CONCLUSIONS
Models of basal ganglia disorders have been advanced in the last two decades. These models have
mostly focused on PD, in part because of the computational burden of simulating large-scale models
that include multiple brain areas. However, recent computational work on frontal, parietal, cerebel-
lar, and basal ganglia dynamics involved in sensorimotor transformations for reaching provide a
window to study widespread pathologies as those seen in APDs. These models can inform the experi-
mentalist about the various potential sources of movement variability in various types of tasks (simple
vs sequential, pantomime vs real tool use, kinesthetic vs visual cueing, etc.). Moreover, simulated
lesions and interventions can be used to test hypotheses and guide new experiments.
For example, we modeled the pharmacokinetics and the pharmacodynamics using a neural net-
work model parameterized by the measurements of the handwriting kinematics of PD patients (12).
Other mathematical treatments of the doseeffect relationship of levodopa and motor behavior treat
the motor control system as a black-box system and do not provide insights on the mechanisms,
although they may still be useful for therapy optimization purposes (56). On the other hand, a bio-
logically inspired, albeit highly simplified neural network model of cortico-basal ganglia dynamics
Fig. 7. Simulations of the bread-slicing gesture commonly used to test ideomotor apraxia in basal ganglia
disorders. Simulations show movement trajectories and joint angles (shoulder, elbow, and wrist) for normal,
PD, and APD simulations. See videoclip on accompanying DVD for real-time simulation.
during normal and neurological conditions would be valuable to assess which parameters might be most
amenable to therapeutic intervention, including individual optimization of pharmacological therapy,
while at the same time informing about abnormal mechanisms.
Limitations of Current Models of Basal Ganglia Disorders

APDs are caused by various diseases, therefore involving a complex neuropathophysiology and a
wide spectrum of abnormal behavioral signs. Currently, there is no mathematical or conceptual model
that can explain all the symptoms based on abnormal mechanisms within the basal ganglia, cerebel-
lum, and/or cortical areas. This limitation is partially because of the necessary simplification of the
neurobiology required to make the model computationally or mathematically tractable for formal
investigation. Thus, it is likely that some aspect of any proposed model may be wrong; however, the
likelihood of this happening can be minimized by developing a step-by-step reconstruction of the
system under study, with each step required to account for additional sources of neural or motor
106 Contreras-Vidal
variability. Moreover, manipulations of model components, such as simulated lesions or deep brain
stimulation paradigms, are also oversimplifications of the processes occurring in the brain in response
to such events.
We hope that computational models of basal ganglia disorders will be developed further to help
elucidate and account for the complexity of the clinical symptoms seen in PD and APDs, in such a
way that these models can guide further theoretical and applied research and foster interactions
between clinicians, modelers, and neuroscientists.
FUTURE DIRECTIONS
A controversial question in apraxia research is the relevance of ideomotor apraxia for real-life
action (57). Earlier reports suggested that patients with apraxia may use single objects appropriately
even when they are unable to pantomime their use (58,59), whereas other have found the same types
of spatiotemporal errors in both object pantomime and during tool use (58) or reported that subjects
with ideomotor apraxia, assessed by gesture pantomime, had more errors with tools while eating than
matched controls (61). The large-scale neural network presented in this chapter may help to elucidate
any potential relationship of ideomotor apraxia to skilled tool use in naturalistic situations. Extension
of the large-scale neural network model to include visual and tactile signals produced by the sight and
on-line interaction with the object would be critical to answer this question. Another important direc-
tion for future work relates to the integration of stored movement primitives (so-called gesture en-
grams) and dynamic movement features required to produce and distinguish a given gesture from
others. Although the simulations of the slicing gesture in anapraxic neural network model pre-
sented in this chapter were based on degraded sensorimotor transformations for movement, it should
also be possible to evaluate the effects of disruptions in the on-line sequential (dynamic) processes
underlying the repetitive nature of the slicing task, which were intact in the present simulations.
Finally, the hypothetical effects of neuromotor noise in different model components could also be
assessed through neural network simulations.
ACKNOWLEDGMENTS
The author thanks Shihua Wen, University of Marylands Department of Mathematics, for run-
ning the simulations shown in Figs. 6 and 7. The authors computational work summarized herein has
been supported in part by INSERM and the National Institutes of Health.
FIGURES (.EPS AND HIGH-QUALITY .JPEG)

Figures are provided in both .eps and .jpeg format in the CD. They were generated in Matlab and
filtered using Abobe Illustrator.
MEDIA (MPEG)
Procedure Used to Generate the MPEG Files:
In the CD disk, there are six (6) mpeg files, the file names represent the simulated tasks, which are
described below. The frames in format .avi were generated by the computational model written in
MatLab's Simulink. The .avi files are generated by a shareware named "HyperCam" produced by
Hypererionics Technology (www.hperionics.com). The mpeg files were obtained using the freeward
softward "avi2meg" written by USH (www.ush.de). All the movies are recorded at a rate of 30 frames
per second.
Description of Movies:
noseControl (duration: 1:48): Simulation shows the end-pont trajectories during the finger-to-
nose task. A three segments arm is shown. These segments are linked by the shoulder, elbow, and
wrist joints. This simulation of an intact (Control) network shows almost linear trajectories.
nose PD (duration: 1:49): This movie shows the performance of the computer model after simulat-
ing severe PD. In this simulation, the movement becomes slower, discrete, and noisy. Moreover,
some of the targeted movements do not reach the nose.
noseAPD (duration: 1:51): This movie shows the finger-to-nose simulations after damage to the
fronto-parietal network involved in sensorimotor trnsformations for reaching, which simulated APD.
The end-point trajectories become irregular, coarse, fragmented, and dyscoordinated.
slicingControl (duration: 2:03): This clip shows a simulation of the "bread slicing" gesture as seen
from directly above. The rectangle represents the loaf of bread. Note that there were not constrains on
the way the virtual arm was supposed to produce the gesture. Note that during the repetitive move-
ment the wrist joint was initially slightly flexed, but gradually became extended. This illustrates the
fact that in a redundant arm there are many possible arm configurations that can be used to move the
end point to a spatial target or along a given spatial trajectory.
slicingPD (duration: 2:03): The PD simulation shows reduced range of motion for all joints, dis-
continuous movements, and a difficulty in generating the repetitive slicing gesture. In this particular
simulation, the wrist is in the extended position from the onset of the movement.
slicing APD (duration 2:03): This video shows the slicing gesture task after simulated APD. This
simulation shows production errors as the arm fails to move the end point along the desired slicing
trajectory. This resulted in highly disrupted spatial and temporal organization.
REFERENCES
1. Beiser DG, Hua SE, Houk JC. Network models of the basal ganglia. Curr Opin Neurobiol 1997;7:185190.
2. Ruppin E, Reggia JA, Glanzman D. Understanding brain and cognitive disorders: the computational perspective. Prog
Brain Res 1999;121:ixxv.
3. Gillies A, Arbuthnott G. Computational models of the basal ganglia. Mov Disord 2000;15:762770.
4. Amos A. A computational model of information processing in the frontal cortex and basal ganglia. J Cogn Neurosci
2000;12:505519.
5. Lorincz A. Static and dynamic state feedback control model of basal ganglia-thalamocortical loops. Int J Neural Syst
1997;8:339357.
6. Wickens JR, Kotter R, Alexander ME. Effects of local connectivity on striatal function: stimulation and analysis of a
model. Synapse 1995;20:281298.
7. Contreras-Vidal JL, Grossberg S, Bullock D. A neural model of cerebellar learning for arm movement control: cortico-
spino-cerebellar dynamics. Learn Mem 1997;3:475502.
8. Burnod Y, Grandguillaume P, Otto I, Ferraina S, Johnson PB, Caminiti R. Visuomotor transformations underlying arm
movements toward visual targets: a neural network model of cerebral cortical operations. J Neurosci 1992;12:14351453.
9. Bullock D, Grossberg S, Guenther FH. A self-organizing neural model of motor equivalent reaching and tool use by a
multijoint arm. J Cogn Neurosci 1993;5:408435.
10. Tagamets MA, Horwitz B. Interpreting PET and fMRI measures of functional neural activity: the effects of synaptic
inhibition on cortical activation in human imaging studies. Brain Res Bull 2001;54:267273.
11. Horwitz B, Poeppel D. How can EEG/MEG and fMRI/PET data be combined? Hum Brain Mapp 2002;17:13.
12. Contreras-Vidal JL, Poluha P, Teulings HL, Stelmach GE. Neural dynamics of short and medium-term motor control
effects of levodopa therapy in Parkinsons disease. Artif Int Med 1998;13:5779.
13. Bower JM. Modeling the nervous system. TINS 1992;15:411412.
14. Schultz W, Dayan P, Montague R. A neural substrate of prediction and reward. Science 1997;275:15931599.
15. Contreras-Vidal JL, Schultz W. A predictive reinforcement model of dopamine neurons for learning approach behav-
ior. J Comput Neurosci 1999;6:191214.
16. Nakahara H, Doya K, Hikosaka O. Parallel cortico-basal ganglia mechanisms for acquisition and execution of
visuomotor sequencesA computational approach. J Cogn Neurosci 2001;13:626647.
17. Suri R, Schultz W. Learning of sequential movements by neural network model with dopamine-like reinforcement
signal. Exp Brain Res 1998;121:350354.
18. Contreras-Vidal, JL. The gating functions of the basal ganglia in movement control. In: JA Reggia, E Ruppin, DL
Glanzman (eds.). Progress in Brain Research. Disorders of Brain, Behavior and Cognition: the Neurocomputational
Perspective. Amsterdam: Elsevier, 1999:261276.
19. Humphries MD, Gurney KN. The role of intra-thalamic and thalamocortical circuits in action selection. Network
2002;13:131156.
108 Contreras-Vidal
20. Gurney K, Prescott TJ, Redgrave P. A computational model of action selection in the basal ganglia. II. Analysis and
simulation of behaviour. Biol Cybern 2001;84:411423.
21. Beiser D, Houk J. Model of cortical-basal ganglia ganglionic processing: encoding the serial order of sensory events.
J Neurophysiol 1998;79:31683188.
22. Fukai T. Sequence generation in arbitrary temporal patterns from theta-nested gamma oscillations: a model of the basal
ganglia-thalamo-cortical loops. Neural Netw 1999;12:975987.
23. Berns GS, Sejnowski TJ. A computational model of how the basal ganglia produce sequences. J Cogn Neurosci
1998;10:108121.
24. Contreras-Vidal JL, Stelmach GE. A neural model of basal gangliathalamocortical relations in normal and Parkinso-
nian movement. Biol Cybern 1995;73:467476.
25. Connolly CI, Burns JB, Jog MS. A dynamical-systems model for Parkinsons disease. Biol Cybern 2000;83:4759.
26. Suri RE, Albani C, Glattfelder AH. A dynamic model of motor basal ganglia functions. Biol Cybern 1997;76:451458.
27. Borrett DS, Yeap TH, Kwan HC. Neural networks and Parkinsons disease. Can J Neurol Sci 1993;20:107113.
28. Litvan I. Recent advances in atypical parkinsonian disorders. Curr Opin Neurol 1999;12:441446.
29. Yekhlef F, Ballan G, Macia F, Delmer O, Sourgen C, Tison F. Routine MRI for the differential diagnosis of Parkinsons
disease, MSA, PSP, and CBD. J Neural Transm 2003;110:151169.
30. Schrag A, Kingsley D, Phatouros C, et al. Clinical usefulness of magnetic resonance imaging in multiple system atro-
phy. J Neurol Neurosurg Psychiatry 1998;65:6571.
31. Schrag A, Good CD, Miszkiel K, et al. Differentiation of atypical parkinsonian syndromes with routine MRI. Neurol-
ogy 2000;54:697702.
32. Kraft E, Schwarz J, Trenkwalder C, Vogl T, Pfluger T, Oertel WH. The combination of hypointense and hyperintense
signal changes on T2-weighted magnetic resonance maging sequences: a specific marker of multiple system atrophy?
Arch Neurol 1999;56:225228.
33. Savoiardo M, Strada L, Girotti F, Zimmerman RA, Grisoli M, Testa D, Petrillo R. Olivopontocerebellar atrophy: MR
diagnosis and relationship to multisystem atrophy. Radiology 1990;174:693669.
34. Savoiardo M, Grisoli M, Girotti F, Testa D, Caraceni T. MRI in sporadic olivopontocerebellar atrophy and striatonigral
degeneration. Neurology 1997;48:790792.
35. Horimoto Y, Aiba I, Yasuda T, et al.Cerebral atrophy in multiple system atrophy by MRI. J Neurol Sci 2000;173:109112.
36. Fahn S, Green PE, Ford B, Bressman SB. Handbook of Movement Disorders. London: Blackwell Science, 1997.
37. Leiguarda RC, Marsden CD. Limb apraxias: higher-order disorders of sensorimotor integration. Brain 2000;123:86079.
38. Leiguarda R, Merello M, Balej J, Starkstein S, Nogues M, Marsden CD. Disruption of spatial organization and interjoint
coordination in Parkinsons disease, progressive supranuclear palsy, and multiple system atrophy. Mov Disord
2000;15:627640.
39. Litvan I. Progressive supranuclear palsy and corticobasal degeneration. Baillieres Clin Neurol 1997;6:167185.
40. Roy EA. Apraxia in diseases of the basal ganglia. Mov Disord 2000;15:598600.
41. Bullock D, Grossberg S. Neural dynamics of planned arm movements: emergent invariants and speed-accuracy proper-
ties during trajectory formation. Psychol Rev 1988;95:4990.
42. Anderson ME, Horak FB. Influence of the globus pallidus on arm movements in monkeys. III. Timing of movement-
related information. J Neurophysiol 1985;54:433448.
43. Brotchie P, Iansek R, Horne MK. Motor function of the monkey globus pallidus. 1. Neuronal discharge and parameters
of movement. Brain. 1991;114:16671683.
44. Cheruel F, Dormont JF, Amalric M, Schmied A, Farin D. The role of putamen and pallidum in motor initiation in the
cat. I. Timing of movement-related single-unit activity. Exp Brain Res 1994;100:250266.
45. Georgopoulos AP, DeLong MR, Crutcher MD. Relations between parameters of step-tracking movements and single
cell discharge in the globus pallidus and subthalamic nucleus of the behaving monkey. J Neurosci 1983;3:15861598.
46. Mink JW, Thach WT. Basal ganglia motor control. I. Nonexclusive relation of pallidal discharge to five movement
modes. J Neurophysiol 1991;65:273300.
47. Nambu A, Yoshida S, Jinnai K. Movement-related activity of thalamic neurons with input from the globus pallidus and
projection to the motor cortex in the monkey. Exp Brain Res 1991;84:279284.
48. Neafsey EJ, Hull CD, Buchwald NA. Preparation for movement in the cat. II. Unit activity in the basal ganglia and
thalamus. Electroencephalogr Clin Neurophysiol 1978;44:714723.
49. Turner RS, Anderson ME. Pallidal discharge related to the kinematics of reaching movements in two dimensions.
J Neurophysiol 1997;77:10511074.
50. Contreras-Vidal JL, Buch ER. Effects of Parkinsons disease on visuomotor adaptation. Exp Brain Res 2003;150:2532.
51. Buch ER, Young S, Contreras-Vidal JL. Visuomotor adaptation in normal aging. Learn Mem 2003;10:5563.
52. Inoue K, Kawashima R, Satoh K, et al. A PET study of visuomotor learning under optical rotation. Neuroimage
2000;11:505516.
53. Balslev D, Nielsen FA, Frutiger SA, et al. Cluster analysis of activity-time series in motor learning. Hum Brain Mapp
2002;15:13545.
54. Klockgether T, Borutta M, Rapp H, Spieker S, Dichgans J. A defect of kinesthesia in Parkinsons disease. Mov Disord
1995;10:460465.
55. Rothi LJG, Ochipa C, Heilman KM. A cognitive neuropsychological model of limb praxis. Cogn Neuropsychol
1991;8:443458.
56. Hacisalihzade SS, Mansour M, Albani C. Optimization of symptomatic therapy in Parkinsons disease. IEEE Trans
Biomed Eng 1989;36:363372.
57. Buxbaum LJ. Ideomotor apraxia: A call to Action. Neurocase 2001;7:445458.
58. Poizner H, Mack L, Verfaellie M, Rothi LJ, Heilman KM. Three-dimensional computer graphic analysis of apraxia.
Neural representations of learned movement. Brain 1990;113:85101.
59. Liepmann H. The left hemisphere and action. London, Ontario: University of Western Ontario, 1905.
60. De Rensi E, Motti F, Nichelli P. Imitating gestures. A quantitative approach to ideomotor apraxia. Arch Neurol
1980;37:610.
61. Foundas AL, Macauley BL, Raymer AM, Maher LM, Heilman KM, Gonzalez Rothi, LJ. Ecological implications of
limb apraxia: evidence from mealtime behavior. J Int Neuropsychol Soc 1995;1:6266.
APDs: Neuropathology and Nosology 111
8
Atypical Parkinsonian Disorders
Neuropathology and Nosology
Charles Duyckaerts
INTRODUCTION
In many neurological diseases the topography of the lesion, whatever its nature, determines the
clinical signs, whereas the nature of the lesion (vascular, inflammatory, degenerative, etc.) whatever
its topography, determines the time course. According to J. P. Martin (1), this general principle can-
not be simply applied to diseases of the basal ganglia since the nature of the lesions directly influence
the clinical signs. Chorea, for instance, is associated with atrophy of the caudate nucleus but infarct
of the caudate nucleus does not generally cause chorea.
What is the localizing value of parkinsonism? Parkinsonism is the clinical syndrome that is fully
developed in idiopathic Parkinsons disease (IPD). Hypokinesia or bradykinesia, rigidity, and resting
tremor are characteristic of IPD. In general, these features are eventually bilateral, but usually largely
predominate on one side of the body (2). In parkinsonian disorders not resulting from IPD, resting
tremor is usually absent.
The Topography of the Lesions Causing Parkinsonism

When Lewy described the cerebral lesions found in patients with IPD, he correctly identified the
cellular inclusions that are now known under his name. He also acknowledged the diffuse nature of
the disease. Numerous figures in his monograph (3) show inclusions in the brainstem next to those in
the basal nuclei. He mentioned the fact that Tretiakoff and the French authors had emphasized the
importance of the alteration of the substantia nigra (which was macroscopically visible as a pallor)
but he failed to appreciate the importance of this topography. In his view, the tonus was modulated by
two antagonist structures, the cerebellumthe destruction of which caused hypotoniaand basal
ganglia, the lesions of which caused hypertonia (rigidity). The equilibrium between both was regu-
lated by a hypothetical mesencephalic tonus center that was not clearly identified and certainly not
recognized as the substantia nigra (Fig. 1). It may seem surprising that Lewy, who had so many deep
insights into the pathogenesis of IPD, did not appreciate the importance of the lesions of the substan-
tia nigra. The reason is, probably, the knowledge of the anatomy at that time. The reading of old
neuroanatomy books, such as the various editions of the classical Carpenters Neuroanatomy, makes
it clear that the connections of the substantia nigra with the striatum escaped the scrutiny of the
anatomists until the development of the histofluorescence technique by Falck and Hillarp (4) (see
Fig. 2). This method, which was able to reveal the thin catecholaminergic fibers, finally established
that, indeed, the substantia nigra was connected with the striatum and truly belonged to the basal
nuclei. The idea that the substantia nigra was the producer of dopamine that flowed into the striatum
and that IPD was just caused by the mere interruption of this flow was put forward at that time.

111
112 Duyckaerts
Fig. 1. A precursor of todays models: Lewy diagram explaining the motor symptoms of Parkinson disease.
Reproduction in black and white of the color picture 546b of Die Lehre vom Tonus und der Bewegung by F. Lewy
(Berlin, 1923). C is the cortex. K stands for Kleinhirn (cerebellum), and S for striatum. T is the
Tonusregulationszentrum, located in A Nucleus Associatorius motorius tegmenti (defined in the text as a set of
mesencephalic tegmental nuclei not identified as substantia nigra). Py is the pyramidal tract. H.H. is
Hinterhornschaltzelle (the cells of the posterior horn [of the spinal cord]) and V.H. is the Vorderhorn (ventral horn).
Fig. 2. (opposite page) Stages in the understanding of the connections of substantia nigra as seen from
anatomy book diagrams. Panel A is part of a diagram, which dates back to 1935 (222). S. nigra , substantia
nigra. Neorubr. , red nucleus - neoruber, i.e., parvocellular part of the nucleus. Paleorubr. = red nucleus -
paleoruber i.e. magnocellular part of the nucleus. Corp quadr., colliculi. Tegm mes., Tegmentum of the mesen-
cephalon. In 1935, the efferent fibers of the substantia nigra were thought to stop in the reticular formation of
the mesencephalon, in or close to the red nucleus. Panel B is a diagram published in 1969 (223). SN, substantia
nigra. GPM, globus pallidus, pars medialis. VLM, medial part of the ventrolateral nucleus of the thalamus.
Refer to the original drawing for other abbreviations. In 1969, the connections of the substantia nigra with the
striatum were not yet illustrated. Panel C comes from the seventh edition of the book: on the diagram, the
efferent fibers from the substantia nigra are indicated as reaching the striatum (putamen) (224).
114 Duyckaerts
We now know that IPD cannot be reduced to a pure dopaminergic deficit (57). F-Synuclein,
which makes up the Lewy bodies, accumulates in many more nuclei or brain structures than just the
substantia nigra. However, it remains true that the substantia nigra is involved in most disorders with
parkinsonism, and that parkinsonism, as a clinical syndrome, points to a lesion of the substantia
nigra. The substantia nigra is indeed, clearly involved in IPD, progressive supranuclear palsy (PSP),
corticobasal degeneration (CBD), and multiple system atrophy (MSA) i.e., striatonigral degeneration,
although most often in association with other structures. Infarction of the substantia nigra, rarely
encountered, has been incriminated in unilateral parkinsonism (8). Lymphoma invading the substan-
tia nigra has been reported to cause parkinsonism (9); postencephalitic parkinsonism, although caus-
ing diffuse alterations, massively affects the substantia nigra. It is also the substantia nigra that is
involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication, which is responsible
for a severe parkinsonian syndrome.
The rule of a nigral involvement in parkinsonism suffers many exceptions, the most noticeable
being patients with lacunes of the basal ganglia who frequently develop a shuffling gait, akinesia, and
rigidity reminiscent of IPD. Vascular lesions of the basal ganglia can also cause a clinical syndrome
of supranuclear palsy (10). How lesions of the basal ganglia cause these symptoms is not clear. Large
destructions of the lenticular nucleus in animals (already mentioned by Kinnear Wilson, ref. 11) or in
humans (12) do not cause a movement disorder that may be described as parkinsonism.
There are other lesions outside the basal ganglia nuclei accompanied by parkinsonism, usually
without tremor; bradykinesia, rigidity, and gait disturbances have been associated with frontal-lobe
infarcts and with periventricular and deep subcortical white matter lesions (13). Bilateral frontal
tumors such as meningioma (14) may also cause rigidity and bradykinesia reminiscent of IPD.
In brief, a lesion involving the substantia nigra, whatever its type, regularly causes parkinsonism,
whereas only some types of alterations in the lenticular nucleus, or more rarely in other parts of the
brain, may be held responsible for similar symptoms.
The Degenerative Processes Affecting the Basal Ganglia and Their Markers
As already briefly outlined, parkinsonism is a syndrome of many causes. The degenerative pro-
cesses commonly involved are difficult to disentangle since the mechanisms leading to neuronal
dysfunction or death are not understood. The topography of the neuronal loss could help to identify
these mechanisms, but little is known presently on the reasons of specific regional vulnerability.
Moreover, the neurons that are lost leave no information on the causes of their death. Microscopic
observation of the brain does not only show neuronal loss (negative signs) but can also reveal
positive alterations. Most of them are characterized by accumulation of proteins in the cell (so-called
inclusions). For instance, Lewy bodies associated with IPD, consist in the accumulation of F-
synuclein in the cell body of neurons. Tau protein fills the processes of so-called tufted astrocytes
found in PSP or accumulates at the tip of these processes in the astrocytic plaques, considered to be
one of the characteristic lesions of CBD.
Just as are clinical signs, these positive alterations (Lewy bodies, tufted astrocytes, astrocytic
plaques, etc.) are signs in the sense that they are but an observable change caused by the disease.
What are they the sign of? Some inclusions are seen in a large number of disorders or even in other-
wise normal cases: amylaceous bodies belong to that category. Others are encountered but in a subset
of disorders: they are described as markers. Lewy bodies, for instance, are found in only a few
circumstances (15), most often IPD or dementia with Lewy bodies (DLB) but also Hallervorden
Spatz disease (NBIA-1 or neurodegeneration with brain iron accumulation type 1). The presence of
the same marker in several diseases strongly suggests that the same metabolic dysfunction occurs in
the various disorders where they are found. Obviously, two disorders looking clinically alike, e.g.,
IPD and parkinsonism owing to parkin mutations, may not share the same marker. In these two
disorders the same cell populations are affected, explaining why they are clinically similar, but two
different mechanisms lead to cell death. In IPD, F-synuclein accumulates in Lewy bodies because it is
overproduced or not correctly consumed or destroyed. By contrast, the accumulation of F-synuclein

does not take place in parkin mutation, perhaps because of a defect in ubiquitination, as it has been
suggested (16) (Fig. 3). It is unfortunate that the same label (Parkinsons disease, ref. 17) was applied
to the two diseases with the logical (but in our view unjustified) conclusion that Lewy bodies, lacking
in some cases of Parkinson disease (i.e., those with Parkin mutations), are just an insignificant
byproduct. There is no reason to believe that all the morphologic markers play the same pathogenic
role. Some may be toxic, others beneficial or innocent bystanders. Markers (or even neuronal loss)
are lacking in some disorders (Fig. 4). Neuroleptics, for instance, cause spectacular extrapyramidal
syndromes without causing any observable change.
Markers are useful in that they may give important information concerning physiopathology and,
as such, contribute to the classification of neurodegenerative diseases. Molecular biology has shown
in several cases that there is a direct relationship between the mutated gene and the protein accumu-
lated in the inclusions. To take two striking examples, F-synuclein, which is mutated in some familial
cases of IPD, is also present in the Lewy body, the marker of IPD. Tau accumulates in neurons and
glia in hereditary fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17);
the mutations causing these disorders affect precisely the tau gene. There are many other examples,
which suggest that one should take the markers seriously and consider them, at the least, as an
indication of a pathogenic mechanism (either its cause or its consequence, ref. 18), and at the most as
indispensable evidence of a specific disease.
In the majority of cases, the lesions, which are observed in degenerative parkinsonism, consist in
the accumulation of F-synuclein or of tau protein. F-Synuclein accumulates in the neuronal cell body
(Lewy body) and in the neurites (Lewy neurites) of IPD. It may also accumulate in the glial inclu-
sions of MSA. Although F-synuclein accumulates in both IPD and MSA, there is presently no evi-
dence that these two disorders are otherwise linked in any way. Tau accumulates in neurons or glia of
many neurodegenerative disorders: PSP, CBD, postencephalitic parkinsonism (PEP), amyotrophic
lateral sclerosis parkinsonismdementia complex of Guam (PDC), and tau mutations. In these dis-
eases, the cellular type and the region of the cell where tau accumulates are important determinants of
the inclusions.
SYNUCLEINOPATHY: IPD AND DLBMULTIPLE SYSTEM ATROPHY

The Lewy Body
The inclusions that Friedrich H. Lewy observed in the brain of IPD patients are illustrated in the
epoch-making monograph that he devoted to that disorder in 1923, titled Die Lehre vom Tonus und
der Bewegung [The science of tonus and movement]. The variety of their shapes and of their topog-
raphy demonstrates that F. Lewy had, in a certain sense, a remarkably modern view of the disorder:
he had seen inclusions in the cell processes of the neurons (a lesion now described as Lewy neurite)
and in locations such as the nucleus basalis of Meynert, the hypothalamus, and the vegetative centers
of the medulla. Historically, the term Lewy body, coined by Tretiakoff (19), came to mean a spheri-
cal inclusion underlined by a clear halo located in the cell body of the neuron. This is indeed their
manifestation in the substantia nigra where Tretiakoff observed them. The inclusion appears red with
standard hematoxylin and eosin (H&E) stain since it exhibits a special affinity for eosin (eosino-
philia). This type of Lewy bodies is mainly observed in the brainstem and is today considered the
indispensable accompaniment of IPD (15,20).
Lewy bodies were also identified in the cerebral cortex but almost 50 yr after their first descrip-
tion. The initial observation was due to Okazaki and his coworkers (21) who found them in two cases
of dementia with quadriparesis in flexion. The peculiar aspect of cortical Lewy bodies explains why
they were discovered much later than their brainstem counterparts. They are also eosinophilic, but
lack the clear halo seen in the brainstem inclusions. Therefore, they may be mistaken for an abnor-
mal, homogenized cytoplasm. The nucleus of the cell that contains the inclusion is often clear and may
lack the large nucleolus typical of neurons: the cell may erroneously be identified as an astrocyte.
116 Duyckaerts
Fig. 3. Three diseases affecting the substantia nigra, with similar clinical consequences. Diagram showing,
in the upper panel, the presence of Lewy bodies in the substantia nigra, causing idiopathic Parkinsons disease,
in the middle panel, F-synuclein containing oligodendroglial and nuclear inclusions characteristic of striato-
nigral degeneration (MSA), and in the lower panel, neuronal death associated with parkin mutations. The clini-
cal signs may be quite similar although the pathogenic mechanisms, and possibly the markers, may be different.
The mechanism of formation of Lewy bodies and neurites is still unknown. With electron micros-
copy, they appear to be made of a dense, osmiophilic center in which vesicles and fibrils, 810 nm in
diameter, can be identified (22). At the periphery of the inclusion, the fibrils are radially oriented.
The first histochemical studies showed that the inclusion was essentially made of proteins. Immu-
nohistochemistry revealed the presence of many epitopes. Pollanen et al. (23) listed as many as 26
epitopes, among which neurofilaments were the most regularly found before ubiquitin and F-synuclein,
the two constituents thought to be the most significant, were identified.
Anti-ubiquitin antibodies strongly label Lewy bodies and Lewy neurites (24). Ubiquitination of
proteins depends on the activity of specific ubiquitin ligases, which target proteins that have to be
degraded. Several ubiquitin molecules make a polyubiquitin chain that serves as a signal to direct the
protein to the proteasome, a large proteolytic complex located outside the lysosome. Epitopes of the
proteasome are also found in the Lewy body (25). Ubiquitin and proteasome components are present
in the Lewy body, most likely because the inclusion is enriched in a protein that they are unable to
degrade or one that is degraded at a slower pace than it is produced.
Fig. 4. Various potential effects of the cellular inclusions used as markers. Although the pathophysiology of
most neurodegenerative diseases remains elusive, observational evidences suggest that at least four types of
relationship may exist between the molecular process causing the neurodegenerative disorders and the cellular
inclusions that may (or may not) be found in those disorders. An arbitrary number was given to each of them to
facilitate their description. Data, supporting the view that each of these mechanisms is indeed encountered in
pathology, are still circumstantial: neuroleptics lead to parkinsonism without neuronal death nor detectable
lesion (type IA). Parkin mutation leads to neuronal death, most of the time without any identified markers (type
IB). Many data indicate that the number of NFTs is correlated with the severity of the symptoms, for instance in
Alzheimers disease (225227), suggesting their direct toxic role (type II). Preventing the formation of nuclear
inclusions in polyglutamine disease may, in some experimental conditions, aggravate neuronal toxicity
(228,229), an observation compatible with their beneficial effect (type III).
F-Synuclein was initially isolated from the torpedo fish electric organ that Marotaux et al. (26)
screened for presynaptic proteins. A fragment of F-synuclein was found to be present in an extract of
senile plaques and called NAC (non-amyloid component of the senile plaque) (27). The precursor of
this protein, called NACP, is identical to F-synuclein. A similar protein, called synelfin, has been
identified in the bird (28). Years after the identification of F-synuclein, the finding of mutations in
the F-synuclein gene in IPD patients from four families living around the Mediterranean Sea came as
a surprise (29). The presence of F-synuclein in the Lewy body was demonstrated shortly after this
initial observation (30). The intensity of the labeling by anti-F-synuclein antibody and its sensitivity
suggest that it is, indeed, a major component of the Lewy body. F-Synuclein immunohistochemistry
facilitates the identification of the lesions and makes it clear that their distribution is more widespread
than initially thought (5).
118 Duyckaerts
There is indirect evidence that Lewy bodies could be responsible for neuronal death. They are,
indeed, associated with neuronal loss in all the subcortical nuclei where they are found. The existence
of a neuronal loss in the cerebral cortex is more difficult to ascertain (31). It could be lacking (32).
Distribution of Lewy Bodies and Lewy Neurites

Lewy body disease is the term proposed by Kosaka (3335) to describe the disorders in which
Lewy bodies are abundant, regardless of the clinical symptoms and signs. It is a neuropathological
term that cannot be considered as the final diagnosis, which has to integrate, as we shall see, the
clinical data. The distribution of the inclusions is not random. In the brainstem, they selectively
involve the pigmented nuclei (substantia nigra, locus coeruleus, dorsal nucleus of the Xth nerve).
They are abundant in subcortical nuclei such as the basal nucleus of Meynert, the amygdala, the
hypothalamus, and the limbic nuclei of the thalamus (36). In the cerebral cortex, they are predomi-
nantly found in the deep layers of the parahippocampal and the cingulate gyri, and in the insula
(32,37,38). They are also present in the peripheral nervous system, particularly in the stellate ganglia
(39), and in the cardiac (40) and myenteric (41) plexuses.
According to Kosaka (34,35), Lewy bodies may be found in the brainstem (brainstem type of
Lewy body disease), the brainstem and the limbic cortices (transitional type), and the brainstem,
limbic cortices, and the isocortex (diffuse type); see Table 1. The borders between these three types
of Lewy body diseases are not as sharp as may appear. It has become apparent (42), particularly with
Fsynuclein immunohistochemistry, that Lewy bodies were nearly always present in the isocortex
when they were found in the substantia nigra.
Association of Cortical Lewy Bodies With Alzheimers Type Pathology

The frequent association of Alzheimers lesions and Lewy bodies has been mentioned in IPD as
well as in Alzheimers disease.
Alzheimers Lesions in IPD Cases
Alzheimers lesions are often found in cases of IPD (4248). They have long been considered the
principal cause of parkinsonism dementia, the intellectual deficit occurring at the late stages of IPD.
The importance of Alzheimers lesions may, however, have been exaggerated. Recent data, obtained
with F-synuclein immunohistochemistry, tend to emphasize the responsibility of cortical Lewy pathol-
ogy in the cognitive deficit (49).
Lewy Bodies in Alzheimers Disease
Lewy bodies have often been associated with senile plaques in large postmortem studies of cases
with initial or predominant dementia (5053). They are particularly abundant in the amygdala, where
the co-occurrence of a neurofibrillary tangle and of a Lewy body in the same neurone has been
reported (54). The low density of neurofibrillary tangles, when Lewy bodies are added to Alzheimers-
type pathology (55), could be owing to a more rapid fatal outcome than in pure Alzheimers disease.
This would explain why Braak stage is usually lower at death in the cases with combined pathology
(56). The presence of Lewy bodies in cases suffering from a disorder that is, in many clinical and
neuropathological aspects, comparable to Alzheimers disease, explains terms such as Lewy body
variant of Alzheimers disease (57) or senile dementia of Lewy body type (58), now replaced by
the general appellation dementia with Lewy bodies (59,60). A high prevalence of Lewy bodies is
not only found in the sporadic form of Alzheimers disease, but has also been mentioned in familial
cases (61,62) or in trisomy 21 (63).
Why are Alzheimers-type and Lewy-type pathology so frequently associated? Alzheimers dis-
ease and IPD are frequent but not to the point of explaining the high prevalence of their common
occurrence. The hypothesis, according to which IPD and Alzheimers disease are extremes of a spec-
trum of neurodegeneration sharing the same pathogenic mechanism, has been put forward (64). It
Table 1
The Three Types of Lewy Body Disease According to Kosaka
Brainstem Type Transitional Type Diffuse Type
Brainstem X X X
Basal nucleus of Meynert X X X
Limbic Areas X X
Isocortex X
According to Kosaka (34,35), the topography of the Lewy bodies is organized in three
different distributions. An X rectangle means presence of Lewy bodies. The brainstem
type is commonly found in Parkinsons disease. The diffuse type is usually associated with
DLB. In the transitional type, cognitive symptoms are common; they may be primary or
complicate IPD. The borders between the three types may be difficult to draw. It has been
shown that even in cases of apparently uncomplicated IPD, the presence of a few Lewy
bodies in the isocortex is common (42).
should, however, be stressed that there are differences in the genetic background of IPD and
Alzheimers disease cases. The prevalence of the ApoE4 allele, a known risk factor for Alzheimers
disease, is normal in IPD cases even with dementia (65,66), but is increased in cases of dementia
even with Lewy bodies (67). Moreover, the mutations causing Alzheimers disease are clearly differ-
ent from those related to IPD, indicating that at least some causal factors are not shared by the two
disorders: they cannot simply be considered as phenotypic variants of the same disease. At the cellular
level, direct interaction between tau and F-synuclein proteins could enhance their fibrillization (68).
Clinico-Pathological Correlations
The final diagnosis in cases with Lewy bodies is clinico-pathological since long-standing IPD and
DLB may present with similar, or possibly identical, neuropathological phenotype. The most charac-
teristic diagnostic combinations are the following (see Table 2):
1. The initial and main complaints concern the motor system. The disorder slowly progresses during decades.
Lewy bodies and Lewy neurites are mainly found in the brainstem (brainstem type of Lewy body disease).
The diagnosis of IPD should be made.
2. The initial and main complaints concern the motor system but in the late stages of the disease, visual
hallucinations occurred and a cognitive deficit was present. Lewy bodies are found not only in the
brainstem and in the limbic cortices, but also in large numbers in the cerebral cortex, often associated with
Alzheimers lesions (diffuse type of Lewy body disease). The diagnosis of PD with dementia is then
warranted.
3. Finally, the disease starts with a fluctuating cognitive deficit that remains as the main symptom and is
associated with visual hallucinations. Numerous Lewy bodies are found not only in the brainstem and in
the limbic cortices, but also in the isocortex. The diagnosis of dementia with Lewy bodies should be made.

Striatonigral degeneration (69,70) was initially an autopsy finding since the symptoms are very
similar to those of IPD, except that there is a resistance to treatment by L-dopa (71). The gross exami-
nation shows a peculiar and often severe atrophy along with a green discoloration of the putamen that
is distinctive of the disease. The substantia nigra is pale. As already mentioned by Adams et al.
(Dgnrescences nigro-stries et crbello-nigro-stries), the cerebellum is often atrophic (69).
This introduces a second group of disorders, which were identified at the beginning of the 20th
century by Dejerine and Thomas under the descriptive term of olivopontocerebellar atrophy. The
sporadic nature of this atrophy contrasted with familial cases previously described by Menzel. Here,
the severity of the cerebellar syndrome is striking. Again, the progression of the disease is relentless,
but it had been noticed since the initial descriptions that parkinsonism may develop secondarily (see
120 Duyckaerts
Table 2
Various Types of Lewy Body Disease Are Clinico-Pathological Diagnoses
Symptoms Distribution of Lewy Bodies Diagnosis
Parkinsonism Brainstem type of Lewy body Idiopathic Parkinsons disease
disease
Initial parkinsonism. Late Diffuse type of Lewy body Idiopathic Parkinson disease with
cognitive symptoms disease +/ Alzheimer lesions dementia
Initial and predominant cognitive Diffuse type of Lewy body Dementia with Lewy bodies
symptoms. disease +/ Alzheimers lesions
? Brainstem type of Lewy body Probable idiopathic Parkinsons
disease disease, possibly incipiens
? Diffuse type of Lewy body Idiopathic Parkinsons disease with
disease dementia or dementia with Lewy
bodies
The diagnosis of the common diseases with Lewy bodies is clinico-pathological. It mainly relies on the chronological
order in which the motor symptoms and the cognitive deficit appear (see first column) and on the distribution of the
Lewy bodies, which can be classified, according to Kosaka, into three types (brainstem, transitional, diffuse)see
second column. When only the pathological information is available (? in the first column), the final diagnosis is ambiguous
in case of diffuse type of Lewy body disease.
e.g., ref. 72). Parkinsonism, when present, masks the cerebellar symptoms. Finally, orthostatic
hypotension is frequently associated both with striatonigral degeneration and olivopontocerebellar
atrophy. Autonomic failure may be the main symptom. Primary autonomic failure is also known
under the eponym of ShyDrager syndrome.
The frequent association of the three disorders (striatonigral degeneration, olivopontocerebellar
atrophy, and primary autonomic failure) led Graham and Oppenheimer, in a case report, to suggest
that they were in fact syndromes belonging to the same disease. They tentatively named it multiple
system atrophy (MSA) (73), the name that is still in use today (71) (see Fig. 5).
An unexpected validation of this concept came from neuropathology. In many of the cases that
were recorded as suffering from MSA, peculiar inclusions were identified by Papp and Lantos (74).
They were initially demonstrated by Gallyas staining method but were perfectly visible with other
silver impregnations (75). They mainly involve the cell body of the oligodendrocytes but may also
affect neurons or astrocytes (see Chapter 4, Neuropathology of Atypical Parkinsonian Disorders, for
detailed description). The high frequency of oligodendroglial lesions helps to understand why the
myelin appears so massively affected in MSA.
It is by chance that these inclusions were found to include F-synuclein epitopes that were identi-
fied by immunohistochemistry. The expression of F-synuclein in glia is poorly explained but can
probably occur normally (76). The attempt of reproducing the disease by introducing an F-synuclein
transgene under the control of an oligodendroglial promoter has, so far, been unsuccessful (77).
THE TAUOPATHIES
Tau Protein: 3R and 4R Tau
A large group of neurodegenerative diseases (including Alzheimers disease, PSP, CBD, argyro-
philic grain disease, Picks disease, PDC, PEP) are characterized by the accumulation of tau protein.
Tau is a phospho-protein that is normally involved in the regulation of tubulin assembly. Tau accu-
mulation is always intracellular and gives rise to inclusions with a variety of shapes, depending on
the disease in which they occur. This diversity in the morphology of the inclusions is not understood
at the present time. It is obviously related to the cellular type in which the accumulation takes place
Fig. 5. Multiple system atrophy. This Venn diagram illustrates the way in which the three syndromes
(olivopontocerebellar atrophy or OPCA, striato-nigral degeneration, and primary autonomic failure) may be
diversely associated. The pure syndromes, as well as their various associations, all belong to multiple system
atrophy or MSA. Areas are not proportional to prevalence in this diagram.
(astrocytes, oligodendrocytes, and neurons), but even within a given cell type, tau protein may aggre-
gate in inclusions of different shapes according to the disorder in which it appears. This suggests that
tau protein interacts with different cofactors or occupy different subcellular compartments. This could
be related to the isoforms of tau: six of them have been identified (78) that are generated by alterna-
tive splicing. These tau isoforms may include three or four of the repetitive motives that bind to the
microtubules (respectively three or four repeats tau: 3R or 4R tau). In 3R tau the second repeat (en-
coded by exon 10) has been spliced out. Western blot analysis reveals three main patterns of migra-
tion of tau protein in neurodegenerative diseases explained by different ratios of tau isoforms (79,80).
The accumulation of tau involves:
3R and 4R tau: This is the case in Alzheimers disease (81,82), PEP (83), and PDC).
4R tau: This occurs in PSP, CBD (79,84), and argyrophilic grain disease (85).
3R tau: As in Picks disease (86).
Several transgenic mice expressing tau transgenes under various promoters have been produced.
Tau-positive inclusions in neurons and glia have been observed in some of these lines (87). The
clinical deficit is related to the site of expression of the tau transgene (88).
We will now consider the diseases in which tau-enriched inclusions are observed either in neurons
or in glia (so called tauopathy). The isoform(s) of tau that accumulate and the shape of the inclu-
sions are characteristic of each one of these disorders. Four-R, 3R, and 3&4R tauopathies are the
diseases in which, respectively, 4R tau, 3R tau, and 3&4R tau accumulate.
The 4R Tauopathies: PSP, CBD, and Argyrophilic Grain DiseaseTheir Borders

and Overlaps
In PSP, CBD (89), and argyrophilic grain disease (85), it is predominantly the tau protein contain-
ing four repetitive motives that accumulates. Parkinsonism is prominent in both PSP and CBD,
whereas dementia is the main symptom of argyrophilic grain disease. Although parkinsonism is lack-
ing in this last disorder, we shall briefly deal with it, since it may be associated with the other two.
The initial description of PSP and CBD (9092) suggested that their neuropathology was quite
different: neurofibrillary tangles (NFTs) were seen in the brainstem of PSP and ballooned neurons in
the cerebral cortex of CBD, two clearly different neuropathological lesions. The realization that tau
pathology was prominent in both disorders made their borders less sharply defined. Moreover, PSP
122 Duyckaerts
and CBD share a common genetic risk factor: several polymorphisms have been identified in the tau
gene (93) and may be grouped in two haplotypes, H1 and H2. The H1 haplotype, is frequent in the
general population (frequency of that haplotype in the general population, around 77%) but this fre-
quency reaches nearly 94% in PSP cases and 92% in CBD (94,95). Despite this resemblance, PSP
and CBD have characteristics of their own that we will now discuss.

There were various reports of cases with hypertonia and gaze palsy of voluntary movements
before the classical description of Steele et al. (90). At the time of that paper, a major issue was to
differentiate postencephalitic parkinsonism from PSP, since both disorders were initially defined by
the presence of NFTs in the brainstem (96). The distinction still remains difficult today, on either
clinical (97) or pathological grounds (98).
Soon after the identification of tau protein epitopes in the NFTs of Alzheimers disease (99,100),
NFTs in PSP were also found to be reactive with tau antibody (101). Tau immunohistochemistry, but
also a particular silver method (Gallyas silver impregnation; see ref. 102), expanded the span of the
morphological alterations thought to be characteristic of PSP. It was discovered that fibrillar struc-
tures, especially in the basal ganglia, were intensely reactive with tau antibody. They were called
neuropil threads (103) by analogy with morphologically similar lesions found in Alzheimers dis-
ease. However, electron microscopy revealed that the accumulation of tau protein, in PSP, occurred
in the myelin rather than in the axon itself (104106). Tau is initially present in the cytoplasm of the
oligodendrocytes, and follows the cytoplasm while it wraps around the axon in the process of myelin
formation (106). In the cell body of the oligodendrocytes, tau precipitates in fibrillar structures, which
seem to coil around the oligodendrocyte nucleus, hence the term coiled body proposed by Braak
and Braak (107). Coiled bodies were initially described in argyrophilic grains disease (another 4R
tauopathy mainly responsible for cognitive deficits, as previously mentioned). Coiled bodies are actu-
ally present in a range of diseases where tau protein accumulates in oligodendrocytes (not only PSP, but
also argyrophilic grains disease, Picks disease and CBD).
Oligodendrocytes are not the only glial cells in which tau protein accumulates. Astrocytes are also
altered. Although this astrocytic lesion happened to be identified much later than the NFTs, it now
seems to be the best marker of PSP (108). Tau accumulation in astrocytes was initially suspected on
the shape of the cell bearing the inclusion: the nucleus was clear and the immunoreactivity filled the
entire length of the cellular processes, which appeared to be equally distributed in all directions
hence the name tuft(ed) astrocyte that was applied to this lesion (109,110). Double labeling showed
a colocalization of tau and glial fibrillary acid protein (GFAP) (108,111113). Tufted astrocytes are
particularly abundant in the putamen and caudate nucleus; they are also found in the red nucleus and
in the superior colliculus (114).
There are still some discussions concerning the ultrastructural aspect of PSP lesions. The first
descriptions concluded that NFTs were made of straight filaments 15 nm in diameter, straight tubules
(115,116) clearly different from the paired helical filaments (PHFs) as seen in Alzheimers disease.
Other reports mention twisted structures, 22 nm in diameter, reminiscent of PHFs and described as
twisted tubules (117,118). A more recent study (119) suggests that straight filaments are present in
glia, either in oligodendrocytes (coiled bodies) where they are 15 nm thick and have a smooth appear-
ance or in astrocytes (tufted astrocytes), where they have jagged contours and their diameter reaches
22 nm. The twisted filaments (22 nm wide) are most commonly seen in neurons (NFTs).
In the initial paper of Steele et al. (90), the pathology was described as largely confined to sub-
cortical structures. Increased sensitivity of the staining procedures and of immunohistochemistry
allowed for the conclusion that the cerebral cortex was not spared and often contained NFTs
(109,120,121). Astrocytic tufts are also present in the cortex, particularly in the precentral and
premotor areas (108,114).
Tau accumulation takes place in selective regions of the brain and the balance between the three
major alterations (tuft astrocytes, neuropil threads, and NFTs) is variable according to the regions
(110,122) (see Chapter 4).
The diagnosis of PSP was previously clinico-pathological and although cases without gaze palsy
had been reported (123,124), the clinical syndrome appeared fairly homogeneous. The recent ten-
dency of relying mainly on morphological markers to make the diagnosis deeply modified the clini-
cal aspect of the disease and greatly expanded its scope (Table 3). Prominent frontal syndrome
(already mentioned by Cambier et al. in ref. 125) and cognitive decline (126128) probably related to
the severity of the cortical involvement (129,130), progressive aphasia (131), limb apraxia, focal
dystonia, and arm levitation more common in CBD (126,132135) have been reported in pathologi-
cally confirmed PSP cases. On the other hand, supranuclear gaze palsy, initially considered to be the
clinical hallmark of the disease, may be absent in as many as half the cases (123,124).
A focus of atypical parkinsonism resembling PSP has also been identified in Guadaloupe, French
West Indies (136). Three cases have been published up to now. In two cases, the diagnosis of PSP
could be reliably made. One case had an unusual tauopathy characterized by pretangles, tangles, and
a large number of threads, without tufted astrocytes nor glial plaques. Tau gene was found normal
(136). In the three cases, the Western blot showed 4R-tau accumulation. The high prevalence of
atypical parkinsonism in Guadaloupe has been attributed to environmental factor. Herbal tea or fruits
of tropical plants, traditionally used by African-Caribbeans, contain alkaloid toxins, which could
play a pathogenic role (137).
Apraxia is an inability of carrying on a purposive movement, not explained by a motor deficit, a
sensory loss, or ataxia. In the absence of a space-occupying or vascular lesion, progressive apraxia of
relentless course is a striking and uncommon clinical sign, which helped to identify the disorder now
known as CBD (91,92). In the first three cases that were published, the emphasis was put on two
basic features of the disorder:
1. The neuronal loss had a peculiar topography for which the forbidding label of corticodentatonigral degen-
eration was proposed.
2. A special lesion of the neurons was observed in the involved areas: having lost their Nissl granules, their
cell body appeared abnormally pale.
In the first days of neuropathology, when Nissl stain was the most commonly used technique in
neuropathology, Nissl granules were the only structures that were stained in the neuronal cell body.
A neuron without Nissl granules was said to be chromatolytic (chroma = color); chromatolysis is, for
instance, the consequence of axon section. Rebeiz, Kolodny, and Richardson (91,92) coined the new
term achromatic to define the neurons that were found in this new disorder and that might, indeed,
be slightly different from those seen in chromatolysis (92). The appearance of these swollen nerve
cells was reminiscent of the central chromatolysis that typifies the retrograde cell change (axonal
reaction) and the neuronal change typical of pellagra but differed in that there was total disappear-
ance of Nissl granules, rather than sparseness or peripheral displacement of them (92).
Strangely enough, CBD, as judged by published reports, remained exceptionally diagnosed for
many years. It was felt at that time that the major difficulty was to distinguish achromatic neurons of
CBD from the ballooned neurons (also called Picks cells) found in Picks disease. Although Picks
disease is essentially a frontal dementia, cases were reported with a predominant parietal syndrome
characterized by a progressive apraxia (138,139). The border with CBD appeared thus difficult to
draw. This may still be the case today but for other reasons.
The diagnosis of CBD has experienced a renaissance when a new name was given to the disease to
emphasize the peculiar distribution of the lesions: they indeed involve both the cortex and the basal
gangliahence corticobasal degeneration (140). Scrutiny of the lesions of the substantia nigra sug-
124
Table 3
Typical and Atypical Clinical Forms of Progressive Supranuclear Palsy and Corticobasal Degeneration
Distinctive Common
Clinical Neuropathological Histopathological Common Genetic Common Biochemical
Symptoms Features Features Risk Factor Characteristic
PSP Typical form Gait disturbance Abundant NFTs (straight filaments) NFTs in substantia nigra
Severe rigidity without tremor in brainstem & pallidum
Poor Dopa responsiveness Astrocytic tufts in putamen,
Gaze supranuclear palsy premotor, and prefrontal cortex.
PSP Atypical clinical Prominent frontal syndrome Generally linked with the severity Coiled bodies
forms Cognitive decline of the involvement of specific areas.
Limb apraxia Astrocytic tuft used as a Tau-positive threads of glial High prevalence of the H1 Accumulation of tau
diagnostic marker. origin (more in CBD than haplotype of tau protein protein with four
in PSP) repetitive motives
Progressive apraxia (4R-tau), i.e., with the
sequence corresponding
Absence of supranuclear palsy ? to exon 10
CBD Typical form Progressive aphasia Ballooned neurons principally in Ballooned neurons in limbic
cortex. Astrocytic plaque in cortex system (especially in PSP if
and caudate. argyrophilic grain disease
associated)
CBD Atypical Supranuclear gaze palsy Generally linked with the severity
clinical forms Frontal syndrome of the involvement of specific areas.
Progressive aphasia Astrocytic plaque used as a
diagnostic marker.
PSP and CBD were initially clinicopathological diagnoses (a typical clinical syndrome was associated with a characteristic neuropathology). Since pathological markers have been used
to define themastrocytic tuft for PSP and astrocytic plaque for DCBtheir clinical phenotype has changed (atypical clinical forms). PSP and CBD have a common genetic risk factor
(tau haplotype H1). In both diseases, it is mainly tau 4-R that accumulates.
Duyckaerts
gested that some type of inclusion could help identifying the disorder: they were basophilic, poorly
argyrophilic with Bielschowsky stain, and filled the neuronal cell body (140). But those corticobasal
inclusions did not survive tau immunohistochemistry, which demonstrated that they were, in fact,
true NFTs.
It may be surprising that it took more than 25 yr to realize that a severe cytoskeletal pathology
occurred in CBD (141144). Such a long delay between the initial description of the disease and the
elucidation of its typical lesions is probably related to the poor reactivity of CBD alterations to stan-
dard silver stain (Gallyas stain, which exquisitely labels them, is an exception) (142). Immunohis-
tochemistry now reveals a whole range of tau accumulations in neurons, glia, and processes. In
neurons, it shows inclusions that resemble Picks bodies, a resemblance that has suggested overlaps
between the two disorders (145,146). However, Picks bodies and neuronal inclusions of CBD may
be distinguished (147): one important difference is the low reactivity of Picks bodies to Gallyas stain
in contrast to the neuronal inclusions of CBD. This contrast in staining properties could be due to a
difference in the isoforms of the tau protein that accumulates: Picks bodies are made of 3R-tau
whereas neuronal inclusions of CBD contain 4-R tau (148,149). The high density of tau-positive
threads in the subcortical white matter and in the deep layers of cortex is quite distinctive of CBD
(150,151). As in PSP, these threads appear to be related to the presence of tau in myelin inner and
outer loops (104). Another lesion is now considered to be more specific of CBD: the astrocytic
plaque (or glial plaque) characterized by an annulus of tau-positive structures surrounding a
clear central core (144). This lesion has been interpreted as the accumulation of tau in the distal pro-
cesses of the astrocyte (144,152): this interpretation is based on double-labeling experiments using tau
and CD44 antibodies. CD44 is a membrane protein found in leukocytes and activated astroglia.
Colocalization is not found with GFAP (144). Astrocytic plaques are particularly abundant in the
prefrontal and premotor areas of the cerebral cortex and in the caudate nucleus (114).
Tau-positive threads, coiled bodies, and tangles are shared lesions of CBD and PSP. Thus, although
it was, initially, with Picks disease that the border of CBD was considered difficult to draw, it was,
later on, with PSP that the differences seemed to be most elusive. Komori et al. proposed using
astrocytic plaques and tufted astrocytes as diagnostic hallmarks, respectively of CBD and PSP
(153,154), an opinion that was essentially endorsed by the diagnostic criteria of CBD (155). When
these neuropathologic markers are taken as diagnostic tools, the clinical presentation of both diseases
appears to be more diverse than initially thought: there are indeed cases of supranuclear gaze palsy
(156), progressive aphasia (131,147,157), or frontal dementia (158,159), which exhibit the typical
lesions of CBD, whereas some patients who meet the neuropathologic diagnostic criteria of PSP
present, as we have seen, with progressive apraxia, reminiscent of CBD.
The use of astrocytic plaques and of tufted astrocytes as the diagnostic markers of CBD and PSP,
respectively, modifies the spectrum of the clinical phenotype of both diseases and makes any predic-
tion concerning the pathology, at least presently, particularly difficult. There are distinctive features
at neuropathological examination (they are fully reviewed in ref. 160), but even at this stage doubts
concerning the diagnosis may remain; cases have been described with neuropathological characteris-
tics of both disorders (161).
Argyrophilic Grain Disease and Neurofibrillary Degeneration of CA2

Argyrophilic grain disease is characterized by the presence of small, spindle-shaped structures
loosely scattered in the neuropil of the hippocampus, entorhinal cortex, and amygdala. It was origi-
nally found in cases with dementia and was frequently associated with Alzheimers disease-type
pathology. Parkinsonism is not a feature of this disease but since the grains are the focal accumula-
tion of 4R-tau (85) in dendritic spines, it is useful to mention here that association of argyrophilic
grain disease and PSP seems particularly frequent (162). Also common to 4R tauopathy is the neu-
rofibrillary degeneration in CA2 sector of the hippocampus, an unusual alteration found in argyro-
philic grain disease, PSP, and CBD (163).
126 Duyckaerts
The 3 and 4R Tauopathies

We turn now to a set of disorders in which tau protein that makes up the inclusions is a various mix
of 3R and 4R isoforms. Alzheimers disease belongs to that category and because of its frequency is
the first disorder to be considered in this chapter.
Alzheimers Disease
Alzheimers-type pathology is the only detectable lesion in a significant proportion of cases in
which the diagnosis of IPD has been made premortem (20,164,165). This observation raises the
possibility that Alzheimers disease, in the absence of dementia, causes the parkinsonian symptoms
by a direct involvement of the nigrostriatal pathway (165). It is not the place to review here the
pathology of Alzheimers disease: suffice it to say that extracellular deposition of AG peptide and
intracellular accumulation of both 3R and 4R tau isoforms are the principal lesions. Tau accumulates
in three compartments: the neuronal cell body (NFT), the dendrites (neuropil threads), and the axonal
component of the corona of the senile plaques (their neuritic component). AG deposition, without a
neuritic component, does not correlate with symptoms or only weakly, whereas tau pathology usually
strongly does. The abundance of AG peptide deposits in the striatum has been known for a long time
(166) but it is doubtful, in view of what has just been said, that they explain the clinical signs. It is
more likely that the NFTs found in many large and in a few medium-size neurons of the same nucleus
(166) play a role. There is also evidence that the NFTs present in the substantia nigra (167) are the
main culprit; their abundance is indeed linked with the severity of the extrapyramidal signs (168).
The existence and the severity of the neuronal loss in this nucleus is discussed (168170).
The involvement of the substantia nigra could be more severe in the common type of DLB, in
which Lewy bodies and NFTs combine their effects. Extrapyramidal symptoms belong to the cardi-
nal signs, which should raise the possibility of DLB in cases of dementia. However, as already men-
tioned, it is difficult to differentiate on a clinical basis Alzheimers disease with and without Lewy
bodies (171) from DLB cases with and without Alzheimers lesions (37).
Dementia pugilistica, the dementia that develops in boxers, is characterized by a severe extrapyra-
midal syndrome. Its pathology resembles Alzheimers disease pathology (172). Quite intriguing is
the finding of isolated neocortical NFTs in a young boxer who died early in his career (173). This
suggests that head trauma could, by itself, induce the formation of NFTs, preceding amyloid deposi-
tion (174) (see Chapter 4 for further developments).
The two disorders that are considered next, PEP and PDC, are rare. The epidemic at the origin of
PEP ended a long time ago. PDC is confined to one small geographic area. Data from these disorders
may help answer two questions: Are the differences in the ratio of tau isoforms between tauopathy
explained by the cell types in which tau accumulates? Are tauopathies explained by a specific etiol-
ogy? (1) To explain that different tau isoforms accumulate in various diseases, the hypothesis has
been put forward that their relative abundance depends on the cellular type, neuronal or glial, in
which the inclusions are found. PEP and PDC show that this is probably not the case: tau accumulates
only in neurones in Alzheimers disease, a 3&4R tauopathy. PEP and PDC are also 3&4R tauopathies
but the inclusions are not limited to the neurones. (2) PEP also indicates that NFTs cannot be consid-
ered as indicating a specific etiology. It is indeed observed in disorders caused by mutations, head
traumas (dementia pugilistica), or, as shown by PEP, an infectious disease of the brain. NFTs could
be a process specific marker, the evidence of a stereotyped reaction of the neurone to injury.
Postencephalitic Parkinsonism
Parkinsonism, and other movement disorders, followed acute episodes of encephalitis lethargica,
initially described by von Economo during an outbreak of the disease in 19161917 in Vienna. Cases
were reported in 1918 in France, England, and North America. The disease presented with a variety
of symptoms such as somnolence, ophthalmoplegia, hyperkinesias, and akinesia. Parkinsonism, described
as the chronic form of the episode, could appear years after the acute episode (175). Most salient clinical
characteristics of PEP are onset below middle age, symptom duration lasting more than 10 yr, pres-
ence of oculogyric crisis, and obviously a history of encephalitis (176). The disease has been linked
to the Spanish influenza pandemic that occurred at approximately the same time. The influenza
virus responsible for the Spanish flu has been isolated from an archival 1918 autopsy lung sample; its
RNA was not detected in archival brain tissues from acute encephalitis lethargica. These data make
the connection between Spanish flu and encephalitis lethargica doubtful (177).
In the acute phase, the disease was characterized by a severe inflammation, with perivascular
cuffing and neuronophagia, in the mesencephalon, particularly the substantia nigra, and in the dien-
cephalon. Pathology is characterized by abundant neurofibrillary tangles present in a wide range of
regions, the substantia nigra being usually massively involved and showing severe neuronal loss. Of
more recent notice is the presence of glial fibrillary tangles or astrocytic tufts (178), characterized by
the presence of tau protein in astrocytes, not necessarily found in the regions most affected by tangle
formation (179).
In the absence of clinical history, the distinction between PSP and PEP may be particularly diffi-
cult. Subtle differences in the distribution of the lesions have been described (180), but the ultrastruc-
tural aspect of the tangles (more often PHFs similar to Alzheimers disease tangles than straight
filaments common in PSP) as well as the biochemical signature of tau accumulation (both 3R and 4R
tau [83] in PEP; 4R tau in PSP) are ways of differentiating both disorders, despite their morphologic
resemblance.
Parkinsonism Dementia Complex of Guam
This disease appears so tightly related to a geographical area that the island of Guam, where it was
initially described, is mentioned in its very name. However, a similar disorder is probably found in
other foci of the worldthe Kii peninsula, in Japan, being one (see refs. 181183 for a review of the
pathology).
The neuropathologist Harry Zimmerman, assigned by the U.S. Navy to Guam during World War
II, was the first to notice there a high incidence of amyotrophic lateral sclerosis (ALS). ALS was said
to affect 10% of the population and the number of deaths attributed to ALS was 100 times higher in
Guam than in other countries (184). It was secondarily noted that another degenerative disease, com-
bining parkinsonism and dementia, was also highly prevalent. The neuropathology of this Guam
parkinsonism dementia complex (PDC) was described by Hirano et al. (184,185). Hirano et al.
divided the cases into three groups: Parkinsonism and dementia; Parkinsonism, dementia, and involve-
ment of the upper motor neuron; cases with symptoms of lower motor neuron disease. The opinion has
recently been expressed that ALS in Guam is not different from ALS in other parts of the world
(181). The presence of Bunina bodies, the marker of classical ALS, in the Guam cases is one of the
data in favor of this view (186).
The neuropathology of PDC combines NFTs and neuronal loss. Most of the tangles are made of
paired helical filaments, similar to those seen in Alzheimers disease. They are tau- and, for some of
them, ubiquitin-positive and have the same immunological profile as Alzheimers tangles. According
to one study (187), they could occupy the cell body of the neuron for 2.5 yr before causing its death.
They are then freed in the neuropil (ghost tangle). The distribution of the NFTs is widespread: isocor-
tex and hippocampus, striatum and pallidum, hypothalamus, amygdala, substantia nigra,
periaqueductal gray, pontine nuclei, dorsal nucleus of the vagus nerve, reticular formation, anterior and
posterior horns of the spinal cord are among the affected structures. Neuronal loss explains the cerebral
atrophy and is usually marked in the substantia nigra and locus coeruleus. The cerebellum is usually
spared. AG pathology and tau-positive threads are not features of PDC. Glial pathology, shown by
Gallyas stain and tau immunohistochemistry, has been observed more recently. It consists in granu-
lar hazy inclusions found in the cell body of the astrocytes and crescent/coiled inclusions in oligo-
dendrocytes (188). Hirano bodies, i.e., eosinophilic rodlike inclusions adjacent to neuronal cell bodies
128 Duyckaerts
(and occasionally within them), in the Sommer sector of the hippocampus, were initially described
in Guam patients but were also found later in other degenerative diseases.
Guam ALS/PDC has raised many still unanswered questions. Since the disease seemed to be con-
fined to the Chamorro population, the native people of Guam, a hereditary disorder was initially
suspected. However, several facts argue against an etiologic role of heredity. The incidence of Guam
ALS has been dramatically decreasing in the last decades (although the incidence of PDC not so
markedly), a change that heredity cannot explain. The risk of developing the disease is lower in
Chamorros that have left Guam but with inertia (a latency of several decades). Finally, Filipinos and
a few Caucasians have also developed the disease (see review in ref. 183).
Many attempts made to identify the cause of Guam ALS/PDC have failed. The principal etiologies
that have been considered are infectious (by a process similar to PEP after encephalitis lethargica)
and toxic. The possibility that cycad, the seed of the false sago palm traditionally used in Chamorro
food, contained toxic species, was put forward by P. Spencer (189). However the amount of seed
necessary to obtain a toxic effect in the monkey seems incompatible with the common use of cycad
by Chamorros (190). More recently, Perl et al. have shown a high concentration of aluminum and
iron in the NFTs of Guam ALS/PDC and have suggested that these metals could play a role in the
pathogenesis (see review in ref. 183). Although the identification of the etiological factor should be
easier for a rare disorder developing in a circumscribed environment than for common diseases that
are geographically widespread, the etiology of Guam ALS/PDC remains elusive.
The Use of the Terms Picks Disease and Picks Complex

Although parkinsonism in Picks disease (in the restricted sense) is a secondary symptom and
raises little diagnostic difficulty, the extensive use of the term Picks disease and the recently intro-
duced Picks complex (which may include conditions otherwise defined as CBD) requires some
explanation.
The clinical symptoms of frontal involvement, which are seen at the onset in some cases of dementia,
contrast strongly with the initial memory problems typical of Alzheimers disease. In the old literature
(191193), those cases were grouped under the heading of Picks disease. The term was historically
incorrect since Pick had initially described cases with focal cortical deficit owing to circumscribed
atrophy (in the language of the time) (194196). Cases of frontal syndrome are not included in his
main articles, which described cases of progressive aphasia (197) and of progressive apraxia (196).
Alzheimer performed the neuropathological examination of cases of circumscribed atrophy (prob-
ably of the frontal lobe but this is barely mentioned in his paper) and found a new inclusion (198)
(English translation in ref. 199), which was later known as Picks body. It is a spherical accumulation
of tau-positive and argyrophilic material, approximately the size of the nucleus, located in the cell
body of the neurons. Picks body is generally considered as almost exclusively made of 3R tau
(148,149,200), although some doubts have been recently expressed concerning the selectivity of the
isoform (201). Picks bodies are particularly abundant in the dentate gyrus, where they are consid-
ered to be constant. They are generally associated with ballooned, chromatolytic neurons, called
Picks cells. Ramified astrocytes and small Picks body-like inclusions, discovered more recently,
are evidence that the disease does not spare the glia (202). Picks bodies are generally found in cases
of dementia with a predominant frontal syndrome.
The meanings of Picks disease have been shaped by the various historical contexts in which the
term has been used (focal cortical syndrome or circumscribed atrophy; frontal syndrome owing to
a degenerative disease with or without Picks bodies; dementia, generally of the frontal-lobe type,
with Picks bodies). A Venn diagram may visualize the relationship between these different mean-
ings, from the least to the most specific ones, and helps explain why Picks disease has come to be
such a confusing label (see Fig. 6). The recent attempt to introduce the term Picks complex for a
large set of disorders with various neuropathology (203209) may, in our view, be discussed since it
Fig. 6. The different meanings of Picks disease. The different meanings of the term Picks disease cover
overlapping subsets of disorders. The concept of Picks complex, more recently proposed (205), would prob-
ably include most of the cases that were historically described under the heading of Picks circumscribed
atrophy. From the point of view adopted in this chapter, it seems more adequate to restrict the use of the term
to its most specific meaning of Picks bodies dementia. Picks bodies are generally found in sporadic cases
with a predominant frontal syndrome. Cases with progressive aphasia (139,209,230) or apraxia (139) have been
described, explaining why the last circle (Picks bodies dementia) overlaps the set of circumscribed atro-
phies (focal cortical syndromes). The surface areas enclosed in the three circles are subjective evaluations of
the prevalence of the various disorders: the figure does not rely on objective data.
lumps diseases that all the recent data tend to separate. We would rather recommend restricting the
use of Picks disease to the cases of dementia with Pick bodies (210,211), as most neurologists and
neuropathologists would (212). In this use, Picks disease is a rare sporadic disease.
The Familial Tauopathies: Frontotemporal Dementia With Parkinsonism

Besides the sporadic cases with Picks bodies, a large number of patients present with a frontal
syndrome of progressive course. A fair proportion of them are familial. Among them, several exhibit
parkinsonian symptoms. A consensus meeting identified some of those families with linkage to chro-
mosome 17 and grouped those cases under the heading of frontotemporal dementia with parkin-
sonism linked to chromosome 17 or FTDP-17 (213). Shortly after, a mutation of the tau gene was
found in some of these families (214,215). Tau mutations are very diverse and so is the neuropathol-
ogy. The isoforms of tau, which accumulate depend on the mutation. Both 3R and 4R tauopathy are
met in this group of disorders. It is not the place here to review the complex picture of FTDP-17
neuropathology (analyzed in details in ref. 216). It is useful however to emphasize here the pheno-
typic mimicry of some specific mutations. The neuropathology of the sporadic diseases that we
have previously considered, more specifically PSP (217), CBD (218,219), and Picks disease
(220,221), can, indeed, be mimicked by tau mutations. This observation suggests that the cellular
type in which tau accumulation occurs, and its subcellular topography, is highly dependent on the tau
molecule itself. The presence of ballooned neurons, NFTs, Picks bodies, and glial inclusions may,
indeed, be determined by one single change in the molecular structure of tau. This is not to say that all
the diseases that were considered here have a genetic origin: PSP, CBD, and Picks disease are, in the
great majority of cases, sporadic. But the similarity of the phenotypes suggests that the pathogenic
mechanism involves directly tau protein in the sporadic as well as in the hereditary tauopathies.
130 Duyckaerts
OTHERS CAUSES
This review did not consider drug-induced parkinsonism, probably its most common etiology and
usually related to neuroleptics. Suffice it to say that up to now, no lesions have been identified in
those cases. Toxic causes (MPTP induced or related to manganese poisoning) are dealt with in
Chapter 4. Several hereditary disordersamong which are spinocerebellar ataxia (SCA),
Huntingtons disease (related to an expansion of the triplet cytosine adenine guanine coding for a
long polyglutamine stretch in the mutated protein), Wilsons disease, neurodegeneration with brain
iron accumulation (formerly HallervordenSpatz disease)may cause extrapyramidal symptoms.
They are considered in the Chapter 4.
FUTURE DIRECTIONS
The nosology of neurodegeneration will ultimately rely on the understanding of mechanisms.
Mechanism, in this context, means the intricate relationship between the cause of a disease and the
beneficial or detrimental processes that the organism triggers in response. A number of
neurodegenerative diseases will probably give their secret in the decades to come, with the help of
molecular biology and of the animal models that are rapidly generated. What will then be the place
of pathology? Will its role be reduced to that of classifying details? Will it still be used as an
important way to unravel the complexity of the postgenomic processes? Time will tell. For the present
time, the morphological markers are important indications that should help both the doctor to reach a
specific and precise diagnosis and the scientist to focus his or her investigations.
REFERENCES
1. Martin JP. The basal ganglia and posture. London: Pitman Medical Publishing, 1967.
2. Fahn S. Description of Parkinsons disease as a clinical syndrome. Ann N Y Acad Sci 2003;991:114.
3. Lewy FH. Die Lehre vom Tonus und der Bewegung zugleich systematische Untersuchungen zur Klinik, Physiologie,
Pathologie und Pathogenese der Paralysis Agitans. Berlin: Julius Springer, 1923.
4. Falck B, Hillarp NA, Thieme G, Torp A. Fluorescence of catecholamine and related compounds condensed with form-
aldehyde. J Histochem Cytochem 1962;10:348354.
5. Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H. Where does Parkinson disease pathology begin in the brain?
6. Jellinger KA. Post mortem studies in Parkinsons diseaseis it possible to detect brain areas for specific symptoms?
J Neural Transm Suppl 1999;56:129.
7. Jellinger KA, Mizuno Y.Parkinsons disease. In: Dickson D, eds. Neurodegeneration: The Molecular Pathology of
Dementia and Movement Disorders. Basel: ISN Neuropath Press, 2003.
8. Hunter R, Smith J, Thomson T, Dayan AD. Hemiparkinsonism with infarction of the ipsilateral substantia nigra.
9. Gherardi R, Roualdes B, Fleury J, Prost C, Poirier J, Degos JD. Parkinsonian syndrome and central nervous system
lymphoma involving the substantia nigra. A case report. Acta Neuropathol (Berl) 1985;65:338343.
10. Josephs KA, Ishizawa T, Tsuboi Y, Cookson N, Dickson DW. A clinicopathological study of vascular progressive supra-
nuclear palsy: a multi-infarct disorder presenting as progressive supranuclear palsy. Arch Neurol 2002;59:15971601.
11. Wilson SAK. An experimental research into the anatomy and physiology of the corpus striatum. Brain 1914;36:437.
12. Russmann H, Vingerhoets F, Ghika J, Maeder P, Bogousslavsky J. Acute infarction limited to the lenticular nucleus:
clinical, etiologic, and topographic features. Arch Neurol 2003;60:351355.
13. Chang CM, Yu YL, Ng HK, Leung SY, Fong KY. Vascular pseudoparkinsonism. Acta Neurol Scand 1992;86:588592.
14. Adhiyaman V, Meara J. Meningioma presenting as bilateral parkinsonism. Age Ageing 2003;32:456458.
15. Gibb WRG, Lees AJ. The significance of the Lewy body in the diagnosis of idiopathic Parkinsons disease. Neuropathol
Appl Neurobiol 1989;15:2744.
16. Shimura H, Schlossmacher MG, Hattori N, et al. Ubiquitination of a new form of Fsynuclein by parkin from human
brain: implications for Parkinsons disease. Science 2001;293:263269.
17. Calne D. Parkinsons disease is not one disease. Parkinsonism Relat Disord 2000;7:37.
18. Armstrong RA, Cairns NJ, Lantos PL. Are pathological lesions in neurodegenerative disorders the cause or the effect of
the degeneration? Neuropathology 2002;22:133146.
19. Tretiakoff C. Contribution ltude de lanatomie pathologique du locus niger de Soemmering avec quelques dductions
relatives la pathognie des troubles du tonus musculaire et de la maladie de Parkinson; Medical Thesis, Paris: Jouve
et Cie, 1919:124p.
20. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinsons disease : a clinico-
pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181184.
21. Okazaki H, Lipkin LE, Aronson SM. Diffuse intracytoplasmic inclusions (Lewy type) associated with progressive
dementia and quadriparesis in flexion. J Neuropathol Exp Neurol 1961;20:237244.
22. Duffy PE, Tennyson VM. Phase and electron microscopic observations of Lewy bodies and melanin granules in the
substantia nigra and locus caeruleus in Parkinsons disease. J Neuropathol Exp Neurol 1965;24:398414.
23. Pollanen MS, Dickson DW, Bergeron C. Pathology and biology of the Lewy body. J Neuropathol Exp Neurol
1993;52:183191.
24. Lowe J, Blanchard A, Morrell K, et al. Ubiquitin is common factor in intermediate filament inclusion bodies of diverse
type in man, including those of Parkinsons disease, Picks disease, and Alzheimers disease, as well as Rosenthal
fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol
1988;155:915.
25. Ii K, Ito H, Tanaka K, Hirano A. Immunocytochemical co-localization of the proteasome in ubiquitinated structures in
neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol 1997;56:125131.
26. Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynap-
tic nerve terminal. J Neurosci 1988;8:28042815.
27. Ueda K, Fukushima H, Masliah E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid
in Alzheimer disease. Proc Natl Acad Sci USA 1993;90:1128211286.
28. George JM, Jin H, Woods WS, Clayton DF. Characterization of a novel protein regulated during the critical period for
song learning in the zebra finch. Neuron 1995;15:361372.
29. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the Fsynuclein gene identified in families with
Parkinsons disease. Science 1997;276:20452047.
30. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. &synuclein in filamentous inclusions of Lewy
bodies from Parkinsons disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 1998;95:64696473.
31. Uchikado H, Iseki E, Tsuchiya K, et al. Dementia with Lewy bodies showing advanced Lewy pathology but minimal
Alzheimer pathologyLewy pathology causes neuronal loss inducing progressive dementia. Clin Neuropathol
2002;21:269277.
32. Gomez-Isla T, Growdon WB, McNamara M, et al. Clinicopathologic correlates in temporal cortex in dementia with
Lewy bodies. Neurology 1999;53:20032009.
33. Kosaka K, Tsuchiya K, Yoshimura M. Lewy body disease with and without dementia: a clinicopathological study of 35
cases. Clin Neuropathol 1988;7:299305.
34. Kosaka K, Yoshimura M, Ikeda K, Budka H. Diffuse type of Lewy body disease: progressive dementia with abundant
cortical Lewy bodies and senile changes of varying degreea new disease? Clin Neuropathol 1984;3:185192.
35. Kosaka K. Diffuse Lewy body disease in Japan. J Neurol 1990;237:197204.
36. Braak H, Braak E, Yilmazer D, Schultz C, Devos RAI, Jansen ENH. Nigral and extranigral pathology in Parkinsons
disease. J Neural Transm 1995;Supp 46:1531.
correlates of dementia with Lewy bodies. Neurology 1999;53:12841291.
38. Marui W, Iseki E, Nakai T, et al. Progression and staging of Lewy pathology in brains from patients with dementia with
Lewy bodies. J Neurol Sci 2002;195:153159.
39. Rajput AH, Rozdilsky B. Dysautonomia in Parkinsonism: a clinicopathological study. J Neurol Neurosurg Psychiatry
1976;39:10921100.
40. Iwanaga K, Wakabayashi K, Yoshimoto M, et al. Lewy body-type degeneration in cardiac plexus in Parkinsons and
incidental Lewy body diseases. Neurology 1999;52:12691271.
41. Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F. Parkinsons disease: the presence of Lewy bodies in
Auerbachs and Meissners plexuses. Acta Neuropathol (Berl) 1988;76:217221.
42. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinsons disease. Arch
Neurol 1993;50:140148.
43. Hakim AM, Mathieson G. Dementia in Parkinson disease: a neuropathologic study. Neurology 1979;29:1209.
44. Boller F, Mizutani R, Roessmann U, Gambetti P. Parkinsons disease, dementia and Alzheimers disease: clinico-
pathological correlations. Ann Neurol 1980;1:329355.
45. Gaspar P, Gray F. Dementia in idiopathic Parkinson disease. A neuropathological study of 32 cases. Acta Neuropathol
(Berl) 1984;64:4352.
46. Mattila PM, Roytta M, Torikka H, Dickson DW, Rinne JO. Cortical Lewy bodies and Alzheimer-type changes in
patients with Parkinsons disease. Acta Neuropathol (Berl) 1998;95:576582.
132 Duyckaerts
47. Jendroska K, Kashiwagi M, Sassoon J, Daniel SE. Amyloid beta-peptide and its relationship with dementia in Lewy
body disease. J Neural Transm Suppl 1997;51:137144.
48. Jellinger KA, Seppi K, Wenning GK, Poewe W. Impact of coexistent Alzheimer pathology on the natural history of
Parkinsons disease. J Neural Transm 2002;109:329339.
49. Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW. Parkinson disease neuropathology: later-developing dementia
and loss of the levodopa response. Arch Neurol 2002;59:102112.
50. Gibb WR, Lees AJ. Prevalence of Lewy bodies in Alzheimers disease. Ann Neurol 1989;26:691693.
51. Bergeron C, Pollanen M. Lewy bodies in Alzheimer diseaseone or two diseases? Alzheimer Dis Assoc Disord
1989;3:197204.
52. Mirra SS. Neuropathological assessment of Alzheimers disease: the experience of the Consortium to Establish a Reg-
istry for Alzheimers Disease. Int Psychogeriatr 1997;9:263268; discussion 269272.
53. Heyman A, Fillenbaum GG, Gearing M, et al. Comparison of Lewy body variant of Alzheimers disease with pure
Alzheimers disease: Consortium to Establish a Registry for Alzheimers Disease, Part XIX. Neurology
1999;52:18391844.
54. Schmidt ML, Martin JA, Lee VM, Trojanowski JQ. Convergence of Lewy bodies and neurofibrillary tangles in
amygdala neurons of Alzheimers disease and Lewy body disorders. Acta Neuropathol 1996;91:475481.
55. Hansen LA, Masliah E, Galasko D, Terry RD. Plaque-only Alzheimer disease is usually the Lewy body variant and vice
versa. J Neuropathol Exp Neurol 1993;52:648654.
56. Gearing M, Lynn M, Mirra SS. Neurofibrillary pathology in Alzheimer disease with Lewy bodies: two subgroups. Arch
Neurol 1999;56:203208.
57. Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimers disease : a clinical and pathologic entity.
Neurology 1990;40:18.
58. Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK. Senile dementia of Lewy body type. A clinically and
neuropathologically distinct form of Lewy body dementia in elderly. J Neurol Sci 1990;95:119139.
with Lewy bodies (DLB) : report of the consortium on DLB international workshop. Neurology 1996;47:11131124.
60. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop: diagnosis
and treatment. Consortium on Dementia with Lewy Bodies. Neurology 1999;53:902905.
61. Lantos PL, Ovenstone IM, Johnson J, Clelland CA, Roques P, Rossor MN. Lewy bodies in the brain of two members of
a family with the 717 (Val to Ile) mutation of the amyloid precursor protein gene. Neurosci Lett 1994;172:7779.
62. Lippa CF, Fujiwara H, Mann DMA, et al. Lewy bodies contain altered Fsynuclein in brains of many familiar
Alzheimers disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol
1998;153:13651370.
63. Lippa CF, Schmidt ML, Lee VM, Trojanowski JQ. Antibodies to Fsynuclein detect Lewy bodies in many Downs
syndrome brains with Alzheimers disease. Ann Neurol 1999;45:353357.
64. Perl DP, Olanow CW, Calne D. Alzheimers disease and Parkinsons disease: distinct entities or extremes of a spec-
trum of neurodegeneration? Ann Neurol 1998;44:S19S31.
65. Egensperger R, Bancher C, Kosel S, Jellinger K, Mehraein P, Graeber MB. The apolipoprotein E epsilon 4 allele in
Parkinsons disease with Alzheimer lesions. Biochem Biophys Res Commun 1996;224:484486.
66. Inzelberg R, Chapman J, Treves TA, et al. Apolipoprotein E4 in Parkinson disease and dementia: new data and meta-
analysis of published studies. Alzheimer Dis Assoc Disord 1998;12:4548.
67. Gearing M, Schneider JA, Rebeck GW, Hyman BT, Mirra SS. Alzheimers disease with and without coexisting Parkinsons
disease changes: apolipoprotein E genotype and neuropathologic correlates. Neurology 1995;45:19851990.
68. Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and Fsynuclein. Science
2003;300:636640.
69. Adams RD, Bogaert van L, Vander Eecken H. Dgnrescences nigro-stries et crbello-nigro-stries. Psychiatria et
Neurologia 1961;142:219.
70. Adams RD, Bogaert van L, Vander Eecken H. Striato-nigral degeneration. J Neuropathol Exp Neurol 1965;23:584608.
1999;163:9498.
72. Konigsmark BW, Weiner LP. The olivopontocerebellar atrophies: a review. Medicine (Baltimore) 1970;49:227241.
73. Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.
J Neurol Neurosurg Psychiatry 1969;32:2834.
74. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy
75. Costa C, Duyckaerts C, Cervera P, Hauw J-J. Les inclusions oligodendrogliales, un marqueur des atrophies
multisystmatises. Rev Neurol (Paris) 1992;148:274280.
76. Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K. Demonstration of F-synuclein immunoreactivity in

neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp
Neurol 2002;176:98104.
77. Kahle PJ, Neumann M, Ozmen L, et al. Hyperphosphorylation and insolubility of F-synuclein in transgenic mouse
oligodendrocytes. EMBO Rep 2002;3:583588.
78. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core
protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau.
Proc Natl Acad Sci U S A 1988;85:40514055.
79. Bue L, Delacourte A. Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration,
FTDP-17 and Picks disease. Brain Pathol 1999;9:681693.
80. Delacourte A, Buee L. Tau pathology: a marker of neurodegenerative disorders. Curr Opin Neurol 2000;13:371376.
81. Vermersch P, Frigard B, Delacourte A. Mapping of neurofibrillary degeneration in Alzheimers diseaseevaluation of
heterogeneity using the quantification of abnormal tau proteins. Acta Neuropathol (Berl) 1992;85:4854.
82. Delacourte A, Defossez A. Alzheimers disease: Tau proteins, the promoting factors of microtubule assembly are major
components of paired helical filaments. J Neurol Sci 1986;76:173186.
83. Buee-Scherrer V, Buee L, Leveugle B, Perl DP, Vermersch P, Hof PR, Delacourte A. Pathological tau proteins in
postencephalitic parkinsonism: comparison with Alzheimers disease and other neurodegenerative disorders. Ann
Neurol 1997;42:356359.
84. Flament S, Delacourte A, Verny M, Hauw J-J, Javoy-Agid F. Abnormal tau proteins in progressive supranuclear palsy.
Similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol (Berl)
1991;591596.
85. Togo T, Sahara N, Yen SH, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol
2002;61:547556.
86. Bue-Scherrer V, Hof PR, Bue L, et al. Hyperphosphorylated tau proteins differentiate corticobasal degeneration and
Picks disease. Acta Neuropathol (Berl) 1996;91:351359.
87. Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW. Filamentous tau in oligodendrocytes and astrocytes of transgenic
mice expressing the human tau isoform with the P301L mutation. Am J Pathol 2003;162:213218.
88. Allen B, Ingram E, Takao M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice
expressing human P301S tau protein. J Neurosci 2002;22:93409351.
89. Sergeant N, Wattez A, Delacourte A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal
degeneration: tau pathologies with exclusively exon 10 isoforms. J Neurochem 1999;72:12431249.
90. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy; a heterogeneous degeneration involving the
brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuclear dystonia and dementia.
Arch Neurol 1964;10:333359.
91. Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentatonigral degeneration with neuronal achromasia: a progressive
disorder of late adult life. Transact Am Neurol Assoc 1967;92:2326.
92. Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol
1968;18:2033.
93. Conrad C, Andreadis A, Trojanowski JQ, et al. Genetic evidence for the involvement of tau in progressive supranuclear
palsy. Ann Neurol 1997;41:277281.
94. Baker M, Litvan I, Houlden H, et al. Association of an extended haplotype in the tau gene with progressive supra-
nuclear palsy. Hum Mol Genet 1999;8:711715.
95. Houlden H, Baker M, Morris HR, et al. Corticobasal degeneration and progressive supranuclear palsy share a common
tau haplotype. Neurology 2001;56:17021706.
96. Steele JC. Progressive supranuclear palsy. Historical notes. J Neural Transm Suppl 1994;42:314.
97. Wenning GK, Jellinger K, Litvan I. Supranuclear gaze palsy and eyelid apraxia in postencephalitic parkinsonism. J
Neural Transm 1997;104:845865.
98. Geddes JF, Hugues AJ, Lees AJ, Daniel SE. Pathological overlap in cases of Parkinsonism associated with neurofibril-
and Guamanian parkinsonism-dementia complex. Brain 1993;116:122.
99. Brion JP, Passareiro H, Nunez J, Flament-Durand J. Mise en vidence immunologique de la protine tau au niveau des
lsions de dgnrescence neurofibrillaire de la maladie dAlzheimer. Arch Biol (Brux) 1985;95:229235.
100. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan H, Wiesniewski HM. Abnormal phosphorylation of the microtubule asso-
ciated protein (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986;83:49134917.
101. Bancher C, Lassmann H, Budka H, et al. Neurofibrillary tangles in Alzheimers disease and progressive supranuclear
palsy; antigenic similarities and differences. Acta Neuropathol (Berl) 1987;74:39.
102. Gallyas F. Silver staining of Alzheimers neurofibrillary changes by means of physical development. Acta Morphol
Acad Sci Hung 1971;19:18.
134 Duyckaerts
103. Probst A, Langui D, Lautenschlager C, Ulrich J, Brion JP, Anderton BH. Progressive supranuclear palsy: extensive
neuropil threads in addition to neurofibrillary tangles. Very similar antigenicity of subcortical neuronal pathology in
progressive supranuclear palsy and Alzheimers disease. Acta Neuropathol (Berl) 1988;77:6168.
104. Ikeda K, Akiyama H, Haga C, Kondo H, Arima K, Oda T. Argyrophilic thread-like structure in corticobasal degenera-
tion and supranuclear palsy. Neurosci Letters 1994;174:157159.
105. Ikeda K, Akiyama H, Aral T, Nishimura T. Glial tau pathology in neurodegenerative diseases; their nature and com-
parison with neuronal tangles. Neurobiol Aging 1998;19:S85S91.
106. Arima K, Nakamura M, Sunohara N, et al. Ultrastructural characterization of the tau-immunoreactive tubules in the
oligodendroglial perikarya and their inner loop processes in progressive supranuclear palsy. Acta Neuropathol (Berl)
1997;93:558566.
107. Braak H, Braak E. Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset de-
mentia. Neuropathol Appl Neurobiol 1989;15:1326.
108. Matsusaka H, Ikeda K, Akiyama H, Arai T, Inoue M, Yagishita S. Astrocytic pathology in progressive supranuclear
palsy: significance for neuropathological diagnosis. Acta Neuropathol (Berl) 1998;96:248252.
109. Hauw J-J, Verny M, Delare P, Cervera P, He Y, Duyckaerts C. Constant neurofibrillary changes in the neocortex in
progressive supranuclear palsy. Basic differences with Alzheimers disease and aging. Neurosci Lett 1990;119:182186.
110. Hauw J-J, Agid Y. Progressive Supranuclear Palsy (PSP) or SteeleRichardsonOlszewski Disease. In: Dickson D, eds.
Neurodegeneration: the molecular pathology of dementia and movement disorders. Basel: ISN Neuropath Press, 2003.
111. Abe H, Yagishita S, Amano N, Bise K. Ultrastructural and immunohistochemical study of astrocytic tangles (ACT)
in patients with progressive supranuclear palsy. Clin Neuropathol 1992;5:278.
112. Yamada T, McGeer PL, McGeer EG. Appearance of paired nucleated, Tau positive glia in patients with progressive
supranuclear palsy brain tissue. Neurosci Lett 1992;135:99102.
113. Yamada T, Calne DB, Akiyama H, McGeer PL. Further observations on tau-postive glia in the brains with progressive
supranuclear palsy. Acta Neuropathol (Berl) 1993;85:308315.
114. Hattori M, Hashizume Y, Yoshida M, et al. Distribution of astrocytic plaques in the corticobasal degeneration brain and
comparison with tuft-shaped astrocytes in the progressive supranuclear palsy brain. Acta Neuropathol 2003;106:143149.
115. Tellez-Nagel I, Wisniewski HM. Ultrastructure of neurofibrillary tangles in SteeleRichardsonOlszewski syndrome.
Arch Neurol 1973;29:324327.
116. Bugiani O, Mancardi GL, Brusa A, Ederli A. The fine structure of subcortical neurofibrillary tangles in progressive
supranuclear palsy. Acta Neuropathol (Berl) 1979;45:147152.
117. Tomonaga M. Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol (Berl)
1977;37:177181.
118. Yagishita S, Itoh Y, Amano N, Nakano T, Saitoh A. Ultrastructure of neurofibrillary tangles in progressive supra-
nuclear palsy. Acta Neuropathol (Berl) 1979;48:2730.
119. Takahashi M, Weidenheim KM, Dickson DW, Ksiezak-Reding H. Morphological and biochemical correlations of abnor-
mal tau filaments in progressive supranuclear palsy. J Neuropathol Exp Neurol 2002;61:3345.
120. Verny M, Duyckaerts M, Delare M, He Y, Hauw J-J. Cortical tangles in progressive supranuclear palsy. J Neural
Transm 1994;(Suppl)42:179188.
121. Verny M, Duyckaerts C, Agid Y, Hauw J-J. The significance of cortical pathology in progressive supranuclear palsy.
Brain 1996;119:11231136.
122. Hauw J-J, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic criteria for SteeleRichardsonOlszewski
123. Dubas F, Gray F, Escourolle R. Maladie de SteeleRichardsonOlszewski sans ophtalmoplgie; six cas anatomo-
cliniques. Rev Neurol (Paris) 1983;139:407416.
124. Birdi S, Rajput AH, Fenton M, et al. Progressive supranuclear palsy diagnosis and confounding features: report on 16
autopsied cases. Mov Disord 2002;17:125564.
125. Cambier J, Masson M, Viader J, Limodin J, Strube A. Le syndrome frontal de la paralysie supranuclaire progressive.
Rev Neurol (Paris) 1985;141:537545.
126. Davis PH, Bergeron C, McLachlan DR. Atypical presentation of progressive supranuclear palsy. Ann Neurol
1985;17:337343.
127. Litvan I. Cognitive disturbances in progressive supranuclear palsy. J Neural Transm 1994;42(Suppl):6978.
129. Bigio EH, Brown DF, White CL, III. Progressive supranuclear palsy with dementia: cortical pathology. J Neuropathol
Exp Neurol 1999;58:359364.
130. Foster NL, Sima AAF, DAmato C, et al. Cerebral cortical pathology in progressive supranuclear palsy is correlated
with severity of dementia. Neurology 1996;46:A363.
131. Boeve B, Dickson D, Duffy J, Bartleson J, Trenerry M, Petersen R. Progressive nonfluent aphasia and subsequent
aphasic dementia associated with atypical progressive supranuclear palsy pathology. Eur Neurol 2003;49:7278.
132. Rafal RD, Friedman JH. Limb dystonia in progressive supranuclear palsy. Neurology 1987;37:15461549.
133. Bergeron C, Pollanen MS, Weyer L, Lang AE. Cortical degeneration in progressive supranuclear palsy. A comparison
with cortico-basal ganglionic degeneration. J Neuropathol Exp Neurol 1997;56:726735.
134. Cordato NJ, Halliday GM, McCann H, Davies L, Williamson P, Fulham M, Morris JG. Corticobasal syndrome with tau
pathology. Mov Disord 2001;16:65667.
135. Leiguarda RC, Pramstaller PP, Merello M, Starkstein S, Lees AJ, Marsden CD. Apraxia in Parkinsons disease, pro-
gressive supranuclear palsy, multiple system atrophy and neuroleptic-induced parkinsonism. Brain 1997;120:7590.
136. Caparros-Lefebvre D, Sergeant N, Lees A, Camuzat A, Daniel S, Lannuzel A, Brice A, Tolosa E, Delacourte A,
Duyckaerts C. Guadeloupean parkinsonism: a cluster of progressive supranuclear palsy-like tauopathy. Brain
2002;125:801811.
137. Caparros-Lefebvre D, Elbaz A. Possible relation of atypical parkinsonism in the French West Indies with consumption
of tropical plants: a case-control study. Caribbean Parkinsonism Study Group. Lancet 1999;354:281286.
138. Cambier J, Masson M, Dairou R, Henin D. Etude anatomo-clinique dune forme paritale de maladie de Pick. Rev
Neurol (Paris) 1981;137:3338.
139. Tsuchiya K, Ikeda M, Hasegawa K, et al. Distribution of cerebral cortical lesions in Picks disease with Pick bodies: a
clinicopathological study of six autopsy cases showing unusual clinical presentations. Acta Neuropathol (Berl)
2001;102:553571.
140. Gibb WRG, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112:11711192.
141. Horoupian DS, Chu PL. Unusual case of corticobasal degeneration with tau/Gallyas-positive neuronal and glial tangles.
Acta Neuropathol (Berl) 1994;88:592598.
142. Uchihara T, Mitani K, Mori H, Kondo H, Yamada M, Ikeda K. Abnormal cytoskeletal pathology peculiar to corticobasal
degeneration is different from that of Alzheimers disease or progressive supranuclear palsy. Acta Neuropathol (Berl)
1994;88:379383.
143. Mori H, Nishimura N, Namba Y, Oda M. Corticobasal degeneration: a disease with widespread appearance of abnor-
mal tau and neurofibrillary tangles, and its relation to progressive supranuclear palsy. Acta Neuropathol (Berl)
1994;88:113121.
144. Feany MB, Dickson DW. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am J Pathol
1995;146:13881396.
145. Daniel SE, Geddes F, Revesz T. Clinicopathological overlap between cases of Picks disease and corticobasal degen-
eration. Brain Pathology 1994;4:516.
146. Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Picks disease and
147. Ikeda K, Akiyama H, Iritani S, et al. Corticobasal degeneration with primary progressive aphasia and accentuated
cortical lesion in superior temporal gyrus: case report and review. Acta Neuropathol (Berl) 1996;92:534539.
148. Arai T, Ikeda K, Akiyama H, et al. Different immunoreactivities of the microtubule-binding region of tau and its
molecular basis in brains from patients with Alzheimers disease, Picks disease, progressive supranuclear palsy and
corticobasal degeneration. Acta Neuropathol (Berl) 2003;105:489498.
149. de Silva R, Lashley T, Gibb G, et al. Pathological inclusion bodies in tauopathies contain distinct complements of tau
with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies.
150. Komori T, Arai N, Oda M, et al. Morphologic difference of neuropil threads in Alzheimers disease, corticobasal
degeneration and progressive supranuclear palsy: a morphometric study. Neurosci Lett 1997;233:8992.
1999;246 Suppl 2:II6II15:
152. Tolnay M, Probst A. Tau protein pathology in Alzheimers disease and related disorders. Neuropathol Appl Neurobiol
1999;25:171187.
153. Komori T, Shibata N, Kobayashi M. Plaque-like structures in the cerebral cortex of corticobasal degeneration: a histo-
pathological marker? Neuropathology 1995;15:175176.
154. Komori T, Arai N, Oda M, et al. Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degenera-
tion and progressive supranuclear palsy. Acta Neuropathol (Berl) 1998;96:401408.
155. Dickson DW, Bergeron C, Chin SS, et al. Office of rare diseases neuropathologic criteria for corticobasal degeneration.
156. Shiozawa M, Fukutani Y, Sasaki K, et al. Corticobasal degeneration: an autopsy case clinically diagnosed as progres-
sive supranuclear palsy. Clin Neuropathol 2000;19:192199.
136 Duyckaerts
157. Mimura M, Oda T, Tsuchiya K, et al. Corticobasal degeneration presenting with nonfluent primary progressive apha-
sia: a clinicopathological study. J Neurol Sci 2001;183:1926.
158. Tsuchiya K, Ikeda K, Uchihara T, Oda T, Shimada H. Distribution of cerebral cortical lesions in corticobasal degenera-
tion: a clinicopathological study of five autopsy cases in Japan. Acta Neuropathol (Berl) 1997;94:416424.
159. Grimes DA, Lang AE, Bergeron CB. Dementia as the most common presentation of cortical-basal ganglionic degenera-
tion. Neurology 1999;53:19691974.
160. Dickson D, Litvan I. Corticobasal degeneration. In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of
Dementia and Movement Disorders. Basel: ISN Neuropath Press, 2003.
161. Katsuse O, Iseki E, Arai T, et al. 4-repeat tauopathy sharing pathological and biochemical features of corticobasal
degeneration and progressive supranuclear palsy. Acta Neuropathol 2003;11:11.
162. Togo T, Dickson DW. Ballooned neurons in progressive supranuclear palsy are usually due to concurrent argyrophilic
grain disease. Acta Neuropathol (Berl) 2002;104:5356.
163. Ishizawa T, Ko LW, Cookson N, Davias P, Espinoza M, Dickson DW. Selective neurofibrillary degeneration of the
hippocampal CA2 sector is associated with four-repeat tauopathies. J Neuropathol Exp Neurol 2002;61:10401047.
164. Morris JC, Drazner M, Fulling K, Grant EA, Goldring J. Clinical and pathological aspects of parkinsonism in
Alzheimers disease. A role for extranigral factors? Arch Neurol 1989;46:651657.
165. Daniel SD, Lees AJ. Neuropathological features of Alzheimers disease in non-demented parkinsonian patients. J Neurol
Neurosurg Psychiatry 1991;54:971975.
166. Braak H, Braak E. Alzheimers disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol
1990;49:215224.
167. Schneider JA, Bienias JL, Gilley DW, Kvarnberg DE, Mufson EJ, Bennett DA. Improved detection of substantia nigra
pathology in Alzheimers disease. J Histochem Cytochem 2002;50:99106.
168. Liu Y, Stern Y, Chun MR, Jacobs DM, Yau P, Goldman JE. Pathological correlates of extrapyramidal signs in
Alzheimers disease. Ann Neurol 1997;41:368374.
169. Kemppainen N, Roytta M, Collan Y, Ma SY, Hinkka S, Rinne JO. Unbiased morphological measurements show no
neuronal loss in the substantia nigra in Alzheimers disease. Acta Neuropathol (Berl) 2002;103:4347.
170. Lyness SA, Zarow C, Chui HC. Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-
analysis. Neurobiol Aging 2003;24:123.
171. Stern Y, Jacobs D, Goldman J, et al. An investigation of clinical correlates of Lewy bodies in autopsy-proven Alzheimer
disease. Arch Neurol 2001;58:460465.
172. Corsellis JAN, Bruton CJ, Freeman-Browne D. The aftermath of boxing. Psychol Med 1973;3:270303.
173. Geddes JF, Vowles GH, Robinson SFD, Sutcliffe JC. Neurofibrillary tangles, but not Alzheimer-type pathology, in a
young boxer. Neuropathol Appl Neurobiol 1996;22:1216.
174. Geddes JF, Vowles GH, Nicoll JA, Revesz T. Neuronal cytoskeletal changes are an early consequence of repetitive
head injury. Acta Neuropathol (Berl) 1999;98:171178.
175. Reid AH, McCall S, Henry JM, Taubenberger JK. Experimenting on the past: the enigma of von Economos encepha-
litis lethargica. J Neuropathol Exp Neurol 2001;60:663670.
176. Litvan II, Jankovic J, Goetz CG, et al. Accuracy of the clinical diagnosis of postencephalitic parkinsonism: a clinico-
pathologic study. Eur J Neurol 1998;5:451457.
177. Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG. Initial genetic characterization of the 1918 Span-
ish influenza virus. Science 1997;275:17931796.
178. Ikeda K, Akiyama H, Kondo H, Ikeda K. Anti-tau-positive glial fibrillary tangles in the brain of postencephalitic
parkinsonism of Economo type. Neurosci Lett 1993;162:176178.
179. Haraguchi T, Ishizu H, Terada S, et al. An autopsy case of postencephalitic parkinsonism of von Economo type: some
new observations concerning neurofibrillary tangles and astrocytic tangles. Neuropathology 2000;20:143148.
180. Geddes JF, Hughes AJ, Lees AJ, Daniel SE. Pathological overlap in cases of parkinsonism associated with neurofibril-
palsy and Guamanian parkinsonism-dementia complex. Brain 1993;116:281302.
181. Oyanagi K. Parkinsonism-dementia complex of Guam. In: Dickson D, ed. Neurodegeneration: the Molecular Pathol-
ogy of Dementia and Movement Disorders. Basel: ISN Neuropath Press, 2003.
182. Oyanagi K, Wada M. Neuropathology of parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam:
an update. J Neurol 1999;246(Suppl 2):1927.
183. Perl DP.Amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam. In: Markesbery WR, ed. Neuropa-
thology of Dementing Disorders. London: Arnold, 1998.
184. Hirano A, Kurland LT, Krooth RS, Lessell S. Parkinsonism-dementia complex, an endemic disease on the island of
Guam. I. Clinical features. Brain 1961;84:642661.
185. Hirano A, Malamud N, Kurtland LT. Parkinsonism-dementia complex, an endemic disease of island of Guam. II.-
Pathological features. Brain 1961;84:662679.
186. Morris HR, Al-Sarraj S, Schwab C, et al. A clinical and pathological study of motor neurone disease on Guam. Brain
2001;124:22152222.
187. Schwab C, Schulzer M, Steele JC, McGeer PL. On the survival time of a tangled neuron in the hippocampal CA4 region
in parkinsonism dementia complex of Guam. Neurobiol Aging 1999;20:5763.
188. Oyanagi K, Makifuchi T, Ohtoh T, Chen KM, Gajdusek DC, Chase TN. Distinct pathological features of the gallyas-
and tau-positive glia in the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. J Neuropathol
Exp Neurol 1997;56:308316.
189. Spencer PS, Nunn PB, Hugon J, et al. Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant
excitant neurotoxin. Science 1987;237:517522.
190. Duncan MW, Steele JC, Kopin IJ, Markey SP. 2-Amino-3-(methylamino)-propanoic acid (BMAA) in cycad flour: an
unlikely cause of amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Neurology 1990;40:767772.
191. Lers T, Spatz H. Picksche Krankheit (Progressive umschriebene Grosshirnatrophie). In: Lubarsch O, Henke F, Rssle
R, eds. Hanbuch der speziellen pathologischen Anatomie und Histologie. Berlin: Springer-Verlag, 1957.
192. Onari K, Spatz H. Anatomische Beitrge zur Lehre von der Pickschen umschriebenen Grosshirnrinde-Atrophie
(Picksche Krankheit). Z ges Neurol 1926;101:470511.
193. Escourolle R. La maladie de Pick. Etude critique densemble et synthse anatomo-clinique. Paris: R.Foulon, 1958.
194. Pick A. Beitrge zur Pathologie und pathologischen Anatomie des Zentralnervensystems. Berlin: S. Karger, 1898.
195. Pick A. Senile Hirnatrophie als Grundlage von Herderscheinungen. Wiener klinische Wschr 1901;14:1617.
196. Pick A. Uber einen weiteren Symptomencomplex im Rahmen der Dementia senilis, bedingt durch umschriebene strkere
Hirnatrophie (gemischte Apraxie). Mschr Psychiat Neurol 1906;19:97108.
197. Pick A. Ueber die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager Med Wschr 1892;17:1517.
198. Alzheimer A. Uber eigenartige Krankheitsflle des spteren Alters. Zentralblatt Gesam Neurol Psychiat 1911;4:356
385.
199. Alzheimer A, Frstl H, Levy R. On certain peculiar diseases of old age. Hist Psychiatry 1991;2:71101.
200. Arai T, Ikeda K, Akiyama H, et al. Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients
with Picks disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol (Berl)
2001;101:16773.
201. Zhukareva V, Mann D, Pickering-Brown S, et al. Sporadic Picks disease: a tauopathy characterized by a spectrum of
pathological tau isoforms in gray and white matter. Ann Neurol 2002;51:730739.
202. Komori T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Picks dis-
ease. Brain Pathol 1999;9:663679.
203. Kertesz A, Hudson L, Mackenzie IRA, Munoz DG. The pathology and nosology of primary progressive aphasia. Neu-
rology 1994;44:20652075.
204. Kertesz A, Munoz D. Clinical and pathological characteristics of primary progressive aphasia and frontal dementia.
Neural Transm (Suppl) 1996;47:133141.
205. Kertesz A. Pick complex and Picks disease, the nosology of frontal lobe dementia, primary progressive aphasia, and
corticobasal ganglionic degeneration. Eur J Neurol 1996;3:280282.
206. Kertesz A, Munoz D. Clinical and pathological overlap between frontal dementia, progressive aphasia and corticobasal
degeneration. The Pick complex. Neurology 1997;48:293.
207. Kertesz A. Frontotemporal dementia, Pick disease, and corticobasal degeneration. One entity or 3? Arch Neurol
1997;54:14271429.
208. Kertesz A, Munoz D. Picks disease, frontotemporal dementia, and Pick complex: emerging concepts. Arch Neurol
1998;55:302304.
209. Kertesz A, Munoz DG. Primary progressive aphasia and Pick complex. J Neurol Sci 2003;206:97107.
210. Duyckaerts C, Drr A, Uchihara T, Boller F, Hauw J-J. Pick complex: too simple? Eur J Neurol 1996; 3:283286.
211. Duyckaerts C, Hauw JJ. Diagnostic controversies: another view. Adv Neurol 2000;82:233240.
212. Kertesz A, Munoz DG, Hillis A. Preferred terminology. Ann Neurol 2003;54(Supp 5):S3S6.
linked to chromosome 17: a consensus conference. Ann Neurol 1997;41:706715.
214. Hutton MJ, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited
system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 1998;95:77377741.
216. Ghetti B, Hutton ML, Wszolek ZK. Fronto-temporal dementia and parkinsonism linked to chromosome 17 associated
with tau gene mutations (FTDP-17T). In:Dickson D, eds. Neurodegeneration: the molecular pathology of dementia and
movement disorders. Basel: ISN Neuropath Press, 2003.
217. Morris HR, Osaki Y, Holton J, et al. Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset
PSP. Neurology 2003;61:102104.
218. Spillantini MG, Yoshida H, Rizzini C, et al. A novel tau mutation (N296N) in familial dementia with swollen achro-
matic neurons and corticobasal inclusion bodies. Ann Neurol 2000;48:939943.
219. Bugiani O, Murrell JR, Giaccone G, et al. Frontotemporal dementia and corticobasal degeneration in a family with a
P301S mutation in tau. J Neuropathol Exp Neurol 1999;58:667677.
138 Duyckaerts
220. Neumann M, Schulz-Schaeffer W, Crowther RA, et al. Picks disease associated with the novel Tau gene mutation
K369I. Ann Neurol 2001;50:503513.
221. Rosso SM, van Herpen E, Deelen W, et al. A novel tau mutation, S320F, causes a tauopathy with inclusions similar to
those in Picks disease. Ann Neurol 2002;51:373376.
222. Bumke O, Foerster O. Allgemeine Neurologie I Anatomie. Berlin: Julius Springer, 1935.
223. Truex RC, Carpenter MB. Human Neuroanatomy. Baltimore: Williams & Wilkins, 1969.
224. Carpenter MB. Human neuroanatomy. Baltimore: Williams & Wilkins, 1976.
225. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel
duration and severity of Alzheimers disease. Ann Neurol 1992;42:631639.
226. Bierer LM, Hof PR, Purohit DP, et al. Neocortical neurofibrillary tangles correlate with dementia severity in
Alzheimers disease. Arch Neurol 1995;52:8188.
227. Duyckaerts C, Bennecib M, Grignon Y, et al. Modeling the relation between neurofibrillary tangles and intellectual
status. Neurobiol Aging 1997;18:267273.
228. Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not
correlate with the formation of intranuclear inclusions. Cell 1998;95:5566.
229. Sisodia SS. Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell
1998;95:14.
230. Graff-Radford NR, Damasio AR, Hyman BT, et al. Progressive aphasia in a patient with Picks disease: a neuropsycho-
logical, radiologic and anatomic study. Neurology 1990;40:620626.
Genetics of Atypical Parkinsonism 139
9
Genetics of Atypical Parkinsonism
Implications for Nosology
Thomas Gasser
INTRODUCTION
Parkinsons disease (PD) is traditionally defined as a clinico-pathologic entity, characterized by a
core syndrome of akinesia, rigidity, tremor, and postural instability, and pathologically by a more or
less selective degeneration of dopaminergic neurons of the substantia nigra, leading to a deficiency
of dopamine in the striatal projection areas of these neurons. Characteristic eosinophilic inclusions,
the Lewy bodies (LBs), are found in surviving dopaminergic neurons but also, although less abun-
dantly, in other parts of the brain in most cases (1).
Approximately 2030% of patients with parkinsonism exhibit additional clinical features and a
neuropathological picture clearly different from idiopathic PD. These disorders are collectively called
atypical parkinsonism. The most common clinico-pathological entities of this group are dementia
with LBs (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal
degeneration (CBD), and frontotemporal dementia with parkinsonism (FTDP). In addition, a number of
other rare familial or sporadic diseases may present with parkinsonism and different atypical features.
The nosologic classification of these entities, however, is not always easy. Considerable overlap
exists, both clinically and pathologically, between some of these syndromes, but also, for example,
between DLB and Alzheimers disease (AD), leading to the concept of the neurodegenerative over-
lap syndromes (2). Although the majority of cases appears to be sporadic in all atypical parkinso-
nian syndromes, it was the recent progress in molecular genetics that has provided an Archimedes
point in the search for a nosologic classification, by identifying the genetic cause of several rare,
monogenic variants.
These findings have brought several key molecules into the focus of research, particularly F-synuclein
and the microtubule-associated protein tau, providing the first rational basis for a very broad molecular
classification of neurodegenerative diseases: in those disorders associated with F-synuclein accumula-
tion (synucleinopathies: PD, DLB, MSA, and neurodegeneration with brain iron accumulation type 1,
NBIA-1), and those characterized by an abnormal accumulation of the microtubule-associated protein
tau (MAPT), the tauopathies such as frontotemporal dementia with parkinsonism linked to chromo-
some 17 (FTDP-17), PSP, and CBD (3). The most common neurodegenerative disease, AD, has
possible links to both groups of disorders, as will be seen below.
Although those findings have greatly advanced our understanding of the etiology of
neurodegenerative diseases, the relationship between genes, mutations, and the associated molecular
pathways (the genotype) on the one hand, and the clinical and pathologic features observed in
patients and families (the phenotype) on the other hand, is increasingly recognized to be highly
complex.

139
140 Gasser
This review will attempt to give an overview of the current knowledge on these issues, focussing
not on PD, but on atypical parkinsonian syndromes. Genetic findings in individual diseases will be
discussed, and the range of phenotypic presentations related to particular genetic causes will be
reviewed.
SYNUCLEINOPATHIES: PARKINSONISM RELATED TO F-SYNUCLEIN

AGGREGATION
F-Synuclein: Its Physiologic Function and Role in Disease
A major breakthrough in the molecular dissection of parkinsonism was the discovery of mutations
in the gene for F-synuclein on the long arm of chromosome 4 as the cause for a dominantly inherited
disorder that resembles idiopathic PD in many ways both clinically and pathologically (4).
F-Synuclein is a relatively small, natively unfolded protein that is abundantly expressed in many
parts of the brain and localized mostly to presynaptic nerve terminals. Many aspects of the normal
function of F-synuclein are still unknown. The protein may functionally be involved in brain plastic-
ity and has been shown to bind to brain vesicles (5) and other cell membranes (6). However, knock-
out mice for F-synuclein show only very subtle alterations in dopamine release under certain
experimental conditions, but no other phenotype (7).
The central role of F-synuclein in the neurodegenerative process became clear when it was dis-
covered that fibrillar aggregates of this protein are not only found in those rare families with muta-
tions of the F-synuclein gene, but also constitute the primary component of the LB, the well-known
pathologic hallmark of idiopathic PD and in DLB. Furthermore, F-synuclein aggregates are also
found in oligodendrocytes in patients with MSA in the form of so-called glial cytoplasmic inclu-
sions (GCIs) (8) and, although less consistently, in NBIA-I (9), the disorder formerly called
HallervordenSpatz disease. All those disorders have therefore been collectively termed
synucleinopathies.
The currently favored hypothesis states that through a hydrophobic 12 amino acid domain in the
center of the protein, F-synuclein has the tendency to form fibrillar structures (10), which go on to
form aggregates in a nucleation-dependent manner. It is assumed that the amino acid changes in the
F-synuclein protein associated with pathogenic mutations may favor the G-pleated sheet conforma-
tion, which in turn may lead to an increased tendency to form aggregates. This has been demonstrated
in vitro (1113). As most cases of synucleinopathies express wt-F-synuclein and not a mutated form,
other factors must be assumed to also promote aggregate formation. In fact, this has been shown for
oxidative stress (14), which is thought to be particulary high in dopaminergic neurons, and also for
dopamine itself (15), possibly explaining the selectivity of the neurodegenerative process.
The precise relationship between the formation of aggregates and cell death is unknown. It is
possible that a failure of proteasomal degradation of F-synuclein and other proteins may lead to an
accumulation of toxic compounds, ultimately leading to cell death (16). Formation of F-synuclein-
containing aggregates would then be only a secondary effect (17). However, other mechanisms of
pathogenesis may also be important. Known F-synuclein mutations appear to alter the vesicle-bind-
ing properties of the protein (5), and the functional homology of F-synuclein to the 14-3-3 protein, a
ubiquitously expressed chaperone, may indicate a more profound role for this protein in cellular
metabolism and suggests still other possible pathogenic mechanisms, which might also differ between
the various synucleinopathies.
Parkinsonism Caused by Mutations Affecting the Gene for F-Synuclein

(PARK1 and PARK4)
The first mutation of the F-synuclein gene was recognized in a large family with autosomal-domi-
nantly inherited parkinsonism, the Contursi-kindred. It consisted of a point mutation leading to the
exchange of the amino acid alanine to threonine at position 53 of the protein. A second point muta-
tion (Ala39Pro) was later discovered in a small German pedigree (18). Patients suffer from L-
dopa-responsive parkinsonism, and neuropathological studies in individuals with the Ala53Thr
mutation showed the characteristic pattern of neuronal degeneration with F-synuclein-positive
LBs in the substantia nigra. In the early descriptions it appeared that only the relatively early age at
onset (with a mean 44 yr in the large Contursi kindred) distinguished this disease from typical
sporadic PD (19). As more families with this mutation are being studied, however, it became clear
that it is associated with a broader range of phenotypes and that patients frequently also exhibit
clinical features that clearly exceed what is usually found in typical PD, including prominent demen-
tia, hypoventilation, and severe autonomic disturbances (20). There are also differences in the patho-
logic picture that distinguish cases with F-synuclein mutations from typical PD. In the inherited
cases, extensive pathology with F-synuclein-positive Lewy neurites are found in brainstem pigmented
nuclei, but also in the hippocampus and the temporal neocortex (20). Unexpectedly, neuritic and less
frequent perikaryal inclusions of tau were also observed (21). Interestingly, the presence of tau
immunoreactivity has been suggested to distinguish between LBs of typical PD and those seen in
DLB (22).
Point mutations in the F-synuclein gene clearly appear to be a very rare cause of parkinsonism.
Only three mutations have been recognized (4,18,22a). The mutation that was found in the original
Contursi family (Ala53Thr) has also been identified in several Greek kindreds (4,23,24). Haplotype
analyses support the hypothesis that this is owing to a founder effect (24), pointing to a single muta-
tional event.
Very recently, a different type of mutation affecting the F-synuclein gene was identified in an-
other family with widespread synuclein pathology. One branch of this family, now called the Iowa-
kindred, was originally described by Spellman, and later in more detail by Muenter and colleagues
(25). A different branch of the family was identified by Waters and Miller (26).
The clinical picture of affected family members is variable, ranging from relatively pure PD to
parkinsonism with prominent dementia, autonomic disturbances, and hypoventilation (25). Age at
onset is rather uniformly in the fourth decade and progression is rapid with a disease duration of less
than 10 yr. Pathologic examination showed nigral cell loss and LBs in pigmented brainstem nuclei,
resembling typical PD, but also extensive neuritic changes and F-synuclein inclusions with vacu-
olization in neocortical areas, most prominent in the superior temporal gyrus (27), remarkably simi-
lar to the findings in the Contursi kindred just described.
The gene locus had originally been mapped to the short arm of chromosome 4 (4p13, PARK4; see
ref. 28), and thus thought to be distinct from the F-synuclein locus on chromosome 4q. It is now
known that this chromosomal assignment was actually because of a typing error, and that the caus-
ative mutation is in fact a triplication of a 2 Mb region containing (in addition to 19 other genes) the
entire F-synuclein gene on chromosome 4q26 (28a). The triplication was associated with a twofold
increase of F-synuclein expression in the brain, determined at both the RNA and the protein level.
This important finding shows that not only a pathogenic alteration of the protein, but also a mere
increase in its expression level, is sufficient to cause neurodegeneration and disease with profound
Lewy pathology. The situation is therefore similar to AD, where point mutations in several genes
(APP, presenilin 1 and 2) but also an increase of expression of the normal APP gene, as in trisomy 21
(Down syndrome) can cause AD pathology.
Taken together, these findings also show that mutations affecting the F-synuclein protein or its
expression level can result, within single families, in a spectrum of phenotypes that can variably
share many clinical and pathologic features with PD (L-dopa-responsive parkinsonism with LBs and
neurodegeneration more or less restricted to brainstem nuclei) as well as with other synucleinopathies,
which should more appropriately be classified as atypical parkinsonism, particularly DLB (dementia,
Lewy pathology in limbic and cortical areas) and even MSA (orthostatic hypotension).
142 Gasser
Dementia With Lewy Bodies

Although the recognition of F-synuclein mutations has extremely important implications for the
understanding of the underlying disease process, it must be recognized that the vast majority of cases
of the common synucleinopathies, such as PD, DLB, and MSA, are sporadic and are not a result of
a recognized F-synuclein gene mutation. It is therefore assumed that in these cases other genetic or
non-genetic factors may lead to an abnormal processing of F-synuclein. As the tried and tested tools
of molecular genetics, such as linkage analysis and positional cloning, are not easily applied to spo-
radic disorders, the identification of these factors may turn out to be a major challenge of future
research. Nevertheless, recent findings have begun to shed some light also on these still enigmatic
diseases.
DLB is a disorder characterized by dementia and parkinsonism with several additional character-
istic features, such as formed visual hallucinations, fluctuating levels of alertness, as well as frequent
falls and increased sensitivity to neuroleptic treatment (29). Neuropathologically, F-synuclein-posi-
tive LBs, Lewy neurites, and neuronal degeneration are found in pigmented brainstem nuclei, but
also, to a variable degree, in limbic and neocortical regions. In addition, a profound cholinergic deficit
occurs owing to degeneration of brainstem and basal forebrain cholinergic projection neurons (30).
The question whether PD and DLB are separate entities or rather different manifestations of a
single disease process has been widely debated. There is in fact considerable evidence suggesting
that PD and DLB are both parts of a continuum of LB diseases. With sensitive F-synuclein
immunostaining, cortical LBs are found in the majority of patients with typical PD (31). Further-
more, the findings in families with F-synuclein mutations described in the previous subheading indi-
cate that the pathology associated with a single mutation can be restricted to the brainstem (clinically
pure PD) or affect limbic and cortical areas as in DLB (clinically PD plus dementia).
However, the situation in sporadic cases is more complex. Density of cortical LBs is not always
correlated with the degree of dementia (32). Pure Lewy pathology is actually found only in a minority
of patients with DLB, whereas Alzheimers-type changes are found, in addition to Lewy pathology,
in the majority of cases. This AD-like pathology differs to some degree from that found in typical
AD. Senile plaques, composed of the AG-fragment of the amyloid precursor protein (APP) are found
in similar density and distribution as in AD, but neurofibrillary tangles, consisting of
hyperphosphorylated tau protein are less prominent and are often not sufficient to allow the diagnosis
of AD according to accepted criteria.
It has therefore been a matter of considerable debate whether to consider DLB a variant of AD,
a variant of PD, or a disease entity of its own. In any case, the overlapping clinical and neuropatho-
logic spectrum suggests that common pathogenic mechanisms may be operating. The identification
of common genetic risk factors could potentially clarify this complex relationship.
Familial DLB
Several large families with parkinsonism and dementia have been published in the literature, but
as far as can be told from the family descriptions, only a few would fulfill the clinical criteria for the
diagnosis of DLB, with dementia preceding or occurring within 1 yr of parkinsonism, and even fewer
with neuropathologic confirmation. However, as shown earlier for the families with F-synuclein
mutations, families who had originally been described as suffering from PD may actually resemble
more closely DLB, both clinically and neuropathologically. It remains to be determined whether the
less than a handful of other families, who have been described under the heading of familial DLB
(33,34), will prove to have F-synuclein mutations.
Families With Coexistence of AD and LB Pathology
The emergence of F-synuclein as the most sensitive histologic marker for Lewy pathology has
revealed unexpected findings in AD: Lewy bodies are found in 2040% of cases of AD, not in
brainstem nucei, but rather in the amygdala (35). Even more striking, in more than half of the patients
developing early-onset familial AD because of a mutation in the APP gene (APP717), LBs are found
in the brainstem and in the neocortex. LBs have also been found in patients with other APP mutations
and with mutations in presenilin 1 (3). The extent and distribution of Lewy pathology varies within
families with the identical APP mutation, indicating that Alzheimer and Lewy pathology are closely
related, but dependent on factors other than the primary APP mutation.
Other dominant families have been described with parkinsonism and a variable degree of demen-
tia, who showed coexisting Lewy and Alzheimer pathology at postmortem examination (36). In two
of these families, the gene has been mapped to chromosome 2p13 (37), but not yet identified. As
affecteds from those families presented clinically with L-dopa-responsive parkinsonism (38) and de-
veloped dementia only later during the course of the disease (36), these kindreds were classified as
dominantly inherited PD (PARK3). Again, follow-up examination and postmortem analysis demon-
strated that the phenotype associated with single mutations may be more variable than initially
thought, and that clinical dementia and plaque-predominant AD and LB changes occur in affecteds
and may share a common genetic susceptibility.
Taken together, family studies in dominant families with mutations in the genes for F-synuclein,
APP, and in as yet unidentified genes indicate that three possible scenarios exist (Fig. 1):
A continuum of restricted brainstem to widespread cortical Lewy pathology without significant AD
changes in families with mutations in F-synuclein.
The occurrence of limbic and cortical AD changes on top of a brainstem LB disorder as the consequence
of single, as yet unidentified gene mutations (e.g., PARK3).
The appearance of LBs, in addition to AD-type changes, in patients with a primary AD-mutation
(APP717).
These findings indicate that the underlying mutation may be viewed as a port of entry to a disease
process, which involves different molecular pathways that lead to overlapping pathologic changes
with disease progression.
Genetic Risk Factors for DLB
As mentioned in the previous subheading, dominantly inherited monogenic cases of PD, AD, and
DLB are very rare. Therefore, no single genetic cause can be identified in the majority of cases.
Nevertheless it is assumed that genetic risk factors are modulating the susceptibility to and the
course of these disorders even in sporadic cases. If common genetic risk factors could be identified
for AD, PD, and DLB, this would strengthen the argument for a common molecular disease process.
The J4-allele of the apolipoprotein E gene (ApoE4) is the only confirmed risk factor for sporadic
AD. ApoE4 has been shown to increase the risk for, and decrease the age of onset of AD (39). This
has been confirmed in a large number of studies. By contrast, the majority of studies does not find an
association of PD with the ApoE4 allele (40,41).
Studies on the influence of ApoE4 on DLB have produced conflicting results, which can in part be
explained by differences in the study design and small sample sizes (4246). Koller (44) and
Egensperger (47) did not find a difference between PD patients with or without dementia, as com-
pared to controls, whereas in the study of Hardy et al. (43) ApoE4 allele frequencies in patients with
DLB were intermediate between controls and AD. A higher proportion of ApoE4 alleles was also
found in patients with PD and concomitant AD changes (B and C according to the CERAD [Con-
sortium to Establish a Registry for Alzheimers Disease] criteria) as compared to PD patients without
such changes (48). The association of neuritic plaques with ApoE4 was confirmed by Olechney (49),
whereas another study supported a role of the ApoE4 allele in the density of cortical LBs, but not AD
changes (50).
A single formal meta-analysis has been published (51) that confirmed a higher rate of ApoE4
alleles in DLB, but did not distinguish between pure DLB and DLB with AD-plaques (which would
144 Gasser
Fig. 1. Hypothetical scheme of the evolution of inherited PD, DLB, and AD. The underlying mutation and
mostly modifying factors act together to determine distribution and type of pathology.
also be very difficult in a meta-analysis because of the heterogeneity of the populations examined
and ambiguous descriptions in the original populations).
Overall the studies seem to indicate that ApoE4 is likely to be a risk factor for dementia in patients
with parkinsonism, although not quite as clearly as in pure AD. It remains unresolved whether this
is because of an increase of AD changes or to the cortical or limbic LB load.
Another risk factor for DLB may be an as yet unidentified gene in the pericentromeric region of
chromosome 12. Linkage with this locus was identified in a genome-wide screen in a group of fami-
lies with late-onset AD (52). Further analysis of this region showed that much of the evidence was
derived from a subset of families with affected individuals with the neuropathologic diagnosis of
DLB (53). Interestingly, linkage to this region was also found in a Japanese family with autosomal-
dominant parkinsonism (PARK8; see ref. 54), and this locus has been confirmed in other families
with dominant parkinsonism (54a). The clinical and neuropathologic spectrum in these families is
variable, including brainstem and diffuse Lewy pathology, again indicating that mutations in a single
gene can cause a range of phenotypes that may be determined more specifically by other genetic or
nongenetic factors.
Multiple System Atrophy (MSA)

MSA is the second most common parkinsonian syndrome after idiopathic PD. In a majority of
patients with MSA, parkinsonism predominates (MSA-P), whereas a smaller proportion have promi-
nent cerebellar disturbances (MSA-C). Regardless of the predominant clinical picture, MSA has been
classified among the synucleinopathies, since it was discovered that a key pathologic feature is the
aggregation of F-synuclein in the form of flame-shaped cytoplasmic inclusions in oligondendrocytes
and in neurons. It is still enigmatic why F-synuclein should accumulate in oligodendrocytes, as these
cells usually express only very low levels of this protein.
By contrast to all other atypical parkinsonian syndromes, no clearly familial cases with MSA have
been described in the literature. It is still conceivable that genetic factors may influence the suscepti-
bility to the disease. Only a few association studies have been performed with polymorphisms in
genes, which were considered candidate genes for MSA, including dopamine beta hydroxylase (55),
apolipoprotein E (56), and debrisoquine hydroxylase (57), without any consistent positive findings.
TAU-RELATED DISORDERS
Several neurodegenerative disorders appear to be related to the abnormal deposition of the micro-
tubule-associated protein tau (MAPTau). A detailled discussion of this complex group of disorders is
beyond the scope of this chapter. Excellent reviews on the clinical (58) and molecular (59) aspects of
tauopathies have been published. The brief discussion here will be restricted to aspects directly related
to their presentation as atypical parkinsonian syndromes.
Tau: Normal Function and Role in Disease

The normal function of tau is to bind to tubulin, to promote its polymerization, and to maintain the
stability of microtubules. As also explained in other chapters of this book, the tau gene gives rise to
six isoforms of the tau protein, generated by alternative splicing of exons 2, 3, and 10. Tau contains
four imperfect repeat sequences in the carboxy terminal part of the protein, referred to as the micro-
tubule binding domains. The fourth domain is encoded by exon 10. Therefore, alternative splicing of
exon 10 determines whether the protein contains three or four copies of repeated sequence. Under
normal conditions, three-repeat and four-repeat tau are present in roughly equal amounts in the brain.
Tau is found as fibrillar aggregates in AD (then called neurofibrillary tangles), but also in a num-
ber of other neurodegenerative disorders, such as PSP, CBD, the parkinsonism dementia complex of
Guam, postencephalitic and posttraumatic parkinsonism, and others. The analysis of mutations of the
tau gene and their functional consequences in inherited tauopathies has provided important informa-
tion on the molecular mechanisms of tau-associated neurodegeneration.
Inherited Tauopathies With Mutations in the MAPTau Gene

The term frontotemporal dementia with parkinsonism linked to chromosome 17, or FTDP-17,
has been adopted for a familial disorder characterized by behavioral and cognitive disturbances, usu-
ally beginning between the ages of 40 and 50, progressing to dementia, and a variable degree of
extrapyramidal, pyramidal, oculomotor, and lower motorneuron signs. Pathologically, atrophy of fron-
tal and temporal lobes is most prominent, together with involvement of the substantia nigra, the
amygdala, and the striatum (60). Only about 10% of all cases of frontotemporal dementia are inher-
ited in an autosomal-dominant manner, but of these, a substantial subset of 1040% turned out to be
genetically linked to a locus on the long arm of chromosome 17 (17q21-22) (60,61). As the tau gene
is located in this region, it had to be considered a primary candidate gene, and in fact, mutations in
this gene have been identified (62) in many families with FTDP-17 (63).
Mutations are clustered around the part of the gene encoding the microtubule binding domain and
have been found in exons 9, 10, 12, and 13, or in adjacent intronic sequences. The variability of the
clinical phenotype is accounted for, at least in part, by the fact that tau mutations appear to lead to
pathology by different mechanisms.
Intronic mutations flanking exon 10, as well as some exonic exon 10 mutations affect the alterna-
tive splicing of this exon, and as a consequence alter the relative abundance of three-repeat and four-
repeat tau, the two major classes of the protein present in the brain (62). Other exon 10 and exon 9
mutations seem to impair the ability of tau to bind microtubules or to promote microtubule assembly,
as shown by functional in vitro assays (64). Whereas mutations affecting exon 10 splicing lead to the
deposition of predominantly four-repeat tau, non-exon 10 coding mutations result in tau aggregates
consisting of three-repeat and four-repeat tau (65).
To some extent, the different functional consequences of the mutations result in a characteristic
clinical picture. If mutations affect exon 10 splicing (and thus lead to the deposition of predominantly
four-repeat tau) L-dopa unresponsive parkinsonism tends to be a a prominent clinical feature (6668)
146 Gasser
(reviewed in ref. 58). This is particularly striking in the family described by Wszolek et al. clinically
and pathologically as pallido-ponto-nigral degeneration (PPND) (69). Affected subjects present with
rapidly progressive L-dopa-unresponsive parkinsonism with supranuclear gaze palsy, with dementia,
frontal-lobe release signs, and perseverative vocalizations developing later. This family was found to
harbor a mutation (N279K) increasing the activity of an exoning splice enhancer of exon 10, thus
leading to increased production of four-repeat tau (70,71).
However, behavioral disturbances may also be prominent in families with this class of mutations.
In the first family linked to chromosome 17 (and in whom the disease had been named disinhibition-
dementia-parkinsonism-amyotrophy complex; see ref. 61) personality changes begin at an average
age of 45, accompanied by hypersexuality and hyperphagia. L-dopa-unresponsive parkinsonism is a
consistent feature. This family bears an intronic mutation adjacent to exon 10.
In other families, a more typical picture of frontotemporal dementia with cognitive and behavioral
disturbances predominates, followed by parkinsonism, and other neurological disturbances such as
supranuclear gaze palsy, pyramidal tract dysfunction, and urinary incontinence to a variable degree
during the later course of the disease. These phenotypes are more commonly associated with mis-
sense mutations in the constitutively spliced exons 9, 12, and 13 (58). Other mutations have been
associated with dementia with epilepsy (72), progressive subcortical sclerosis (73), or familial mul-
tiple system tauopathy (74).
The same mutation may lead to different clinical manifestations in different families and also
within single pedigrees. The most common mutation, P301L, has been found to be associated with a
variety of clinical phenotypes, more or less closely resembling Picks disease (75), CBD (76), or
PSP. The considerable variability within single families (77,78) indicates that other factors in addi-
tion to tau mutations are influencing the clinical characteristics of the disease in a given patient.
Although a reduced penetrance of tau mutations has been reported (62), heterozygous (dominant)
mutations are almost exclusively found in individuals with a clearly positive dominant family history
and are very rare in series of patients with sporadic dementing syndromes (< 0.2%) (79). However,
recent evidence raises the possibility of autosomal-recessive mutations causing an apparently spo-
radic PSP-like phenotype (80) (see below).
The relationship between the tau gene, FTDP-17, and PSP is particularly interesting. As will be
discussed below, typical PSP is nearly always a sporadic disorder, but the prominent accumulation of
four-repeat tau strongly suggests that the tau protein, and hence possibly also the tau gene, is inti-
mately involved in the disease process. Given the high variability of the clinical picture in families
with tau mutations and the predominance of extrapyramidal symptoms associated with some of them,
it is not too surprising that, as noted above, some tau mutations lead to a phenotype more or less
resembling typical PSP. One interesting mutation causing a PSP-like phenotype, the S305S-muta-
tion, is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor
site (81). Although the mutation does not give rise to an amino acid change in the tau protein, func-
tional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing
of exon 10, resulting in the overproduction of tau containing four microtubule-binding repeats.
Although the clinical phenotype in this family, as well as in other families with mutations that
affect splicing of exon 10, share features of PSP, both clinically and neuropathologically, others have
emphazised the differences that distinguish those families from typical PSP and have questioned
whether the disorder should be called familial PSP (82). Regardless of terminology, this finding
emphasizes the close relationship between FTDP-17 and PSP.
Another interesting observation strengthening this link is that in rare cases, homozygous or com-
pound heterozygous mutations of the tau gene can cause a PSP-like syndrome (80,83), whereas het-
erozygous mutation carriers were either unaffected or showed only mild parkinsonism with late onset.
Again, although this recessive form of FTDP-17 shared several features with PSP, both cases also
differed from typical PSP by their early onset (40 yr or less) and by the presence of additional neuro-
logic deficits, such as apraxia, cortical sensory deficits, or speech disturbances.
Other Diseases Associated With Tau Deposits

As in the synucleinopathies, the majority of cases of neurodegeneration with tau deposition is
sporadic. Two disease entities are usually distinguished, but as will become apparent, are probably
closely related: PSP and CBD.
Progressive Supranuclear Palsy (PSP)
PSP is a disease characterized by predominantly axial, L-dopa-unresponsive parkinsonism, early
postural instability, supranuclear gaze palsy, and subcortical dementia (84).
PSP is, with exception of the cases described above, a sporadic disorder. It is pathologically char-
acterized by the deposition of abnormally phosphorylized tau protein as neurofibrillary tangles and
neuropil threads, consisting predominantly of four-repeat tau. Tangles are also present in astrocytes
(tufted astrocytes) and oligodendroglia (coiled bodies). Based on this pathologic pattern and on the
insights gained into the molecular mechansisms from the inherited tauopathies described in the pre-
vious subheading, it seems likely that an abnormality of the splicing of the tau gene may be the
underlying molecular defect.
Although no coding region or splice site mutations in the tau gene can be identified in typical PSP,
there appears to be a genetic susceptibility to the disease that is related to the tau gene. Initially,
Conrad and coworkers observed that one particular allele (which they called the A0 allele) of a
dinucleotide repeat marker within the tau gene is highly associated, in homozygous form, with PSP
(85). This allele was later found to be part of an extended haplotype (the H1-haplotype) of more than
100 kb, that is usually inherited en bloc (86,87). It is unclear why no recombinations occur within this
region in the human population.
As the H1-haplotype is common in the general population (~ 60% of chromosomes) it does per se
not carry a high risk for the development of a tau-related disorder. It is possible, however, that a more
recent mutation that has occurred on the background of this haplotype is responsible, or that the H1-
haplotype is merely permissive for the development of typical PSP, although the ultimate cause
remains unknown.
Much of what has been said for PSP also holds true for CBD. CBD is in most instances a sporadic
syndrome that shares with PSP the relentless progression of L-dopa-unresponsive parkinsonism and
predominantly subcortical cognitive disturbances, but differs in the additional presence of a usually
marked asymmetry of signs, dystonia and irregular reflex myoclonus in the most affected limb, as
well as cortical sensory loss and, in about 40% of cases, the characteristic alien limb sign. In addi-
tion to the subcortical changes, asymmetric cortical atrophy is often observed. Neuropathology reveals
characteristic tau accumulation in the form of neuropil threads throughout gray and white matter. Tau
filaments in CBD include both paired helical filament (PHF)-like filaments and straight tubules (59).
As in PSP, the filaments are composed predominantly of four-repeat tau.
As was also described for PSP, in a few families with dominant tau mutations, the disease
resembles CBD (76). It is probably a matter of semantics whether the disease in these cases should
be called familial CBD or FTDP resembling CBD, as long as it is kept in mind that there are
similarities and differences: sporadic CBD is not caused by detectable exonic or splice site mutations
in the tau gene, but it shares the same tau-related genetic background with PSP, the homozygocity for
the H1-haplotype, supporting the close relationship between these two disorders (88,89).
TAUOPATHIES, SYNUCLEINOPATHIES, AND BEYOND

Although recent genetic and pathologic evidence lead to the distinction of two major groups of
neurodegenerative disorders, the tauopathies and the synucleinopathies, based on the predominant
pathology and on mutations of the respective genes in rare familial forms of these diseases, there is
also evidence accumulating that the pathogenic mechanisms may in fact be related.
148 Gasser
As detailed above, there appears to be considerable overlap both clinically and pathologically
between PD, DLB, and AD. Various combinations of Lewy pathology and AD-type pathology are
found even in monogenically inherited forms.
However, there is also neuropathologic and genetic evidence linking Lewy pathology to alter-
ations of tau: LBs in DLB have been distinguished from LBs in PD by tau staining (22). Similarly,
some LBs found in the brain of patients with the F-synuclein mutation A53T could be stained with
antibodies to the tau protein (21).
An association of the H1 haplotype, which is present in homozygous form in the great majority of
PSP-patients, with idiopathic PD has been reported (90) but not confirmed (91). However, in a total
genome screen in a large number of sib pairs and small families with PD, the tau locus on chromo-
some 17 was identified as one of the five loci with suggestive lod scores (although not reaching
statistical significance) (92).
Finally, in a recent report, Wszolek et al. describe a family with autosomal-dominant inheritance,
initially presenting with pure L-dopa-responsive parkinsonism (93). Some affecteds progressed to
show symptoms of atypical parkinsonism, including supranuclear gaze palsy. Interestingly, pathol-
ogy in different members of this family varied, from typical brainstem LB disease to diffuse LB
disease to a tauopathy resembling PSP (106). The gene locus in this family most likely maps to the
PARK8 locus on chromosome 12. If in fact the disease in all affected subjects of this family is owing
to a mutation in a single gene, this would bridge the gap between the two major categories of
neurodegenerative disease recognized today, and strongly argue for a common pathogenic process.
OTHER GENETIC DISEASES OCCASIONALLY PRESENTING

WITH ATYPICAL PARKINSONISM
Huntingtons Disease
Huntingtons disease (HD) is an autosomal-dominantly inherited disorder, usually characterized
by a hyperkinetic movement disorder, personality changes, and dementia. It is caused by the patho-
logic expansion of a CAG-trinucleotide repeat sequence in the gene for Huntingtin on chromosome 4
(94). The fact that particularly cases of early onset frequently present with dystonia and parkin-
sonism, rather than with chorea, has long been recognized (95). In addition, the widespread use of
molecular diagnosis for HD has shown that the phenotypic spectrum may even include late-onset
levodopa-responsive parkinsonism (96) and atypical parkinsonian syndromes (97).
Spinocerebellar Ataxias
Like HD, the spinocerebellar ataxias (SCAs) are caused by expansions of CAG repeat sequences.
The core syndrome is usually that of a progressive cerebellar ataxia with or without additional neuro-
logic features. Particularly in SCA1, 2, and 3, extrapyramidal symptoms are relatively common, and
have been described in 1050% of patients (98). Patients with SCA3 have occasionally been found to
present with parkinsonism (99). This has recently been confirmed in another family (100) and
extended to a family with SCA2 (101). It is therefore not unlikely that other forms of SCA might
also, occasionally, mimic parkinsonian syndromes. The reason for the variable expressivity of the
genes with expanded CAG repeat expansion is still largely unknown.
Neurodegeneration With Brain Iron Accumulation Type 1 (NBIA-1)

NBIA-1 (formerly called HallervordenSpatz disease) is an autosomal-recessive disorder present-
ing during childhood or adolescence with a progressive syndrome of parkinsonism, dystonia, spastic-
ity, epileptic seizures, and cognitive decline. The characteristic iron accumulations in the basal ganglia
are visible on magnetic resonance imaging (MRI) as hypointensities with a central region of
hyperintensity reflecting gliosis (eye of the tiger sign). The disease gene maps to chromosome 20,
and has been identified to code for pantothenate kinase 2 (PANK2), an enzyme catalyzing an impor-
Table 1
Genes and Mutations Associated With Atypical Parkinsonian Syndromes
Range of Age
Chromosomal of Disease Onset Response
Name Region Gene Mutation (Mean), in Years Phenotype to Levodopa Pathology
Autosomal dominant
PARK 1/4 4q21 F-synuclein 2085 (46) PD, some cases with dementia Good Lewy bodies in
three missense mutations brainstem, Lewy
Genetics of Atypical Parkinsonism
one triplication neurite, and vacuolization

in temporal cortex
PARK 3 2p13 Unknown 3689 (58) PD, some cases with dementia Good Lewy bodies and amyloid
plaques
PARK 8 12p11.2- q13.11 Unknown 3868 (51) PD Good Variable: pure nigral
degeneration, Lewy body,
tau pathology
FTDP-17 17q21-22 tau/multiple mutations 2576 (49) FTD, PD, PSP, CBgD, ALS Poor Tau pathology
DYT12 19q13 Unknown 1245 (23) Rapid-onset dystonia-parkinsonism Poor Unknown
Autosomal recessive
NBIA I 20p12.3 Pantothenate kinase/ 464 Parkinsonism, dystonia, spasticity, Poor Iron accumulation, Lewy
multiple mutations dementia bodies
PARK 9 1p36 Unknown 1116 (10s) PD, dementia, gaze palsy Good Unknown
X-linked recessive
DYT3 Xq13.1 Unknown 1248 (35) Dystonia-parkinsonism Poor No Lewy bodies
149
150 Gasser
tant step in the acyl-CoA-metabolism (102). As with many other diseases, the discovery of the gene
led to the appreciation of a broader phenotype, including cases of adult-onset atypical parkinsonism.
It seems that all cases show the typical MRI changes, leading to the correct diagnosis.
CONCLUSIONS: IMPACT OF GENETICS ON NOSOLOGY

The identification of several genes that lead to monogenic forms of the major neurodegenerative
disorders has greatly advanced our understanding of the molecular mechanisms involved. However,
the careful analysis of their clinical and pathologic features reveals that, although they share many
features with the respective sporadic diseases, there are clearly also important differences. Therefore,
those disorders should be viewed as natural models, recapitulating some, but certainly not all features
of their molecular pathogenesis. Perhaps most remarkably, both the variability of the phenotypes
associated with single gene mutations, as well as the similarities and overlap between disorders caused
by alterations in different genes appear to indicate that we are dealing in fact not with strictly distinct
pathways, but rather with a complex metabolic network, consisting of pathogenic mutations, genetic
modifiers, and probably also environmental influences, which defines the course of the disease in a
given patient.
FUTURE RESEARCH
In order to better understand the relationship between genetic alterations on one hand, and patho-
logic and clinical phenotypes on the other, further research will be needed: (1) To identify additional
loci and genes in large informative pedigrees with monogenically inherited forms of parkinsonism.
(2) To study the role of genes identified in monogenic forms also in large, well-characterized patient
populations. (3) To identify the metabolic pathways involved in the disease process in monogenic
forms, in order to identify new candidate genes for the sporadic disease.
REFERENCE
1. Gibb WR, Lees AJ. The significance of the Lewy body in the diagnosis of idiopathic Parkinsons disease. Neuropathol
Appl Neurobiol 1989;15(1):2744.
2. Perl DP, Olanow CW, Calne D. Alzheimers disease and Parkinsons disease: distinct entities or extremes of a spec-
trum of neurodegeneration? Ann Neurol 1998;44(3 Suppl 1):S19S31.
3. Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M. Genetic dissection of Alzheimers disease and related dementias:
amyloid and its relationship to tau. Nat Neurosci 1998;1(5):355358.
4. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the F-synuclein gene identi-
fied in families with Parkinsons disease. Science 1997;276:20452047.
5. Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M. Binding of alpha-synuclein to brain vesicles is abolished by
familial Parkinsons disease mutation. J Biol Chem 1998;273(41):2629226294.
6. McLean PJ, Kawamata H, Ribich S, Hyman BT. Membrane association and protein conformation of alpha-synuclein in
intact neurons. Effect of Parkinsons diseaselinked mutations. J Biol Chem 2000;275(12):88128816.
7. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE et al. Mice lacking alpha-synuclein display
functional deficits in the nigrostriatal dopamine system. Neuron 2000;25(1):239252.
8. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous alpha-synuclein inclusions link
multiple system atrophy with Parkinsons disease and dementia with Lewy bodies. Neurosci Lett 1998;251(3):205208.
9. Neumann M, Adler S, Schluter O, Kremmer E, Benecke R, Kretzschmar HA. Alpha-synuclein accumulation in a case
of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly HallervordenSpatz syndrome) with
widespread cortical and brainstem-type Lewy bodies. Acta Neuropathol (Berl) 2000;100(5):568574.
10. Giasson BI, Uryu K, Trojanowski JQ, Lee VM. Mutant and wild type human alpha-synucleins assemble into elongated
filaments with distinct morphologies in vitro. J Biol Chem 1999;274(12):76197622.
11. Biere AL, Wood SJ, Wypych J, Steavenson S, Jiang Y, Anafi D, et al. Parkinsons disease-associated alpha-synuclein
is more fibrillogenic than beta- and gamma-synuclein and cannot cross-seed its homologs. J Biol Chem
2000;275(44):3457434579.
12. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PTJ. Acceleration of oligomerization, not
fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinsons disease: implica-
tions for pathogenesis and therapy. Proc Natl Acad Sci USA 2000;97(2):571576.
13. Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to
early-onset Parkinson disease. Nat Med 1998;4(11):13181320.
14. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, et al. Oxidative stress induces amyloid-like aggregate
formation of NACP/alpha-synuclein in vitro. Neuroreport 1999;10(4):717721.
15. Conway KA, Rochet JC, Bieganski RM, Lansbury PT, Jr. Kinetic stabilization of the alpha-synuclein protofibril by a
dopamine-alpha-synuclein adduct. Science 2001;294(5545):13461349.
16. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P. Failure of the ubiquitin-proteasome system in Parkinsons
disease. Nat Rev Neurosci 2001;2(8):589594.
17. McNaught KS, Jenner P. Proteasomal function is impaired in substantia nigra in Parkinsons disease. Neurosci Lett
2001;297(3):191194.
18. Krger R, Kuhn W, Mller T, Woitalla D, Graeber M, Ksel S, et al. Ala39Pro mutation in the gene encoding F-synuclein
in Parkinsons disease. Nat Genet 1998;18:106108.
19. Golbe LI, Di Iorio G, Sanges G, Lazzarini A, LaSala S, Bonavita V, et al. Clinical genetic analysis of Parkinsons
disease in the Contursi kindred. Ann Neurol 1996;40:767775.
20. Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA. Clinical and pathological features of a Parkinsonian
syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 2001;49(3):313319.
21. Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM et al. Concurrence of alpha-synuclein and tau brain
pathology in the Contursi kindred. Acta Neuropathol (Berl) 2002;104(1):711.
22. Galloway PG, Bergeron C, Perry G. The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from
those of idiopathic Parkinson disease. Neurosci Lett 1989;100(13):610.
22a. Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and
Lewy body dementia. Ann Neurol 2004;55(2):164173.
23. Markopoulou K, Wszolek ZK, Pfeiffer RF. A Greek-American kindred with autosomal dominant, levodopa-responsive
parkinsonism and anticipation. Ann Neurol 1995;38(3):373378.
24. Papadimitriou A, Veletza V, Hadjigeorgiou GM, Patrikiou A, Hirano M, Anastasopoulos I. Mutated alpha-synuclein
gene in two Greek kindreds with familial PD: incomplete penetrance? Neurology 1999;52(3):651654.
25. Muenter MD, Forno LS, Hornykiewicz O, Kish SJ, Maraganore DM, Caselli RJ et al. Hereditary form of parkin-
sonismdementia. Ann Neurol 1998;43(6):768781.
26. Waters CH, Miller CA. Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann Neurol
1994;35(1):5964.
27. Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, et al. Distinctive neuropathology revealed
by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol
(Berl) 2000;99(6):663672.
28. Farrer M, Gwinn-Hardy K, Muenter M, Wavrant DF, Crook R, Perez-Tur J, et al. A chromosome 4p haplotype segre-
gating with Parkinsons disease and postural tremor. Hum Mol Genet 1999;8(1):8185.
28a. Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science
2003;302(5456):841.
29. McKeith IG. Dementia with Lewy bodies. Br J Psychiatry 2002;180(2):144147.
30. Dickson DW, Davies P, Mayeux R, Crystal H, Horoupian DS, Thompson A, et al. Diffuse Lewy body disease. Neuro-
pathological and biochemical studies of six patients. Acta Neuropathol (Berl) 1987;75(1):815.
Neurol 1993;50(2):140148.
32. Colosimo C, Hughes AJ, Kilford L, Lees AJ. Lewy body cortical involvement may not always predict dementia in
Parkinsons disease. J Neurol Neurosurg Psychiatry 2003;74(7):852856.
33. Tsuang DW, Dalan AM, Eugenio CJ, Poorkaj P, Limprasert P, La Spada AR, et al. Familial dementia with lewy bodies:
a clinical and neuropathological study of 2 families. Arch Neurol 2002;59(10):16221630.
34. Wakabayashi K, Hayashi S, Ishikawa A, Hayashi T, Okuizumi K, Tanaka H, et al. Autosomal dominant diffuse Lewy
body disease. Acta Neuropathol (Berl) 1998;96(2):207210.
35. Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y. Alpha-synuclein-positive structures in cases with
sporadic Alzheimers disease: morphology and its relationship to tau aggregation. Brain Res 2001;888(2):287296.
36. Wszolek K, Gwinn-Hardy K, Wszolek K, Muenter D, Pfeiffer F, Rodnitzky L, et al. Neuropathology of two members of
a German-American kindred (Family C) with late onset parkinsonism. Acta Neuropathol (Berl) 2002;103(4):344350.
37. Gasser T, Mller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, Bonifati V, et al. A susceptibility locus for
Parkinsons disease maps to chromosome 2p13. Nat Genet 1998;18:262265.
38. Wszolek ZK, Cordes M, Calne DB, Munter MD, Cordes I, Pfeifer RF. Hereditary Parkinson disease: report of 3 fami-
lies with dominant autosomal inheritance. Nervenarzt 1993;64(5):331335.
39. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein
E type 4 allele and the risk of Alzheimers disease in late onset families. Science 1993;261(5123):921923.
40. Apolipoprotein E genotype in familial Parkinsons disease. The French Parkinsons Disease Genetics Study Group. J
Neurol Neurosurg Psychiatry 1997;63(3):394395.
152 Gasser
41. Benjamin R, Leake A, Edwardson JA, McKeith IG, Ince PG, Perry RH, et al. Apolipoprotein E genes in Lewy body and
Parkinsons disease [letter]. Lancet 1994;343(8912):15651565.
42. Arai H, Higuchi S, Muramatsu T, Iwatsubo T, Sasaki H, Trojanowski JQ. Apolipoprotein E gene in diffuse Lewy body
disease with or without co-existing Alzheimers disease [letter]. Lancet 1994;344(8932):13071307.
43. Hardy J, Crook R, Prihar G, Roberts G, Raghavan R, Perry R. Senile dementia of the Lewy body type has an
apolipoprotein E epsilon 4 allele frequency intermediate between controls and Alzheimers disease. Neurosci Lett
1994;182(1):12.
44. Koller WC, Glatt SL, Hubble JP, Paolo A, Troster AI, Handler MS, et al. Apolipoprotein E genotypes in Parkinsons
disease with and without dementia. Ann Neurol 1995;37(2):242245.
45. Lippa CF, Smith TW, Saunders AM, Crook R, Pulaski Salo D, Davies P, et al. Apolipoprotein E genotype and Lewy
body disease. Neurology 1995;45(1):97103.
46. St Clair D, Norrman J, Perry R, Yates C, Wilcock G, Brookes A. Apolipoprotein E epsilon 4 allele frequency in patients
with Lewy body dementia, Alzheimers disease and age-matched controls. Neurosci Lett 1994;176(1):4546.
47. Egensperger R, Bancher C, Kosel S, Jellinger K, Mehraein P, Graeber MB. The apolipoprotein E epsilon 4 allele in
Parkinsons disease with Alzheimer lesions. Biochem Biophys Res Commun 1996;224(2):484486.
48. Mattila PM, Koskela T, Roytta M, Lehtimaki T, Pirttila TA, Ilveskoski E, et al. Apolipoprotein E epsilon4 allele
frequency is increased in Parkinsons disease only with co-existing Alzheimer pathology. Acta Neuropathol (Berl)
1998;96(4):417420.
49. Olichney JM, Hansen LA, Galasko D, Saitoh T, Hofstetter CR, Katzman R, et al. The apolipoprotein E epsilon 4 allele
is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimers disease and Lewy body
variant. Neurology 1996;47(1):190196.
50. Wakabayashi K, Kakita A, Hayashi S, Okuizumi K, Onodera O, Tanaka H, et al. Apolipoprotein E epsilon4 allele and
progression of cortical Lewy body pathology in Parkinsons disease. Acta Neuropathol (Berl) 1998;95(5):450454.
51. Bang OY, Kwak YT, Joo IS, Huh K. Important link between dementia subtype and apolipoprotein E: a meta-analysis.
Yonsei Med J 2003;44(3):401413.
52. Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, et al. Complete genomic screen in
late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 1997;278(15):12371241.
53. Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, et al. Fine mapping of the chromosome
12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet
2000;66(3):922932.
54. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinsons disease (PARK8) maps to
chromosome 12p11.2-q13.1. Ann Neurol 2002;51(3):296301.
54a. Zimprich A, Muller-Myhsok B, Farrer M, et al. The PARK8 locus in autosomal dominant Parkinsonism: confirmation
of linkage and further delineation of the disease-containing interval. Am J Hum Genet 2004;74(1):1119.
55. Cho S, Kim CH, Cubells JF, Zabetian CP, Hwang DY, Kim JW, et al. Variations in the dopamine beta-hydroxylase
gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy. Am J Med
Genet 2003;120A(2):234236.
56. Morris HR, Schrag A, Nath U, Burn D, Quinn NP, Daniel S et al. Effect of ApoE and tau on age of onset of progressive
supranuclear palsy and multiple system atrophy. Neurosci Lett 2001;312(2):118120.
57. Plante-Bordeneuve V, Bandmann O, Wenning G, Quinn NP, Daniel SE, Harding AE. CYP2D6-debrisoquine hydroxy-
lase gene polymorphism in multiple system atrophy. Mov Disord 1995;10(3):277278.
58. Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22(1):89107.
59. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24:112159.:11211159.
linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 1997;41(6):706715.
61. Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG. Localization of disinhibition-dementia-parkinsonism-
amyotrophy complex to 17q21-22. Am J Hum Genet 1994;55(6):11591165.
62. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5'-splice-site
mutations in tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702705.
63. Hutton M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neu-
rology 2001;56(11 Suppl 4):S21S25.
64. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, et al. Mutation-specific functional
impairments in distinct tau isoforms of hereditary FTDP-17. Science 1998;282(5395):19141917.
65. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group
of tauopathies. Brain Pathol 1998;8(2):387402.
66. Yasuda M, Takamatsu J, DSouza I, Crowther RA, Kawamata T, Hasegawa M, et al. A novel mutation at position +12
in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol
2000;47(4):422429.
67. Delisle MB, Murrell JR, Richardson R, Trofatter JA, Rascol O, Soulages X, et al. A mutation at codon 279 (N279K) in
exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol (Berl)
1999;98(1):6277.
68. Tsuboi Y, Uitti RJ, Delisle MB, Ferreira JJ, Brefel-Courbon C, Rascol O, et al. Clinical features and disease haplotypes
of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a
French family. Arch Neurol 2002;59(6):943950.
69. Wszolek ZK, Pfeiffer RF, Bhatt MH, Schelper RL, Cordes M, Snow BJ, et al. Rapidly progressive autosomal dominant
parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol 1992;32(3):312320.
70. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, et al. Pathogenic implications of mutations
in the tau gene in pallido-ponto- nigral degeneration and related neurodegenerative disorders linked to chromosome 17.
Proc Natl Acad Sci USA 1998;95(22):1310313107.
71. Reed LA, Schmidt ML, Wszolek ZK, Balin BJ, Soontornniyomkij V, Lee VM, et al. The neuropathology of a chromo-
some 17-linked autosomal dominant parkinsonism and dementia (pallido-ponto-nigral degeneration). J Neuropathol
Exp Neurol 1998;57(6):588601.
72. Sperfeld AD, Collatz MB, Baier H, Palmbach M, Storch A, Schwarz J, et al. FTDP-17: an early-onset phenotype with
parkinsonism and epileptic seizures caused by a novel mutation. Ann Neurol 1999;46(5):708715.
73. Goedert M, Spillantini MG, Crowther RA, Chen SG, Parchi P, Tabaton M, et al. Tau gene mutation in familial progres-
sive subcortical gliosis. Nat Med 1999;5(4):454457.
system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 1998;95(13):77377741.
75. Rizzini C, Goedert M, Hodges JR, Smith MJ, Jakes R, Hills R, et al. Tau gene mutation K257T causes a tauopathy
similar to Picks disease. J Neuropathol Exp Neurol 2000;59(11):9901001.
76. Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, et al. Frontotemporal dementia and corticobasal
degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999;58(6):667677.
77. Mirra SS, Murrell JR, Gearing M, Spillantini MG, Goedert M, Crowther RA, et al. Tau pathology in a family with
dementia and a P301L mutation in tau. J Neuropathol Exp Neurol 1999;58(4):335345.
78. Nasreddine ZS, Loginov M, Clark LN, Lamarche J, Miller BL, Lamontagne A, et al. From genotype to phenotype: a
clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused
by the P301L tau mutation. Ann Neurol 1999;45(6):704715.
79. Houlden H, Baker M, Adamson J, Grover A, Waring S, Dickson D, et al. Frequency of tau mutations in three series of
non-Alzheimers degenerative dementia. Ann Neurol 1999;46(2):243248.
80. Pastor P, Pastor E, Carnero C, Vela R, Garcia T, Amer G, et al. Familial atypical progressive supranuclear palsy
associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol 2001;49(2):263267.
81. Stanford PM, Halliday GM, Brooks WS, Kwok JB, Storey CE, Creasey H, et al. Progressive supranuclear palsy pathol-
ogy caused by a novel silent mutation in exon 10 of the tau gene: Expansion of the disease phenotype caused by tau
gene mutations. Brain 2000;123(Pt 5):880893.
82. Wszolek ZK, Tsuboi Y, Uitti RJ, Reed L, Hutton ML, Dickson DW. Progressive supranuclear palsy as a disease pheno-
type caused by the S305S tau gene mutation. Brain 2001;124(Pt 8):16661670.
83. Morris HR, Osaki Y, Holton J, Lees AJ, Wood NW, Revesz T, et al. Tau exon 10 +16 mutation FTDP-17 presenting
clinically as sporadic young onset PSP. Neurology 2003;61(1):102104.
84. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of
progressive supranuclear palsy (SteeleRichardsonOlszewski syndrome): report of the NINDS-SPSP international
workshop. Neurology 1996;47(1):19.
85. Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, et al. Genetic evidence for the involvement of
tau in progressive supranuclear palsy. Ann Neurol 1997;41(2):277281.
86. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, et al. Association of an extended haplotype in the
tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8(4):711715.
87. Pastor P, Ezquerra M, Tolosa E, Munoz E, Marti MJ, Valldeoriola F, et al. Further extension of the H1 haplotype
associated with progressive supranuclear palsy. Mov Disord 2002;17(3):550556.
88. Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati C, et al. Corticobasal degeneration shares a common
genetic background with progressive supranuclear palsy. Ann Neurol 2000;47(3):374377.
89. Houlden H, Baker M, Morris HR, MacDonald N, Pickering-Brown S, Adamson J, et al. Corticobasal degeneration and
progressive supranuclear palsy share a common tau haplotype. Neurology 2001;56(12):17021706.
90. Pastor P, Ezquerra M, Munoz E, Marti MJ, Blesa R, Tolosa E, et al. Significant association between the tau gene A0/A0
genotype and Parkinsons disease. Ann Neurol 2000;47(2):242245.
91. de Silva R, Hardy J, Crook J, Khan N, Graham E, Morris C, et al. The tau locus is not significantly associated with
pathologically confirmed sporadic Parkinsons disease. Neurosci Lett 2002;330(2):201.
154 Gasser
92. Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, et al. Complete genomic screen in Parkinson
disease: evidence for multiple genes. JAMA 2001;286(18):22392244.
93. Wszolek ZK, Pfeiffer B, Fulgham JR, Parisi JE, Thompson BM, Uitti RJ, et al. Western Nebraska family (family D)
with autosomal dominant parkinsonism. Neurology 1995;45(3 Pt 1):502505.
94. Huntingtons Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded
and unstable on Huntingtons disease chromosomes. Cell 1993;72(6):971983.
95. van Dijk JG, van der Velde EA, Roos RA, Bruyn GW. Juvenile Huntington disease. Hum Genet 1986;73(3):235239.
96. Racette BA, Perlmutter JS. Levodopa responsive parkinsonism in an adult with Huntingtons disease. J Neurol
Neurosurg Psychiatry 1998;65(4):577579.
97. Reuter I, Hu MT, Andrews TC, Brooks DJ, Clough C, Chaudhuri KR. Late onset levodopa responsive Huntingtons
disease with minimal chorea masquerading as Parkinson plus syndrome. J Neurol Neurosurg Psychiatry
2000;68(2):238241.
98. Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic
differences in genetically defined subtypes? Ann Neurol 1997;42(6):924932.
99. Tuite PJ, Rogaeva EA, St George Hyslop PH, Lang AE. Dopa-responsive parkinsonism phenotype of MachadoJoseph
disease: confirmation of 14q CAG expansion. Ann Neurol 1995;38(4):684687.
100. Gwinn-Hardy K, Singleton A, OSuilleabhain P, Boss M, Nicholl D, Adam A, et al. Spinocerebellar ataxia type 3
phenotypically resembling Parkinson disease in a black family. Arch Neurol 2001;58(2):296299.
101. Gwinn-Hardy K, Chen JY, Liu HC, Liu TY, Boss M, Seltzer W, et al. Spinocerebellar ataxia type 2 with parkinsonism
in ethnic Chinese. Neurology 2000;55(6):800805.
102. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2)
is defective in HallervordenSpatz syndrome. Nat Genet 2001;28(4):345349.
103. Wszolek ZK, Pfeiffer RF, Tsuboi Y, et al. Autosomal dominant Parkinsonism associated with variable synuclein and
tau pathology. Neurology 2004, in press.
Medical History and Physical Examination 155
10
Medical History and Physical Examination
in Parkinsonian Syndromes
How to Examine a Parkinsonian Syndrome
Marie Vidailhet, Frdric Bourdain, and Jean-Marc Trocello
The current chapter was prepared to help clinicians examine patients with parkinsonian syndromes
and to detect clinical signs and clues that should alert to the appropriate diagnosis. For the main
clinical diagnosis criteria of various parkinsonian syndromes (Parkinsons disease [PD], multiple
system atrophy [MSA], progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], and
dementia with Lewy bodies [DLB],), the semiology will be detailed. The validity and reliability of
these criteria will not be touched upon, as they were extensively reviewed recently in a reference
paper by Litvan and colleagues (1).
We will consider (a) medical history and clinical description of the cardinal signs and helpful
clues and (b) how they relate to the established diagnostic criteria of various parkinsonian syndromes.
PARKINSONISM
Major signs are resting tremor, rigidity, akinesia, and postural instability (2). Advanced PD rarely
presents a diagnostic problem, but careful medical history and clinical examination is necessary at an
early stage of a parkinsonian syndrome and in very old patients, especially because of other superim-
posed neurological or non-neurological disturbances (vascular lesions, musculoskeletal disease,
vision and auditory problems).
Interview of Patient and Spouse or Family

Lack of spontaneous gestures and smiling commented on by the family.
Slowing of activities of daily living with increase in the length of time needed to get up and to get dressed,
difficulties using the involved hand (buttons, toothbrush, lack of dexterity), slowness of gait, dragging of
the involved leg, stooped posture; and insidious, and progressive and mistaken by the patient as related to
normal aging.
Difficulties in sports (altered tennis and golf swing, lack of coordination while swimming).
Micrographia and slowness of handwriting (the size of the handwriting progressively decreases after a
few words or sentences in patients with PD; there is a fast micrographia with small letters from the begin-
ning in PSP patients).
Uncomfortable sensation of fatigue, tightness, stiffness of the limbs.

155
156 Vidailhet, Bourdain, and Trocello
Mild depression and withdrawal.

Resting tremor when sitting in an armchair or while walking.
Miscellaneous: profuse sweating or dry skin; sleep disturbances; daytime sleepiness; pain, numbness, or
tingling in the limbs; shoulder arthralgia; radiculopathy.
In all cases, the examiner has to obtain a complete drug history as drug-induced parkinsonism and
PD can present with the same clinical signs.
Clinical Examination
Tremor
The 45 Hz tremor is most apparent when the arm is fully relaxed (supported and at rest, in an
armchair). It is increased by mental calculation and stress and best seen during walking. It is reduced
by action and intention (tricks used by the patients to hide the tremor). The classical description is the
pill-rolling rhythmic alternating opposition of the thumb and forefinger. Some patients have pos-
tural tremor in particular conditions (holding a phone) with a different frequency (6 Hz).
Bradykinesia
This is the most disabling feature in PD as it involves the whole range of motor activity with a
decrease in amplitude and rhythm of movement. Automatic movements disappear. Bradykinesia is
well explored in the motor items of UPDRS III, the Unified Parkinson Disease Rating Scale (finger
tapping, alternating pronation/supination movements, foot tapping, etc.), with rapid decline in ampli-
tude and frequency.
Rigidity
Abnormal tone is observed when the patient is relaxed and the limb passively flexed and extended.
Passive circling movements are better to test rigidity, as the patient cannot voluntarily help the
passive movement (whereas active movement is sometimes superimposed to the passive movement
during simple flexionextension movements).
The Froment sign is classically described as an increase in tone of the limb during contralateral
active movements. The actual sign, described by Jules Froment, was an increase of tone in the exam-
ined limb as the patient bent to reach a glass of water on the table (both postural adaptation and
voluntary movement of the contralateral limb).
The cogwheel phenomenon is not pathognomonic of PD or parkinsonism and reflects the
underlying tremor (can be observed in severe and disabling postural tremor) (2,3).
Impairment of Postural-Reflexes
This is observed when the patient moves spontaneously (rising from a chair, pivoting when turn-
ing, etc.). The patient will take extra steps in pivoting and may have a careful gait. Postural challenge
consists of a thrust to the shoulders (the examiner stays behind the patient to prevent a fall and the
patient is instructed to resist the thrust). According to the UPDRS III score, one can observe a retro-
pulsion (more than one step backward), but the patient recovers unaided (score 1); absence of pos-
tural response, the patient would fall if not caught by the examiner (score 2); the patient is very
unstable, tends to lose balance spontaneously (score 3); the patient is unable to stand without assis-
tance (score 4). This pull test is not standardized and each neurologist has his or her own technique.
As a consequence, the examiner may adapt (consciously or not) the intensity of the thrust to the
expected reaction of the patient! (see video segment 1.)
Only scores 0 (normal) and 1 are observed in PD until a later stage. In contrast, early postural
instability is observed in MSA (with walking difficulties) and particularly in PSP (cardinal sign).
Spontaneous falls (without warning or obstacle, occasional then frequent) occur in PSP (4) with loss
of anticipatory postural reflexes, reactive postural responses, or rescue and protective reactions (the
patient does not use his arms to keep balance and does not throw out his arms to break the fall and
protect the head from injuries).
Gait Disorders
At an early stage of parkinsonism, slowing and shuffling of gait with dragging of the affected limb
is common. A flexed posture of the arms (unilateral then bilateral) with a loss of arm swing is ob-
served.
In contrast, in vascular parkinsonism or normal-pressure hydrocephalus, the arm swing is pre-
served or even exaggerated (to keep the balance) and the arms are not flexed. In that case, parkin-
sonism predominates in the lower limbs (thus the name of lower body parkinsonism). The marche
petits pas described by Djerine is suitable for the description of these patients. The gait is charac-
terized by short quick steps, initially without dragging or shuffling the feet on the ground (in contrast
to PD), with start and turn hesitation (take several steps on turning), slight wide base (but can be
narrow), and moderate disequilibrium (described by Nutt and colleagues as frontal gait disorder)
(5). Visual clues (contrasted lines on the ground) do not help these patients (in contrast to PD). The
diagnosis of vascular origin (differential diagnosis from degenerative parkinsonism) is made by the
company it keeps: pyramidal signs, dysarthria and pseudo-bulbar signs, urinary disturbances, cogni-
tive signs, and stepwise progression with past medical history of acute motor deficits. In time, pa-
tients may develop a magnetic gait (the feet are glued to the ground) and astasia-abasia (they do not
know how to walk anymore). Overall, the gait is different from those of patients with late PD or even
PSP or MSA.
Gait disorders in PSP have been described as subcortical disequilibrium. This gait pattern is
characterized by a severe postural instability, loss of postural reflexes (cf. supra), and inappropriate
response to disequilibrium (e.g., when rising from a chair, the patient will extend the trunk and neck
and fall backward). The gait is also impaired by the disequilibrium, and is characterized by a wide
base. Some patients do not hesitate to walk briskly, and are careless of the risk of falls (as if they did
not realize they were in danger of falling).
Freezing and gait ignition failure are defined by a marked difficulty with initiating gait and diffi-
culties maintaining locomotion in front of various obstacles (door, modification of the pattern of the
floor, turning). They are observed at a late stage in PD or at earlier stages in MSA patients. They may
be associated with various gait disturbances. Pure gait ignition failure is a different disorder, still
poorly defined and, to date, with few clinical-pathological correlations (mostly associated with PSP).
In summary, a parkinsonian syndrome is easily explored, and may take only a few minutes. Spon-
taneous movements (or the lack of them) are observed when the patient and spouse are providing the
medical history. Clumsiness and slowness are detected when patients are searching for documents or
glasses in their bag, and when they take off or put on their jacket and shirt (buttons). Writing a few
sentences will demonstrate the micrographia; walking in the examination room or corridor will help
to detect a resting tremor, loss of arm swing, flexed posture, general slowness, and difficulties of gait
and turning. The pull test will explore postural instability. In the end, the UPDRS III motor score will
give a quantification of the severity of the parkinsonian syndrome.
FRONTAL SYNDROME
Clinical Examination: Utilization and Imitation Behaviors (Video Segment 2
on Companion DVD)
The classic signs of frontal syndrome are usually well known. Distractibility and attentional dis-
turbances are easy to detect when several people are present in addition to the patient and the exam-
iner. Therefore, it is very important that all of them remain completely neutral and indifferent toward
the patient, and do not react during the clinical examination.
As described by Lhermitte the test begins with the solicitation of manual grasping behavior. The
examiner places his or her hands on the patients palms and stimulates them with slow and rapid
rubbing movements. A bilateral grasping reflex is obtained, even if the patient is instructed not to
take the hands of the examiner. Moreover, the patient holds the hands so tightly that the examiner can
lift the patient from the chair.
Then, while the hands of the patient are free, the examiner displays various objects in the field of
vision of the patient. The patient may grasp the object and collect as many objects as he or she can
hold (collectionism). Moreover, he or she usually starts to use them in a proper manner (utilization
behavior) (6). When the patients are asked why they took them and used them, the answer is because
I thought I had to take them and use them. Normal subjects do not react this way.
Moreover, even when the examiner tells the patient whatever I do, do not imitate me, the
patient will still do it, all the same. The patient may copy funny behaviors, with or without actual
objects (imitation behavior) (7). When asked why they imitated the examiner, they answer, Because
I thought I had to imitate. Again, a normal subject never imitates the examiner (except to make fun
of him!).
These tests are very sensitive, easy to do at the bedside and take only a few minutes.
EYE MOVEMENTS
Bedside Examination (Video Segments 3 and 4)
The patient may complain of problems with visual acuity as they cannot read properly anymore.
Several pairs of glasses have been changed unsuccessfully. The upward- and downward-gaze impair-
ment are rarely detected by the patient. In contrast, the family will observe a reptilian gaze, with a
staring and terrified look.
The bedside examination will mainly explore the visually guided saccades in four directions (up,
down, left, and right). The targets should be at a certain distance (arm length). The best way to have
the right distance and to prevent movements of the head is to hold the chin of the patient at arm
length. The targets should be clearly visible (colorful balls or pens). The midline target should be
neutral (e.g., the switch of the light) and the lateral should be 25 from the midline target. Voluntary
saccades are made after verbal instruction: look at the switch, look at the red pencil. Note the time
taken to initiate the saccade, its speed, and its amplitude (the target is reached with the initial saccade or
correction with additional small saccades are needed). In normal subjects, the displacement of the
eyes cannot be detected by the examiner (who sees the initial and the final positions of the eyes). Any
perception of the displacement (like in oil) is abnormal. People usually focus on vertical gaze (be-
cause of the diagnostic criteria of PSP). However, horizontal saccades are impaired at a early stage of
the disease and bedside examination can also detect this abnormality.
In summary, as Drs. Leigh and Riley stated, it is saccadic speed that counts and the key finding is
slowing of the saccade (8). This can be observed before reduced amplitude is detected.
Testing visual pursuit is not very useful as pursuit is frequently altered (including by drugs). More-
over, testing pursuit is testing the velocity of the target, more than those of the eyes.
Vestibular ocular reflexes (VORs) are normal in PSP patients, by definition (supranuclear palsy).
In summary, eye movement examination is very helpful for the diagnosis of PSP (9), and does not
help as much for PD or MSA. Useful clues are:
Slowing of vertical or horizontal saccades.
Decreased amplitude of saccades (vertical and/or horizontal). Several small and slow saccades are needed
to reach the target (steplike displacement of the eyes).
Square-wave jerks can be observed in the neutral (central position), and better seen through the use of an
ophtalmoscope (small movements take the eye away from the fixation point).
Patients often blink before they move their eyes when they have mild supranuclear gaze palsy, or they use
their VOR (vestibular ocular reflex) to help movement of the eyes at more severe stages.
In all cases, the VORs are normal.
Although pathologically proven cases of PSP without abnormal eye movements have been
described, eye movements were usually not quite normal. Indeed, these patients did not have a
downward oculomotor palsy, but Birdy and colleagues (10) observed that they had a slowed down-
ward-command saccades, square-wave jerks, slow horizontal saccades, and blepharospasm. This
should be considered probable PSP, even if the best specificity for PSP (NINDS-SPSP) criteria are
postural instability leading to falls within the first year of onset coupled with a vertical supranuclear
gaze paresis (1,4).
DYSAUTONOMIA
Dysautonomia is characterized by urogenital and/or orthostatic dysfunction. Orthostatic hypoten-
sion is defined by an orthostatic fall in blood pressure by 20 mmHg systolic or 10 mmHg diastolic,
but a 30-mmHg systolic or 15-mmHg diastolic is required for the consensus diagnosis criteria by
Gilman (11). Although this is considered to be a frequent and early sign in the disease (12,13), it is
rarely symptomatic (syncope or faintness), and autonomic nervous system testing may not distin-
guish MSA from PD (14).
Urinary disturbances often appear early in the course of the disease, or are a presenting symptom
(impotence common in men). Urinary incontinence (70% of MSA) or retention (30%) may be de-
tected by medical history, leading to more refined explorations. MSA, PSP, as well as PD patients
complain of urgency, frequent voiding, or dysuria. Some describe difficulties voiding but are not
aware of chronic urinary retention. Incontinence is never observed in patients with PD and rarely in
late stages in PSP. In all cases, additional laboratory tests such as urodynamic tests and sphincter
electromyogram (EMG) may make the association between urinary symptoms and urinary tract den-
ervation (13). Patients with PD have less severe urinary dysfunction, by contrast with these common
findings in MSA. However, sphincter EMG does not distinguish MSA from PSP.
In summary, the detection of autonomic and urinary features by medical history and, if necessary,
laboratory tests, may be a good clue at early stages of the parkinsonian syndrome, but the diagnosis
should take into account other clinical clues to reach the diagnostic criteria for PD, MSA, or PSP.
HALLUCINATIONS
Most of the time, the patient does not spontaneously report hallucinations and only a small portion
of them are detected by the spouse (emerged part of the iceberg). Patients should be specifically
questioned on the presence of minor, visual, and auditory hallucinations. As reported by Fnelon and
colleagues, (15) the most frequent type are visual hallucinations. The patient has a vivid sensation of
the presence of somebody either somewhere in the room or, less often, behind him or her. The pres-
ence is often a relative (alive or deceased) who is often perceived as benevolent like a guardian
angel. However, the patient is ready to accept that the presence is not real.
Formed visual hallucinations are more complex with vivid scenes like a film, sometimes close
to real (members of family), sometimes full of fantasy (ninja turtles, dancing Russians, medieval
stories), but soundless. In some cases, the hallucinations may be frightening (house burning, wild
animals). Auditory hallucinations are rare and tactile hallucinations often involve animals. As they
are more frequent in the evening they may be associated with vivid dreams and sleep disorders (15).
In all cases, the main risk factor for hallucinations is cognitive impairment. Therefore, it is impor-
tant to detect them as they are among features used for the diagnostic criteria of dementia with Lewy
bodies (DLB) in addition to cognitive impairment, attentional and visuospatial deficits, fluctuating
cognition, and parkinsonism (16).
MOVEMENT DISORDERS
Dystonia
Dystonia associated with parkinsonian syndromes is often manifested by dystonic postures (video
segments 5 and 6) more than abnormal movements and they are rarely modified by a geste
Fig. 1. Clinical examination at a glance from head to feet.
antagoniste. They include limb dystonia (from writers cramp to a dystonic posture of the arm or
foot), blepharospasm (and/or eyelid apraxia), orofacial dystonia, stridor, axial dystonia, and cervical
dystonia. Axial dystonia is sometimes difficult to differentiate from rigidity, especially in the neck. In
cervical dystonia, torticollis, retrocollis, or laterocollis are easy to define but antecollis can range from
severe bent neck (considered to be a good clue for MSA) to abnormal neck flexion; in such cases,
cervical dystonia can be found in up to 25% of MSA patients (17) and in most PSP patients (18).
As a rule of thumb, dystonia predominantly affects cranio-cervical musculature in MSA and PSP,
although limb dystonia may be observed in PSP (leading to misdiagnosis of CBD). In fact, in CBD,
the best predictors for the diagnosis are limb dystonia, ideomotor apraxia, myoclonus, asymmetric
akinetic-rigid syndrome with late-onset gait or balance disturbances (19).
Levodopa-induced dyskinesias are observed in PD but are not infrequent in MSA. In MSA the
presence of painful, dystonic, postural as well as orofacial and cervical dyskinesias are good clues for
its diagnosis.
Myoclonus
Myoclonus is sometimes difficult to differentiate from irregular tremor by clinical examination.
Stimulus-sensitive myoclonus is elicited by either pinprick or light touch of the skin. It can be ob-
served in MSA and in CBD patients. In PD patients, myoclonus is rare and may be related to levodopa
(levodopa-induced myoclonus). Electrophysiologic testing helps to differentiate the stimulus-sen-
sitive myoclonus in CBD with a pattern characteristic of cortical myoclonus (20) (video segments
5 and 6).
CONCLUSION: EXAMINATION AT A GLANCE

Very simple tests will help to get the most out of the clinical examination and medical history.
This is particularly true for the bedside neuropsychological examination and eye movement explora-
tion, which appear complicated but are not (video segments 3 and 4). Moreover, a refined and precise
evaluation will increase the accuracy of the diagnostic criteria in clinico-pathological studies. For
example, the precision of the information in the clinical vignettes is of great importance. This may
allow clinicians to rename probable criteria into clinically definite or clinically probable. This high
specificity of criteria is important for research studies, especially genetics or therapeutic studies.
As a rule of thumb, we suggest examining the patient from head to feet (see Fig. 1) in order to
check all the diagnostic features included in the criteria for PD, MSA (video segment 7), PSP (video
segments 14), CBD (video segments 5 and 6), and DLB.
VIDEO LEGENDS
Video 1: Corticobasal degeneration with myoclonus. Right upper limb dystonia with shoulder abduction,
and elbow + wrist + fingers flexion, associated with myoclonic jerks (at rest and triggered by posture and
action).
PolygraphicEMG recordings show brief and synchronous bursts on the upper arm muscles. (1.mpg)
Video 2: Corticobasal degeneration with apraxia. Tremor, akinesia, myoclonic jerks and left hand dystonia.
Symbolic motor sequences are not properly performed: cross sign is performed from right to left shoulder,
thumbing ones nose is replaced by a kiss, showing that someone is a fool is done uncompletely and cross sign
is not possible with left hand. (2.mpg)
Video 3: Multiple system atrophy (MSA-P). At a early stage, DOPA-resistant akineto-rigid syndrome is
associated with inability to walk without aid and postural instability. (3.mpg)
Video 4: Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Vertical voluntary sac-
cades are slow and with limitation of the maplitude of the saccades. Horizontal voluntary saccades are reduced
and several ocular movements (several small saccades) are needed to move the eyes from side to another.
Oculocephalic reflexes (VOR) are normal, demonstrating the supranuclear location of the dysfunction. Postural
instability is associated. (4.mpg)
Video 5: Abnormal eye movements in Progressive supranuclear palsy. Vertical and horizontal volontary
saccades are reduced. Several saccades are needed to reach the target. Presevations are observed, the patient is
looking at the previous target while asked to look in another direction. Frontalis muscle contractions are asso-
ciated with upward saccades.
Oculocephalic reflexes are normal (but difficult to perform because of distractibility and cervical stiffness),
demonstrating the supranuclear location of the dysfunction. (5.mpg)
Video 6: Frontal behavior in Progressive supranuclear palsy. As described by Lhermitte, frontal behavioral
signs include grasping reflex (even when forbidden), utilization behavior and collection of the examinators
personal stuff without order, imitation behavior with imitation of all the mimics and gestural activities of the
examinator, including nonsense as eating a metallic object. (6.mpg)
Video 7: Postural instability in Progressive supranuclear palsy. Spontaneous postural instability. A gentle
pulling test marked the patent fall, without any attempt or ability to recover his balance (loss of postural
reflexes). (7.mpg)
REFERENCES
1. Litvan I, Bhatia KP, Burn DJ, et al. SIC task force appraisal of clinical diagnostic criteria for parkinsonian disorders.
Mov Disord 2003;18:467486.
2. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:3339.
3. Rao G, Fisch L, Srinivasan S, et al. Does this patient have Parkinson disease? JAMA 2003;289:347353.
4. Litvan I, Campbell G, Mangone CA, et al. Which clinical features differentiate progressive supranuclear palsy (Steele
RichardsonOlszewski syndrome) from related disorders? A clinicopathological study. Brain 1997;120:6574.
5. Nutt JG, Marsden CD, Thompson PD. H walking and higher-level gait disorders particularly in the elderly. Neurology
1993;43:268279.
6. Lhermitte F. Utilization behaviour and its relation to lesions of the frontal lobe. Brain 1983;106:237255.
7. Lhermitte F, Pillon B, Serdaru M. Human autonomy and the frontal lobes. Part I: imitation and utilization behavior: a
neuropsychological study of 75 patients. Ann Neurol 1986;19:326334.
8. Leigh RJ, Riley DE. Eye movements in parkinsonism. Its saccadic speed that counts. Neurology 2000; 54:10181019.
9. Rivaud-Pechoux S, Vidailhet M, Gallouedec G, Litvan I, Gaymard B, Pierrot-deseilligny C. Longitudinal oculomotor
study in corticobasal degeneration and progressive supranuclear palsy. Neurology 2000;54:10291032.
10. Birdi S, Rajput AH, Fenton M, et al. Progressive supranuclear palsy diagnosis and confounding features: report on 16
autopsied cases. Mov Disord 2002;17:12551264.
11. Gilman S, Low PA, Quinn N. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci
1999;163:9498.
12. Chaudhuri KR. Autonomic dysfunction in movement disorders. Curr Opin Neurol. 2001;14:505511.
13. Wenning GK, Scherfler C, Granata R, et al. Time course of symptomatic orthostatic hypotension and urinary inconti-
nence in patients with postmortem confirmed parkinsonian syndromes: a clinicopathological study. J Neurol Neurosurg
Psychiatry 1999;67:620623.
14. Riley DE, Chelimsky TC. Autonomic nervous system testing may not distinguish multiple system atrophy from
Parkinsons disease J Neurol Neurosurg Psychiatry 2003;74:5660.
15. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinsons disease: prevalence, phenomenology and risk
factors. Brain 2000;123:733745.
17. Boesch SM, Wenning GK, Ransmayr G, Poewe W. Dystonia in multiple system atrophy. J Neurol Neurosurg Psychia-
try 2002;72:300303.
18. Barclay CL, Lang AE. Dystonia in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1997;62:352356.
19. Litvan I, Grimes DA, Lang AE et al. Clinical features differentiating patients with postmortem confirmed progressive
supranuclear palsy and corticobasal degeneration. J Neurol 1999;246(Suppl 2):II1II5.
20. Monza D, Ciano C, Scaioli V, et al. Neurophysiological features in relation to clinical signs in clinically diagnosed
corticobasal degeneration. Neurol Sci 2003;24:1623.
Role of Neuropsychiatric Assessment 163
11
Role of Neuropsychiatric Assessment in Diagnosis
and Research
Dag Aarsland, Uwe Ehrt, and Clive Ballard
INTRODUCTION
Although the basal ganglia have traditionally been considered as primarily involved in the regula-
tion of motor functioning, their role in the integration of emotions with cognitive and motor behavior
is increasingly recognized. Psychiatric symptoms, including disturbance of affect (anxiety and
depression), perception (hallucinations), thought (delusions), as well as behavioral and personality
changes (apathy and disinhibition) are commonly observed in most basal ganglia diseases. They
produce increased suffering and distress both for the patients themselves as well as for the caregivers,
and are associated with increased need for care. Thus, psychiatric symptoms should not be viewed as
a secondary or additional feature of the movement disorders, but rather, representing important and
inherent aspects of these disorders. Although this is true for Parkinsons disease (PD), it is even more
so for several of the atypical parkinsonian disorders, where psychiatric symptoms may represent key
features of the clinical syndrome. For instance, in dementia with Lewy bodies, visual hallucinations
are among the three cardinal features (1), and in focal lesions of the caudate, neuropsychiatric symp-
toms occur more commonly than motor disorders (2). Knowledge of the wide variety of psychiatric
symptoms and having the diagnostic skills to identify and optimize treatment of these symptoms are
thus of major importance in the management of patients with movement disorders. In addition to
providing important diagnostic information, they help elucidate the relationship between key brain
circuits and psychiatric symptoms.
The studies of patients with various parkinsonian disorders differ markedly with regard to diag-
nostic criteria used, the number and selection of patients with a high risk for random error and selec-
tion bias, the level of cognitive functioning within each diagnostic group and between the groups
compared, and the use of instruments to measure neuropsychiatric symptoms. Thus, firm conclusions
regarding comparisons of the frequency, severity, and profile of psychiatric symptoms in different
parkinsonian disorders are premature.
This chapter will define the most common psychiatric symptoms in parkinsonian disorders and
how they can be reliably measured, explore the relationship between basal ganglia structure and
functioning with neuropsychiatric symptoms, and review studies of the frequency and characteris-
tics, clinical implications as well as the so far limited data pertaining to treatment.

163
164 Aarsland, Ehrt, and Ballard
DEFINITION AND IDENTIFICATION OF KEY NEUROPSYCHIATRIC

SYMPTOMS
The definition of psychotic symptoms (i.e., delusions, delusional misidentification, and hallucina-
tions) requires particular consideration as these symptoms are very frequent in some parkinsonian
disorders, particularly in patients with dementia. In addition, as they are phenomenologically differ-
ent from psychotic symptoms occurring in patients with functional psychoses and cannot be reliably
observed or inferred from behavior, a specific method is required to identify these symptoms in
patients with cognitive impairments. According to Burns, delusions are defined as false, unshakable
ideas or beliefs that are held with extraordinary conviction and subjective certainty (3). To minimize
overlap with confabulation and delirium, they should be reiterated on at least two occasions more than
1 wk apart. Hallucinations are described as percepts in the absence of a stimulus, reported directly by
either the patient or indirectly via an informant, and may occur in any modality. Typically, visual
hallucinations are the most common type of hallucinations encountered in patients with parkinsonian
disorders. Delusional misidentification, including the Capgras syndrome (the belief that a person,
object, or environment has been replaced by a double or replica), delusional misidentification of
visual images (whereby figures on television or in photographs are thought to exist in the real envi-
ronment), delusional misidentification of mirror images (ones reflection is perceived as the image of
a separate person), and the phantom boarder delusion (believing that strangers are living in or visiting
the house) are also commonly encountered in parkinsonian patients.
The diagnosis of depression in parkinsonian disorders may be difficult, and both over- and
underdiagnosis may occur. The motor symptoms may mask the affective features, leading to
underdiagnosis, whereas the psychomotor slowing, apathy and masked facies may be erroneously
interpreted as depression. Although most reports indicate that the symptoms of depression are broadly
similar in people with or without a parkinsonian disorder, patients with PD may have more com-
monly dysphoria and pessisimism, but less commonly guilt, self-blame, and suicidal behavior than
subjects without a parkinsonian disorder. Symptoms such as fatigue, apathy, sleep, and appetite dis-
turbance may occur independently of mood as an intrinsic part of the neurodegenerative process. The
nonsomatic symptoms of depression appear to be the most important for distinguishing between
depressed and nondepressed patients with parkinsonism (4). Dementia may further complicate the
diagnosis of depression in these patients because patients are unable to verbalize their subjective
experience. Despite this, there is evidence that depression can be reliably and validly diagnosed even
in patients with a parkinsonian disorder using standardized depression-rating scales (see below).
Apathy consists of lack of motivation with diminished goal-directed behavior, reduced goal-
directed cognition, and decreased emotional engagement. Apathy may accompany depression, but
it is often an independent syndrome without the sadness, despair, and intense suffering typically
experienced by depressed patients (5). Apathy is commonly accompanied by evidence of executive
dysfunction.
Anxiety is characterized by excessive and unjustified apprehension, feelings of foreboding, and
thoughts of impending doom. Patients are tense and irritable, and frequently exhibit autonomic dis-
turbances including sweating, palpitations, gastrointestinal distress, and shortness of breath. Both
low-grade, free-floating anxiety and acute and intense panic attacks may occur.
Although less frequently reported, a number of other neuropsychiatric symptoms need to be men-
tioned. Agitation, such as aggression, restlessness, and shouting, can usually be observed, and thus
the identification of these symptoms is less problematic. However, key symptoms of agitation are
often secondary to other psychiatric syndromes. For example, anxiety may lead to restlessness, shout-
ing, or trailing carers, or aggression may be secondary to delusional beliefs. Disinhibition is charac-
terized by inappropriate social and interpersonal interactions. Elation/euphoria refers to an elevated
mood with excessive happiness and overconfidence, and obsessional and compulsory symptoms,
with recurrent thoughts, vocalizations, or rituals, may also occur in basal ganglia disorders.
MEASURING PSYCHIATRIC SYMPTOMS

The measurement of psychiatric disturbances in patients with neurological disorders presents
unique challenges. Because of the commonly co-occurring cognitive deficits, patients may not remem-
ber or report their symptoms. Furthermore, since these symptoms may fluctuate, the patients may not
exhibit the symptoms at the time of the examination. It may thus be useful to infer symptoms from
behavior or ascertain symptoms from an informant interview referring to a specific time period, in
addition to the direct observation and interview of the patient.
A number of different instruments have been used to measure neuropsychiatric symptoms in patients
with parkinsonian disorders. These can be divided into clinical interviews that focus upon a broad range
of symptoms or more focused scales. Examples of the first group include the Present Behavioural
Examination (PBE) (6), Neuropsychiatric Inventory (NPI) (7), and Brief Psychiatric Rating Scale
(BPRS) (8). The PBE is a lengthy interview with a detailed assessment of behavior in patients with
dementia, and requires a trained observer. The NPI is a highly structured, caregiver-based interview,
which can be completed in a relatively short time depending on the amount of disturbances (see
below). The BPRS was constructed essentially for schizophrenic states, and requires a trained rater.
Examples of scales that assess specific syndromes in more detail are the Hamilton Depression Rating
Scale (HAM-D) (9); and self-rating scales completed by the patients themselves (i.e., Beck Depres-
sion Inventory [BDI]) (10) and Geriatric Depression Scale (11). Acceptable psychometric properties
of the PBE, BPRS, and NPI have been demonstrated in patients without parkinsonian disorders only,
although interrater reliability of the NPI has been reported to be high in PD patients (12). The depres-
sion scales HAM-D, Montgomery & sberg Depression Rating Scale (MADRS) (13), BDI (14), and
Hospital Anxiety and Depression Scale (HAD) (15) have been validated in patients with PD. How-
ever, the cutoff scores may differ from nonparkinsonian subjects, and whereas lower cutoff scores
are useful for screening purposes, higher scores are needed to make these scales good diagnostic
instruments in these populations (13,14). Although qualitative differences of depression prevalence
and phenomenology may exist between different parkinsonian disorders (16), it is reasonable to as-
sume that the psychometric properties achieved in PD patients may apply for patients with atypical
parkinsonian disorders as well.
The most widely used scale for the measurement of a broad range of psychiatric and behavioral
symptoms among recently published studies in patients with neurological disorders is the NPI (see
video). This is a highly structured, caregiver-based interview that rates frequency and severity of 10
psychiatric disturbances commonly observed in patients with different dementing conditions: delu-
sions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, disinhibition, apathy, irrita-
bility, and aberrant motor activity. The use of screening questions makes it easy to use in clinical
practice, and the highly structured design suggests that the tool can be reliably used by individuals
with low levels of training when provided with appropriate instruction regarding how to use the
instrument. Since the NPI is scored on the basis of information provided by a caregiver, it avoids the
problem inherent in observer-based strategies. On the other hand, it is subject to bias if the caregiver
lacks or distorts information, and a caregiver with daily contact with the patient may not always be
available.
THE NEUROPSYCHIATRY OF THE BASAL GANGLIA

The basal ganglia are involved in two major brain systems associated with the regulation of emo-
tions, mood, and behavior: (a) the limbic structures with widely distributed brainstem, striatal, and
paralimbic sites, with rich reciprocal connections to the basal ganglia, in particular between the
amygdalae and caudate (17); and (b) five frontosubcortical circuits, linking frontal lobe regions to
subcortical structures, including the basal ganglia, and back to frontal lobe areas (18). These circuits
receive input from brainstem nuclei, including dopaminergic input from substantia nigra and pars
compacta. In addition to motor and eye movement control, the frontosubcortical circuits subserve
key behaviors including executive functioning, motivated behavior, and integration of emotional
information into contextually appropriate behavior. Thus, the basal ganglia are interpositioned as an
interface between internal personal drives (mood and motivation) and behavioral responses to exter-
nal stimuli.
On the other hand, imaging studies have revealed that the basal ganglia are involved in func-
tional psychiatric disorders. Magnetic resonance imaging (MRI) studies report reductions in cau-
date and putamen volume in unipolar and bipolar depression in addition to the prefrontal cortex, and
positron emission tomography (PET) studies reveal hypermetabolism of globus pallidus in patients
with unipolar and bipolar depression (19). Similarly, in obsessive compulsive disorder (20); changes
in caudate activity have been reported. Thus, it is not surprising that diseases of the basal ganglia are
associated with a wide range of neuropsychiatric disturbances. Furthermore, since the three
frontosubcortical circuits mediating cognitive and emotional control transverse different regions of
the basal ganglia, it is likely that the differential involvement of the basal ganglia in different diseases
results in different patterns of neuropsychiatric symptoms.
Since parkinsonian disorders usually involve several subcortical structures, particularly at more
advanced disease stages, focal lesions may provide a better opportunity to unravel the relationship
between different basal ganglia regions and neuropsychiatric symptoms. In a literature review, Bhatia
and Marsden reported the motor and behavioral changes in 240 patients with lesions affecting the
basal ganglia (2). Although publication bias and wide variations in the assessment of neuropsychiat-
ric symptoms employed limit the generalizability of the findings, some interesting results emerged.
First, behavioral disturbances were reported in 46% of the cases. Second, such disturbances occurred
nearly exclusively in patients with lesions involving the caudate nucleus, whereas lesions confined to
the putamen or globus pallidus, or the combination of these, rarely were associated with neuropsychi-
atric changes. Finally, in lesions involving the caudate nucleus, apathy (28%), disinhibition (11%),
and depression (29%) were the most common neuropsychiatric symptoms. Notably, neuropsychiatric
symptoms were more common than motor disturbances after such lesions (2). Thus, lesions involv-
ing the caudate nucleus or other aspects of the three frontosubcortical circuits mediating behavior are
associated with neuropsychiatric symptoms. Apathy, disinhibition, depression, and obsessive-com-
pulsive symptoms are common behavioral correlates of such disturbances. Further empirical support
for the involvement of basal ganglia in cognition and emotion was reported in a study of 143 patients
with bilateral basal ganglia mineralization, which was associated with an increased risk for affective
and paranoid disorders (21).
Cummings proposed an integrating hypothesis linking observations from molecular biologic, neu-
ropathologic, and neurochemical studies in neurodegenerative disorders to neuropsychiatric mani-
festations of these disorders. According to this model, proteinopathies, such as tauopathies and
alpha-synucleinopathies, are associated with a distinct anatomic pattern of degeneration. Cell death
in specific brain nuclei responsible for transmitter synthesis leads to deficits in a variety of transmit-
ter systems. Specifically, F-synuclein disturbances, such as PD, dementia with Lewy bodies (DLB),
and multiple system atrophy (MSA), mainly involve substantia nigra, brainstem, and limbic sys-
tem neurons, whereas frontal and basal ganglionic neurons are predominantly affected in tau
metabolism disturbances, such as progressive supranuclear palsy (PSP) and corticobasal degenera-
tion (CBD), resulting in frontal and subcortical abnormalities (22). These differential regional and
transmitter involvements may result in differential patterns of motor, cognitive, and neuropsychiatric
changes.
EPIDEMIOLOGY AND IMPLICATIONS OF NEUROPSYCHIATRIC

FEATURES IN PARKINSONIAN DISORDERS
There are few epidemiological studies of neuropsychiatric symptoms in parkinsonian disorders. In
one study of a relatively large, representative community-based sample of patients with PD, 61% had
a positive score on at least one NPI item, and 45% had a positive score on at least two items. Patients
in nursing homes, with more advanced parkinsonism, and with dementia had more frequent and
severe neuropsychiatric symptoms (12). Studies of patients with atypical parkinsonian disorders have
typically involved small convenience samples from highly specialized movement disorder clinics,
and thus may not necessarily be representative of the general population. The exception is DLB, and
two studies, both including 98 patients with DLB, showed a high prevalence of neuropsychiatric
symptoms (23,24). In one study, 98% had at least one positive symptom as measured by the NPI (24)
demonstrating the importance of neuropsychiatric symptoms in this common disorder, which affects
5% of the elderly aged 75 or more (25). Unlike other dementias, neuropsychiatric symptoms in DLB
are not associated with declining cognition (23), nor with age or gender (26). In PSP, 88% of patients
had at least one positive NPI item (27) and 87% of CBD patients (28), again underlining the impor-
tance of neuropsychiatric symptoms in patients with parkinsonian disorders. In PSP and CBD, there
is little correlation between neuropsychiatric symptoms and motor and cognition scores, indicating
that in these disorders, the frontosubcortical circuits mediating behavior and motor symptoms degen-
erate independently.
What are the clinical implications of neuropsychiatric symptoms in patients with parkinsonian
disorders? Again, most research has been performed on patients with PD, and it seems reasonable to
extrapolate the findings from these studies to patients with atypical parkinsonian disorders. First,
several studies have consistently demonstrated that neuropsychiatric symptoms have strong negative
influences on the quality of life, including physical, social, and psychological well-being of patients
with PD, even after controlling for motor, functional, and cognitive disturbances. For instance,
depression has consistently, and irrespective of instruments used to assess depression, been found
to be among the most important independent predictors of impaired quality of life in PD patients
(2931), and a longitudinal study reported that depression and insomnia were the most important
factors associated with poor quality of life (32). Although there is overlap between the symptoms of
depression and quality of life, these findings highlight the need to diagnose and treat depression in
patients with parkinsonian disorders.
Second, caring for a patient with a parkinsonian disorder is associated with considerable emo-
tional, social, and physical distress (3335). Neuropsychiatric symptoms of PD patients, such as
depression, cognitive impairment, delusions, and hallucinations, have been found to be significant
and independent contributors to the perceived burden in spouses of these patients (33). Third, a sub-
stantial proportion of patients with parkinsonian disorders are admitted to nursing homes (36). In
addition to motor symptoms and functional impairment, neuropsychiatric symptoms such as cogni-
tive impairment and psychosis have been found to be independent predictors of nursing home admis-
sion in parkinsonsian patients (37,38). Both higher need for care and increased caregiver burden may
contribute to the relationship between nursing home admission and neuropsychiatric symptoms.
Fourth, neuropsychiatric symptoms may increase the economic costs in patients with parkinsonism.
In a recent study of patients with Alzheimers disease (AD), health-related costs were substantially
higher in patients with higher scores on the NPI compared to those with low levels (39), and a similar
relationship may exist in patients with parkinsonian disorders as well. Finally, there is some evidence
that neuropsychiatric symptoms are associated with a more severe disease course. PD patients with
depression have been related to a more rapid cognitive decline (40), although other studies have not
found a relationship between neuropsychiatric symptoms and cognitive decline (41) or mortality
(42). In summary, the importance of neuropsychiatric symptoms for the quality of life and prognosis
of patients with parkinsonian disorders, perceived stress of their spouses as well as the need for
health care resources is well established, highlighting the need for proper diagnosis and management
of these aspects of the parkinsonian disorder.
THE ROLE OF NEUROPSYCHIATRIC ASSESSMENT IN DIAGNOSIS

OF PARKINSONIAN DISORDERS
Methodological Considerations
Given the assumption that the neuropsychiatric profile of a neurological disorder reflects the under-
lying neuropathology, the neuropsychiatric assessment may also provide important information per-
taining to the diagnosis. The differential neuropsychiatric profile may be most pronounced at early
stages because of the disappearance during later stages of the relatively distinct anatomical involve-
ment observed initially.
During the last decade an increasing number of studies describing the neuropsychiatric character-
istics of patients with neurodegenerative disorders have been published. Among the group of move-
ment disorders, however, the majority of studies have focused on patients with PD, and only few
studies with a low number of participants have explored the pattern of neuropsychiatric symptoms in
atypical parkinsonian disorders, and thus the knowledge of the neuropsychiatric characteristics of
these disorders is still limited. In addition, there are several other methodological caveats to consider
when comparing different studies of the neuropsychiatric profile of patients with parkinsonism. First,
patients can be selected from different sources. Clinical and demographic characteristics of patients
attending a specialized movement disorder clinic may differ from patients referred to a neuropsychi-
atric unit or residing in the community with regard to age, education, duration of disease, cognitive
functioning, and social and economic status. Such differences may influence the frequency of neu-
ropsychiatric symptoms. Second, the clinical diagnostic accuracy of movement disorders is not opti-
mal as (4346) clinico-pathologic studies have shown significant false-positive and false-negative
rates for diagnosing parkinsonian disorders (47). Studies using patients with autopsy confirmed diag-
noses are rare, and the clinical diagnostic criteria employed may vary. Third, the assessment of neu-
ropsychiatric symptoms varies. Some studies are retrospective chart reviews using unstructured
clinical notes, whereas others have prospectively assessed patients using standardized instruments
with established reliability and validity. In addition, different instruments may yield different results.
For instance, highly different frequencies of depression may occur depending on whether a diagnosis
of major depression according to the DSM (Diagnostic and Statistical manual of Mental Disorders)
system IV is used, or whether rating scales such as NPI, HAM-D, or BDI, with different possible
cutoff scores are used (13,14). In addition, the time frame is of importance since the prevalence may
differ depending on whether a point-prevalence, a 1-wk, 1-mo, or even lifetime diagnosis of depres-
sion is recorded. Finally, the neuropsychiatric profile may vary with disease duration. For example,
psychosis is more common in later stages rather than in earlier stages of PD (42,48,49), and thus
comparative studies should control for disease duration or disease stage.
With these caveats in mind, some information with potential diagnostic value can nevertheless be
drawn from the literature of neuropsychiatric symptoms in parkinsonian disorders. The interpretation
of existing studies benefits from the fact that several studies have used the NPI to assess neuropsy-
chiatric symptoms, and thus it is possible to compare the NPI profile of the different parkinsonian
disorders.
NEUROPSYCHIATRIC SYMPTOMS IN PARKINSONS DISEASE

The cardinal pathological feature of PD is Lewy body degeneration of the substantia nigra, caus-
ing loss of dopaminergic innervation of the striatum. In addition, other pigmented brainstem and
cholinergic nuclei are involved, and Lewy bodies are found in the neocortex of most patients. The
cardinal clinical features are resting tremor, bradykinesia, and rigidity.
Neuropsychiatric symptoms are common, and their prevalence, phenomenology, and clinical impli-
cations have been extensively studied during the last decade. The majority of PD patients develop
dementia with cortical and subcortical features when disease duration exceeds 10 yr (41). Depression
is the most common psychiatric symptom in PD (12,50), and may occur in up to 40% of patients (51).
Different studies report wide variations in prevalence rates, however, and population-based studies
suggest that major depression according to the DSM system is uncommon, occurring in less than
10% of cases (52,53).
The etiology of depression in PD is not yet determined. Although psychosocial factors, i.e., social
support, psychological reaction to the disease, and coping strategies, certainly play a role (54), bio-
logical factors are also thought to contribute. Serotonergic, dopaminergic, and noradrenergic deficits,
cortical and subcortical neurodegeneration, and genetic factors may contribute to depression in PD
(55). Stefurak and Mayberg proposed a model for depression in PD based on clinical, imaging, treat-
ment, and behavioral challenge studies, which involves cortical-limbic and frontostriatal pathways.
According to this model, a dorsal-cortical compartment (prefrontal, premotor, and parietal cortices
and dorsal and posterior cingulate) is postulated to mediate the cognitive aspects of depression
(including apathy, attentional, and executive dysfunction), whereas a ventral-limbic compartment
(ventral cingulate, hippocampus, and hypothalamus) mediates circadian, somatic, and vegetative
aspects of depression (sleep, appetite, libidinal, and endocrine disturbances). Finally, the rostral
cingulate, with reciprocal connections to both compartments, is suggested to serve a regulatory role,
including a major role in determining the response to treatment (19). Key neurotransmitters involved
in these structures include dopamine and serotonin.
Is depression more prevalent in PD compared to other conditions with comparable functional
impairment? If not, there is little reason to assume a disease-specific association between PD and
depression. Studies of this question have usually included small samples subject to selection and
participation biases. Nilsson et al. used the Danish registers of somatic and psychiatric in-patients to
address this question. Data from more than 200,000 persons were analyzed, and more than 12,000
subjects with PD were identified. A significant increased risk for hospitalization owing to depression
in patients with PD compared to subjects with osteoarthritis or diabetes mellitus was found, and the
authors suggest that the increased risk was not a mere psychological reaction to the disease, but rather
because of disease-specific brain changes in PD patients (56).
Visual hallucinations are also common in PD, and typically involve people of normal size and
configuration who do not communicate with the patient. A substantial proportion of patients report
vague feelings of a presence (57). The patients may or may not be aware of the abnormality of the
experience, and the visions usually do not cause emotional disturbance. However, more severe psy-
chotic symptoms with delusions and behavioral disturbances may occur as well, particularly in
patients with dementia (48). Although these symptoms have previously been considered secondary
to dopaminergic treatment, there is evidence suggesting that other factors may be even more impor-
tant. First, psychotic symptoms were described in PD before levodopa was introduced and in untreated
patients. Second, most studies find that psychotic symptoms are not related to the dose, duration of
treatment, or number of dopaminergic agents (57). Third, hallucinations do not relate to levodopa
plasma level or to sudden changes in plasma level (58). Fourth, although dopaminergic agents may
induce psychotic symptoms in non-PD patients, PSP patients treated with dopaminergic agents do
not develop hallucinations (49). Similarly, the phenomenology of well-formed images of people,
usually not threatening to the patients and sometimes with insight retained, as well as the content of
delusions, is very similar to the symptoms in DLB, which usually occur without dopaminergic treat-
ment (59). Thus, dopaminergic agents may provide a neurochemical milieu with a high risk for psy-
chosis in PD, but are not necessary or sufficient to cause psychosis. The association between duration
and severity of disease, dementia, depression, sleep disturbance, visual disturbances, and psychotic
symptoms suggests a multifactorial etiology, including brain changes associated with the disease
itself. Neurochemical changes potentially contributing to hallucinations in PD include limbic dopam-
inergic hypersensitivity and cholinergic and serotonergic changes. Sensory deprivation may also con-
tribute, and patients with PD may process retinal images abnormally. In fact, there is evidence that
visual hallucinations in PD and DLB arise as a result of abnormal activation of higher order. This
would fit well with the finding that visual hallucinations are associated with Lewy bodies in the
temporal lobe (60).
The NPI profile of a community-based sample of 139 patients with PD was characterized by
relatively high levels of depression (38%), hallucinations (27%), and anxiety (20%), whereas eupho-
ria and disinhibition were uncommon (12) (Table 1). A positive score on at least one NPI item was
Table 1
Frequency of Neuropsychiatric Symptoms in Parkinsonian Disorders Using the NPI
PD (ref. 12) PSP (ref. 49) CBD (ref. 28) DLB (ref. 71)
N 139 61 15 93
Age 74.4 (7.9) 67.1 (6.5) 67.9 (SEM 2) 73.9 (6.4)
M/F 61/78 38/23 8/7 55/36
MMSE score 25.2 (5.9) 27.0 (4.2) 26.1 (SEM 1.2) 17.9 (4.6)
Delusion 16 3 7 62
Hallucinations 27 2 0 77
Agitation 17 21 20 58
Depression 38 25 73 72
Anxiety 20 18 13 67
Euphoria 1 0 0 17
Disinhibition 7 56 13 23
Irritability 10 20 20 55
Apathy 19 84 40 46
Aberrant motor behavior 11 9 7 52
Total with NPI symptom 61 88 87 98
Mean total NPI score 7.1 (12.0) 12.4 (9.4) 9.0 (SEM 3.2) 22.8 (15.4)
The numbers represent percentage with symptom present or mean (SD) values. NPI, Neuropsychiatric
Inventory; PD, Parkinsons disease; PSP, progressive supranuclear palsy; CBD, corticobasal degeneration;
DLB, dementia with Lewy bodies; MMSE, Mini Mental State Examination.
reported for 61%, and 45% had more than one symptom. Neither age, duration of disease, nor
levodopa dosage correlated with NPI subscores. Hallucination, delusion, and agitation scores corre-
lated with more advanced disease stage and cognitive impairment, and apathy with cognitive impair-
ment. Compared with AD, PD patients with a similar level of dementia had significantly higher
hallucination scores and a nonsignificant trend toward higher depression scores than AD patients,
whereas AD patients had higher scores on most other items (61). The NPI profile of this PD popula-
tion has also been used for direct comparisons with DLB and PSP patients.
PSYCHIATRIC ASPECTS OF DEMENTIA WITH LEWY BODIES

DLB is characterized clinically by dementia, visual hallucinations, and fluctuating consciousness
in addition to parkinsonism. Neuropathological characteristics include alpha-synucleinopathy, such
as Lewy bodies and Lewy neurites in the brainstem, particularly the substantia nigra, subcortical
structures, limbic cortex, and neocortex. Some amyloid deposition is also found in most patients.
Neurochemically marked cholinergic deficits are reported in addition to a moderate nigro-striatal
dopaminergic, and monoaminergic deficits have also been reported. It is estimated that at least 80%
of DLB patients experience some form of neuropsychiatric symptoms (23), such as visual hallucina-
tions, auditory hallucinations, delusions, delusional misidentification, and depression. These visual
hallucinations are consistently reported to be more frequent in DLB than in AD, also in samples
diagnosed at autopsy, and constitute one of the key diagnostic features of the disorder. Although rates
vary from 25% to 83%, most prospective studies indicate a frequency of more than 50%. Delusions,
including delusional misidentifications, are also common in DLB patients (frequency 1375%). The
rate reported for depression has varied from 14% to 50% in patients with DLB depending upon the
study definition, with a frequency of major depression that is probably greater than 30%.
Sleep disturbances, such as insomnia and increased daytime sleepiness, are more common in DLB
than AD (62), and are also pronounced in PD (63). REM sleep behavior disorder (RBD) is character-
ized by loss of normal skeletal muscle atonia during REM sleep with prominent motor activity and
dreaming. RBD is particularly common in DLB (64). When associated with dementia or parkin-
sonism, RBD usually predicts an underlying synucleinopathy, and it has been proposed that RBD
should be included in the clinical diagnostic criteria for DLB (64). In PD, an association between
RBD and visual hallucinations has been reported (65). Interestingly, during clonazepam treatment,
which may improve RBD, the frequency of visual hallucinations decreased, suggesting a causal link
between RBD and halucinations (65).
Autopsy studies have identified greater cholinergic deficits in the cortex of hallucinating patients
when compared to nonhallucinating patients (66,67). A provisional report of a prospective clinico-
pathological study (68) indicates an association between visual hallucinations and less severe neu-
rofibrillary tangle pathology, the reverse association to that seen in AD, highlighting an important
difference in the biological substrates of key neuropsychiatric symptoms in the two conditions. Recent
neuropathological studies have also indicated a significantly higher number of Lewy bodies in the
temporal cortex of DLB patients with visual hallucinations compared to those without (60).
Neuroimaging studies using SPECT (single photon emission computed tomography) report reduced
blood flow to the primary visual areas in the occipital cortex as the main association of visual hallu-
cinations (69). Delusions have been less studied, but were associated with increased muscarinic M1
receptor binding (70). One preliminary study has examined the neurochemical associations of depres-
sion, indicating that DLB patients with major depression had a relative preservation of 5HT
reuptake sites, compared to those without (68). The associations of other neuropsychiatric features
await evaluation.
In a direct comparison with PD and dementia, DLB and PD patients showed very similar profiles
of neuropsychiatric symptoms, although the frequency of most symptoms was higher in DLB than in
PD patients (59). The majority of DLB patients were diagnosed by autopsy, but the methods of
assessing neuropsychiatric symptoms differed slightly in the two groups. In 93 DLB patients recruited
to an international multicenter study of rivastigmine (24), neuropsychiatric symptoms were assessed
using the NPI. On most items, a positive score was reported in more than 50% of the patients, except
euphoria, disinhibition, and apathy. The highest frequency was found for hallucinations, depression,
and anxiety (see Table 1) (Janet Grace & Ian McKeith, personal communication) (71), a pattern
similar to that reported in PD. There was a trend toward higher NPI scores in patients with more
cognitive impairment as measured with the Mini Mental State Examination (MMSE), and this was
significant for the four-item NPI (the sum of hallucination, delusion, depression, and apathy items)
(24). In summary, psychiatric symptoms, in particular visual hallucinations, are extremely common
in DLB, and help distinguish these patients from patients with AD and other disorders (46), although
DLB may be diagnosed also in the absence of visual hallucinations (72). The profile of neuropsychi-
atric symptoms, as well as the cognitive profile (73) in DLB patients are similar to the symptoms
observed in PD patients.
NEUROPSYCHIATRIC SYMPTOMS IN PROGRESSIVE SUPRANUCLEAR

PALSY
Few studies have explored the neuropsychiatric symptoms of patients with PSP, a disorder charac-
terized neuropathologically by abundant neurofibrillary tangles in several subcortical nuclei (stria-
tum, pallidum, subthalamic nucleus), in addition to the substantia nigra (74). Prefrontal and
parahippocampal cortices may also be involved. Locus ceruleus and raphe nuclei are relatively pre-
served, and noradrenaline and serotonin concentrations are usually not affected (28). Clinical symp-
toms include supranuclear vertical gaze palsy, akineto-rigid predominant parkinsonism, early postural
instability, and subcortical dementia. Some studies of the clinical features in patients with PSP have
included neuropsychiatric aspects, although most studies have employed only unstructured assessments
based on retrospective review of clinical records. In one study of 52 patients, at the time of diagnosis
45% had memory impairment, 15% were depressed, 23% had personality changes, and 17% emo-
tional lability (75). In another study, caregivers of 437 of the 1184 members of the Society for Pro-
gressive Supranuclear Palsy (SPSP) (76) completed a structured questionnaire assessing common
symptoms and signs, including cognitive and emotional/personality problems. Personality and emo-
tional problems were uncommon 2 yr prior to the diagnosis. At the time of diagnosis, however,
changes in personality appeared in 46% and depression in 44%. Other personality problems, such as
losing control over emotions, lack of emotions, and excessive anger, were reported in less than 30%
of patients at the time of diagnosis. A UK sample of 187 patients was diagnosed according to the
National Institute of Neurological Disorders and Stroke (NINDS)SPSP criteria for probable or pos-
sible PSP. Sixty-two patients were drawn from a prevalence study and examined by the investigators,
49 of these with a structured clinical examination. At onset, 15% had neuropsychiatric features, in-
cluding memory impairment (7%), personality change (4%), and depression/anxiety/apathy (3%).
Apathy was noted in 50% of the patients during the disease course (77). Seven patients had responded
to an antidepressive drug. In a group of 24 patients with an autopsy-confirmed diagnosis of PSP,
frontal lobe symptomatology, including executive dysfunction and personality changes such as apa-
thy and depression, was the presenting symptom in 8%, 55% had such symptoms at the first visit, and
58% at the last visit (78).
A clinical series of 25 PSP patients were assessed for depression using the BDI. The majority of
patients (55%) had scores above the cutoff for probable depression: mild (score 1117, n = 7), mod-
erate (1823; n = 3) or severe depression (24 or above, n = 3) (79). Depression scores did not corre-
late with neuropsychological performance. The proportion of subjects with a BDI score of 18 or more
in PSP (24%) is identical to the findings in a large PD population (52). A cutoff score of 16/17 has
received empirical support for diagnosing clinically relevant depression in PD (14).
Few studies have focused specifically on neuropsychiatric aspects using standardized assessment
procedures. The NPI profile was reported in 61 patients with PSP (49), 13 of whom were diagnosed
as definite PSP according to the NINDSPSP (43) (i.e., autopsy confirmed); the remaining met the
criteria for probable (n = 36) or possible (n = 12) NINDSSPSP criteria, which have high diagnostic
specificity. The most common NPI items were apathy (positive score in 84%) and disinhibition (56%),
whereas hallucinations and delusions were very rare (Table 1). Compared to age- and gender-matched
PD patients, the severity of apathy and disinhibition was higher in PSP than PD patients, whereas
hallucinations, delusions, and agitation scores were higher in PD than PSP patients. Interestingly,
44% of the PSP patients were taking at least one anti-parkinsonian agent, usually levodopa, at similar
doses as the PD group. Thus, hallucinations and delusions do not seem to occur in PSP even when
taking dopaminergic agents. The same group of PSP patients was compared with Huntingtons dis-
ease and Gilles de la Tourette syndrome, both typical hyperkinetic movement disorders. Patients
with PSP, a hypoactive movement disorder, had lower scores on NPI items assessing hyperactive
behaviors (i.e., agitation, irritability, euphoria, and anxiety), but higher scores on apathy, a
hypoactive behavior (27,80). Thus, in summary, the neuropsychiatric profile of PSP is character-
ized by early subcortical dementia and frequent occurrence of apathy and disinhibition, whereas
hallucinations, delusions, and agitation are rare, irrespective of whether the patients are treated with
anti-parkinsonian agents.
NEUROPSYCHIATRIC SYMPTOMS IN CORTICOBASAL DEGENERATION

CBD is characterized pathologically by neurodegeneration of frontal and parietal cortices, sub-
stantia nigra, and several basal ganglia nuclei including subthalamic nucleus, striatum, and pallidum.
Other brainstem nuclei, including locus ceruleus, raphe nucleus, and midbrain tegmentum, are also
involved, with marked reductions of noradrenaline and serotonin in addition to the nigrostriatal
dopamine deficiency (81). Tau protein-positive inclusions and achromatic neurons are found. Sev-
eral studies have characterized the motor and cognitive features of CBD, but the patients neuropsy-
chiatric symptoms have rarely been described.
The clinical studies have usually been retrospective chart reviews of clinically or
neuropathologically diagnosed patients with CBD conducted at movement disorders clinics, focus-
ing more on the motor than the neuropsychiatric features. Rinne et al. performed a retrospective chart
review of 36 cases with a clinical or a pathological diagnosis of CBD (82). Initially, seven (19%)
patients showed slight generalized cognitive impairment, and one had prominent personality and
behavioral changes with impulsiveness and excessive eating and drinking. Subsequently, nine (25%)
patients had evidence of generalized higher mental function involvement. Further characterization of
neuropsychiatric symptoms was not provided. In a study of neuropsychological functioning in 21
patients with CBD and 21 with AD, significantly more severe depression as measured by the Geriat-
ric Depression Scale, a self-rating instrument, was reported in CBD (mean [SD] score 14.8 [8.6])
compared to AD (6.8 [6.2]). Both groups had a cognitive performance in the mildly demented range.
Eight (38%) CBD patients exceeded the cutoff for probable depression (a score of 15 or greater),
compared to only one (5%) of the AD patients (83). In the CBD group, depression severity was
correlated with duration of symptoms and verbal fluency and attention, but not with memory, lan-
guage, and intellectual test scores.
In 14 patients with a neuropathological diagnosis of CBD selected from the research and neuro-
pathological files of seven medical centers, the presenting symptom was dementia in 21%, frontal
behavior (i.e., apathy, disinhibition, and irritability) in 21% and depression in 7%. Subsequently,
dementia and depression had developed in 3040%, and at the last visit, 58% showed frontal behav-
iors (84). Dementia as a presenting symptom in CBD was also reported in another postmortem study
(85). A high prevalence of frontal behaviors was also reported in one of the few prospective studies
reported. Kertesz et al. followed 35 patients with a clinical diagnosis of CBD and included a struc-
tured evaluation of language, cognition, and personality changes (Frontal Behavioral Inventory or
FBI; see ref. 86), which was specifically designed to assess the spectrum of apathy and disinhibition
in frontotemporal dementias (87). They found two groups of patients according to the initial presen-
tation: 15 (43%) patients presented with the extrapyramidal or apractic symptoms, but later devel-
oped behavioral or language symptoms, and 20 cases (57%) presented with behavioral or language
symptoms followed by movement disorder. During the disease course, 20 (57%) patients developed
frontotemporal dementia. In the largest clinical series to date, a retrospective chart review was per-
formed in 147 clinically diagnosed CBD patients from eight major movement disorder clinics (88).
Except for dementia, reported in 25%, neuropsychiatric symptoms were not described in detail. How-
ever, it was reported that antidepressants, used by 11%, were not effective in treating depression.
Of 92% who received dopaminergic drugs, hallucinations had occurred in five (3.7%) patients. Six
patients had been exposed to neuroleptics, with clinical improvement in four, but the reasons for
using neuroleptic drugs were not reported. One detailed case report documented the presence of
depression and obsessive-compulsive symptoms in a patient with pathological confirmed CBD (89).
In the only prospective and detailed study of neuropsychiatric symptoms in CBD to date, Litvan et
al. administered the NPI to 15 CBD and 34 PSP patients (28). The duration of disease of the CBD
patients was relatively short, less than 2 yr, and the mean MMSE score was relatively high, 26.0.
Patients with CBD exhibited depression (73%), apathy (40%), irritability (20%), and agitation (20%),
but rarely delusions and hallucinations, and, surprisingly, disinhibition (13%) (Table 1). The depres-
sion and irritability of patients with CBD were significantly more frequent and severe than those of
patients with PSP and normal controls, whereas PSP patients exhibited significantly more apathy. A
pattern of high depression and irritability and low apathy scores correctly identified 88% of the CBD
patients. In CBD patients, irritability was associated with disinhibition and apathy. Neuropsychiatric
symptoms were not associated with motor or cognitive/executive functions, leading the authors to
conclude that the various frontosubcortical pathways in CBD are not affected in parallel, at the rela-
tively early stages of the disease. Thus, in conclusion, the neuropsychiatric profile in the early stages
of CBD is characterized by depression and apathy, combined with a mild cognitive impairment. Later
in the disease course, frontal-type behaviors predominate, with more severe apathy and disinhibition
combined with a more severe dementia. In addition to the basal ganglia pathology, the involvement
of prefrontal cortex and noradrenergic and serotonergic nuclei may contribute to this neuropsychiat-
ric pattern. However, more detailed neuropsychiatric studies of patients at different stages of CBD
are needed.
NEUROPSYCHIATRIC SYMPTOMS IN MULTIPLE SYSTEM ATROPHY

MSA is clinically characterized by the variable combination of autonomic failure, parkinsonism,
cerebellar ataxia, and pyramidal signs, and includes the previously called striatonigral degeneration
(parkinsonian features predominate), sporadic olivopontocerebellar atrophy (OPCA) (cerebellar fea-
tures predominate), and the ShyDrager syndrome (autonomic dysfunction predominates). Histo-
logically, all subtypes of MSA show glial cytoplasmic inclusions in oligodendrocytes of the cerebral
white matter, which contain alpha-synuclein. Therefore MSA ranks among the synucleinopathies,
but the reason explaining the different cellular topography of F-synuclein (neuronal in PD, glial in
MSA) is still unknown (90).
The majority of data describing neuropsychiatric disturbances in MSA are case reports. Although
these reports demonstrate that neuropsychiatric symptoms occur in MSA, few systematical studies
have been published. In one of the largest retrospective chart reviews of pathologically proven MSA,
clinical data of 203 patients were reported. Unfortunately, neuropsychiatric assessment was restricted
to bedside impressions of cognition. Mild intellectual impairment was noted in 22%, moderate im-
pairment in 2%, and only one patient had severe dementia (91).
Several reports have described depressive symptoms in MSA (16,9295). In a study of 15 patients
clinically diagnosed with ShyDrager syndrome using the BDI, 86% scored in the depressed range
(i.e., BDI score 1015), and 29% scored in the moderately depressed range (BDI score 1619). The
mean BDI score was 14.4. This score is comparable to that reported in a community-based sample of
patients with PD, who had a mean BDI score of 12.8, compared to 7.9 in patients with non-neurologi-
cal chronic disease (diabetes mellitus) and 5.9 in healthy elderly controls (52). Severity of depression
did not correlate with disability or ability to perform activities of daily living (ADL) (95). In another
study using the BDI, 3 of 15 (20%) patients had a score over 15, and MSA patients had similar
severity of depression as PD patients (94). The importance of depression in MSA is underlined by
reports showing that MSA patients may initially present with an affective disturbance (92,96). Fetoni
et al. compared 12 MSA with 12 PD patients matched for age and motor disability at baseline before
and after levodopa therapy using the HAM-D and the BPRS. Only 1 of the 12 MSA patients had a
HAM-D score of 18 (indicating a moderate-severe depression). At baseline patients with PD were
more depressed and anxious than patients with MSA who, by contrast, showed apathy. After
levodopa, depression and anxiety of patients with PD improved significantly, whereas the apathy in
patients with MSA did not change (16).
Psychotic symptoms have been described in MSA (97100), also as part of affective disturbances
(101). Of special interest for diagnostic thinking is the observation that paranoid-hallucinatory psy-
chosis with organic character can be initial manifestation of MSA (97,99). The patients described by
Ehrt et al. also exhibited visual hallucinations, a symptom typically seen in other synucleinopathies
such as DLB and PD. However, in a relatively large clinico-pathologic comparative study, neurop-
sychiatric toxicity was reported to be less common in MSA (n = 38) than PD patients (102). How-
ever, this term included confusion or hallucinations or the combination of both, the proportion of
dementia was higher in PD than MSA, the number and dosage of dopaminergic drugs in the two
groups were not comparable, and the assessments were retrospective and unstructured. Thus, it is not
yet proven that visual hallucinations are less common in MSA than PD.
Several studies have reported sleep disorders in MSA (64,103107). Wright et al. describe a
polysomnographically confirmed RBD associated with ShyDrager syndrome (108). Motor
dyscontrol in REM sleep has been described in 90% of patients with MSA (104). Among 93 patients
with RBD, 14 patients had MSA, 25 PD, and only 1 had PSP (109). And similarly, in a recent study
of 15 patients with RBD, the neuropathological diagnosis was DLB in 12 and MSA in 3 cases (64). In
a comparison of unselected patients with MSA (n = 57) with 62 age- and sex-matched PD patients,
70% of patients with MSA complained of sleep disorders compared with 51% of patients with PD,
and RBD was present in 48% of the MSA patients (106). Decreased nigrostriatal dopaminergic pro-
jections may contribute to RBD in MSA (107).
In summary, MSA patients frequently suffer from depression and sleep disorders, including RBD,
and visual hallucinations, also seem to be quite common. Thus, the neuropsychiatric pattern resembles
that of DLB and PD, suggesting clinical similarities in disorders with F-synuclein pathology (110).
In fact, one patient with a clinical diagnosis of MSA turned out at autopsy to have diffuse Lewy body
disease (111), supporting the interrelationship of these disorders.
Summary
Although few studies have explored the neuropsychiatric symptoms of parkinsonian disorders
other than PD and DLB, some preliminary hypotheses regarding the potential diagnostic value of the
neuropsychiatric assessment can be postulated. The F-synucleinopathies DLB and PD, as well as
MSA, are characterized by the frequent occurrence of hallucinations and delusions, which may be
related to Lewy bodies in the temporal lobe or cholinergic deficits. In addition, depression and anxi-
ety are common, and are possibly related to the additional involvement of monoaminergic brainstem
nuclei. Finally, RBD seem to be a marker for these disorders. In contrast, tauopathies such as PSP and
CBD are characterized by very high frequency of apathy, possibly related to the marked
hypostimulation of orbital and medial frontosubcortical circuits owing to involvement of several
basal ganglia nuclei, and disinhibition, possibly secondary to frontal lobe involvement. A high fre-
quency of depression has been reported in CBD, which may be caused in part by involvement of
brainstem monoaminergic nuclei. However, depression in parkinsonian disorders probably has a
multifactorial etiology, including a wide range of neurological and neurochemical changes in combi-
nation, and interaction, with psychosocial factors. Future research should further explore the symp-
tom pattern using standardized diagnostic instruments and the underlying brain pathology of
neuropsychiatric features in patients with PSP, CBD, and MSA (see Future Research Issues).
MANAGEMENT OF NEUROPSYCHIATRIC SYMPTOMS

Pharmacological Treatment of PD
In light of the high prevalence and clinical importance of neuropsychiatric symptoms in patients
with parkinsonian disorders, relatively few adequately designed clinical trials have been reported. In
a recent evidence-based review of management of PD, including psychosocial treatments, produced
by The Movement Disorder Society (112), the only neuropsychiatric treatment that was concluded to
be efficacious was the atypical antipsychotic agent clozapine for hallucinations/psychosis. In addi-
tion, the tricyclic antidepressant nortriptyline was considered to be likely efficacious. Too few or
methodologically inadequate studies precluded positive conclusions for other treatments.
To our knowledge, only nine randomized, placebo-controlled studies of neuropsychiatric symp-
toms in parkinsonian disorders have been reported: four trials with cholinergic agents in DLB
(rivastigmine) (113), PD (donepezil) (114), and PSP (donepezil and RS-86, a cholinergic agonist)
(115,116), two trials with clozapine in PD (117,118), and three trials with antidepressants in PD
(119121). The studies have usually included few subjects, with a total number of 356 patients in the
nine studies. Further details are provided in Table 2. In addition to the two studies showing efficacy
of clozapine in PD with psychosis, rivastigmine improved neuropsychiatric symptoms in DLB (113),
176
Table 2
Placebo-Controlled Studies of Neuropsychiatric Symptoms in Patients With Parkinsonian Disorders
Duration, Main outcome
Author Disorder Drug Dose, mg/d N Weeks Design Measures Result
The Parkinson study PD psychosis clozapine Mean 25 60 4 Parallel BPRS Positive
group (118)
The French Clozapine PD psychosis clozapine Mean 36 60 4 Parallel PANSS, CGIC Positive
Parkinson Study Group (117)
Andersen 1980 (119) PD depression nortriptyline Max 150 22 8+8 Cross-over Andersen scale (119) Positive
Wermuth 1998 (120) PD depression citalopram 65+: max 10 37 6 Parallel HDRS Negative
<65: max 20
Leentjens 2003 (121) PD depression sertraline Max 100 12 10 Parallel MADRS Negative
Aarsland 2002 (114) PD dementia donepezil 10 14 10 + 10 Cross-over CGIC, MMSE Positive
McKeith 2000 (113) DLB rivastigmine Mean 9,4 120 20 Parallel CGIC, NPI Positive
Litvan 2001 (116) PSP donepezil 10 21 6+4+6 Cross-over NPI, AES*, HDRS, Negative
MMSE
Foster 1989 (115) PSP + dementia RS-86 4 10 4+1+4 Cross-over Neuropsycholog Negative
Battery, MMSE
POMS**
*Apathy Evaluation Scale (135).
**Profileof Mood States (136).
NPI, Neuropsychiatric Inventory; PD, Parkinsons disease; PSP, Progressive supranuclear palsy, DLB, Dementia with Lewy bodies; MMSE, Mini-Mental State Examina-
tion; BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; CGIC, Clinical Global Impression of Change; HDRS, Hamilton Depression Scale;
MADRS, Montgomery & sberg Depression Rating Scale.
Aarsland, Ehrt, and Ballard
donepezil improved cognition in PD (114) but not in PSP (115,116), whereas nortriptyline (119) but
neither citalopram (120) nor sertraline (121) were more effective than placebo for depression in PD.
Two randomized studies suggest that in PD with psychosis, clozapine is better tolerated than
olanzapine (122) and risperidone (123). In addition, a range of case reports and case series reporting
the use of cholinesterase inhibitors, antidepressants, and atypical antipsychotics have been published.
The vast majority of these studies have included patients with PD or DLB. Although positive results
have been reported, these should be interpreted with caution because of the open, uncontrolled design.
The literature of treatment studies of the atypical parkinsonian disorders is reviewed below. (See recent
excellent reviews for the treatment of neuropsychiatric symptoms in PD in refs. 55, 112, and 124.)
Importantly, in patients with parkinsonism and neuropsychiatric symptoms, general measures, includ-
ing counseling, education, and supportive measures, should be considered. Attention to general medi-
cal conditions that could contribute to neuropsychiatric symptoms, such as hypoxemia, infection, or
electrolyte disturbances, and the taking of nonessential drugs are important in the management of
patients with parkinsonian disorders and neuropsychiatric disorders. Anticholinergic agents can in-
duce delirium and psychosis and should be discontinued. Curtailing doses of dopaminergic agents
should also be considered in patients with psychotic or delirious symptoms.
PHARMACOLOGICAL TREATMENT OF DLB

Several open-label studies suggest that atypical antipsychotic agents can improve psychotic symp-
toms in DLB (125,126). However, DLB sufferers seem to be particularly vulnerable to a specific type
of adverse reaction to neuroleptic agents. Patients develop severe parkinsonism, impairment of con-
sciousness, autonomic instability, and frequently experience falls and a marked drop in their level of
cognitive performance and functioning (127,128). Furthermore, even in DLB patients who do not
experience severe neuroleptic sensitivity, there is some evidence that neuronal loss in the caudate and
putamen may be exacerbated by neuroleptic treatment (129). Given the major concerns regarding
severe neuroleptic sensitivity reactions, neuroleptic agents cannot be considered to be the first-choice
management approach for neuropsychiatric symptoms, but may possibly still have a role in severe
and intractable cases with psychosis.
A number of case reports and case series indicate that cholinesterase inhibitors may improve not
only the cognitive impairment, but also the psychiatric symptoms in approx 170% of DLB cases with
good tolerability (with no exacerbation of parkinsonism in most reports). The first double-blind,
placebo-controlled trial of cholinesterase inhibitor therapy for the treatment of DLB confirms these
encouraging results (113). The total NPI score improved in 61% of patients on rivastigmine com-
pared with 28% in the placebo group. Hallucinations and delusions, apathy, anxiety, and motor
overactivity were the symptoms that improved most markedly. Rivastigmine was well tolerated with
no increase in adverse events requiring withdrawal in comparison with the placebo group. Further-
more, there was no deterioration in parkinsonism in the treatment group. Given the potential hazards
of neuroleptic treatment, most specialists would now recommend cholinesterase inhibitor therapy as
a first-line treatment for neuropsychiatric symptoms in DLB patients. The evidence is still however
preliminary, and further double-blind, placebo-controlled trials are probably needed before confi-
dent, evidence-based practice guidelines could be developed.
A variety of other psychotropic drugs are used in the short-term clinical management of DLB.
Anxiety and insomnia are common symptoms that may respond well to benzodiazepine sedatives and
antidepressant, and anticonvulsants may be useful in controlling behavioral and psychotic symp-
toms. Most of these observations are based upon clinical experience and anecdote, rather than evi-
dence; and given the poor tolerability of DLB patients to psychotropic drugs, it is probably best to
avoid all pharmacological interventions with psychotropic agents other than cholinesterase inhibi-
tors, unless the clinical situation makes it imperative. Given the potential adverse response to
neuroleptics, studies evaluating the potential value of nonpharmacological treatment approaches are
also needed. Another key issue for future trials is the management of depression in these patients (see
Future Research Issues), since no pharmacological or nonpharmacological studies have been pub-
lished so far.
TREATMENT OF PSP, CBD, AND MSA

Few trials of neuropsychiatric symptoms have been reported in PSP. In a recent placebo-con-
trolled trial, the cholinesterase inhibitor donepezil did not improve neuropsychiatric symptoms. A
slight improvement in memory was noted, but because of worsening of motor symptoms, a worsen-
ing of ADL was found in patients receiving donepezil (116). Similarly, a small placebo-controlled
trial with RS-86, a cholinergic agonist, did not improve cognition or mood in PSP patients with
dementia (115). In a clinical survey, it was reported that some PSP patients responded to antidepres-
sive drugs (77). In a chart review, 7 of 12 autopsy-diagnosed PSP patients responded to a dopaminer-
gic drugs, and 1 of 3 to a tricyclic antidepressant. None of the patients responded markedly, however.
The serotonergic agent trazodone, but not the neuroleptic drug thiotixine or carbamazepine, improved
agitation in patients with PSP (130). Another case report suggested that electroconvulsive therapy
(ECT) could improve depression without affecting motor symptoms in PSP (131). Similar findings
have been reported in PD patients (132). Very few reports of the treatment of neuropsychiatric symp-
toms exist for patients with CBD and MSA. In a large clinical survey of CBD patients, antidepressive
therapy was reported not to improve depression, whereas four of six patients exposed to neuroleptics
showed clinical improvement (88). Further details of the treatments were not provided, however. In a
patient with MSA, clozapine was reported to improve psychotic depression without aggravating neu-
rological abnormalities (98). ECT was reported to be a safe and effective treatment for major depres-
sion in some patients with MSA (101,133), with long-term benefit in some (134).
In summary, although some placebo-controlled drug trials of neuropsychiatric symptoms in par-
kinsonian disorders have been reported, there is limited evidence available to guide pharmacological
treatment for patients with atypical parkinsonian disorders.
FUTURE RESEARCH ISSUES

1. Descriptive studies of the neuropsychiatric features in PSP, MSA, and CBD using standardized psychiat-
ric rating scales.
2. Study the diagnostic properties of the neuropsychiatric profile in parkinsonian disorders.
3. Exploring the neurochemical underpinnings of neuropsychiatric symptoms in patients with parkinsonian
disorders.
4. In DLB, placebo-controlled trials of antidepressive and antipsychotic agents, and further trials of cho-
linesterase inhibitors need to be conducted.
5. In PSP, MSA, and CBD, pilot studies of the potential benefit of psychotropic agents are needed.
6. Systematic studies of non-pharmacological strategies should be conducted for patients with parkinsonian
disorders.
ACKNOWLEDGMENT
We want to thank Jeffrey L. Cummings for the permission to use the Neuropsychiatric Inventory
video.
REFERENCES
2. Bhatia KP, Marsden CD. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain
1994;117(Pt 4):859876.
3. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimers disease. I: Disorders of thought content. Br J
Psychiatry 1990;157:7276, 9294.
4. Leentjens AF, Marinus J, Van Hilten JJ, Lousberg R, Verhey FR. The contribution of somatic symptoms to the diagno-
sis of depressive disorder in Parkinsons disease: a discriminant analytic approach. J Neuropsychiatry Clin Neurosci
2003;15:7477.
5. Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci
1998;10:314319.
6. Hope T, Fairburn CG. The Present Behavioural Examination (PBE): the development of an interview to measure cur-
rent behavioural abnormalities. Psychol Med 1992;22:223230.
7. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory:
comprehensive assessment of psychopathology in dementia. Neurology 1994;44:23082314.
8. Andersen J, Larsen JK, Schultz V, et al. The Brief Psychiatric Rating Scale. Dimension of schizophreniareliability
and construct validity. Psychopathology 1989;22:168176.
9. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:5662.
10. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry
1961;4:561571.
11. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a pre-
liminary report. J Psychiatr Res 1982;17:3749.
12. Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinsons disease.
13. Leentjens AF, Verhey FR, Lousberg R, Spitsbergen H, Wilmink FW. The validity of the Hamilton and Montgomery-
Asberg depression rating scales as screening and diagnostic tools for depression in Parkinsons disease. Int J Geriatr
Psychiatry 2000;15:644649.
14. Leentjens AF, Verhey FR, Luijckx GJ, Troost J. The validity of the Beck Depression Inventory as a screening and
diagnostic instrument for depression in patients with Parkinsons disease. Mov Disord 2000;15:12211224.
15. Marinus J, Leentjens AF, Visser M, Stiggelbout AM, Van Hilten JJ. Evaluation of the hospital anxiety and depression
scale in patients with Parkinsons disease. Clin Neuropharmacol 2002;25:318324.
16. Fetoni V, Soliveri P, Monza D, Testa D, Girotti F. Affective symptoms in multiple system atrophy and Parkinsons
disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 1999;66:541544.
17. Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: an anatomic, phylogenetic, and clinical perspec-
tive. J Neuropsychiatry Clin Neurosci 1997;9:315330.
18. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873880.
19. Stefurak TL, Mayberg HS. Critical-limbic-striatal dysfunction in depression. In: Chouinard S, ed. Mental and Behav-
ioral Dysfunction in Movement Disorders. Totowa, NJ: Humana, 2003:321338.
20. Lucey JV, Costa DC, Busatto G, et al. Caudate regional cerebral blood flow in obsessive-compulsive disorder, panic
disorder and healthy controls on single photon emission computerised tomography. Psychiatry Res 1997;74:2533.
21. Forstl H, Krumm B, Eden S, Kohlmeyer K. What is the psychiatric significance of bilateral basal ganglia mineraliza-
tion? Biol Psychiatry 1991;29:827833.
22. Cummings JL. Toward a molecular neuropsychiatry of neurodegenerative diseases. Ann Neurol 2003;54:147154.
23. Ballard C, Holmes C, McKeith I, et al. Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and
neuropathological comparative study with Alzheimers disease. Am J Psychiatry 1999;156:10391045.
24. Del Ser T, McKeith I, Anand R, Cicin-Sain A, Ferrara R, Spiegel R. Dementia with lewy bodies: findings from an
international multicentre study. Int J Geriatr Psychiatry 2000;15:10341045.
25. Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. Dementia with Lewy bodies according
to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry 2003;74:720724.
26. Del Ser T, Hachinski V, Merskey H, Munoz DG. Clinical and pathologic features of two groups of patients with dementia
with Lewy bodies: effect of coexisting Alzheimer-type lesion load. Alzheimer Dis Assoc Disord 2001;15:3144.
27. Litvan I, Paulsen JS, Mega MS, Cummings JL. Neuropsychiatric assessment of patients with hyperkinetic and
hypokinetic movement disorders. Arch Neurol 1998;55:13131319.
28. Litvan I, Cummings JL, Mega M. Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychia-
try 1998;65:717721.
29. Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinsons disease? J Neurol
30. Karlsen KH, Larsen JP, Tandberg E, Maland JG. Quality of life measurements in patients with Parkinsons disease: A
community-based study. Eur J Neurol 1998;5:443450.
31. Kuopio AM, Marttila RJ, Helenius H, Toivonen M, Rinne UK. The quality of life in Parkinsons disease. Mov Disord
2000;15:216223.
32. Karlsen KH, Tandberg E, Arsland D, Larsen JP. Health related quality of life in Parkinsons disease: a prospective
longitudinal study. J Neurol Neurosurg Psychiatry 2000;69:584589.
33. Aarsland D, Larsen JP, Karlsen K, Lim NG, Tandberg E. Mental symptoms in Parkinsons disease are important con-
tributors to caregiver distress. Int J Geriatr Psychiatry 1999;14:866874.
34. Caap-Ahlgren M, Dehlin O. Factors of importance to the caregiver burden experienced by family caregivers of
Parkinsons disease patients. Aging Clin Exp Res 2002;14:371377.
35. Uttl B, Santacruz P, Litvan I, Grafman J. Caregiving in progressive supranuclear palsy. Neurology 1998;51:13031309.
36. Larsen JP. Parkinsons disease as community health problem: study in Norwegian nursing homes. The Norwegian
Study Group of Parkinsons Disease in the Elderly. BMJ 1991;303:741743.
37. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinsons disease: a popula-
tion-based, prospective study. J Am Geriatr Soc 2000;48:938942.
38. Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinsons disease.
Neurology 1995;45:669671.
39. Murman DL, Chen Q, Powell MC, Kuo SB, Bradley CJ, Colenda CC. The incremental direct costs associated with
behavioral symptoms in AD. Neurology 2002;59:17211729.
40. Starkstein SE, Mayberg HS, Leiguarda R, Preziosi TJ, Robinson RG. A prospective longitudinal study of depression,
cognitive decline, and physical impairments in patients with Parkinsons disease. J Neurol Neurosurg Psychiatry
1992;55:377382.
41. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson
disease: an 8-year prospective study. Arch Neurol 2003;60:387392.
42. Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinsons disease patients with psychosis. Neu-
rology 2003;60:17561761.
RichardsonOlszewski syndrome): report of the NINDSSPSP international workshop. Neurology 1996;47:19.
clinicopathologic study. Arch Neurol 1997;54:937944.
46. Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease,
and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol 1998;55:969978.
Mov Disord 2003;18:467486.
48. Aarsland D, Larsen JP, Cummins JL, Laake K. Prevalence and clinical correlates of psychotic symptoms in Parkinson
disease: a community-based study. Arch Neurol 1999;56:595601.
49. Aarsland D, Litvan I, Larsen JP. Neuropsychiatric symptoms of patients with progressive supranuclear palsy and
Parkinsons disease. J Neuropsychiatry Clin Neurosci 2001;13:4249.
50. Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P. Risk of dementia in Parkinsons disease: a
community-based, prospective study. Neurology 2001;56:730736.
51. Cummings JL. Depression and Parkinsons disease: a review. Am J Psychiatry 1992;149:443454.
52. Tandberg E, Larsen JP, Aarsland D, Cummings JL. The occurrence of depression in Parkinsons disease. A commu-
nity-based study. Arch Neurol 1996;53:175179.
53. Hantz P, Caradoc-Davies G, Caradoc-Davies T, Weatherall M, Dixon G. Depression in Parkinsons disease. Am J
Psychiatry 1994;151:10101014.
54. Brown R, Jahanshahi M. Depression in Parkinsons disease: a psychosocial viewpoint. Adv Neurol 1995;65:6184.
55. Burn DJ. Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinsons
disease. Mov Disord 2002;17:445454.
56. Nilsson FM, Kessing LV, Sorensen TM, Andersen PK, Bolwig TG. Major depressive disorder in Parkinsons disease:
a register-based study. Acta Psychiatr Scand 2002;106:202211.
57. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinsons disease: prevalence, phenomenology and risk
factors. Brain 2000;123(Pt 4):733745.
58. Goetz CG, Leurgans S, Pappert EJ, Raman R, Stemer AB. Prospective longitudinal assessment of hallucinations in
Parkinsons disease. Neurology 2001;57:20782082.
59. Aarsland D, Ballard C, Larsen JP, McKeith I. A comparative study of psychiatric symptoms in dementia with Lewy
bodies and Parkinsons disease with and without dementia. Int J Geriatr Psychiatry 2001;16:528536.
60. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal
lobe. Brain 2002;125:391403.
61. Aarsland D, Cummings JL, Larsen JP. Neuropsychiatric differences between Parkinsons disease with dementia and
Alzheimers disease. Int J Geriatr Psychiatry 2001;16:184191.
62. Grace JB, Walker MP, McKeith IG. A comparison of sleep profiles in patients with dementia with lewy bodies and
63. Larsen JP. Sleep disorders in Parkinsons disease. Adv Neurol 2003;91:329334.
64. Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or
parkinsonism. Neurology 2003;61:4045.
65. Nomura T, Inoue Y, Mitani H, Kawahara R, Miyake M, Nakashima K. Visual hallucinations as REM sleep behavior
disorders in patients with Parkinsons disease. Mov Disord 2003;18:812817.
66. Perry EK, Marshall E, Kerwin J, et al. Evidence of a monoaminergic-cholinergic imbalance related to visual hallucina-
tions in Lewy body dementia. J Neurochem 1990;55:14541456.
67. Perry EK, Marshall E, Perry RH, et al. Cholinergic and dopaminergic activities in senile dementia of Lewy body type.
Alzheimer Dis Assoc Disord 1990;4:8795.
68. Ballard C, Johnson M, Piggott M, et al. A positive association between 5HT re-uptake binding sites and depression in
dementia with Lewy bodies. J Affect Disord 2002;69:219223.
69. Colloby SJ, Fenwick JD, Williams ED, et al. A comparison of (99m)Tc-HMPAO SPET changes in dementia with Lewy
bodies and Alzheimers disease using statistical parametric mapping. Eur J Nucl Med Mol Imaging 2002;29:615622.
70. Ballard C, Piggott M, Johnson M, et al. Delusions associated with elevated muscarinic binding in dementia with Lewy
bodies. Ann Neurol 2000;48:868876.
71. Grace J, McKeith I. Personal Communication, 2003.
73. Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel-Larsen T, Larsen JP. Cognitive impairment in PD and dementia
with Lewy bodies. Comparison with Progressive supranuclear palsy and AD. J Neurology Neurosurg Psychiatry
2003;74:12151220.
74. Litvan I. Progressive supranuclear palsy revisited. Acta Neurol Scand 1998; 98:7384.
75. Maher ER, Lees AJ. The clinical features and natural history of the Steele-Richardson-Olszewski syndrome (progres-
76. Santacruz P, Uttl B, Litvan I, Grafman J. Progressive supranuclear palsy: a survey of the disease course. Neurology
1998;50:16371647.
nuclear palsy: a clinical cohort study. Neurology 2003;60:910916.
78. Litvan I, Mangone CA, McKee A, et al. Natural history of progressive supranuclear palsy (SteeleRichardson
Olszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiatry
1996;60:615620.
79. Esmonde T, Giles E, Gibson M, Hodges JR. Neuropsychological performance, disease severity, and depression in
progressive supranuclear palsy. J Neurol 1996;243:638643.
80. Kulisevsky J, Litvan I, Berthier ML, Pascual-Sedano B, Paulsen JS, Cummings JL. Neuropsychiatric assessment of
Gilles de la Tourette patients: comparative study with other hyperkinetic and hypokinetic movement disorders. Mov
Disord 2001;16:10981104.
81. Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112(Pt 5):11711192.
82. Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration. A clinical study of 36 cases. Brain
1994;117(Pt 5):11831196.
83. Massman PJ, Kreiter KT, Jankovic J, Doody RS. Neuropsychological functioning in cortical-basal ganglionic degen-
eration: differentiation from Alzheimers disease. Neurology 1996;46:720726.
tion. Neurology 1999;53:19691974.
86. Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J
Neurol Sci 1997;24:2936.
88. Kompoliti K, Goetz CG, Boeve BF, et al. Clinical presentation and pharmacological therapy in corticobasal degenera-
tion. Arch Neurol 1998;55:957961.
89. Rey GJ, Tomer R, Levin BE, Sanchez-Ramos J, Bowen B, Bruce JH. Psychiatric symptoms, atypical dementia, and left
visual field inattention in corticobasal ganglionic degeneration. Mov Disord 1995;10:106110.
90. Duyckaerts C, Verny M, Hauw JJ. [Recent neuropathology of parkinsonian syndromes]. Rev Neurol (Paris)
2003;159:1118.
91. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically
proven cases. Mov Disord 1997;12:133147.
92. Kwentus JA, Auth TL, Foy JL. ShyDrager syndrome presenting as depression: case report. J Clin Psychiatry
1984;45:137139.
93. Rizzoli AA. Psychiatric disturbances in the ShyDrager syndrome. Br J Psychiatry 1986;148:484.
94. Pilo L, Ring H, Quinn N, Trimble M. Depression in multiple system atrophy and in idiopathic Parkinsons disease: a
pilot comparative study. Biol Psychiatry 1996;39:803807.
95. Gill CE, Khurana RK, Hibler RJ. Occurrence of depressive symptoms in ShyDrager syndrome. Clin Auton Res
1999;9:14.
96. Goto K, Ueki A, Shimode H, Shinjo H, Miwa C, Morita Y. Depression in multiple system atrophy: a case report.
Psychiatry Clin Neurosci 2000;54:507511.
97. Ehrt U, Brieger P, Broich K, Marneros A. [Psychotic symptoms as initial manifestation of a multiple system atrophy].
Fortschr Neurol Psychiatr 1999;67:104107.
98. Parsa MA, Simon M, Dubrow C, Ramirez LF, Meltzer HY. Psychiatric manifestations of olivo-ponto-cerebellar atro-
phy and treatment with clozapine. Int J Psychiatry Med 1993;23:149156.
99. Ziegler B, Tonjes W, Trabert W, Kolles H. [Cerebral multisystem atrophy in a patient with depressive hallucinatory
syndrome. A case report]. Nervenarzt 1992;63:510514.
100. Fukutani Y, Takeuchi N, Kobayashi K, et al. Striatonigral degeneration combined with olivopontocerebellar atrophy
with subcortical dementia and hallucinatory state. Dementia 1995;6:235240.
101. Hooten WM, Melin G, Richardson JW. Response of the Parkinsonian symptoms of multiple system atrophy to ECT.
Am J Psychiatry 1998;155:1628.
103. Coccagna G, Martinelli P, Zucconi M, Cirignotta F, Ambrosetto G. Sleep-related respiratory and haemodynamic
changes in ShyDrager syndrome: a case report. J Neurol 1985;232:310313.
104. Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders in multiple system atrophy. Neurology
1997;48:10941097.
105. Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Association of REM sleep behavior disorder and
neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16:622630.
106. Ghorayeb I, Yekhlef F, Chrysostome V, Balestre E, Bioulac B, Tison F. Sleep disorders and their determinants in
multiple system atrophy. J Neurol Neurosurg Psychiatry 2002;72:798800.
107. Gilman S, Koeppe RA, Chervin RD, et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in
MSA. Neurology 2003;61:2934.
108. Wright BA, Rosen JR, Buysse DJ, Reynolds CF, Zubenko GS. ShyDrager syndrome presenting as a REM behavioral
disorder. J Geriatr Psychiatry Neurol 1990;3:110113.
109. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory
findings in 93 cases. Brain 2000;123(Pt 2):331339.
110. Cummings JL. The Neuropsychiatry of Alzheimers Disease and Related Dementias. London: Martin Dunitz, Taylor &
Francis Group, 2003.
111. Pakiam AS, Bergeron C, Lang AE. Diffuse Lewy body disease presenting as multiple system atrophy. Can J Neurol Sci
1999;26:127131.
112. Lang AE, Lees A. Management of Parkinsons disease: an evidence-based review. Movement Disorders 2002;17:1166.
113. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-
blind, placebo-controlled international study. Lancet 2000;356:20312036.
114. Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinsons disease: a randomised
controlled study. J Neurol Neurosurg Psychiatry 2002;72:708712.
115. Foster NL, Aldrich MS, Bluemlein L, White RF, Berent S. Failure of cholinergic agonist RS-86 to improve cognition
and movement in PSP despite effects on sleep. Neurology 1989;39:257261.
116. Litvan I, Phipps M, Pharr VL, Hallett M, Grafman J, Salazar A. Randomized placebo-controlled trial of donepezil in
patients with progressive supranuclear palsy. Neurology 2001;57:467473.
117. Aarsland D, Karlsen K. Neuropsychiatric aspects of Parkinsons disease. Curr Psychiatry Rep 1999;1:6168.
118. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinsons disease. The Parkinson Study Group. N
Engl J Med 1999;340(10):757763.
119. Andersen J, Aabro E, Gulmann N, Hjelmsted A, Pedersen HE. Anti-depressive treatment in Parkinsons disease. A
controlled trial of the effect of nortriptyline in patients with Parkinsons disease treated with L-DOPA. Acta Neurol
Scand 1980;62:210219.
120. Wermuth L, Srensen P, Timm B. Depression in idiopathic Parkinsons disease treated with citalopram. A placebo-
controlled trial. Nord J Psychiatry 1998;52:163169.
121. Leentjens AF, Vreeling FW, Luijckx GJ, Verhey FR. SSRIs in the treatment of depression in Parkinsons disease. Int J
Geriatr Psychiatry 2003;18:552554.
122. Goetz CG, Blasucci LM, Leurgans S, Pappert EJ. Olanzapine and clozapine: comparative effects on motor function in
hallucinating PD patients. Neurology 2000;55:789794.
123. Ellis T, Cudkowicz ME, Sexton PM, Growdon JH. Clozapine and risperidone treatment of psychosis in Parkinsons
disease. J Neuropsychiatry Clin Neurosci 2000;12:364369.
124. Friedman JH, Factor SA. Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinsons disease.
Mov Disord 2000;15:201211.
125. Walker Z, Grace J, Overshot R, et al. Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychia-
try 1999;14:459466.
126. Fernandez HH, Trieschmann ME, Burke MA, Friedman JH. Quetiapine for psychosis in Parkinsons disease versus
dementia with Lewy bodies. J Clin Psychiatry 2002;63:513515.
127. McKeith I, Fairbairn A, Perry R, Thompson P, Perry E. Neuroleptic sensitivity in patients with senile dementia of Lewy
body type. BMJ 1992;305:673678.
128. Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimers
disease. Lancet 1998;351:10321033.
129. Court JA, Piggott MA, Lloyd S, et al. Nicotine binding in human striatum: elevation in schizophrenia and reductions in
dementia with Lewy bodies, Parkinsons disease and Alzheimers disease and in relation to neuroleptic medication.
Neuroscience 2000;98:7987.
130. Schneider LS, Gleason RP, Chui HC. Progressive supranuclear palsy with agitation: response to trazodone but not to
thiothixine or carbamazepine. J Geriatr Psychiatry Neurol 1989;2:109112.
131. Netzel PJ, Sutor B. Electroconvulsive therapy-responsive depression in a patient with progressive supranuclear palsy.
J Ect 2001;17:6870.
132. Moellentine C, Rummans T, Ahlskog JE, et al. Effectiveness of ECT in patients with parkinsonism. J Neuropsychiatry
Clin Neurosci 1998;10:187193.
133. Ruxin RJ, Ruedrich S. ECT in combined multiple system atrophy and major depression. Convuls Ther 1994;10:298300.
134. Roane DM, Rogers JD, Helew L, Zarate J. Electroconvulsive therapy for elderly patients with multiple system atrophy:
a case series. Am J Geriatr Psychiatry 2000;8:171174.
135. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res
1991;38:143162.
136. McNair D, Lorr M, Droppleman L. Profile of Mood States. San Diego: Eucational and Industrial Testing Service, 1971.
Added Value of the Neuropsychological Evaluation 185
12
Added Value of the Neuropsychological Evaluation
for Diagnosis and Research of Atypical Parkinsonian
Disorders
Bruno Dubois and Bernard Pillon
INTRODUCTION
Diseases with movement disorders may be difficult to diagnose, both at the onset when motor
symptoms are mild and not sufficiently specific (e.g., difficulty in manipulating objects), or at the
end stage when distinctive motor signs are diluted into a severe and polymorphous clinical picture
(e.g., gait disorder with postural instability and cognitive decline in aged patients). Erroneous diag-
noses are frequent (1,2), even in the most common idiopathic Parkinsons disease (PD) (3). Some of
these errors may be avoided if the cognitive dysfunctions that often accompany these diseases are
included in the diagnostic criteria.
Subtle but specific cognitive deficits can frequently be detected in patients with a variety of dis-
eases accompanied by movement disorders. We used to say except for essential tremor but some
cognitive changes have recently been reported even in this case (4). This is explained by the fact that
the neuronal pathways connecting the basal ganglia to the cortex project not only to regions involved
in the control of movements (motor, premotor, supplementary motor areas) but also to cortical areas
contributing to cognitive functions (prefrontal cortex) and to emotional-processing behavior (cingu-
lum and orbitofrontal cortex). In each of these diseases, the loss of different specific populations of
neurons in the basal ganglia produces not only a characteristic motor syndrome, but also a recogniz-
able pattern of neuropsychological deficits. Why not include these cognitive and behavioral changes
in diagnosis decision trees? Indeed, the use of appropriate neuropsychological tests or questionnaires
to detect these deficits can contribute to the diagnosis of such diseases (Table 1).
In this review, we will (1) present the different types of deficits that can be usually encountered
following lesions of the basal ganglia; (2) characterize the neuropsychological pattern of the main
movement disorders: idiopathic PD, multiple system atrophy (MSA), progressive supranuclear palsy
(PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB); and (3) show that
the contribution of neuropsychological deficits to diagnosis varies from one parkinsonian disorder to
another.

185
186 Dubois and Pillon
Table 1
Proposed Neuropsychological Battery to Evaluate Cognitive and Behavioral Deficits
in Parkinsonian Disorders
Domain of Investigation Proposed Tool
Global cognitive efficiency Mattis Dementia Rating Scale (5)
Global executive syndrome Frontal Assessment Battery (6)
Set elaboration and monitoring Wisconsin Card Sorting Test (7)
Set maintenance Lexical fluency (8)
Set shifting Trail Making Test (9)
Inhibition of interferences Stroop Test (10)
Motor programming Graphic and motor series (11)
Resistance to environmental dependency Imitation, prehension, utilization (12)
Strategic components of memory California Verbal Learning Test (13)
Opposition between free and cued recall Grober and Buschke Test (14)
Linguistic functions Boston Diagnostic Aphasia Examination (15)
Gestures Apraxia examination (16)
Emotional behavior Neuropsychiatric Inventory (17)
WHAT ARE THE COGNITIVE AND BEHAVIORAL CHANGES CURRENTLY

ENCOUNTERED IN PARKINSONIAN DISORDERS?
The neuropsychological picture of patients may vary from subtle behavioral abnormalities to florid
dementia with delusions and hallucinations. The nature and severity of cognitive disorders, the type
of impaired memory processes, the presence or absence of instrumental deficits, the precocity of the
dysexecutive syndrome, and the frequency of behavioral disorders depend on the underlying neu-
ronal lesions.
Dementia
According to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) criteria
(18), dementia is defined by the development of multiple cognitive deficits, severe enough to inter-
fere with social activity or personal relationships and representing a decline from a previously higher
level of functioning. The term dementia needs to be used with caution in diseases in which motor
impairment, mood, and behavioral disorders may be part of the clinical picture. In these patients the
loss of intellectual capacities can, however, be evaluated by psychometric criteria, using global scales,
such as the Mattis Dementia Rating Scale (5), which is more appropriate than the Mini Mental State
Exam for predominantly subcortical degenerative diseases, given the inclusion of tests evaluating
attention and executive functions. Such tools provide cutoff scores that permit a psychometric dis-
tinction between demented and nondemented patients. Dementia is usually not observed in PD with
early onset (19) or in the early stages of PD (20) or MSA (21,22). Dementia may occur in patients
with late-onset PD (23), PSP (24,25), or CBD (26). It is a major feature of DLB, although there may
be fluctuations of intellectual functioning from one day to another (27).
Memory
Learning disorders in neurodegenerative diseases may be assessed by tools, such as the California
Verbal Learning Test (13) or the Grober and Buschke Test (14) that make it possible to analyze
specific memory processes and distinguish between storage and retrieval difficulties. The key for
understanding the relationship between memory disorders and degenerative diseases implicates the
functional mediotemporal vs frontal dissociation. Encoding deficits, loss of information after a
delay, low effect of cuing on recall, high number of extralist intrusions, and false positives in recog-
nition characterize diseases associated with lesion of hippocampal and perihippocampal areas such
as Alzheimers disease (AD) (28). By contrast, predominant retrieval deficits, manifested by the
opposition between impaired free recall and correct cued recall and recognition, are present in dis-
eases associated with dysfunction of striatofrontal neuronal circuits such as PSP or PD with dementia
(PDD) (29). Milder deficient activation of the frontal component of memory processes occurs in PD
(30,31), MSA (22), and CBD (32,33). Little has been published on learning disorders in DLB, but a
study with autopsy-confirmed cases show that they are less severe than in AD (34). Clinical evidence
suggests that although cued recall is less efficient in DLB than in PD or PSP, it is better preserved
than in AD. A similar contrast between a true loss of information in AD and retrieval deficits in PDD
also applies to retrograde amnesia.
Instrumental Activities
Instrumental dysfunction, suggestive of temporoparietal lesions, include aphasia, apraxia, and
visuospatial deficits. Aphasia and apraxia may be investigated by clinical batteries, such as the Bos-
ton Diagnostic Aphasia Examination (15) or the Heilman and Gonzalez Rothi battery for apraxia
(16). Visuospatial deficits are less clearly defined and do not allow the differential diagnosis of the
different diseases, since various cognitive abilities, such as visuospatial perception, drawing, or con-
structive aptitude, and conceptual thinking may affect performance (35). Impairment of instrumental
activities is specific to neurodegenerative diseases with a cortical involvement. Aphasia may be observed
in DLB (27), whereas apraxia is more characteristic of CBD (32,36). In contrast, instrumental functions
are mildly disturbed in PSP (37) and PDD (38) and are preserved in PD (39) and MSA (22).
Executive Functions
Executive functions, namely the mental processes involved in behavioral planning, particularly
when the environment requires adaptation to a new situation, are under the control of striatofrontal
circuits. These functions may be investigated at the patients bedside (6) (see video) or by a neurop-
sychological evaluation assessing the main processes mediated by striatofrontal loops such as set
elaboration, set maintenance, and set shifting, inhibition of interferences, motor programming, and
environmental autonomy (Table 1). These functions are impaired at an early stage of all parkinsonian
disorders, but are much less severe in PD and MSA than in the other parkinsonian syndromes (25,40).
Behavioral Disorders
Delusions and hallucinations, as diagnosed in accordance with the DSMIV criteria (18), are com-
mon at early stages of DLB (27). They occur in PD, particularly in demented patients or as a result of
treatment with anticholinergic or dopaminergic drugs, but are not characteristic of MSA, PSP, or
CBD (41). Apathy and disinhibition may also be observed in parkinsonian disorders (42). Apathy has
been defined as a lack of motivation and responsiveness to both positive and negative events in the
absence of emotional distress or negative thoughts. It can be distinguished from depression using
new scales, such as the Neuropsychiatric Inventory (17). Apathy is particularly frequent in PSP
(43) and DLB (44), whereas irritability predominates in CBD (45) and depression in PD (44) (see
Chapter 11).
WHICH NEUROPSYCHOLOGICAL PATTERN CHARACTERIZES EACH

OF THE MAIN PARKINSONIAN DISORDERS?
Well-characterized neuropsychological profiles can be drawn from the clustering of the cognitive
and behavioral characteristics found in each parkinsonian disorder (Table 2). The absence of marked
cognitive or behavioral changes makes more probable the diagnosis of PD or MSA, whereas a severe
dysexecutive syndrome suggestive of a striatofrontal dysfunction reinforces the diagnosis of PSP and
specific deficits related to a cortical involvement contribute to the diagnosis of CBD or DLB.
Table 2
Neuropsychological Pattern of Each Disease
PD MSA PSP PDD CBD DLB
Dementia
Mattis DRS (144) >130 >130 <130 <130 <130 <130
Fluctuations - - - + - +
Dysexecutive syndrome
FAB (18) 16 14 11 11 11 11
Envt Dependency ++ + +
Memory deficits
Free recall (48) 25 22 16 12 19 10
Total recall (48) 46 46 44 42 42 34
Instrumental deficits
Language - - + +
Gesture - - ++
Psychosis - - - + - ++
Mean indicative values adapted from refs. 6, 22, 29, 32, 52.
-, absent; , mild or discussed; +, moderate or present in a proportion of patients;
++, severe and present in a majority of patients.
Parkinsons Disease
Cognitive changes in the majority of patients with PD are subtle and mainly restricted to attentional
and retrieval deficits. It is only by using appropriate neuropsychological tests that these cognitive
changes can be detected. They mainly concern (a) the visuospatial domain, observed in visuospatial
paradigms that require self-elaboration of the response or forward-planning capacity; (b) memory,
that is, working memory and long-term memory, especially in tasks that involve self-organization of
the to-be-remembered material, temporal ordering and conditional associative learning, and proce-
dural learning; and (c) executive functions, namely concept formation and problem solving, set-
maintenance and set-shifting (for a review, see ref. 46).
Mood and behavioral changes are also described in PD. Depression is encountered in about 30%
of patients and has been the focus of a large number of studies (47). It is important to diagnose it
because depression induces attention and memory disorders and, if sufficiently severe, impairs cog-
nitive functions especially those of the executive system in relation to a significant decrease in frontal
metabolism evidenced on positron emission tomography (PET) scan studies. More recently, attention
has been drawn to apathy and its relation to basal ganglia disorders. Apathy is not infrequent in PD
and has repercussions on cognitive functions, affect, and behavior (48,49).
Unlike depression, anxiety symptoms almost always begin after the onset of the motor symptoms
and are related to medication-induced onoff fluctuations and wearing-off condition in most of the
cases. Drug-induced psychiatric disorders are frequently found in PD and mainly consist of halluci-
nations and delusions. These disorders are, however, much more frequent in PDD or DLB (44).
To conclude, the clinical diagnosis of PD relies on the evidence of a parkinsonian syndrome respon-
sive to levodopa in the absence of severe intellectual or memory dysfunction. This is the rule, at least, in
the young-onset form of the disease. In the late-onset one, however, a subcorticofrontal dementia
may occur after several years of evolution, which may result from the compounding effect of disease-
related neuronal lesions and age-related neuronal changes (50). PDD is characterized by a marked
dysexecutive syndrome, accompanied by a severe amnesic syndrome with a persistent response to
cuing, in the absence of true aphasia, apraxia, or agnosia, and may be difficult to diagnose. DSMIV
criteria of dementia (18) are well suited to AD, but less appropriate for PD because the severe motor
deficits may themselves affect patients autonomy. Moreover, an overestimation of the severity of
cognitive impairment may result from nonspecific factors (akinesia, hypophonia, depression, anxi-
ety, marked cognitive slowing with delay in responses, uncontrolled dyskinesias) that interfere with
the evaluation of cognitive functions.

Cognitive changes are mild in the parkinsonian variant of MSA (MSA-P, previously called
striatonigral degeneration), at least in the early stage of the disease, before patients reach a severe
akinetic state with dysarthria, which may affect the cognitive evaluation. The few studies of cogni-
tion in MSA, including the MSA-P variant, display few differences from the neuropsychological
pattern of PD: some more severe deficits in the Stroop test (51) or in verbal fluency (52). In our
experience, neuropsychological testing does not help to distinguish between the two disorders. In
contrast, when faced to an axial parkinsonian syndrome poorly responsive to levodopa, the absence
of a severe subcorticofrontal syndrome strongly favors the diagnosis of MSA-P and decreases the
probability for PSP (22,53).
Psychiatric disorders have been poorly studied in MSA-P. Depression, anxiety, and emotional
lability have been described, but not psychosis (54).

Cognitive and behavioral changes are consistent even in the early stages of the disease. Cognitive
slowing and inertia occur in the first year in 52% of cases. As the disease progresses, these changes
progressively worsen. From 24 patients who underwent two or more neuropsychological evaluations
over time, 38% showed a global impairment at their first examination, and 70% 15 mo later. The
changes may become severe enough to warrant the diagnosis of dementia, but the deficits still con-
form to the pattern of subcorticofrontal dementia. The dysexecutive syndrome of PSP is much more
severe than that observed in any other subcortical disorders, and the memory deficit is dramatically
improved in conditions that facilitate retrieval processing such as cueing and recognition.
Cognitive slowing appears evident in patients with PSP, who answer questions and solve even the
simplest problems with delay. It is a genuine slowing of central-processing time unrelated to motor or
affective disorders, as demonstrated experimentally using reaction time tasks (55) and event-related
brain potentials (56).
Cognitive slowing may contribute to decreased lexical fluency that is more severely impaired in
patients with PSP than in patients with PD or AD, although naming is more affected in the latter (25).
The deficit is observed in different types of fluency, including semantic fluency, where patients have
to list animal names or objects that can be found in a supermarket, phonemic fluency, where patients
are required to produce words beginning with a given letter, and design fluency, where patients must
produce abstract designs (57).
A tendency to perseverate may also account for some of the deficits, particularly in tasks involv-
ing concept formation and shifting ability. In the Wisconsin Card Sorting Test, PSP patients com-
plete a smaller number of categories than patients with PD or MSA-P. This lack of flexibility affects
both categorical and motor sequencing, as shown by the poor performance of patients with PSP in the
Trail Making Test and in the motor series of Luria. Patients with PSP also experience difficulty in
conceptualization and problem-solving ability, which may account for their poor performance in
similarities, interpretation of proverbs, comprehension of abstract concepts, arithmetic and lineage
problems, tower tasks, and picture arrangement.
This severe dysexecutive syndrome contributes to the memory deficits and instrumental disorders
observed in PSP. Short-term memory was found to be impaired using the BrownPeterson paradigm,
a working memory task in which the patients were more sensitive than controls to interference. Long-
term memory is also disturbed in PSP, as shown by immediate and delayed recall of the subtests of
the Wechsler Memory Scale, the Rey Auditory Verbal Learning Test, and the California Verbal
Learning Test. However, when encoding is controlled by using semantic category cues and when
recall is performed with the same cues, as in the Grober and Buschke procedure, recall perfor-
mance of the patients dramatically improves, confirming that there is no genuine amnesia in the
disease (29).
Various speech disorders have been described in PSP. A severe reduction of spontaneous speech
resembling dynamic aphasia is usually observed (58), but abnormal loquacity has also been reported.
Word-finding difficulty may occur, but it is generally less severe than in AD patients. Semantic or
syntactic comprehension disorders are absent or mild. Dynamic apraxia may be found (32). Bilateral
apraxic errors for transitive and intransitive movements have been reported, but they are much less
severe than in CBD (59). Visual and auditory perception may be disturbed, but there is no evidence of
object agnosia or alexia. Therefore, instrumental disorders of patients with PSP, when present, are
rather considered to be a consequence of impaired executive and perceptual-motor functions or
attentional disorders.
Besides cognitive impairment, patients with PSP exhibit behavioral disorders. They show severe
difficulty in self-guided behavior and are abnormally dependent on stimuli from the environment.
They involuntarily grasp all the objects presented in front of them; they imitate the examiners ges-
tures passively and use objects in the absence of any explicit verbal orders (25). Such uncontrolled
behaviors are never observed in normal control subjects in the absence of explicit demands and are
considered to result from a lack of the inhibitory control normally exerted by the frontal lobes (12).
PSP patients also have difficulty in inhibiting an automatic motor program once it is initiated. This
can easily be evaluated with the signe de lapplaudissement [clapping sign] (60): when asked to
clap their hands three times consecutively, as quickly as possible, these patients have a tendency to
clap more (four or five times), sometimes initiating an automatic program of clapping that they are
unable to stop, as if they had difficulty in programming voluntary acts that compete with overlearned
motor skills. This sign seems to be specific to striatal dysfunction occurring in PSP (61). Changes in
mood, emotion, and personality have also been described: most frequently bluntness of affective
expression and lack of concern about personal behavior or the behavior of others, but sometimes
obsessive disorders or disinhibition with bulimia, inappropriate sexual behavior, or aggressiveness.
These changes are difficult to investigate, given the lack of insight and the transient nature of the
emotions expressed. The testimony of caregivers is therefore required. Administering the Neurop-
sychiatric Inventory (NPI) to patients informants showed that patients with PSP exhibited apathy
almost as a rule, since it was observed in 91% of the cases (43). Apathy was more frequent in PSP
than in any other parkinsonian syndrome.
The cognitive profile of this disease is distinct from that of PSP, because of the presence of signs
suggestive of cortical involvement. Many patients present only limb clumsiness and gesture disor-
ders at the first examination, without anyor with fewcognitive or behavioral symptoms (26). In
contrast, the disease may begin by other signs of cortical involvement, particularly nonfluent pro-
gressive aphasia (62). Finally, a severe frontal cognitive and behavioral syndrome may initiate the
disease in some patients (63).
CBD is typically defined by unilateral rigidity of one arm with apraxic features, accounting for the
proposition of the new term progressive asymmetric rigidity and apraxia syndrome (64). Gesture
disorders are so characteristic of the disease that the diagnosis can be suspected on the simple analy-
sis of the motor disturbances. They consist, at first, of the patient experiencing difficulty or showing
perplexity in the performance of delicate and fine movements of the fingers of one hand. At this
stage, patients complain of clumsiness and loss of manual dexterity, reminiscent of limb apraxia,
variously described as kinesthetic in patients with lesions of the parietal cortex, or kinetic in
patients with lesions of the premotor cortex. Systematic evaluation shows disorders of dynamic motor
execution (impaired bimanual coordination, temporal organization, control, and inhibition) (32). Asym-
metric praxis disorders (difficulty in posture imitation, symbolic gesture execution, and object utili-
zation) are also regularly observed, even at this stage. Ideomotor apraxia is frequent, especially in
patients who have initial symptoms in the right limb, in agreement with the hypothesis of a predomi-
nant storage of movement formulae in the left hemisphere (65). In addition, central deficits in
action knowledge and mechanical problem solving have been linked to parietal lobe pathology (66).
Alien limb phenomenon, in which a limb behaves in an uncooperative or foreign way, has been
attributed to lesions affecting the supplementary motor area. Its occurrence, in the absence of a known
callosal lesion, would be highly suggestive of the diagnosis of CBD.
Other signs of cortical involvement have been observed in CBD. Linguistic disturbances are found,
consisting of word-finding difficulties, decreased lexical fluency, transcortical motor aphasia, or pro-
gressive phonetic disintegration (67). These deficits resembling primary progressive nonfluent apha-
sia can even be an initial symptom of CBD. Neglect and visuospatial deficits have also been reported.
Constructive apraxia is observed in patients with predominant right-hemisphere lesions, in relation
with the well-known influence of this hemisphere on visuospatial function.
Other cognitive changes resemble the subcorticofrontal dysfunction of PSP: a dysexecutive syn-
drome and a learning deficit that can be alleviated by semantic cuing (32). The environmental depen-
dency syndrome, thought to be related to a release of the inhibition normally exerted by the frontal
lobes on the activity of the parietal lobes (12), is less frequent, however, in CBD than in PSP, prob-
ably because of the parietal lobe dysfunction in this disease. Early subcorticofrontal syndrome in
CBD would predict a shorter survival.
In most of the clinical studies performed on CBD patients, the level of intellectual deterioration
was mild or moderate until an advanced stage of the disease. In some cases, however, patients with a
severe dysexecutive syndrome associated with memory disorders and impaired instrumental activi-
ties may reach the threshold of dementia in which both cortical and subcorticofrontal components
play a role. Thus, dementia is not infrequent in CBD and may even be observed from the onset in
unusual clinical presentation. In 10 out of 13 cases with pathologically proven CBD, dementia was
noticed within 3 yr of onset of symptoms (68).
Besides frontal lobetype behavioral alterations, patients with CBD may present neuropsychiatric
disorders. In a series of CBD patients, the NPI showed that depression, apathy, irritability, and agita-
tion were the symptoms most commonly exhibited (45). The depression and irritability of patients
with CBD were more frequent and severe than those of patients with PSP, whereas patients with PSP
exhibited more apathy.

The diagnosis of DLB can be suspected clinically on the basis of the early occurrence of a cogni-
tive decline resembling a chronic confusional state with fluctuating cognitive signs and visual and/or
auditive hallucinations in a patient with mild parkinsonism (69). The rapidly progressive dementia is
accompanied by aphasia, dyspraxia, or spatial disorientation, suggestive of temporoparietal dysfunc-
tion. The neuropsychological profile differs from that of patients with AD: cognitive deficits are
more acute, attentional fluctuations more intense, and psychotic features appear earlier. Moreover,
patients with DLB present a more severe dysexecutive impairment but less severe memory deficits
than patients with AD (34). The neuropsychological pattern of DLB can also be distinguished from
the subcortical dementia of PD on the basis of the early occurrence of cognitive deficits and psy-
chotic features, and the presence of linguistic and visuospatial disorders (44,70). It is, however, con-
troversial whether DLB constitutes a disorder different from or overlapping with PDD. By convention,
DLB is only considered when the cognitive changes appear before, with or within 1 yr after the
occurrence of parkinsonism and cannot be proposed when they appear several years later (69). At a
Table 3
Diagnostic Contribution of Motor and Cognitive Deficits
Motor Syndrome Cognitive Changes
L-dopa React Axial Synd Severity Occurrence Cortical Signs
MDP + - early -
MSA + early -
PDD + + + late -
PSP - + + early -
DLB + + early +
CBD - - late +
-, absent; , mild or discussed; +, moderate or present in a proportion of patients; ++, severe and present in
a majority of patients.
first glance, the clinical and cognitive profiles of both diseases are rather different with cortical signs
only in DLB. The profile of attentional impairments and fluctuating attention (71) and the cognitive
pattern at the Mattis Dementia Rating Scale (72) would be, however, rather similar in PDD and DLB,
and postmortem examination revealed cortical Lewy bodies in both diseases, suggesting that their
differential diagnosis may be more difficult than previously thought (73).
CONCLUSION
Appropriate tests may help to differentiate among diseases associated with parkinsonism (Table 3).
Schematically, three categories can be distinguished. The first group is defined by mild cognitive defi-
cits. It includes PD and MSA, which have a similar subcorticofrontal pattern of impairment. In the
second group (PSP), striatofrontal dysfunction is so severe that it leads to dramatic planning, moni-
toring, and recall deficits, evolving toward dementia. The third group of diseases (CBD and DLB) is
characterized by signs of cortical involvement with asymmetric instrumental disorders in CBD (praxic
and linguistic deficits) and more severe dementia with hallucinations in DLB. The inclusion of PDD
in the second or the third category is an object of debate and further studies are required.
The neuropsychological profiles described herein are valid when applied to a group of patients
with a particular disease. To assess individuals is more difficult. The distribution of the subcortical
lesions and the severity of the resulting denervation can vary. The association of cortical lesions with
those of the basal ganglia can produce composite pictures. Age at onset and disease duration can alter
the neuropsychological picture at different points in time. Nevertheless, appropriate neuropsycho-
logical testing is a useful technique for investigating the neuronal pathways affected in these dis-
eases, and can contribute, not only to the diagnosis, but also to our understanding of the underlying
pathology. A better clinical knowledge of these diseases will allow the progressive selection and
elaboration of shorter and more discriminant tools. Longitudinal studies with pathological confirma-
tion are necessary to attain this aim (see box).
RESEARCH TO BE DONE TO AMELIORATE

THE NEUROPSYCHOLOGICAL EVALUATION
OF ATYPICAL PARKINSONIAN DISORDERS
Three directions:
Elaboration of diagnostic criteria for subcorticofrontal dementia.
Validation of new neuropsychological tools more sensitive to the specific aspects of each disease.
Longitudinal evaluation of each disease with the same tools to better evaluate their sensitivity and speci-
ficity and postmortem anatomo-pathological correlation when possible.
REFERENCES
RichardsonOlszewski syndrome): Report of the NINDS-SPSP International Workshop. Neurology 1996;47:19.
2. Litvan I, Agid Y, Goetz C, et al. Accuracy of clinical diagnosis of corticobasal degeneration. Neurology 1997;48:119125.
3. Hughes AJ, Daniel SE, Kilford L, Lees AJ. The accuracy of clinical diagnosis of idiopathic Parkinsons disease: a
clinicopathological study. J Neurol Neurosurg Psychiatry 1992;55:181184.
4. Troster AI, Woods SP, Fields JA, et al. Neuropsychological deficits in essential tremor: an expression of cerebello-
thalamo-cortical pathophysiology? Eur J Neurol 2002;9:143151.
5. Mattis S. Dementia Rating Scale. Odessa, FL: Psychological Assessment Resources Inc., 1988.
6. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology
2000;55:16211626.
7. Nelson HE. A modified Card Sorting Test sensitive to frontal lobe defect. Cortex 1976;12:313324.
8. Benton AL. Differential behavioral effects in frontal lobe disease. Neuropsychologia 1968;6:5360.
9. Reitan RM. Validity of the Trail Making Test as an indication of organic brain damage. Percept Mot Skills 1958;8:271276.
10. Golden CJ. Stroop Color and Word Test. Chicago: Stoelting Company, 1978.
11. Luria AR. Higher Cortical Functions in Man. New York, NY: Basic Books, 1966.
12. Lhermitte F, Pillon B, Serdaru M. Human autonomy and the frontal lobes, I: imitation and utilization behaviors: a
neuropsychological study of 75 patients. Ann Neurol 1986;19:326334.
13. Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test: Research Edition. New York: Psychologi-
cal Corporation, 1987.
14. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol 1987;3:1336.
15. Goodglass H, Kaplan E. The Assessment of Aphasia and Related Disorders. Philadelphia: Lea & Febiger, 1976.
16. Heilman KM, Gonzalez Rothi LJ. Apraxia. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology, 2nd ed.
Oxford: Oxford University Press, 1985:131150.
17. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory:
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC:
American Psychiatric Association, 1994.
19. Quinn N, Critchley P, Marsden CD. Young onset Parkinsons disease. Mov Disord 1987; 2:7391.
20. Cooper JA, Sagar HJ, Jordan N, Harvey NS, Sullivan EV. Cognitive impairment in early untreated Parkinsons disease
and its relationship to motor disability. Brain 1991;114:20952122.
21. Robbins TW, James M, Lange KW, Owen AM, Quinn NA, Marsden CD. Cognitive performance in Multiple System
Atrophy. Brain 1992;115:271291.
22. Pillon B, Gouider-Khouja N, Deweer B, et al. Neuropsychological pattern of striatonigral degeneration: comparison
with Parkinsons disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1995;58:174179.
23. Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinsons disease: clinical and prognostic implications.
Neurology 1985;35:522526.
25. Pillon B, Dubois B, Ploska A, Agid Y. Severity and specificity of cognitive impairment in Alzheimers, Huntingtons,
and Parkinsons diseases and progressive supranuclear palsy. Neurology 1991;41:634643.
27. Byrne EJ, Lennox G, Lowe J, Godwin-Austen RB. Diffuse Lewy body disease: clinical features in 15 cases. J Neurol
28. Tounsi H, Deweer B, Ergis AM, et al. Sensitivity to semantic cuing: An index of episodic memory dysfunction in early
Alzheimers disease. Alzheimer disease and associated disorders 1999;13:3846.
29. Pillon B, Deweer B, Michon A, Malpand C, Agid Y, Dubois B. Are explicit memory disorders of progressive supra-
nuclear palsy related to damage to striatofrontal circuits? Comparison with Alzheimers, Parkinsons, and Huntingtons
diseases. Neurology 1994;44:12541270.
30. Taylor AE, Saint-Cyr JA, Lang AE. Memory and learning in early Parkinsons disease: evidence for a frontal lobe
syndrome. Brain Cogn 1990;13:211232.
31. Buytenhuijs EJ, Berger JC, van Spaendonck KP, Horstink MW, Borm GF, Cools AR. Memory and learning strategies
in patients with Parkinsons disease. Neuropsychologia 1994;32:335342.
32. Pillon B, Blin J, Vidailhet M, et al. The neuropsychological pattern of corticobasal degeneration. Comparison with
progressive supranuclear palsy and Alzheimers disease. Neurology 1995; 45:14771483.
33. Massman PJ, Kreiter KT, Jankovic J, Doody RS. Neuropsychological functioning in cortical-basal ganglionic degen-
eration: differenciation from Alzheimers disease. Neurology 1996;46:720726.
34. Connor DJ, Salmon DP, Sandy TJ, Galasko D, Hansen LA, Thal L. Cognitive profiles of autopsy-confirmed Lewy body
variant vs pure Alzheimers disease. Arch Neurol 1998; 55:9941000.
35. Brown RG, Marsden CD. Subcortical dementia: the neuropsychological evidence. Neurosci 1988;25:363387.
36. Leiguarda R, Merello M, Nouzeilles MI, Balej J, Rivero A, Nagues M. Limb-kinetic apraxia in corticobasal degenera-
tion: clinical and kinematic features. Mov Disord 2003;18:4959.
37. Maher ER, Smith EM, Lees AJ. Cognitive deficits in the SteeleRichardsonOlszewski syndrome (progressive supra-
nuclear palsy). J Neurol Neurosurg Psychiatry 1985;48:12341239.
38. Ross GW, Mahler ME, Cummings JL. The dementia syndromes of Parkinsons disease: cortical and subcortical fea-
tures. In: Huber SJ, Cummings JL, eds. Parkinsons Disease: Neurobehavioral Aspects. Oxford: Oxford University
Press,1992:132148.
39. Taylor AE, Saint-Cyr JA, Lang AE. Frontal lobe dysfunction in Parkinsons disease. Brain 1986;109:845883.
40. Owen AM, Robbins TW. Comparative neuropsychology of Parkinsonian syndromes. In: Wolters EC, Scheltens P, eds.
Mental Dysfunction in Parkinsons Disease. Proceedings of the European Congress on Mental Dysfunction in
Parkinsons Disease held in Amsterdam on 2023 October 1993. Amsterdam: Vrije Universiteit, 1993:221241.
41. Cummings JL. Psychosis in basal ganglia disorders. In: E Wolters E, Scheltens P, eds. Mental Dysfunction in
Parkinsons Disease. Proceedings of the European Congress on Mental Dysfunction in Parkinsons Disease held in
Amsterdam on 2023 October 1993. Amsterdam: Vrije Universiteit, 1993:257268.
hypokinetic movement disorders. Arch Neurol 1998;55:13131319
43. Litvan I, Mega MS, Cummings JL, Fairbanks L. Neuropsychiatric aspects of progressive supranuclear palsy. Neurol-
ogy 1996;47:11841189.
44. Aarsland D, Ballard G, Larsen JP, McKeith I. A comparative study of psychiatric symptoms in dementia with diffuse
Lewy body disease and Parkinsons disease with and without dementia. Int J Geriatr Psychiatry 2001;16:528536.
45. Cummings JL, Litvan I. Neuropsychiatric aspects of corticobasal degeneration. In: Litvan I, Goetz CG, Lang AE,
eds. Corticobasal Degeneration. Advances in Neurology, vol. 82. Philadelphia: Lippincott, Williams & Wilkins,
2000:147152.
46. Pillon B, Boller F, Levy R, Dubois B. Cognitive deficits and dementia in Parkinsons disease. In: Boller F, Grafman J
(eds.). Handbook of Neuropsychology, vol 6. Aging and Dementia. Amsterdam: Elsevier, 2001:311371.
47. Slaughter JR, Slaughter KA, Nichols D, Holmes SE, Martens MP. Prevalence, clinical manifestations, etiology, and
treatment of depression in Parkinsons disease. J Neuropsychiatry Clin Neurosci 2001;13:187196.
48. Pluck GC, Brown RG. Apathy in Parkinsons disease. J Neurol Neurosurg Psychiatry 2002;73:636642.
49. Czernecki V, Pillon B, Houeto JL, Pachon JB, Levy R, Dubois B. Motivation, reward, and Parkinsons disease: influ-
ence of dopatherapy. Neuropsychologia 2002;40:22572267.
50. Katzen HL, Levin BE, Llabre ML. Age of disease onset influences cognition in Parkinsons disease. J Int Neuropsychol
Soc 1998;4:285290.
51. Meco G, Gasparini M, Doricchi F. Attentional functions in multiple system atrophy and Parkinsons disease. J Neurol
52. Soliveri P, Monza D, Paridi D, et al. Neuropsychological follow-up in patients with Parkinsons disease, striatonigral
degeneration-type multisystem atrophy, and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry
2000;69:313318.
53. Brown RG, Pillon B, Uttner I, and Members of the Neuropsychology Working Group and NNIPPS Consortium, France,
Germany, UK. Cognitive function in patients with progressive supranuclear palsy and multiple system atrophy. The
Movement Disorder Society, 7th International Congress of Parkinsons disease and Movement Disorders, November
2002. Book of Abstracts, 2002, P706.
54. Ghika J. Mood and behavior in disorders of the basal ganglia. In: Bogousslavsky J, Cummings JL, eds. Behavior and
Mood Disorders in Focal Brain Lesions. Cambridge: Cambridge University Press, 2000:122200.
55. Dubois B, Pillon B, Legault F, Ajid Y, Lhermitte F. Slowing of cognitive processing in progressive supranuclear palsy.
A comparison with Parkinsons disease. Arch Neurol 1988;45:11941199.
56. Johnson R. Event-related brain potentials. In: Litvan I, Agid Y, eds. Progressive Supranuclear Palsy. Oxford: Oxford
University Press, 1992:122154.
57. Grafman J, Litvan I, Stark M. Neuropsychological features of progressive supranuclear palsy. Brain Cogn 1995;28:311320.
58. Esmonde T, Giles E, Xuereb J, Hodges J. Progressive supranuclear palsy presenting with dynamic aphasia. J Neurol
59. Pharr V, Uttl B, Stark M, Litvan I, Fantie B, Grafman J. Comparison of apraxia in corticobasal degeneration and
progressive supranuclear palsy. Neurology 2001;56:957963.
60. Dubois B, Dfontaines B, Deweer B, Malapani C, Pillon B. Cognitive and behavioral changes in patients with focal
lesions of the basal ganglia. In: Weiner WJ, Lang AE, eds. Behavioral Neurology of Movement Disorders. Advances in
Neurology, vol. 65. New York: Raven, 1995: 2941.
61. Slachevsky A, Pillon B, Beato R, et al. The Signe de lApplaudissement in PSP. American Academy of Neurology
54th Annual Meeting, Denver, April 1320, 2002. Neurology 2002;58(Suppl 3):P06.139.
62. Kertez A, Martinez-Lage P, Davidson W, Munoz DJ. The corticobasal degeneration syndrome overlaps progressive
with cognitive decline. Brain Pathology 1998;8:355365.
64. Lang AE, Maragonore D, Marsden CD, et al. Movement Disorder Society Symposium on cortico-basal ganglionic
degeneration (CBGD) and its relationship to other asymmetrical cortical degeneration syndromes. Mov Disord
1996;11:346357.
65. Leiguarda R, Lees AJ, Merello M, Starkstein S, Marsden CD. The nature of apraxia in corticobasal degeneration. J Neurol
66. Spatt J, Bak T, Bozeat S, Patterson K, Hodges JR. Apraxia, mechanical problem solving and semantic knowledge:
contributions to object usage in corticobasal degeneration. J Neurol 2002;249:601608.
67. Frattali CM, Grafman J, Patronas N, Makhlouf MS, Litvan I. Language disturbances in corticobasal degeneration.
Neurology 2000;54:990992.
68. Grimes DA, Lang AE, Bergeron C. Dementia is the most common presentation of corticobasal ganglionic degenera-
tion. Neurology 1999;53:19691974.
69. Barber R, Panikkar A, McKeith IG. Dementia with Lewy bodies: diagnosis and management. Int J Geriatr Psychiatry
2001;16(Suppl 1):1218.
70. Gnanalingham K, Byrne E, Thornton A, Samabrook MA, Bannister P. Motor and cognitive function in Lewy body
dementia: comparison with Alzheimers and Parkinsons disease. J Neurol Neurosurg Psychiatry 1997;62:243252.
71. Ballard CG, Aarsland D, McKeith I, et al. Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurol-
ogy 2002;59:17141720.
72. Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel-larsen T, Larsen JP. Performance on the dementia rating scale in
Parkinsons disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy
and Alzheimers disease. J Neurol Neurosurg Psychiatry 2003;74:12151220.
73. Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW. Parkinson disease neuropathology: later-developing de-
mentia and loss of the levodopa response. Arch Neurol 2002;59:102112.
Role of Praxis in Diagnosis and Assessment 197
13
Role of Praxis in Diagnosis and Assessment
Ramn Leiguarda
INTRODUCTION
Apraxia is a term used to denote a wide spectrum of higher-order motor disorders that result from
acquired brain disease affecting the performance of skilled and/or learned movements with or with-
out preservation of the ability to perform the same movement outside the clinical setting in the appro-
priate situation or environment. The disturbance of purposive movements cannot be termed apraxia,
however, if the patient suffers from any elementary motor or sensory deficit (i.e., paresis, dystonia,
ataxia) that could fully explain the abnormal motor behavior or if it results from a language com-
prehension disorder or from dementia (1,2). Nevertheless, praxic errors are at present much better
defined clinically and kinematically and may be distinguished from other nonapractic motor behav-
iors (3,4). Praxic disturbances may affect specific parts of the body (i.e., limb apraxia, facial apraxia)
and may involve both sides of the body (i.e., ideational [IA] and ideomotor apraxias [IMA]), prefer-
entially one side (i.e., limb-kinetic apraxia [LKA]), or alternatively, interlimb coordination, as in the
case of gait apraxia.
Apraxias are poorly recognized but common disorders that can result from a wide variety of focal
or diffuse brain damage. There are two main reasons why apraxia may go unrecognised. First, many
patients with apraxia, particularly IMA, show a voluntary-automatic dissociation, which means that
the patient does not complain about the deficit because the execution of the movement in the natural
context is relatively well preserved, and the deficit appears mainly in the clinical setting when the
patient is required to represent explicitly the content of the action outside the situational props. Sec-
ondly, although in apraxic and aphasic patients specific functions are selectively affected, language
and praxic disturbances frequently coexist and the former may interfere with the proper evaluation of
the latter (5).
Limb apraxia is a hallmark clinical feature and one of the presenting clinical manifestations of
corticobasal degeneration (CBD); it is seen in about 80% of patients (612). Roughly 25 and 65% of
patients with Parkinsons disease (PD) and progressive supranuclear palsy (PSP), respectively, may
exhibit limb apraxia (13). It also seems to be a relatively frequent motor-behavioral deficit in
Huntingtons disease (HD) (14), but very rare indeed or an absent clinical feature in multiple system
atrophy (MSA) (13,15). Moreover, not only the incidence of apraxia differs among different diseases
but also and more important, there are specific features that characterize the praxic deficits observed
in some of these diseases. Therefore, the adequate assessment of apraxia is essential because it may
lead to the proper clinical diagnosis of the disease. In the present chapter, I will first describe the
assessment of apraxia and the classical types of praxic disorders, as well as their putative physio-
pathological mechanisms, to thereafter present the characteristic features of the praxic deficit observed
in patients with atypical parkinsonisms, in particular CBD and PSP.
197
198 Leiguarda
Table 1
Assessment of Limb Praxis
Intransitive movements nonrepresentational (e.g., touch your nose, wriggle your fingers).
representational (e.g., wave goodbye, hitch-hike)
Transitive movements (e.g., use a hammer, use a screwdriver) under verbal, visual, and
tactile modalities
Imitation of meaningful and meaningless movements, postures, and sequences.
Toola selection tasks to select the appropriate tool to complete a task, such as a hammer
for a partially driven nail
Alternative tool selection tasks to select an alternative tool such as pliers to complete a task as
pounding a nail, when the appropriate tool (i.e., hammer) is not
available
Mechanical problem-solving task (e.g., select the appropriate one of three novel tools for lifting a
wooden cylinder out of a socket).
Multiple step tasks (e.g., prepare a letter for mailing)
Gesture recognition and discrimination tasks to assess the capacity to comprehend gestures, verbally (to name
gestures performed by the examiner), as well as nonverbally (to
match a gesture performed by the examiner with cards depicting
the tool/objectb corresponding to the pantomime); and to assess the
ability to discriminate a well- from a wrongly performed gesture.
aTool:implement with which an action is performed (e.g., hammer, screwdriver).
bObject:the recipient of the action (e.g., nail, screw).
From refs. 2, 3, and 39.
ASSESSMENT OF LIMB PRAXIS

A systematic evaluation of praxis is critical in order: (a) to identify the presence of apraxia; (b) to
classify correctly the nature of praxis deficit according to the errors committed by the patient and
through the modality by which the errors are elicited; and (c) to gain an insight into the underlying
mechanism of the patients abnormal motor behavior (Table 1).
Patients performance should be assessed in both forelimbs if an elementary motor-sensory deficit
does not preclude testing the limb contralateral to the damaged hemisphere. Intransitive and transi-
tive movements should be evaluated. The sample of intransitive gestures tested has to include move-
ments performed toward or on the body (salute, crazy) vs away from the body (okay sign, wave
goodbye), repetitive (beckon, go away) or nonrepetitive (sign of victory), since the dimensions of
spatial location relative to the body and repetitiveness contribute to the overall complexity of the task
and may be differentially influenced by the disorder. Likewise, several types of transitive movements
have to be evaluated since it is not an uncommon finding that apraxic patients perform some but not
all movements in a particularly abnormal fashion and/or that individual differences appear in some
but not all components of a given movement. Therefore, the dissimilar complexity and features of
transitive movements should also be considered in order to analyze and interpret praxic errors accu-
rately. For instance, (a) movements may or may not be repetitive in nature (e.g., hammering vs using
a bottle opener to remove the cap); (b) an action may be composed of sequential movements (e.g., to
reach for a glass and take it to the lips in drinking); (c) a movement may primarily reflect proximal
limb control (transport) such as transporting the wrist when carving a turkey, proximal and distal
limb control such as reaching and grasping a glass of water, or primarily distal control as when the
patient is asked to manipulate a pair of scissors; and (d) movements may be performed in the peripersonal
space (e.g., carving a turkey), in body-centered space (e.g., tooth brushing), or require the integration of
both, such as the drinking action (4).
Transitive movements should be assessed under different modalities, including verbal, visual (see-
ing the tool or the object upon which the tool works), and tactile (using actual tools and/or objects) as
well as on imitation, since impairment can be seen under some performance conditions but not oth-
ers. Nevertheless, the most sensitive test for apraxia is asking patients to pantomime to verbal com-
mands because this test provides the least cues and is almost entirely dependent on stored movement
representations. In addition to the specific praxis assessment tasks listed in Table 1, it is important to
evaluate other cognitive functions, since they may contribute to understand the neural mechanisms of
some praxic deficits. Thus, the evaluation of conceptual tool and object knowledge, such as correct
naming, descriptions, or correct associative semantic judgement, may help to discern the specific
nature of an object/tool use deficit. Knowledge about body image, body structural description, and
the effects of changing viewing angles when matching gestures as well as tests of body rotation are
necessary to establish the involvement of the processes coding the dynamic position of the body parts
of self and others, that is, the body schema, which may also facilitate the comprehension of the praxic
defect (16).
Analysis of a patients performance is based on both accuracy and error patterns (Table 2).
One problem with many investigations of apraxia is that the analysis of gestural performance
may be insensitive to subtle apraxic deficits, which may have led to an uncorrected estimation about
the frequency and degree of apraxia. Therefore, detailed error analysis is crucial to unveil and to
properly classify an apraxic disorder. The patient with IA has difficulty mainly is sequencing actions
(e.g., making coffee) and exhibits content errors or semantic parapraxias (e.g., mimicking a hammer
use when requested to use a knife). Ideomotor apraxia patients show primarily temporal and spatial
errors, which are more evident when they perform transitive than intransitive movements. Errors in
LKA represent slowness, coarseness, and fragmentation of finger and hand movements (4,17).
Three-dimensional analysis of different types of movements has provided a better and more accu-
rate method to capture objectively the nature of the praxis errors observed in clinical examination.
Patients with IMA, due to focal left-hemisphere lesions (18,19), different asymmetric cortical degen-
erative syndromes (20,21), CBD, PSP, and PD (21,22), have shown several kinematic abnormalities
of dissimilar severity, such as slow and hesitant build-up of hand velocity, irregular and non-sinusoi-
dal velocity profiles, abnormal amplitudes, alterations in the plane of motion and in the direction and
shapes of wrist trajectories, decoupling of hand speed and trajectory curvature, and loss of interjoint
coordination. All these studies have evaluated gestures, such as carving a turkey or slicing a loaf of
bread, which mainly explore the transport or reaching phase of the movement. However, the majority
of transitive gestures included in most apraxia batteries include prehension (reaching and grasping)
movements that reflect proximal (transport) as well as distal limb control (grasping). The kinematic
analysis of aiming movements in apraxic patients has demonstrated spatial deficits, in particular
when visual feedback is unavailable (23), whereas the analysis of prehension movements in CBD has
shown disruption of both the transport and grasp phases of the movements as well as transport-
grasping uncoupling (21,24). Furthermore, the study of manipulating finger movements in patients
with CBD and LKA has disclosed several abnormalities, which more fully unveil the nature of the
deficit. The workspace is highly irregular and of variable amplitude, there is breakdown of the tem-
poral profiles of the scanning movements, and overall, a severe interfinger uncoordination is found
(25). Thus, exploration into the kinematics of reaching, grasping, and manipulating may provide
useful information regarding the specific neural subsystems involved in patients with different types
of limb praxic disorders.
Most of the errors exhibited by IMA cases are equally seen in left- or right-hemisphere-damaged
patients when they pantomime nonrepresentative and representative/intransitive gestures, but are
observed predominantly in left-hemisphere-damaged patients when they pantomime transitive move-
ments, because it is this action type that is performed outside the natural context (25). The left hemi-
sphere would not only be dominant for the abstract performance (i.e., pantomiming to verbal
command) of transitive movements but also for learning and reproducing novel movements such as
meaningless actions and sequences (27), as well as for action selection (28) and motor attention (29).
200 Leiguarda
Table 2
Types of Praxis Errors
I. Temporal
S= sequencing: some pantomimes require multiple positionings that are performed in a characteristic
sequence. Sequencing errors involve any perturbation of this sequence including addition, dele
tion, or transposition of movement elements as long as the overall movement structure remains
recognizable.
T= timing: this error reflects any alterations from the typical timing or speed of a pantomime and
may include abnormally increased, decreased, or irregular rate of production or searching or
groping behavior.
O= occurrence: pantomimes may involve either single (i.e., unlocking a door with a key) or repetitive
(i.e., screwing in a screw with a screwdriver) movement cycles. This error type reflects any mul
tiplication of single cycles or reduction of a repetitive cycle to a single event.
II. Spatial
A= amplitude: any amplification, reduction, or irregularity of the characteristic amplitude of a target
pantomime.
IC = internal configuration: when pantomiming, the fingers and hand must be in specific spatial rela
tion to one another to reflect recognition and respect for the imagined tool. This error type
reflects any abnormality of the required finger/hand posture and its relationship to the target tool.
For example, when asked to pretend to brush teeth, the subjects hand may close tightly into a fist
with no space allowed for the imagined toothbrush handle.
BPO = body-part-as-object: the subject uses his or her finger, hand, or arm as the imagined tool of the
pantomime. For example, when asked to smoke a cigarette, the subject might puff on his or her
index finger.
ECO = external configuration orientation: when pantomiming, the fingers/hand/arm and the imagined
tool must be in a specific relationship to the object receiving the action. Errors of this type
involve difficulties orienting to the object or in placing the object in space. For example, the
subject might pantomime brushing teeth by holding his hand next to his mouth without reflecting
the distance necessary to accommodate an imagined toothbrush. Another example would be when
asked to hammer a nail, the subject might hammer in differing locations in space reflecting diffi
culty in placing the imagined nail in a stable orientation or in a proper plane of motion (abnormal
planar orientation of the movement).
M= movement: when acting on an object with a tool, a movement characteristic of the action and
necessary to accomplish the goal is required. Any disturbance of the characteristic movement
reflects a movement error. For example, a subject, when asked to pantomime using a screwdriver,
may orient the imagined screwdriver correctly to the imagined screw but instead of stabilizing the
shoulder and wrist and twisting at the elbow, the subject stabilizes the elbow and twists at the
wrist or shoulder.
III.Content
P= perseverative: the subject produces a response that includes all or part of a previously produced
pantomime.
R= related: the pantomime is an accurately produced pantomime associated in content with the
target. For example, the subject might pantomime playing a trombone for a target of a bugle.
N= nonrelated: the pantomime is an accurately produced pantomime not associated in content with
the target. For example, the subject might pantomime playing a trombone for a target of shaving.
H= the patient performs the action without benefit of a real or imagined tool. For example, when
asked to cut a piece of paper with scissors, he or she pretends to rip the paper.
IV. Other
C= concretization. The patient performs a transitive pantomime not on an imagined object but
instead on a real object not normally used in the task. For example, when asked to pantomime
sawing wood, the patient pantomimes sawing on his or her leg.
NR = no response.
UR= unrecognizable response: the response shares no temporal or spatial features of the target.
From ref. 3.
TYPES OF LIMB APRAXIA

Ideational Apraxia
Liepmann defined IA as impairment in tasks requiring a sequence of several acts with tools and
objects (17). However, other authors use the term to denote a failure to use single tools appropriately
(2). To overcome this confusion, Ochipa et al. have suggested restricting the term IA to a failure to
conceive a series of acts leading to an action goal, and introduced the term conceptual apraxia (CA)
to denote loss of diverse types of tool-action knowledge (30). However, patients with IA not only fail
on tests of multiple-object use but also when using single objects (31); thus, a strict difference between
IA and CA is not always feasible. Therefore, according to Freund (5) and following Liepmann (17), IA
could be defined as a deficit in the conception of the movement so that the patient does not know
what to do (5,17). Patients with IA or CA exhibit primarily content errors, in the performance of
transitive movements (Table 2) or semantic parapraxias (e.g., use a comb as a toothbrush). They may
also lose the ability to associate tools with the object that receives their action; thus, when a partially
driven nail is shown, the patient may select a pair of scissors rather than a hammer from an array of
tools to perform the action. Not only are patients unable to select the appropriate tool to complete an
action, but they may also fail to describe a function of a tool or point to a tool when the function is
described by the examiner, even when the patient names the tool properly when shown to him or her
and may have difficulties in matching objects for shared purposes as well as being unable to solve
novel mechanical problems (30,32). However, selection and application of novel tools seem to rely
on the direct influence of structure on function, which in turn would depend upon a parietal lobe-
based system of nonsemantic sensorimotor representation that may be triggered by object affordance
rather than conceptual knowledge (33). These patients may also be impaired in the sequencing of
tool/object use (2,17). Patients with IA or CA are disabled in everyday life, because they use tools/
objects improperly, misselect tools/objects for an intended activity, perform a complex sequential
activity (e.g., make express coffee) in a mistaken order, or entirely fail to complete the task (3).
Ideational apraxia was traditionally allocated to the left parieto-occipital and parieto-temporal
regions (2,17), although frontal and frontotemporal lesions may also cause CA (32). Nevertheless,
semantic or conceptual errors are particularly observed in patients with temporal lobe pathology
(e.g., semantic dementia); these patients are impaired in the use of objects for which they have lost
conceptual knowledge (34).
Ideomotor Apraxia
IMA has been defined as a disturbance in programming the timing, sequencing and spatial
organisation of gestural movements (3). Patients with IMA exhibit mainly temporal and spatial
errors. Movements are incorrectly produced but the goal of the action can usually be recognized,
though on occasion performance is so severely deranged that the examiner cannot recognize the
movement. Transitive movements are more affected than intransitive ones on pantomiming to com-
mand. Patients usually improve on imitation when performance is compared to responses to verbal
command and acting with tools/objects is usually carried out better than pantomiming their use, but
even so, movements are not normal (2,3).
IMA is commonly associated with damage to the parietal association areas, less frequently with
lesions of the premotor (PM) cortex and supplementary motor area (SMA), and usually with disrup-
tion of the intrahemispheric white matter bundles interconnecting them, as well as with basal gan-
glion and thalamic damage (4). Although small lesions of the basal ganglia may cause IMA, most
patients sustained larger lesions to the basal ganglia and/or thalamus together with the internal cap-
sule and periventricular and peristriatal white matter, interrupting association fibers, in particular
those of the superior longitudinal fasciculus and frontostriatal connections (35). Most studies exam-
ining possible clinico-anatomical correlation for IMA have found a strong association of apraxia
with large cortico-subcortical lesions in the suprasylvian, perirolandic region of the left-dominant
202 Leiguarda
hemisphere, but no specific lesion site correlating with apraxia (4,36). However, a recent study using
quantitative structural image analysis to determine the location and greatest lesion overlap in patients
with left-hemisphere stroke and IMAas determined by assessing spatiotemporal errors on imitat-
ing meaningful and meaningless gesturesfound that damage to the left middle frontal gyrus (BA
46, 9, 8, and 6) and left superior and inferior parietal cortex surrounding the intraparietal sulcus (BA
7, 39, and 40) more commonly produce IMA than damage to other areas (37). Some patients with
apraxia commit errors only, or predominantly, when the movement is evoked by one but not all
modalities (modality-specific or dissociation apraxias) (3). The most frequent dissociation found in
apraxic patients is related with movement and posture imitation; unlike those with the classic form of
ideomotor apraxia, these patients are more impaired when imitating than when pantomiming to com-
mand, or could not imitate but performed flawlessly under other modalities. Deficits may be restricted
solely to the imitation of meaningless gestures with preserved imitation to meaningful gestures (38,39).
IMA may coexist with LKA; nevertheless, both types of apraxia can be clinically distinguished on
the basis of the following aspects. First, though usually asymmetric IMA is invariably bilateral,
whereas LKA is always contralateral to the affected hemisphere. Second, all movements in LKA,
whether symbolic or nonsymbolic, intransitive or transitive, are affected irrespective of the modality
(i.e., verbal, visual, tactile) through which they are evoked, whereas in IMA intransitive are less
compromised than transitive movements and these are unequally involved depending on the modality
under which they are tested. Third, finger and hand movements and posture errors typical of LKA are
readily distinguished from temporospatial errors (i.e., external configuration, movement trajectory,
body part as object) exhibited by patients with IMA, which predominantly involve the arm and hand
rather than the fingers, although internal configuration type of errors may be common to both disor-
ders; however, such errors in IMA are usually characterized by abnormal postures and movements of
the whole hand but fail to reflect the severe distortion of individual finger movements and postures so
typical of LKA (25).
There are several possible physiopathological mechanisms underlying the ideomotor type of
praxic deficits that depend on lesion location and are disclosed by the specific gesture evaluated
and the modality through which they are evoked. The most common subgroup of patients with IMA
are those who usually commit spatial and temporal errors when performing transitive as well as
intransitive symbolic or communicative movements under all modalities of elicitation (i.e., verbal
command, imitation, seeing and handling the object), although performance usually improves on
imitation and with object use. These patients also exhibit errors when imitating meaningless pos-
tures and novel motor sequences. We originally suggested that the crucial underlying neural mecha-
nism in this group of IMA patients was a disruption of the parallel parieto-frontal circuits and their
subcortical connection (4), subserving the computations required to translate an action goal into
movements by integrating sensory input with central representation of actions based on prior expe-
rience (37). Damage to circuits devoted to sensorimotor transformation for grasping, reaching, and
posture, for transformation of body part location into information required to control body part
movements, as well as for coding extrapersonal space, would produce incorrect finger and hand
posture and abnormal orientation of the tool/object, inappropriate arm configuration, and faulty
movement orientation (with respect to both the body and the target of the movement in extrapersonal
space) as well as movement trajectory abnormalities. These patients usually complain of disability
on everyday activities.
In another subgroup of patients, the ideomotor type of praxic deficits may be a result of disruption
of action selection processes (28); they exhibit spatial and temporal errors predominantly when pan-
tomiming to verbal command with the left hand, i.e., outside the appropriate context; they markedly
improve on imitation and performance is usually normal when handling the object. These patients do
not complain of difficulties in everyday activities; there is an automatic-voluntary dissociation.
There are also patients who are particularly impaired when using familiar objects and on tasks
requiring selection and use of novel tools, but with preserved semantic knowledge of object functions
(33,40,41). Most patients with difficulties in mechanical problem solving (novel tool selection), which
unveil the incapacity to infer functions from structure, also fail on pantomime of object use and
commit errors on actual use of familiar tools, so they are disabled in everyday life. Errors are mainly
of the spatiotemporal type, usually characterized by marked abnormal hand postures, but without
semantic parapraxias (33,40). Defective tool selection is particularly seen in patients with parietal
damage (41). Thus, this type of apraxic deficit can be ascribed to the disruption of a parietal lobe base
system specialized for visuomotor interaction with the environment, which may be triggered by visual
and perhaps tactile object affordance (33,40).
Neuroimaging and neuropsychological data support the existence of at least two partly indepen-
dent routes for imitation of meaningful and meaningless actions (42,43). Briefly, (a) imitation of a
meaningful movement/posture activates the dorsal pathway extending to the premotor cortex from
MT/V5 (BA 18/19) and always involving the inferior parietal lobule (IPL), with the participation of
the temporal cortex; whereas (b) imitation of a meaningless movement/posture also involves the
dorsal pathway, with predominant activation of the left IPL (area 40), with hand gestures, and right
intraparietal sulcus (IPS) and medial visual association areas (BA 18/19) for finger gestures; the
lateral occipito-temporal junction is activated by both hand and finger postures (42,43). Thus, imita-
tion of a meaningful movement/posture uses the temporal cortex for gestural meaning, whereas the
imitation of a meaningless ones seems to be more body part specific; the gestures visual appearance
is translated into categories of body part relationships mainly in the left IPL when hand postures are
to be imitated, and the addition of the right occipito-parietal cortex for precise perceptual analysis
and spatial attention for finger gesture imitation (43,44).
Finally, patients with IMA may exhibit several types of errors such as omissions, deletions, addi-
tions, transpositions, and perseverations when performing sequential limb movements (14). Abnor-
malities in movement sequencing have been reported more commonly in patients with left parietal
lobe lesions, but also with left frontal and basal ganglion involvement. Several clinical studies have
shown that impairment in sequencing is particularly apparent for the left-hemisphere-damaged patients
when the tasks place demands on memory; or when the temporal aspects of sequencing are considered,
when patients have to select movements in a sequence, or when the process of motor attention is
involved (4).
Which are the putative roles of basal ganglia in praxis? All the motor areas of the cerebral cortex,
as well as of the prefrontal cortex, send projections as part of parallel segregated circuits to diverse
regions of the basal ganglia (46). The parietal areas reciprocally interconnected with such areas of the
motor cortex making up the parietofrontal circuits also send extensive projections to the basal ganglia
(47). Thus, it seems likely that the basal ganglia are an integral part of a series of specialized circuits
for sensorimotor transformation. As regards reaching, Burnod et al. have recently suggested that the
basal ganglia could provide the cortex with gating signals capable of triggering the sequence of
movements at the appropriate time and in the appropriate order, when several outputs are possible for
a given task and when the decision has to be made between concurrent tasks (48). In addition to their
putative roles in sensorimotor transformation for reaching and grasping, the basal ganglia may par-
ticipate in praxis in other ways, whether in the selection of the kinematics and direction of arm
movements, by encoding peripersonal space for limb movements, by contributing to diverse mecha-
nisms of response selection, including inhibition of competing input from cortex, or by acting as an
integral part of brain systems involved in the representation of action sequences (36).
Limb-Kinetic Apraxia
This type of apraxia was originally described by Kleist, who called it innervatory apraxia to
stress the loss of hand and finger dexterity owing to inability to connect and to isolate individual
innervation and attributed it to damage to the PM cortex (47,48). The deficit is mainly confined to
finger and hand movements contralateral to the lesion, regardless of its hemispheric side, with pres-
ervation of power and sensation. Manipulatory finger movements are predominantly affected, but in
204 Leiguarda
most cases all movements, whether complex or routine, independently of the evoking modality, are
coarse and mutilated. The virtuosity given to movements by practice is lost and they become clumsy,
awkward, and amorphous. Fruitless attempts usually precede wrong movements, which in turn are
often contaminated by extraneous movements. Imitation of finger postures is also abnormal and some
patients use the less affected or normal hand to reproduce the requested posture. The deficit clearly
interferes with daily activities (25,47,49,50).
LKA has been scantily reported with focal lesions. There are basically two potential explanations:
first, most PM lesions also involve the precentral cortex, so that the contralateral paresis or paralysis
precludes expression of the praxic deficit; and second, bilateral activation of the PM cortex is often
observed with unilateral movements. Thus, a unilateral lesion would not be enough for the deficit to
become clearly manifested, since bilateral involvement would be most likely necessary. As a matter
of fact, all recently pathologically confirmed cases of LKA had undergone a degenerative process
such as CBD and Picks disease, involving frontal and parietal cortices, or predominantly, the PM
cortex (4).
DISTRIBUTION OF THE APRAXIAS IN OTHER BODY PARTS

Face apraxia refers to a disturbance of upper and lower face movements not explained by elemen-
tary motor or sensory deficits. Patients exhibit spatial and temporal errors of similar quality to those
observed in the limbs when performing representational and nonrepresentational movements such as
sticking out the tongue, blowing out a match, smiling, blowing a kiss, showing the teeth, blinking the
left or right eye, looking down, or sucking on a straw. Although lower face or buccofacial apraxia
often coexists with Brocas aphasia, and thus is more frequently observed with left-hemisphere le-
sions, in particular involving the frontal and central operculum, insula, centrum semiovale, and basal
ganglia (51), it can also be seen with lesions confined to left posterior cortical regions as well as with
right-hemisphere damage (52).
Apraxia of eyelid opening has been defined as a nonparalytic inability to open the eyes at will, in
the absence of visible contraction of the orbicularis oculi muscle owing to involuntary palpebral
levator inhibition (53). Many patients show a forceful contraction of the frontalis muscle and/or a
backward thrusting of the head on attempting eyelid opening and use different types of maneuvers to
help open the eyes including opening the mouth, massaging the lids, and manual elevation of the lids.
However, apraxia of eyelid opening can hardly be considered a true apraxia but rather a subclinical
form of blepharospasm because (a) most patients exhibit abnormal persistence of orbicularis oculi
activity detected at electromyography; (b) it is commonly associated with overt blepharospasm; and
(c) it is particularly observed in patients with basal ganglion disorders (54).
Truncal or whole body apraxia is a disorder of axial movements neither attributable to elementary
motor (e.g., extrapyramidal) or sensory deficit nor to dementia. Patients have difficulties dancing or
turning around and may be unable to adapt the body to the furniture; patients have difficulty sitting
down in a chair, showing hesitation, sitting in a wrong position (e.g., on the edge of the chair) and in
incorrect directions (e.g., facing the back of the chair). When lying in bed, their body is not aligned
parallel to the major axis of the bed and they place the pillow in an unusual position. Patients may
have minimal or no difficulty in standing or getting up, in contrast to features of some basal ganglion
disorders such as parkinsonism. Truncal apraxia is seen with bilateral hemispheric damage involving
the parietal or parieto-temporal cortex or affecting parieto-frontal connections (55,56).
THE NATURE OF APRAXIA IN ATYPICAL PARKINSONISMS

Limb apraxia is a prominent clinical feature and the most widely studied cognitive deficit in CBD.
It is almost invariably asymmetric and more frequent in patients whose initial symptoms were in the
right limb (left-hemisphere dominance) than in the left limb (right-hemisphere dominance), in agree-
ment with the fact that most right-handers develop IMA as well as IA predominantly with left-hemi-
sphere lesions (10,21). In CBD, IMA is the most common type of limb praxic deficit. Patients exhibit
temporal and spatial errors more frequently when performing transitive than intransitive movements.
Spatial errors such as incorrect positioning of the hand to grasp the tool (internal configuration errors),
difficulty in orienting the hand with respect to the body and the tool with respect to the object receiving
the tools action in extrapersonal space (external configuration errors), abnormal movement trajecto-
ries, and timing errors were those more frequently found whereas body-part-as-object and sequenc-
ing errors were not so common (videotapes 1 and 2). All these patients have difficulties when imitating
meaningful and meaningless postures and movements and some exhibited even more errors when
imitating than pantomiming gestures to command. Thus, there is no consistent pattern when compar-
ing performance on gestures to command with imitation and the use of the real object/tool, since
some patients may have more difficulties when imitating than pantomiming gestures and occasional
patients perform worse when handling the objects than pantomiming to command or the reverse,
show a dramatic improvement when holding the tool/object (10,21,5763).
CBD patients may not only exhibit spatiotemporal errors when handling objects but in addition
may often show impairment in the selection and usage of novel tools in the mechanical problem-
solving task (63); on occasion, they may also commit content errors and perform wrongly the sequen-
tial arm movement test, displaying errors such as omissions, misuse, mislocations, and intrusions, as
well as pantomime recognition deficits (10). Therefore, a consistent production or executive deficit
may frequently combine with mechanical problem-solving impairment and less commonly with seman-
tic knowledge breakdown as well (63). However, disruption of conceptual knowledge and IA (content
errors or semantic parapraxias) are uncommon in CBD patients; this type of praxic deficit is particu-
larly observed in patients with cognitive impairment including aphasia and dementia (10,64), or in
the presence of primitive reflexes (10). The combination of several types of limb praxic deficits
relevant for object use clearly explains why CBD patients are far more disabled in everyday life than
any patients with other atypical parkinsonian diseases.
The limb-kinetic type of apraxia has also been frequently reported in CBD (21,25,49,50,65). Patients
show slow, awkward, and mutilated finger and hand movements; on occasion, movements are amor-
phous and contaminated by extraneous movements. Difficulties are particularly evident with motor
skills requiring fractionated or sequential fingers movements. Imitation of finger postures is abnor-
mal and some patients use the other hand to move the abnormal one to reproduce the requested
posture. At times, the fingers and hand remain in an abnormal posture while the patient performs
other tasks with the contralateral hand. Perseveration of postures and movements is commonly
observed. Patients are aware of the poor performance but are unable to correct their errors (21)
(video 3, see companion DVD). Kinematic studies in these patients showed severe disruption of
manipulative movements with marked interfinger uncoordination (25).
The prevalence of facial (buccofacial) apraxia in CBD is unclear. Pillon et al. (58) found orofacial
apraxia in their patients though milder than limb apraxia. We only demonstrated orofacial apraxia in
4 out of 16 patients (21) but other authors failed to mention it in their studies (57,59). However, in a
recent study by Ozsancak et al., orofacial apraxia, as evaluated by means of simple and sequential
gestures, was found in 9 of 10 patients with a clinical diagnosis of CBD (66). Lastly, truncal apraxia
has also been recorded in CBD patients (56).
The brunt of the pathology in CBD is located in the superior frontal gyrus, which is more often
affected than the middle and inferior gyri, the pre- and postcentral regions, the anterior corpus callo-
sum, the caudate, putamen, globus pallidus, thalamus, and substantia nigra, with atypical asymmetric
distribution (67). Functional brain-imaging studies have disclosed decreased metabolism in the fron-
toparietal region, particularly in the superior prefrontal cortex, lateral and mesial premotor areas, in
the sensorimotor and parietal association cortices, as well as in the caudate, lenticular, and thalamic
regions with striking interhemispheric asymmetries, the hemisphere contralateral to the more affected
limb proving more severely involved (68).
206 Leiguarda
The particular distribution of the pathological process in patients with CBD clearly explains the
disruption of the cortical and subcortical components of the multiple, parallel, sensorimotor transfor-
mation circuits, and hence the severe IMA observed in these patients. An action selection deficit
owing to involvement of parietal and premotor cortices and basal ganglia on the left hemisphere may
further aggravate the praxic disorder. Moreover, frequent breakdown in mechanical problem solving
as a result of parietal lobe pathology and the occasionally observed impairment in object-specific
conceptual knowledge, probably related to temporofrontal pathology, explain the IA disorder and the
rarely observed gesture recognition deficit (10). The limb-kinetic type of praxic deficit is mainly
related to damage to the circuits subserving grasping and manipulation; in addition, it may be further
aggravated by derangement of independent finger movements and by dysfunction of somatosensory
control of manipulation (25). Involvement of inhibitory areas in the inferior and superior frontal gyri
and damage to subcortical structures may reduce facilitation of inhibitory interneurones, causing
defective cortical inhibition, which in turn may also interfere with the selection and control of finger
muscle activity. We found reduced cortical inhibition, as reflected by a short silent period, in CBD
patients with LKA (25). Finally, an associated sensory defect because of parietal damage may inter-
fere with the kinaesthetic and tactile information necessary for somatosensory control of manipula-
tion; however, as a defect in somaesthesis may not be present and parietal involvement may be absent
in patients with CBD, LKA may basically result from bilateral dysfunction of nonprimary cortical
motor areas (25).
APRAXIA IN OTHER ATYPICAL PARKINSONIAN DISORDERS

Although frequent (13,62), limb apraxia is not a clinical feature included in the diagnostic criteria
of PSP (69,70). Bilateral IMA mainly for transitive movements, slightly asymmetric, and almost
always more pronounced in the nondominant limb is the most consistent finding. IMA for intransi-
tive movements is usually less frequent and severe. The praxic deficit is particularly evident when
patients pantomime under verbal command, improve on imitation and more with the use of the tool/
object (13,58,62). Spatial (i.e., internal and external configuration, trajectory) are more prominent
than temporal errors (i.e., hesitation, delay); perseveration and sequencing errors are uncommon;
content errors are not found (13) (video 4). PSP patients rarely develop abnormal motor behavior
compatible with LKA (13,58). Ideomotor apraxia seems to correlate significantly with cognitive
deficits as measured with Mini Mental State Examination (MMSE). Recognition of pantomimes is
normal, but on occasion patients may fail on the multiple-step task (13). Facial (orofacial) apraxia
may be found, though it may be difficult to interpret the exact nature of the abnormal performance
given the unique facial appearance usually present in PSP patients (13). In turn, apraxia of eyelid
opening is common and may be very disabling (70).
The ideomotor type of praxic deficit is qualitatively similar in PSP and PD patients, though more
frequent and usually more severe in the former (13), as also demonstrated by the use of three-dimen-
sional motor analysis (22).
Limb apraxia is not observed (13), or exceptionally found with MSA (15) and has not been sys-
tematically studied in patients with demential Lewy bodies (DLB). However, we have found IMA
with predominantly imitative deficits in three patients with mild to moderate DLB as clinically diag-
nosed by McKeith et al. criteria (72) (see also Abeleyra et al., in preparation) (videotape 5).
Limb apraxic deficits in PSP seem to correlate with low MMSE, whereas in PD they appear to
correlate with neuropsychological tests reflecting frontal lobe dysfunction and visuospatial cognitive
deficits (13). Since focal lesions restricted to the basal ganglia only rarely cause apraxia and patients
with MSA, which is characterized by severe basal ganglion and slight cortical involvement, fail to
exhibit praxic deficits, we suggested that apraxia in PSP and PD reflect combined corticostriatal
dysfunction (13). Cortical degeneration is now recognized to be common in PSP and identified mainly
in the cingulate, superior, and medial frontal gyri (72,74). However, in PSP patients with limb apraxia
cortical pathology may predominate in motor cortices or coexist with Alzheimers disease pathology (74).
Table 3
Comparison of Different Types of Praxic Disorders Among CBD, PSP, MSA, and DLB
Praxic Disorder CBD PSP MSA DLB
Limb Apraxia
Ideomotor
Transitive gestures
Pantomiming to verbal commands +++ ++ +/ ++
Object use ++ +
Imitation ++ + +/++
Intransitive gestures ++ +/ +
Asymmetry +++ + + +
Voluntary / automatic dissociation ++
Mechanical problem solving +++ Unknown
Ideational
Conceptual errors +
Sequencing + +/
Limb-kinetic +++ +
Pantomime recognition / discrimination + Unknown
Facial apraxia ++ +
Apraxia eyelid opening +/ ++
Truncal apraxia ++ Unknown Unknown Unknown
+++, severe; ++, moderate; +, mild; , absent.
In PD patients, impairment of neuropsychological tests reflecting frontal lobe function correlated

with reduced fluorodopa uptake in caudate nucleus (75), and proton magnetic resonance spectros-
copy (MRS) may detect temporoparietal cortical dysfunction in nondemented patients with PD (76).
Therefore, it seems plausible that the subgroups of PD patients developing limb apraxia and more
severe kinematic abnormalities in the spatial precision of movements and interjoint coordination (22)
are those with greater caudate nucleus and frontal lobe involvement with or without temporoparietal
cortical dysfunction (36). Thus, basal ganglion pathology per se would not cause overt apraxia. How-
ever, when combined with dysfunction of the cortical components of the neural circuits devoted to
sensorimotor transformation, sequencing, and action selection, various types of praxic deficits would
become clinically manifested (36).
CONCLUSION
The main clinical features of the diverse types of praxic disorders observed in CBD, PSP, MSA,
and DLB are summarized in Table 3. IMA and LKA are both particularly severe in CBD. Compared
with PSP and DLB, IMA is more asymmetric and intransitive movements are invariably affected.
CBD patients are more severely disabled with object use, although some may exhibit deficits mainly
in gesture imitation. Unlike PSP and probably DLB, there is no voluntary automatic dissociation in
CBD. Ideational praxic deficit and pantomime recognition defects may be seen in CBD but neither in
PSP nor in MSA. Facial apraxia is more severe in CBD than in PSP and truncal apraxia has not yet
been properly described in the latter. Apraxia of eyelid opening is a salient feature in PSP. Further
studies are required to characterize the nature of apraxia in DLB.
However, the design of clinical studies regarding specific apraxic deficits in patients with atypical
parkinsonism first requires improving our knowledge of the neural components that subserve the
multiple processes involved in limb praxis and their precise distribution over the large cortical and
subcortical network of neural structures, made up by many interrelated systems pertaining to dissimi-
lar levels of action representation. In turn, this will require the separate study of the functional neu-
roanatomical correlates of each of the different manifestations of limb apraxia (i.e., pantomiming to
208 Leiguarda
verbal command, imitation of meaningful and meaningless movements, tool/object use in real life,
everyday actions, and action recognition, among others). Thus, a more refined cognitive neuroana-
tomical model of limb praxis will guide an accurate assessment and diagnosis of apraxia subtypes
and allow developing rehabilitation programs to target specific apraxic deficits.
SOME AREAS FOR FUTURE RESEARCH IN LIMB PRAXIS

1. Clinical and kinematical studies correlating disruption of specific spatiomotor or sensorimotor processes
with lesion location in patients with restricted focal cortical and subcortical damage.
2. Functional neuroimaging studies exploring distinct praxis processes in normal subjects and in patients
with specific apraxic deficits and acute lesions, as well as following recovery.
3. To study the clinical implications of several cognitive processes, such as motor attention and action selec-
tion, in patients with diverse subtypes of apraxic disorders.
4. To study through motor imagery the premovement neural processes involved in limb praxis.
LEGENDS TO VIDEO
*Sequence 1
Patient with CBD and severe bilateral IMA.
1. When pantomiming to use a screwdriver, the patient exhibits diverse types of errors: irregu-
lar production rate, variable amplitude, abnormal arm posture, and abnormal hand orienta-
tion. Instead of twisting at the elbow, the patient moves the wrist and/or fingers. Performance
improves with object use but remains abnormal.
2. When requested to pantomime drinking a glass of water, he places the hand in an abnormal
posture, and there is no place for the glass between the hand and the mouth.
*Sequence 2
Patient with CBD and bilateral IMA.
Note the abnormal posture of the hand, the incorrect orientation, and variable amplitude of the
movement when pantomiming to use a hammer.
*Sequence 3
Patient with CBD and unilateral LKA.
Note the difficulty for coordinating finger movements when requested to oppose the thumb
against the other fingers, to throw pebbles, and to make the sign of victory. Movements are
slow, coarse, and fragmented and on occasion amorphous. Finger selection is wrong and
fingers fail to act in concert. He uses his normal hand to achieve the requested posture.
*Sequence 4
Patient with PSP and IMA.
When pantomiming to use a screwdriver, the patient shows hesitation, uses the wrong joints
(wrist instead of elbow), and perseveres in the wrong movement.
*Sequence 5
Patient with Lewy Body dementia, IMA, and severe imitation deficits.
Note the abnormal hand configuration and position when requested to imitate meaningless
hand posture.
REFERENCES
1. Roy EA, Square PA. Common considerations in the study of limb, verbal, and oral apraxia. In Roy EA, ed. Neuropsy-
chological Studies of Apraxia and Related Disorders. Amsterdam: North-Holland, 1985:111161.
2. De Renzi E. Apraxia. In Boller F, Grafman J, eds. Handbook of Neuropsychology. Amsterdam: Elsevier Science ,
1989:245263.
3. Rothi LJ, Heilman KM, eds. Apraxia: The Neuropsychology of Action. East Sussex: Psychology Press, 1997.
4. Leiguarda R, Marsden CD. Limb apraxias: higher-order disorders of sensorimotor integration [Review]. Brain
2000;123:860879.
5. Freund HJ. The apraxias. In: Asbury Ak, McKhann GM, McDonald WJ, eds. Diseases of the Nervous System. Clinical
Neurobiology, 2nd ed. Philadelphia: Saunders, 1992:751767.
6. Rebeiz JJ, Kolodny EH, Richardson EP. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol
1968;18:2033.
7. Riley DE, Lang AE, Lewis A, et al. Corticobasal ganglionic degeneration. Neurology 1990;40:12031212.
9. Rinne J, Lee M, Thompson P, Marsden CD. Corticobasal degeneration: A clinical study of 36 cases. Brain
1994;117:11831196.
10. Leiguarda R, Lees AJ, Merello M, Starkstein S, Marsden CD. The nature of apraxia in corticobasal degeneration. J
11. Kampoliti K, Goetz CG, Boeve BF, et al. Clinical presentation and pharmacological therapy in corticobasal degenera-
tion. Arch Neurol 1998;55:957961.
13. Leiguarda R, Pramstaller P, Merello M, Starkstein S, Lees AJ, Marsden CD. Apraxia in Parkinsons disease, progres-
sive supranuclear palsy, multiple system atrophy, and neuroleptic induced parkinsonism. Brain 1997;120:7590.
14. Hamilton JM, Haaland KY, Adair JC, Brandt J. Ideomotor limb apraxia in Huntingtons disease: implications for
corticostriatal involvement. Neuropsychologia 2003;41:614621.
15. Monza D, Soliveri P, Radice D, et al. Cognitive dysfunction and impaired organization of complex mobility in degen-
erative parkinsonian syndromes. Arch Neurol 1998;55:372378.
16. Buxbaum LJ, Giovannetti, Libon D. The role of the dynamic body schema in praxis: evidence from primary progressive
apraxia. Brain Cog 2000;44:166191.
17. Liepmann H. Apraxia. Ergeb Gesamten Medizin 1920;1:516543.
18. Clark MA, Merians AS, Kothari A, et al. Spatial planning deficits in limb apraxia. Brain 1994;117:10931106.
19. Poizner H, Clark MA, Merians AS, Macauley B, Gonzalez Rothi LJ, Heilman KM. Joint coordination deficits in limb
apraxia. Brain 1995;118:227242.
20. Leiguarda R, Starkstein S. Apraxia in the syndromes of Pick Complex. In Kertesz A, Muoz DG, eds. Picks Disease
and Pick Complex. New York: Wiley-Liss, 1998:129143.
21. Leiguarda R, Merello M, Balej J. Apraxia in corticobasal degeneration. In: Litvan I, Goetz CG, Lang A, eds.
Corticobasal Degeneration and Related Disorders. Advances in Neurology, vol. 82. Philadelphia: Lippincott Williams
&Wilkins, 2000:103121.
22. Leiguarda R, Merello M, Balej J, Starkstein S, Nogus M, Marsden C. D. Disruption of spatial organization and
interjoint coordination in Parkinsons disease, progressive supranuclear palsy and multiple system atrophy. Mov Disord
2000;15:627640.
23. Haaland KY, Harrington DL, Knight RT. Spatial deficits in ideomotor limb apraxia. A kinematic analysis of aiming
movements. Brain 1999;122:11691182.
24. Caselli RJ, Stelmach GE, Caviness JV, et al. A kinematic study of progressive apraxia with and without dementia. Mov
Disord 1999;14:276287.
25. Leiguarda R, Merello M, Nouzeilles MI, Balej J, Rivero A, Nogus M. Limb-kinetic apraxia in corticobasal degenera-
tion: clinical and kinematic features. Mov Disord 2003;18(1):4959.
26. Haaland KY, Flaherty D. The different types of limb apraxia errors made by patients with left vs. right hemisphere
damage. Brain Cog 1984;3:370384.
27. Rapcsak SZ, Ochipa C, Beeson PM, Rubens A. Apraxia and the right hemisphere. Brain Cog 1993;23:181202.
28. Rushworth MFS, Nixon PD, Wade DT, Renowden S, Passingham RE. The left hemisphere and the selection of learned
actions. Neuropsychologia 1998;36:1124.
29. Rushworth MFS, Krams M, Passingham RE. The attentional role of the left parietal cortex: the distinct lateralization
and localization of motor attention in the human brain. J Cogn Neurosci 2001;13(5):698710.
30. Ochipa C, Rothi LJG, Heilman KM. Conceptual apraxia in Alzheimers disease. Brain 1992;115:10611071.
31. De Renzi E, Lucchelli F. Ideational apraxia. Brain 1988;113:11731188.
32. Heilman KM, Maher LH, Greenwald L, Rothi LJ. Conceptual apraxia from lateralized lesions. Neurology 1997;49:
457464.
33. Hodges JR, Spatt J, Patterson K. What and how: Evidence for the dissociation of object knowledge and mechanical
problem-solving skills in the human brain. Proc Natl Acad Sci USA 1999;96:94449448.
34. Hodges J, Bozeat S, Lambon Ralph M, Patterson K, Spatt J. The role of conceptual knowledge in object use evidence
from semantic dementia. Brain 2000;123:19131925.
35. Pramstaller PP, Marsden CD. The basal ganglia and apraxia [Review]. Brain 1996;119:319340.
36. Leiguarda R. Limb-apraxia: cortical or subcortical. Neuroimage 2001;14:S137S141.
210 Leiguarda
37. Haaland KY, Harington DL, Knight RT. Neural representations of skilled movement. Brain 2000;123:23062313.
38. Ochipa C, Rothi LJ, Heilman KM. Conduction apraxia. J Neurol Neurosurg Psychiatry 1994;57:12411244.
39. Goldenberg G, Hagmann S. The meaning of meaningless gestures: a study of visuo-imitative apraxia. Neuropsychologia
1997;35:333341.
40. Spatt J, Bak T, Bozeat S, Patterson K, Hodges JR. Apraxia, mechanical problem solving and semantic knowledge.
Contribution to object usage in corticobasal degeneration. J Neurol 2002;249:601608.
41. Goldenberg G, Hagmann S. Tool use and mechanical problem solving in apraxia. Neuropsychologia 1998;36:581589.
42. Grzes J, Costes N, Decety J. The effects of learning and intention on the neural network involved in the perception of
meaningless actions. Brain 1999;122:18751887.
43. Hermsdrfer J, Goldenberg G, Wachsmuth C, et al. Cortical correlates of gesture processing: clues to the cerebral
mechanisms underlying apraxia during the imitation of meaningless gestures. Neuroimage 2001;14:149161.
44. Goldenberg G, Straus S. Hemisphere asymmetries for imitation of novel gestures. Neurology 2002;59:893897.
45. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia
and cortex. Ann Rev Neurosci 1986;9:357381.
46. Yeterian EH, Pandya DN. Striatal connections of the parietal association cortices in rhesus monkeys. J Comp Neurol
1993;332:175197.
47. Kleist K. Kortikate (innervatorische) Apraxie. J Psychiat Neurol 1907;25:46112.
48. Kleist K. Gehirnpathologische und lokalisatorische Ergebnisse: das Stirnhirn im engeren Sinne und seine Strungen.
Zeitschrift ges Neurologie und Psychiatrie 1931;131:442448.
49. Denes G, Mantovan MC, Gallana A, Cappelletti JV. Limb-kinetic apraxia. Mov Disord 1998;13:468476.
50. Blasi V, Labruna L, Soricelli A, Carlomagno S. Limb-kinetic apraxia: a neuropsychological description. Neurocase
1999;5:201211.
51. Raade AS, Rothi LJG, Helman KM. The relationship between buccofacial and limb apraxia. Brain Cog 1991;16:130146.
52. Bizzozero I, Costato D, Della Sala S, Papagno C, Spinnler H, Venneri A. Upper and lower face apraxia: role of the right
hemisphere. Brain 2000;123:22132230.
53. Boghen D. Apraxia of lid opening: a review. Neurology 1997; 48:14911494.
54. Tozlovanu V, Forget R, Iancu A. Boghen D. Prolonged orbicularis oculi activity. A major factor in apraxia of lid
opening. Neurology 2001;57:10131018.
55. Kase CS, Troncoso JF, Court JE, Tapia JF, Mohr JP. Global spatial disorientation: clinico-pathologic correlations. J Neurol
Sci 1977;34:267278.
56. Okuda B, Tanaka H, Kawabata K, Tachibana H, Sugita M. Truncal and limb apraxia in corticobasal degeneration. Mov
Disord 2001;16:760762.
57. Jacobs DH, Adair JC, Macauley BL, Gold M, Gonzalez Rothi LJ, Heilman KM. Apraxia in corticobasal degeneration.
Brain Cogn 1999;40:336354.
58. Pillon B, Blin J, Vadailhet M, et al. The neuropsychological pattern of corticobasal degeneration: comparison with
supranuclear palsy and Alzheimers disease: Neurology 1995;45:14771483.
59. Blondel A, Eustache F, Schaeffer S, Maire R, Lechvalier B, Sayette V. Etudie clinique et cognitive de lapraxie dans
latrophie cortico-basale. Rev Neurol (Paris) 1997;153:737747.
60. Peigneux P, Van Der Linden M, Andres-Benito P, Sadzot B, Franck G, Salmon E. Exploration neuropsychologique et
par imagerie fonctionnalle crbrale dune apraxia visuo-imitative. Rev Neurol (Paris) 2000;156(5):459472.
61. Graham NL, Zenan A, Young AW, Patterson K, Hodges JR. Dyspraxia in a patient with corticobasal degeneration: the
role of visual and tactile inputs to action. J Neurol Neurosurg Psychiatry 1999;67:334344.
62. Pharr V, Utte B, Stark M, Litvan I, Fantie B, Grafman J. Comparision of apraxia in corticobasal degeneration and
progressive supranuclear palsy. Neurology 2001;56:957963.
63. Spatt J, Bak T, Bozeat S, Patterson K, Hodges JR. Apraxia, mechanical problem solving and semantic knowledge.
Contributions to object usage in corticobasal degeneration. J Neurol 2002;249:601608.
64. Kertesz A, Martnez-Lange P, Davidson W, Muoz DG. The corticobasal degeneration syndrome overlaps progressive
65. Okuda B, Tachibana H, Kawabata K, Takeda M, Sugita M. Slowly progressive limb-kinetic apraxia with a decrease in
unilateral cerebral blood flow. Acta Neurol Scand 1992;86:7681.
66. Ozsancak C, Auzou P, Hannequin D. Dysarthria and orofacial apraxia in corticobasal degeneration. Mov Disord
2000;15:905910.
67. Dickson DW, Liu WK, Reding HK, Yen SH. Neuropathologic and molecular considerations, in corticobasal degenera-
tion and related disorders. In: Litvan I, Goetz CG, Lang AE, eds. Advances in Neurology, vol. 82. Philadelphia:
Lippincott Williams & Wilkins, 2000:928.
68. Brooks DJ. Functional imaging studies in corticobasal degeneration, in corticobasal degeneration and related disorders.
In: Litvan I, Goetz CG, Lang AE, eds. Advances in Neurology, vol. 82. Philadepphia: Lippincott Williams & Wilkins,
2000:209216.
69. Litvan I, Agid I, Calue D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele
RichardsonOlszewski syndrome): report of the NINDSSPSP international workshop. Neurology 1996;47:19.
70. Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Buru DJ. Clinical features and natural history of progressive supra-
nuclear palsy. Neurology 2003;60:910916.
71. McKeith IG, Galasco D, Kosaba K. Consensus guidelines for the clinical and pathological diagnosis of dementia with
lewy bodies (DLB): report of the consortium on DLB international work shop. Neurology 1996;47:113124.
72. Daniel SE, de Bruin V, Lees AJ. The clinical and pathological spectrum of SteeleRichardsonOlszewski syndrome
(progressive supranuclear palsy): a reappraises [Review]. Brain 1995;118:759770.
73. Abeleyra C, Marello, M, Manes F, Leiguarda R. Defective imitation of limbgestures in Lewy body dementia, in prepa-
ration.
74. Bergeron C, Pollamen MS, Weyer L, Lang AE. Cortical degeneration in progressive supranuclear palsy. A comparison
with cortical-basal ganglionic degeneration. J Neuropathol Exp Neurol 1997;56:726734.
75. Rinne J, Portin R, Routtinen H, et al. Cognitive impairment and the brain dopaminergic system in Parkinson disease.
Arch Neurol 2000;57:470475.
76. Hu MTM, Taylor-Robinson SD, Ray Chaudhuri K, et. al. Evidence for cortical dysfunction in clinically non-demented
patients with Parkinsons disease: a proton MR spectroscopy study. J Neurol Neurosurg Psychiatry 1999;67:2026.
Visuospatial Cognition in Parkisonian Disorders 213
14
Role of Visuospatial Cognition Assessment
in the Diagnosis and Research of Atypical
Parkinsonian Disorders
Paolo Nichelli and Anna Magherini
INTRODUCTION
Visuospatial abilities play a pivotal role in our daily living. Indeed, our survival depends, to a
great extent, on our ability to navigate sensory space. This means our ability to use spatial maps
dependent on visual, tactile, and auditory information to form and guide motor programs. Visuospatial
abilities are complex brain operations requiring integration of occipital, parietal, and frontal lobe
function, as well as the contribution of subcortical structures. Consequently, it is not surprising that
visuospatial skills are often impaired in diseases with movement disordersan impairment that
depends both on the type and on the stage of the disease in question.
Investigating visuospatial skills is helpful not only for differentiating among various diseases with
movement disorders, but also for analyzing the source of patients everyday life impairment, as this
can, in turn, generate useful pointers for the development of remedial strategies.
Also, in the detailed analysis of visuospatial performance in patients with movement disorders,
particular care must be taken to separate motor from cognitive components. In the devising of neu-
ropsychological tools that can help us to gain a new insight into cortical and subcortical contributions
to these activities, this represents a constant challenge.
The aim of this chapter is to review the contribution of visuospatial assessment in the differential
diagnosis of movement disorders. After presenting a classification of visuospatial skills, we will
discuss the evidence of visuospatial dysfunction in Parkinsons disease (PD) and in the various atypi-
cal parkinsonian disorders. We will then advance our own proposal for visuospatial assessment in
this group of patients.
CLASSIFICATION OF VISUOSPATIAL DISORDERS

Visuospatial activities have been classified according to different criteria. OKeefe and Nadel (1)
divided them on the basis of the sensorimotor responses of persons moving in their own environment,
classifying them as position (or egocentric) responses when subjects use their body as a reference,
as cued responses when movements are guided by external cues, and as place responses when
movements are guided by relationships between external references. Grsser (2) classified the space
around the subject as consisting of three functionally different subspaces: the body surface, the
grasping space, and the distal space. It seems that different brain regions are responsible for direct-
ing attention to different regions of space. For example, experimental studies on monkeys have local-

213
214 Nichelli and Magherini
ized the representation of personal space to parietal area 7a and postarcuate frontal area 6. Peripersonal
space seems to be encoded by parietal areas 7a and 7b and frontal areas 6 and 8. Extrapersonal space
is represented in frontal area 8, parietal area 7a, and the superior colliculus (3).
For the purpose of this review we present a classification of visuospatial abilities that divides them
into spatial perception, visuomotor coordination, visuospatial attention, perception of size, spatial
memory, and visuospatial imagery. Although any classification of this sort is somewhat arbitrary, we
believe it is useful to list the different domains to be examined during neuropsychological testing.
Furthermore, the various parkinsonian disorders can affect some of these skills while leaving others
intact.
Spatial Perception
Spatial perception is the ability to analyze the spatial relationships both between the stimulus and
the observer and between different stimuli. Visual, tactile, and auditory information can contribute to
spatial perception. However, visual-perceptual skills predominate disproportionately over the other
perceptual skills. According to current theories (4,5) visual information is processed by two distinct
pathways: the occipito-temporal (ventral) pathway, which conveys information about shape and pat-
terns, and the occipito-parietal (dorsal) pathway, which is involved in spatial analysis. Three funda-
mental aspects of spatial perception are stimulus localization, perception of line orientation, and
depth perception. All can be impaired after brain damage.
Stimulus Localization
Different methods have been proposed to examine stimulus localization. Warrington and Rabin
(6) presented two cards, either simultaneously or in succession, and asked subjects to evaluate whether
the position of a point was the same or different on the two cards. Hannay et al. (7) projected onto a
screen one or two dots for 300 ms, then, after a 2-s delay, they presented a display showing 25
numbers in different positions: the subjects task was to read aloud the numbers corresponding to the
correct dot positions. The performances of right-posterior brain-damaged patients are typically
impaired.
Perception of Line Orientation
The most widely used instrument in the assessment of this component of visuospatial perception is
the Bentons Judgement of Line Orientation Test (8). This test requires subjects to identify the orien-
tation of a pair of lines on an 11-line multiple-choice display. A number of studies have used this test
to assess visuospatial abilities in PD patients, and given varying results. Boller et al. (9) demonstrated
that PD patients with a normal IQ are impaired in line orientation judgement. Similar results were
obtained by Goldenberg et al. (10). However, Richards, Cote, and Stern (11) did not find differences
between 14 patients with idiopathic PD and 12 normal controls matched for age and education. Simi-
larly Levin and colleagues (12,13) did not identify line orientation abnormalities in their mildly and
moderately affected PD patients. In a large sample (76 patients and an equal number of matched
normal controls), Montse et al. (14) demonstrated that, in line orientation judgment, PD patients
make proportionally more complex intraquadrant and horizontal line errors, but fewer simple
intraquadrant errors than controls. Girotti et al. (15) reported that when PD patients were divided into
those with and those without dementia, the line orientation test was one of the few tasks that distin-
guished the nondemented PD patients from controls, whereas many tasks differentiated the demented
PD patients from controls. In conclusion, the line orientation test is often abnormal in PD patients but
may be normal in patients in whom the disease is less advanced.
Depth Perception
The perception of depth is based on both monocular and binocular sources (16,17). Monocular
cues include apparent size of familiar objects, texture and brightness gradient, linear perspective,
occluding contours, shading, and monocular parallax (i.e., the ability to analyze disparate retinal
images successively produced by the same object on the retina). Stereopsis is the ability to discrimi-
nate depth on the basis of binocular information. Stereoacuity is commonly tested using the quantita-
tive Titmus stereotest, which requires the subject, who is wearing appropriately polarized lenses, to
detect circles that appear on a closer plane with respect to the background. Global stereopsis is tested
using Julezs random dot stereograms, geometric forms that canif viewed stereoscopicallybe
seen from below or above the background plane.
Both the striate and the peristriate and parietal visual areas play a pivotal role in depth perception
based on binocular cues (1820). To the best of our knowledge, no systematic study of depth percep-
tion in patients with parkinsonian disorders has to date been conducted.
Visuomotor Coordination
The impaired ability to reach for visually presented stimuli, not related to motor, somatosensory,
visual-acuity, or visual-field deficits, is named optic (visuomotor) ataxia. To detect subtle visuomotor
ataxia, the subject is asked to reach for an object that requires a precision grip (i.e., true opposition of
thumb and index finger). In a clinical setting, the examiner will hold the object (a coin or a paper clip)
by its edge while the patient attempts to grasp it between the index finger and thumb. In the most
severe cases, the disorder is apparent even when the patient is fixating when reaching for the object.
More frequently, the impairment is only apparent when the target is located at the periphery of the
visual field, or when the patient is not allowed to look at his reaching arm (21).
Reaching for an object is a movement that can be divided into two components: the proximal
component (the reaching or transportation phase) and the distal component (the grasping or ma-
nipulation phase). This dichotomy has received particular attention because it reveals the difference
between two pathways of visuospatial perception respectively devoted to determining the target coordi-
nates in a body-centered space (the occipito-parietal pathway) and to computing shape, size, and
weight of the target object (the occipito-temporal pathway) (4).
Examining in detail the different components of reaching for an object requires frame-by-frame
analysis of a video recording of the movement. Studies of visuomotor coordination in PD patients
show no deficit in the transportation and in the manipulation components of the reaching-to-
grasp movement (22). On the contrary, PD patients demonstrate some dysfunction when they are
required to respond appropriately to modification of object size and location (23,24). Rearick et al.
(25) demonstrated that global features observed in five-digit grasping are preserved in PD patients.
However, more subtle aspects of the coordination between digits, as revealed by frequency domain
analysis, are not preserved, possibly owing to action tremor.
Visuospatial Attention
When we move in the environment, we are confronted with a vast array of sensory information
that the nervous system cannot deal with on an equal basis. Thus, the brain must select which infor-
mation to process. Visuospatial attention refers to the processes engaged by the nervous system in the
selection of relevant information from the mass of information presented by the visual environment.
The neglect syndrome has been characterized as a failure to report, respond to, or orient attention
to novel or meaningful stimuli presented to the side opposite to a brain lesion, when this failure
cannot be attributed to either sensory or motor defects (26). In severe neglect, patients may behave as
though one-half of the world had suddenly ceased to exist. They may fail to eat the food on the left
side of their plate, or omit to shave, groom, and dress the left side of the body. In other patients, the
symptoms are much subtler and might not be detected by observation of their spontaneous behavior.
In the latter cases, special maneuvers may be needed in order to disclose the presence of neglect.
Cancellation tasks are often used for diagnosis of the syndrome. Albert (27) developed the sim-
plest form of these tasks, a test in which subjects are required to cancel each item in an array of 40
scattered lines. In the Bells Test (28), rather than scattered lines, 315 small, silhouetted objects are
distributed in a pseudorandom manner on the page, with 35 bells scattered among them. Despite their
apparently random positions, the bells are actually arranged in seven columns with five bells to a
column. The subjects task is to circle the bells as quickly as possible. Similarly, Mesulam (29), with
the purpose of enhancing the methods sensitivity to inattention to the right as well as to the left side,
devised verbal and nonverbal cancellation tasks consisting of four sheets, two (nonverbal) with vari-
ous shapes, and two (verbal) with randomized letters.
A different technique for investigating unilateral inattention is to ask the patient to bisect a line. In
the traditional version, patients are asked to mark the midpoint of a horizontal line drawn on a sheet
of paper. Normal subjects tend to bisect the line 12 mm left of its true center (30,31). Patients with
left hemineglect tend to place their mark rightward of the center. To interpret this finding, both space
representation and premotor impairment have been invoked. Assuming perceptual factors are respon-
sible, bisection toward the right would be a result of underestimation of the length of the left part of the
line, whereas the influence of premotor factors would result in reduced action toward the left (direc-
tional hypokinesia) or in reduced amplitude movement toward the left (directional hypometria). Dif-
ferent modifications of the line bisection paradigm have been devised to disentangle the
representational and premotor component of bisecting a line. In the landmark test (32), the subjects
task is to point to the shorter side of a correctly prebisected line: when patients choose the left side as
the shorter their neglect can be attributed to a representational deficit. In the line extension test (33),
patients are requested to extend a horizontal line leftward to double its original length. If premotor
factors dominate, they should cause a relative left underextension (compared to the right) because of
left hypokinesia-hypometria.
Animal studies have shown a central role of the dopaminergic system in the regulation of direc-
tional attention. Some authors believe that these circuits are purely premotor (34), whereas others
maintain that dopaminergic circuits also mediate perceptual aspects (35,36). In humans, some case
reports have shown significant improvement of patients with chronic neglect syndrome after therapy
with dopaminergic drugs (37,38). Asymmetric degeneration of the dopaminergic nigrostriatal path-
ways is the major mechanism underlying the motor symptoms of PD.
A number of early studies have found that patients with left hemi-PD tend to neglect the left side of
space (13,3941). However, the rightward bias of left hemi-PD is at most mild and some authors
(42,44) were not able to demonstrate visual neglect in their patients. In a more recent study Lee et al.
(43) examined PD patients with two line bisection tasks. One was a conventional paper- and pencil-
test. In the other, subjects were required to bisect a line presented on a computer screen by adjusting
the position of a cursor operated by two pushbuttons, one in each hand. No significant differences
were found on the paper-and-pencil test. On the contrary, predominantly left-sided PD patients showed
significant rightward bias in their setting of the cursor. The same bias was found when subjects re-
peated the task with the pushbuttons switched between the hands, so that the cursor was moved to the
left by the right hand and vice versa, thus suggesting a perceptual rather than a premotor bias.
Adopting a different approach, Ebersbach et al. (44) demonstrated that patients with predomi-
nantly right-sided PD, as well as normal controls, were more likely to start visual exploration on the
left side of texture arrays requiring attentive oculomotor scanning. On the contrary, PD patients with
predominantly left-sided disease showed a rightward directional bias for initial exploration, a behav-
ior similar to that demonstrated by patients affected by visuospatial neglect following cortical lesions
of the right parietal lobe.
Work by Posner and colleagues (45) has provided a theoretical framework within which the dif-
ferent processes involved in orienting attention might be interpreted. They distinguish between two
distinct modes of spatial orienting. Overt orienting involves turning the eyes toward a particular
location of interest, whereas covert orienting requires attention to be shifted to this location while
the eyes remain fixated elsewhere. Several studies have examined overt orienting in PD patients, and
there is a general consensus that internal control of eye movements through voluntary saccades
(remembered, delayed, and predictive saccades and antisaccades) is deficient in PD patients (46
49). At the same time there appears to be no deficit in PD patients for purely reflexive (or visually
guided) saccades (46,47,50,51). Thus, studies in PD patients suggest deficits in voluntary (internal)
control, but no deficit in reflexive (external) control of overt orienting of attention. To evaluate covert
orienting, subjects, all the time maintaining central fixation, are asked to press a key as soon as a periph-
eral stimulus appears. At the beginning of each trial subjects are given a visual cue, meant to draw
their attention to the side where the stimulus is to appear. In most trials the target is presented where
it was cued to appear (valid trials), but in some it appears on the opposite side (invalid trials). As it
might be expected, normal subjects are significantly faster on valid than invalid trials. Patients with
parietal lesions, even if nearly as good as normal controls on valid trials, are severely impaired on
invalid trials, which require them to respond to a stimulus contralateral to the lesion. This impairment
indicates defective attentional disengagement from a cued location. A number of researchers have
reported conflicting results regarding the performance of PD patients in covert orienting tasks, with
some studies reporting small covert orienting effects in PD patients (52,53), and others finding no
difference (5456). It turns out that, as for overt attention, it is important to distinguish between
voluntary and reflexive control of spatial attention. Voluntary covert attention is assessed by using
symbolic cues (e.g., arrows) presented at a central location. The purpose of these cues is to make the
subject shift his or her attention to the intended location. Reflexive covert attention is evaluated by
presenting a brief cue stimulus in the visual periphery that automatically draws attention to the loca-
tion of the cue. A couple of studies (57,58) compared voluntary and reflexive covert control of spatial
attention in PD patients. Both reported relatively normal cuing effects with voluntary (i.e., internally
controlled) cues at short (250 ms) and intermediate (500 ms) intervals between cue and target. How-
ever, in PD patients facilitatory effects were eliminated with longer (8001000 ms) intervals, thus
demonstrating defective voluntary control of covert attention. On the contrary, PD patients appear to
be significantly faster than control subjects on covert reflexive orienting (59). Progressive supra-
nuclear palsy (PSP) and corticobasal degeneration patients (CBD) can show specific impairments in
visual-orienting tasks that will be discussed later in this chapter.
Perception of Size
In human perception theories, it is commonly assumed that size is processed independently of
shape. Experimental animal studies in monkeys (60,61) have confirmed that object size is processed
in the brain independently of other stimulus characteristics. An important consequence of this dis-
tinction between form and size concerns our general ability to identify objects of different size as
identically shaped. The disorder of size perception of which patients are aware is termed dysmetropsia
(also called dysmegalopsia or metamorphopsia). Objects can appear either shrunk (micropsia) or
enlarged (macropsia), compared to their actual size (62). Size perception can be also distorted in
visuospatial neglect (63), but in this case patients are unaware of the symptom.
It has recently been demonstrated (64) that predominantly left PD patients, probably because of
right-hemisphere impairment, perceive a rectangle presented in the left and upper visual space as
smaller compared to rectangles presented in different regions of space. The same authors (65) have
raised the possibility that perceptual errors might have a causal role in determining PD patients
difficulties in negotiating doorways, narrow corridors, and other confined spaces. They asked PD
patients to judge whether or not they would fit through a life-size schematic doorway shown on a
large screen. Predominantly left PD patients obtained an increased ratio between the door width for
which 50% of the judgments were positive and the width of the participants body at the shoulders.
This finding was interpreted as suggesting that the visual representation of the doorway (or of its
relationship to perceived body size) is compressed in left PD. However, the clinical implications of
this finding are not yet clear, since the authors could not demonstrate a causal role of these perceptual
distortions in freezing episodes experienced by PD patients.
Spatial Memory
Within spatial memory it is possible to identify short- and long-term components.
Short-Term Spatial Memory
According to a widely accepted theoretical model (66) short-term memory is viewed as a work-
ing memory, where information can be temporarily stored and accessed for use in a wide range of
cognitive tasks. Working memory, on the other hand, is made up of an attentional system of limited
capacity (the so-called central executive) and of at least two slave subsystems: the articulatory
loop and the visuospatial sketchpad, respectively dealing with phonological and visuospatial items.
In this scheme, the visuospatial sketchpad would appear to keep visuospatial information on line
for subsequent processing by the central executive. This hierarchical organization could allow the
concurrent performance of phonological and visual tasks as long as they remain within the capacity
limits of the two slave systems, whereas the central executive would be called upon should the
information to be processed exceed these limits. A series of neuroimaging studies (67) has deter-
mined that spatial working memory is mediated by a network of predominantly right-hemisphere
regions that include posterior parietal (BA 40 and BA 7), anterior occipital (BA 19), and inferior
prefrontal (BA 47) sites. It has been hypothesized that the premotor area and the superior parietal
area might mediate spatial rehearsal, whereas the inferior posterior parietal area and the anterior
occipital area might mediate storage of spatial information (67,68).
A simple way to test the visuospatial short-term memory is to measure its span with the Corsi
Block Tapping Test (69). The test consists of nine blocks arranged on a board. The examiner taps the
blocks in sequences of increasing length, and after each one the subject is requested to copy the
sequence just tapped out. The longest sequence correctly tapped out by the subject constitutes his or
her visuospatial memory span. An important limitation regarding use of this task in a clinical setting
with parkinsonian patients is the fact that it requires a motor response: the spatial span might be
underestimated owing to the presence of bradykinesia. Nonetheless, studies that have used Corsis
test (70) failed to find any difference between PD patients and normal controls. On the contrary,
Bradley, Welch, and Dick (71) found that PD patients are slower that normal controls when perform-
ing complex visuospatial memory, but not verbal memory, tasks. Postle et al. (72) also found a selec-
tive impairment of spatial (but not object) delayed response in PD, indicating a selective disruption
of spatial working memory. A selective impairment of spatial working memory was also demon-
strated in PD patients by Owen et al. (73) using a computerized battery of tests designed to assess
spatial, verbal, and visual working memory. In the spatial working memory task, subjects were
required to search systematically through a number of boxes to find tokens while avoiding those
boxes in which tokens had previously been found. In the visual and verbal conditions, the subjects
were required to search in exactly the same manner, but through a number of abstract designs or
surnames, respectively, avoiding designs or names in which a token had previously been found.
Medicated PD patients with severe clinical symptoms were impaired on all three tests of working
memory. In contrast, medicated patients with mild clinical symptoms were impaired on the test of
spatial working memory, but not on the verbal or visual working memory tasks. Nonmedicated patients
with mild clinical symptoms were unimpaired on all three tasks. Further investigations by the same
group (7376) focused on the cognitive heterogeneity in PD. Taken together, the results demonstrate
that impairment of spatial working memory can occur in the early stages of the disease in a subgroup
of PD patients with frontostriatal circuitry involvement.
Using the dual-task paradigm to measure the ability to cope with concurrent task demands, a
number of investigators (7780) have hypothesized that the central executive is impaired in PD
patients. Le Bras et al. (81), using a specifically designed testing procedure, concluded that PD pa-
tients are impaired in all steps of executive information processing involved in spatial working
memory (stimulus encoding, storage, and response programming). More recently, Lewis et al. (76)
have found that PD patients performing badly on the Tower of London Test (a standard visuospatial
task of executive functioning) were specifically impaired in manipulating information within verbal
working memory.
Recent functional magnetic resonance imaging studies (82) have implicated the rostral caudate
nucleus in the transformation of spatial information in memory to guide the action. Dorsal premotor
cortex (82) and premotor cortex (Brodmanns areas 46 and 9) are also involved (8385) in perform-
ing spatial memory tasks. PD patients are known to suffer loss of dopaminergic input to the rostral
caudate. Extensive two-way connections link the striatum, the premotor, and the dorsolateral pre-
frontal cortices. It is therefore conceivable that the functional impairment of these brain regions is the
basis of spatial working memory impairment in PD patients.
Long-Term Spatial Memory
Memory for location is commonly tested by presenting a sheet showing a number of figures,
representing objects, and then asking patients, after various time intervals, to relocate them on another
sheet in exactly the same position (86). Using a similar procedure Pillon et al. (87) demonstrated that,
compared to controls, PD patients show significantly impaired spatial location of pictures, a result
that contrasts with their relatively preserved verbal memory and only mildly impaired perceptual
visuospatial and executive functions. Subsequently, the same group (88,89) carried out a number of
experiments specifically aimed at determining the nature of the deficit and its relationship with the
dopaminergic depletion that characterizes the disease. Results suggested that the memory deficit for
spatial location observed in PD patients is a consequence of a disturbance of strategic processing and
of decreased attentional resources, which may be a result of dopaminergic depletion and related
striatofrontal dysfunction.
Postle et al. (72) examined the performances of PD patients and normal controls on a visual delayed-
response test with a spatial condition and a (nonspatial) object condition, equating the perceptual diffi-
culty of the tests for each participant. The stimuli were irregular polygons presented at different
locations on a computer screen. Results revealed a disruption of spatial memory unconfounded by
sensory processing difficulties. The authors hypothesized that the selectivity of this deficit might
reflect the circumscribed nature of pathophysiological change affecting the caudate nucleus in
early PD.
Maze learning can also be used to evaluate long-term spatial learning. Wallesch et al. (90), to
analyze spatial learning and cognitive processes described as impaired in PD, used a computerized
maze task that allowed only partial vision of the maze. Results demonstrated that PD patients require
more trials than controls to solve the maze problems. Differences between the performances of patients
and controls were interpreted as owing to a response bias in the PD patients that resulted in a tendency
to repeat the previous action and in impaired multistep plan generation.
Spatial Imagery
The ability to create and manipulate images plays a central role in many daily activities: from
navigation to memory and to creative problem solving. According to Kosslyn (91) imagery abilities
fall into at least four categories: image generation, image inspection, image maintenance, and image
transformation. Several neuroimaging studies (9294) have provided strong evidence that visuospatial
imagery activates the same brain areas that are involved in visuospatial processing. In line with this
finding Levin et al., on the basis of the double dissociating performance of two patients, demon-
strated that the distinction between the what and where cortical visual systems extends to mental
imagery tasks. An open question is whether or not image generation, besides being associated with
activation of the same representations that are involved in visuospatial processing, also involves the
activation of circuits specifically devoted to mental image generating per se. In investigating
visuospatial impairments of patients with movement disorders, imagery tasks have the advantage
that they do not involve overt motor components liable to interfere with the recording of subjects
responses.
Image generation was investigated by Jacobs et al. (95). These authors demonstrated that PD
patients are impaired on a task of emotional facial imagery but not on an object imagery control task.
They are also impaired on tasks of perceiving and making emotional faces. Performance on both the
perceptual and motor tasks of facial expression correlated significantly with performance on the
emotional facial imagery task.
Image transformation was investigated in Brown and Marsdens study (96). They employed a
mental rotation task that required subjects to align mentally an arrow with one arm of a Maltese cross
and to decide whether a dot was on the left or the right of the arrow. PD patients, although slower than
controls, did not perform differentially worse in the conditions that required a greater amount of
reorientation (e.g., when the arrow was pointing down), thus demonstrating lack of a generalized
visuospatial deficit in PD. However, in a subsequent study, Lee et al. (97), using both two- and three-
dimensional visual rotation tasks, demonstrated that PD patients make more errors on mental rota-
tions involving larger rotations in depth (or three-dimensional rotations). Furthermore, when
three-dimensional rotation is involved, they showed a pattern of reaction time suggesting a specific
impairment with larger rotations, thus indicating that PD patients may indeed have some problems in
extrapersonal space image transformation.
Disorders of Topographical Orientation

An individuals successful navigation of the environment depends on his or her ability to establish
an integrated viewpoint from which objects are represented spatially in relation to her or himself and
to each other. To achieve this, visual inputs have to be processed and the results of visuospatial
processing associated with information already stored in long-term memory (2). Disorders at any of
these levels may affect route finding. Bowen et al. (98) demonstrated that a standardized route
walking test yields deficiencies in PD patients, especially those with left-sided or bilateral symp-
toms. However, natural environments usually provide a subject with a much richer supply of external
cues, which have been shown to facilitate performance (99). Indeed, there is one report in the litera-
ture that may account for the thesis that mild-to-moderate PD patients object-in-location memory
does not show spatial deficits when tested in a natural setting (100). Yet, Montgomery et al. (101)
compared the ability of mild and moderate PD patients and controls to remain oriented to the starting
position after being transported passively in a wheelchair. They examined subjects under the condi-
tion of either visual or vestibular processing. The moderate PD group demonstrated the poorest per-
formance in both sensory conditions. The visual condition discriminated between the mild PD group
and the controls, but both groups gave similar performances in the vestibular condition. Poor perfor-
mance in the visual condition correlated significantly with poor performance on judgment of line
orientation in the mild PD group. The authors concluded that spatial updating, or maintaining a sense
of orientation while being moved in the environment, is impaired in PD. More recently, Leplow et al.
(102) corroborated the view that PD patients show spatial memory deficits also in real-life settings.
They devised a search through locomotor task incorporating the basic features of two paradigms
(the radial maze and the water maze) widely used to assess spatial behavior in animal research
(103,104). The participants had to find and remember 5 out of 20 hidden locations within a com-
pletely controlled environment. The performances of PD patients were found to worsen if the starting
position was moved by 90 and the proximal cues were deleted simultaneously. The results were
interpreted as indicating patients inability to generate rules that can be used flexibly in changing
environments.
VISUOSPATIAL DISORDERS IN PARKINSON DISEASE

Visuospatial abnormalities have often been reported in PD patients. Early in 1964, Proctor et al.
(105) demonstrated that PD patients have difficulty in determining when a rod is vertical if they are
in a darkened room. Later, this abnormality was confirmed both in patients seated in a chair that is
tilted either to the right or to the left (13), and in patients who are upright (106). Subsequently, as we
have already documented, a number of authors reported that PD is associated with disproportionate
impairments in visuospatial abilities. However, for a long time, consensus on the specificity and
significance of experimental data was lacking. Part of the debate stemmed from methodological inad-
equacies of early studies that did not account for factors such as motor speed, dexterity, and presence or
absence of pharmacological treatment. On this basis, it was suggested (107) that impaired visuospatial
ability in PD patients may be owing to generic increase in reaction time or other aspects of
attentional disorders.
More refined neuropsychological studies both in de novo PD patients (88) and using tasks either
requiring no motor response or minimizing the dexterity, speed, and coordination, provided insight
into the existence of visuospatial disturbances free of such confounding motor factors. In addition,
statistical techniques were used to explore relationships between motor and visuospatial deficits and
helped to determine whether or not spatial deficits are of the same magnitude as, or in excess of, those
attributable to motor abnormalities.
Since degeneration of dopaminergic neurons constitutes the main biochemical abnormality found
in PD, dopamine depletion has been considered to account for most of the symptoms, including
behavioral abnormalities and cognitive deficits (89). If striatal dopamine deficiency plays a role in
PD patients cognitive deficit, specialized hemispheric functions contralateral to the motor symp-
toms should be altered in patients with hemiparkinsonism, providing a unique opportunity to study
the effect of asymmetrical subcortical degeneration on cognitive functions (108). Yet, the results of
these studies have been controversial. A number of studies were not able to demonstrate a specific
pattern of difference between patients with predominantly left and right symptoms (9,109111).
However, a number of more recent studies (43,44) did find a specific directional bias related to the
side of the predominant symptoms. On the other hand, Pillon et al. (112) demonstrated that cognitive
impairment is poorly correlated with symptoms responding well to levodopa treatment (e.g., akinesia
and rigidity) and is strongly related to axial symptoms (such as gait disorders and dysarthria), which
respond little if at all to levodopa treatment. This finding was interpreted as suggesting that cognitive
impairment in PD patients is, to a great extent, a result of dysfunction of non-dopaminergic neuronal
systems. A further suggestion that the visuospatial deficits of PD patients do not always depend on
the same mechanisms subserving motor impairments derives from the observation that patients treated
with bilateral deep brain stimulation of the subthalamic nucleus, despite obtaining clinical motor
benefits, show a significant decline in their ability to encode visuospatial material (113). According
to this study, the decline was more consistently observed in patients over the age of 69 yr and it led to
a mental state that the authors describe as similar to that observed in progressive supranuclear palsy
(PSP) patients.
In conclusion, it is still possible that striatal dopamine deficiency, even if it is not the major deter-
minant of visuospatial deficits, could play a role in determining attentional bias underlying the subtle
neglect phenomena that are encountered in predominant left-sided PD patients.

The most striking feature of PSP patients is the fixity of gaze that, resulting from supranuclear
ophthalmoplegia, gives the disease its name. However, far from being a purely oculomotor problem,
PSP patients ocular movement difficulties are accompanied by a severe deficit in orienting attention.
Rafal (114) has outlined very well the difficulties that PSP patients encounter in everyday life and
how these difficulties interact with other components of the disease (gait disorder, dysphagia, and
nuchal dystonia). When conversing with others, reaching for objects, eating, or dressing, PSP patients
typically tend not to look at what they are doing. This failure to orient spontaneously the lower visual
field contributes to gait disequilibrium (the source of falls) and to the ingestion of boluses that are too
large to swallow (the source of ab ingestis). Loss of spontaneous social orienting is also a striking
feature of PSP and it is kind of unique to this disease. Relatives tend to note this as an early sign and
often attribute it to a change of mood or to carelessness.
A further characteristic trait of visuomotor impairment in some PSP patients is, conversely, diffi-
culty in inhibiting orienting responses in situations in which orienting is disadvantageous. One need
only think of patients who, as they walk, tend to orient toward the door or a wall mirror or TV set they
have just passed, as if they were magnetically attracted to and fixed upon that object in the environ-
ment. This visual behavior, also called visual grasping by Ghika et al. (115), is associated with
repeated backward head movements while walking and is, consequently, a further cause of backward
falls (114).
As early as 1981, Kimura et al. (116) demonstrated that PSP patients are impaired in visual search
and scanning tasks. Subsequently, Fisk et al. (117) performed systematic observations in an attempt
to relate the performances of PSP patients on visual search and scanning tasks to the pattern of their
oculomotor deficits. In one of these tasks, subjects were required to scan lines composed of a variable
number of dots and dashes and to report either the number of dashes or the number of dots. Scanning
in each of the four directions was measured: left to right, right to left, top to bottom, and bottom to
top. PSP patients were less accurate than controls only when scanning along the vertical plane. This
confirmed that bradykinesia and psychomotor retardation could not account for impaired perfor-
mance and that some specific defect of visual search and scanning along the vertical plane had to be
assumed.
Impaired performance on a visual search task, as well as on the Bentons Judgement of Line
Orientation Test (8), was also demonstrated by Soliveri and coworkers, in comparison with both
normal controls (118) and PD patients (119). The same authors could not demonstrate any difference
on these tasks between PSP and CBD patients (119).
In a detailed study of 25 patients, Esmonde et al. (120) confirmed a severe visuo-perceptual deficit
in PSP. They found marked differences between patients and controls in two subtests of the Visual
Object and Space Perception Battery (121), (the Fragmented Letter and Cube analysis tests) which
were explicitly chosen to minimize the effect of oculomotor scanning on performance.
Subsequently, in a series of experiments, Rafal, Posner, and colleagues (45,122,123) demonstrated
that PSP patients are not only slow in scanning and searching when allowed to move their eyes, but
also in covertly shifting their visual attention, especially in the vertical plane. However, unlike PD
patients, who demonstrate defective voluntary control of covert attention, PSP patients are especially
impaired in reflexive orienting.
The authors came to this conclusion after comparing attentional movements from both endog-
enous and exogenous cues. In both cases the subjects task was to press a button upon detecting a
target. In these tasks, targets are preceded by cues that may orient the attention to the target location
(valid cue) or to another location (invalid cue), or may have only an alerting value and provide no
spatial information (neutral cue). For testing voluntary control of attention, the (endogenous) cue is
typically an arrow in the center of the display, instructing the subject where to expect the forthcoming
target. Reflexive orienting is tested by an exogenous cue, e.g., lighting up of the box where the target
might appear. In this case, unlike the case of the central cue paradigm, the cue has no predictive value
and the target is equally likely to appear in an uncued as in the cued location. Results demonstrated
that PSP patients show no validity effect on reflexive orienting of attention along the vertical plane:
i.e., they are no faster in responding to a target when it is preceded by a valid exogenous cue. A
similar trend for smaller orienting effects in the vertical plane is also seen in endogenous orienting
but it is not as dramatic as in reflexive orienting. In other words PSP patients have problems in
shifting attention, especially in the vertical plane and especially in response to exogenous signals.
Kertzman et al. (124) also provided evidence consistent with the conclusion that PSP has little or
no effect on endogenous orienting of attention. In their experiment the cue was lighting up of a
peripheral box that predicted the location of the forthcoming target. Vertical and horizontal attention
movements were tested in separate blocks, thus giving the subjects maximum opportunity to use the
cue to shift attention. Under these conditions the PSP patients did not show a smaller effect of cue
validity in the vertical plane. This demonstrated that PSP patients attentional deficit can be con-
trasted with that of inferior parietal lobe patients. These latter patients are typically impaired in the
presence of endogenous cues, in the horizontal plane, and in the invalid cue condition, i.e., when they
have to disengage attention that was cued by a central signal to the side opposite the target.
Rafal et al. (114) demonstrated quite convincingly that PSP attentional deficit is likely to be a
result of the degenerative damage to the superior colliculus and the adjacent tectal nuclei. This part of
the midbrain constitutes the phylogenetically older retinotectal pathway, which retains important
functions for regulating visual attention and visually guided behavior. The frontal eye fields are also
important in controlling saccadic eye movements (125), show dramatic hypometabolism in PSP
patients (126), and might also be responsible for visual attention deficits. Nonetheless, patients
with lesions restricted to the dorsolateral prefrontal cortex (including the frontal eye fields) perform
normally in covert orienting of attention (127), even if they show increased latencies for endogenous
saccades to targets contralateral to the lesion (128). Furthermore, converging evidence from normal
subjects (129) and from hemianopic patients (130) demonstrates that the midbrain retinotectal path-
way is important in reflexive orienting to exogenous signals and corroborate the view that it is deci-
sive in determining the visuomotor and attentional deficit typically found in PSP patients.
Corticobasal degeneration (CBD) is clinically characterized by the combination of motor with
cognitive disorders. Neuropathologically, it features circumscribed parietal or frontoparietal atrophy,
associated with basophilic and tau-postive inclusions in the neurons of the substantia nigra and basal
ganglia.
Reflecting this definite pattern of neuronal damage, neuropsychological deficits of CBD patients
most commonly include deficits of executive functions and of retrieval processes (in relation to the
damage of the prefrontal cortex and the striatum) and apraxia (owing to the involvement of the pari-
etal cortex). Leiguarda et al. (131) described the nature of apraxia in CBD. To minimize the con-
founding effects of the primary motor disorder, they examined the least affected limb. They found
that ideomotor apraxia is the most frequent type of apraxia in CBD patients and they hypothesized
that it was because of the dysfunction of the supplementary motor area (SMA). They also examined
a subgroup of CBD patients with severe (ideomotor and ideational) apraxia, correlating this with
global cognitive impairment, and attributed it to additional parietal or diffuse cortical damage. Sev-
eral authors have hypothesized that SMA dysfunction underlies limb apraxia in CBD (132,133), but
a similar role has also been attributed to the lateral premotor cortex (133,134) and to the parietal
regions (135,136).
Indeed, the left supplementary motor cortex has been repeatedly implicated in the genesis of
apraxia (137140). However, the role of the left posterior parietal lobe in determining ideomotor
(141,142) and ideational (143) apraxia is well documented. Furthermore, the assumption that ide-
ational apraxia is an extreme form of ideomotor apraxia (a result of brain damage superimposed on
that causing the latter form of apraxia) is disproved by the lack of correlation between the two
deficits (144).
A couple of studies have tried to determine the origin of apraxia in CBD patients. Blondel et al.
(132) tried to characterize the different processes underlying apraxic disorders in these patients ac-
cording to a theoretical framework postulating a two-step system controlling limb gestures: the con-
ceptual system and the production system. The results, extremely similar in the three patients they
studied, showed a sparing of the conceptual system and an impairment of the production system with
a dramatic deficit in the control of the temporal and spatial aspects of the gestures. The authors inter-
preted these results as suggesting a dysfunction of the SMA. Similarly, Jacobs et al. (133) reported the
results of testing three nondemented CBD subjects on tasks requiring the production of meaningful
or meaningless gestures to command, gesture imitation, gesture discrimination, and novel gesture
learning. The results suggested that apraxia associated with CBD is initially induced by a production-
execution defect with relative sparing of the movement representations. However, combining neu-
ropsychological and neuroimaging investigations, Peigneux et al. (145) found that, in CBD patients,
the anterior cingulate cortex is involved when visuospatial attention and conflict monitoring is neces-
sary or when task difficulty, motor output, and recent memory requirements must be combined. How-
ever, when apraxia is defined according to a more stringent test of the integrity of the components of
the praxic system (measuring the patients ability to correct their errors on a second attempt), hypome-
tabolism is found in the superior parietal lobule and in the SMA. This demonstrates the importance of
parietofrontal circuits in the transformation of sensory input into action. Damage to these systems is
likely to produce different types of limb apraxia depending on the injured site, the context in which
the movement is performed, and the cognitive demands of the action (146,147).
The superior parietal lobule appears to be crucial in visually guided movements (148), mental
transformation of the body in space (149), and elaboration and maintenance of working representa-
tion of gestures to perform (150,151). It is also involved in successful integration of internal and
external representations to direct action (152). In turn, the SMA is most likely to be involved in
transcoding stored space-time representations of movement into limb innervatory patterns (153).
Wenning et al. (154) have reported that constructive apraxia, possibly demonstrable as a failure to
copy drawings, is reported at the first visit in 64% of pathologically confirmed CBD patients. Since
constructive apraxia is unlikely to be an early sign in a patient with an asymmetric parkinsonism,
drawing copying might be a useful test to corroborate the CBD diagnosis.
Interestingly, in the same study, two patients with onset of motor symptoms on the left side devel-
oped left-sided visuospatial neglect, whereas patients with onset of right motor symptoms developed
aphasia. A further pathologically confirmed CBD demonstrating left neglect was reported by Rey et al.
(155). More recently, Kleiner-Fisman et al. (156) reported a single case study of a professional artist in
whom presumed CBD was associated with left hemispatial neglect. It led to a complex alteration of
his artistic judgment and production. From a clinical standpoint it should be concluded that in the
absence of focal lesions (e.g., of vascular or neoplastic origin), the presence of both ideomotor apraxia
and left neglect should give rise to suspicion of CBD.
Following bilateral involvement of the parieto-occipital junction, CBD patients can also show a
complete BalintHolmes syndrome (157), consisting of gaze apraxia (defective visual scanning),
optical ataxia (defective visual reaching), impaired visual attention, defective estimation of distance,
and impaired depth perception. Mendez (158) recently described a patient whose illness began with a
slow, rigid gait, abnormal postures of his right hand, and retrocollis. As the disease progressed, he
developed prominent visuospatial deficits that, after 8 yr, included a BalintHolmes syndrome. We
have personally observed (159) a patient with an opposite disease progression: i.e., beginning with
the visuospatial symptoms of the BalintHolmes syndrome and showing signs and symptoms of
basal ganglia involvement only 4 yr after disease onset. Examples of BalintHolmes syndrome can
also be found in early stages of Alzheimers dementia (160,161). There has been some suggestion
that cognitive impairment is a common feature of CBD (162,163). According to Grimes, Lang, and
Bergeron (163) CBD patients fulfilling classical diagnostic criteria might represent a minority of
those with a pathologically confirmed diagnosis. They argue that case series emphasizing motor
deficits, originating prevalently from movement disorder clinics, might slight the importance of cog-
nitive impairment in CBD. Such a bias would indeed make the differential diagnosis of a patient
presenting with BalintHolmes syndrome particularly challenging, including besides CBD,
CreutzfeldJakob disease, multifocal progressive leucoencephalopathy, strokes (164), and a progres-
sive posterior atrophy occurring in isolation (165168).
DIFFUSE LEWY BODY DISEASE

Dementia with Lewy bodies (DLB) is the second most common type of cognitive degeneration
after Alzheimers disease (AD) (169). Clinically, DLB is characterized by spontaneous parkinsonism
and progressive dementia associated with fluctuating cognitive functions, and hallucination (169).
Parkinsonism and dementia tend to co-occur. A history of Parkinsonism predating dementia by more
than 1 yr might be better designated Parkinsons disease with dementia. Since publication of the
clinical and pathological diagnosis criteria (169), several studies have tried to delineate the neuropsy-
chological features that distinguish DLB disease from AD. A number of them have demonstrated
that, compared with AD, visuospatial and visuoconstructive abilities are disproportionately impaired
in patients with DLB disease (170173). Compared with AD patients matched for age, sex, educa-
tion, and Mini Mental State Examination (MMSE) score, DLB patients perform worse on the Raven
Colored Progressive Matrices test and on the picture arrangement, block design, object assembly,
and digit symbol substitution subtests of the Wechsler Adult Intelligence ScaleRevised (173). They
also perform worse on size discrimination, form discrimination, visual counting, and overlapping
figure identification (174).
Mori et al. (174) also demonstrated that, in the DLB group, patients with visual hallucinations
scored significantly lower on overlapping figure identification than those without, whereas patients
with television misidentifications gave significantly lower scores on the size discrimination, form
discrimination, and visual counting tasks than those without. The underlying assumption is that spe-
cific brain regions are involved in the performance of these tests: the occipital visual association
cortex for size discrimination, the occipito-temporal visual association cortex for size discrimination,
and the occipito-parietal cortex for visual counting.
Similar results were obtained by Simard, Rikum, and Myran (175). These authors compared the
performance on the Benton Judgement Line Orientation Test of patients with DLB and predominant
parkinsonism, with DLB and predominant psychosis, and with AD. For this purpose they analyzed
errors as resulting from visual attention and visuospatial perception failures. The study did not find
significant differences on the total score of the Benton Judgement Line Orientation Test. However,
error analysis demonstrated that subjects with DLB and psychosis have more severe visual-percep-
tion (VH errors) impairments than subjects with DLB and predominant parkinsonian features, and
AD subjects.
These results suggest that defective visual input caused by visual-system damage can result in
hallucinations from defective visual processing or abnormal cortical release phenomena (176). Indeed,
Imamura et al. (177) using positron emission tomography, found that visual hallucinations in DLB
patients are associated with relatively preserved metabolism in the right temporoparietal association
cortex and severe hypometabolism in the primary and secondary visual cortex.
A practical implication of the disproportionate impairment of DLB patients in visuospatial tasks
has been demonstrated by Ala et al. (178). These authors analyzed accuracy in copying the interlock-
ing pentagon item of the MMSE in patients with neuropathologically confirmed DLB and AD. They
concluded that in patients with MMSE scores 13 an inability to accurately copy the pentagons
suggests that the diagnosis is more likely DLB than AD with a sensitivity of 88% and a specificity
of 59%.

Multiple system atrophy (MSA) is a term used to describe a progressive neurological condition
incorporating a parkinsonian syndrome (striatonigral degeneration), often accompanied by autonomic
failure (ShyDrager syndrome) or cerebellar and/or pyramidal signs (olivopontocerebellar atrophy
OPCA) (179,180).
Cognitive deterioration is not generally considered to be an integral feature of MSA (181). Indeed,
lack of dementia throughout the course of the disease has been proposed as a feature that might help
to differentiate between MSA and PD premortem (182).
However, routine neuropsychological assessment often reveals multiple cognitive deficits sug-
gesting a prominent involvement of the frontal lobe (183). MSA patients perform normally on tasks
of spatial and pattern recognition, which are sensitive to deficits in patients with AD and medicated
PD (183,184). On the contrary, Robbins et al. (183) demonstrated that MSA patients are impaired in
comparison with matched controls on test of visual memory and learning but in specific and unusual
ways. Thus on a matching-to-sample test they were significantly impaired at the simultaneous stage,
when no memory was involved, but showed normal delayed matching performance. This particular
pattern of deficit is distinct from that reported in PD patients (184). Moreover, on the test of visual
learning, unlike PD patients (184), the MSA subjects performed surprisingly well at the more diffi-
cult levels of the task but were inefficient at the early stages.
Taken together, this pattern of performance is suggestive of problems in attention and orientation
rather than of primary visual learning or memory deficits. Visuospatial contrast thresholds are also
unimpaired in MSA, unlike PD patients, who normally exhibit a reduction in contrast sensitivity (185).
This finding suggests that reduced contrast sensitivity is related to a dopaminergic pathology, possibly
at the level of retinal amacrine cells, which might be affected in PD (186188) but not in MSA (185).
CONCLUSION
Abnormalities of visuospatial functions are common in PD and in atypical parkinsonian disorders.
They have been described in several domains of visuospatial ability. In some tasks the alteration can
reflect the motor disorders. However, in many instances it is possible to demonstrate that the contri-
bution of motor skills to a task is either minimal or absent. Different disorders have different patterns
of impairment. For instance, in CBD, apraxia and optic ataxia are most common, whereas PSP patients
show a characteristic impairment in shifting their visual attention downward.
To date, no systematic study of atypical parkinsonian syndromes has been performed using a
predefined battery of visuospatial tasks aimed at helping the clinician in the differential diagnosis at
disease onset. We would propose that such a battery (see Table 1) should at least contain a perceptual
task such as the Bentons Judgement of Line Orientation Test (8), a task of visuospatial working
memory and a task of visuospatial learning. To examine visuospatial working memory we would
propose a visuospatial span task as proposed by Le Bras et al. (81). A computerized maze task (90)
could be used to test visuospatial learning. The Tower of London task (189,190) or one of the several
versions of the Tower of Hanoi Test (191) could be useful to test visuospatial working memory and
some aspects of planning. If administered repeatedly, it can also allow exploration of implicit rule
learning, which is typically impaired in PD and in Huntingtons disease patients (192). Three-dimen-
sional visual rotation tasks (97) appear to be most sensitive to test visuospatial transformation in the
imagery domain.
In the clinical setting, we have found it extremely useful to test visuomotor coordination by asking
patients to reach for an object that requires precision gripping. Patients with damage to the posterior
parietal lobe (as in CBD) show early impairment on this task. A standardization of the procedures for
testing visuomotor coordination is likely to improve the sensitivity of this procedure.
To test visuospatial attention in this group of patients we prefer to use visuospatial search tasks.
For this purpose, it is important to present the stimuli on a screen in front of the subject and to prepare
visual displays that can allow exploration of attentional movements in both the horizontal and the
vertical direction. Finally, testing visuospatial functions may be extremely useful in the differential
diagnosis of disorders associating parkinsonian features and early cognitive damage. For this pur-
pose, a copying drawing task should be included in the test battery. In this case the motor components
cannot be eliminated. However, in most cases it is not difficult to separate them from errors owing to
faulty organization of the spatial arrangement of the design to be copied.
Table 1
Visuospatial Test for the Assessment of Parkinsonian Disorders
Test Reason to Include It in the Visuospatial Assessment
Judgement of Line Orientation (6) Can help differentiate demented from nondemented PD patients.
Copying Drawing Task (154,178) Early impaired in CBD and DLB patients.
Optic Ataxia Assessment (*) CBD patients are particularly impaired at this task
Tower of London (76) A sensitive task to detect visuospatial working memory deficit in early
stages of PD.
Tower of Hanoi (191,192) Comparison of repeated performance at this task allows exploration of
implicit rule learning, which is typically impaired after basal ganglia
damage.
Wilson-Le Bras test (81) It can measure of the visuospatial span without the motor component
involved by the Corsi Block Tapping Test.
Posner test (45,122,123) At this task, PD patients demonstrate defective voluntary control of
covert attention. PSP patients, on the contrary, are especially impaired
in reflexive orienting.
3D mental rotation (97) PD patients are impaired in 3D mental rotation. Little is known about
the performance of atypical parkinsonism patients at this task.
*There is no standardized bedside procedure to administer this task.
SPECIFIC ISSUES THAT CAN BE ADDRESSED BY FUTURE RESEARCH

OF VISUOSPATIAL COGNITION IN PARKINSON DISEASE AND
IN ATYPICAL PARKINSONIAN DISORDERS
1. What is the role of the colliculus and of the dorsal frontallobe damage in the visuospatial impairment of
PSP patients?
2. To develop a suitable method for assessing attentional movements both in the horizontal and in the verti-
cal direction in a clinical setting.
3. Does unilateral neglect in CBD patients have a different qualitative pattern than in PD patients?
4. Which is the physiological basis of neglect in unilateral PD patients compared with parietal lobe damaged
patients?
5. Which is the role of the dopaminergic system in controlling visuospatial exploration in PD patients? Can
dopaminergic drugs improve directional attention deficits in PD patients?
6. Is there any difference in depth perception and in reaching performance between PD and atypical parkin-
sonian syndromes?
7. Can a careful assessment of visuospatial skill help diagnostic accuracy in the early stage of parkinsonian
diseases?
8. Is there any role of impairment in size discrimination in determining freezing episodes in PD patients?
REFERENCES
1. O Keefe J, Nadel L. The Hippocampus as a Cognitive Map. New York: Clarendon, 1978.
2. Grsser OJ. Multimodal structure of the extrapersonal space. In: Hein A, Jeannerod M, eds. Spatially Oriented Behav-
ior. New York: Springer-Verlag, 1987:327352.
3. Rizzolatti G, Gentilucci M, Matelli M. Selective spatial attention: One centre, one circuit, or many centres? In: Posner
MI, Marin OSM, eds. Attention and Performance IX. Hillsdale, NJ: Erlbaum, 1985:251265.
4. Goodale MA, Milner AD. Separate visual pathways for perception and action. Trends Neurosci 1992;15:2025.
5. Ungerleider LG, Haxby JV. What and where in the human brain. Curr Opin Neurobiol 1994;4:157165.
6. Warrington EK, Rabin P. Perceptual matching in patients with cerebral lesions. Neuropsychologia 1970;8:475487.
7. Hannay HJ, Varney NR, Benton AL. Visual localization in patients with unilateral disease. J Neurol Neurosurg Psy-
chiatry 1976;39:307313.
8. Benton AL, Varney NR, Hamsher KD. Visuospatial judgment: a clinical test. Arch Neurol 1978;35:364367.
9. Boller F, Passafiume D, Keefe NC, Rogers K, Morrow L, Kim Y. Visuospatial impairment in Parkinsons disease: Role
of perceptual and motor factors. Arch Neurol 1984;41:485490.
10. Goldenberg G, Wimmer A, Auff E, Schnaberth G. Impairment of motor planning in patients with Parkinsons disease:
evidence from ideomotor apraxia testing. J Neurol Neurosurg Psychiatry 1986;49:12661272.
11. Richards M, Cote LJ, Stern Y. The relationship between visuospatial ability and perceptual motor function in
Parkinsons disease. J Neurol Neurosurg Psychiatry 1993;56:400406.
12. Levin BE, Llabre MM, Weiner WJ. Cognitive impairment associated with early Parkinsons disease. Neurology
1989;39:557561.
13. Levin BE. Spatial cognition in Parkinson disease. Alzheimer Dis Assoc Disord 1990;4:161170.
14. Montse A, Pere V, Carme J, Francesc V, Eduardo T. Visuospatial deficits in Parkinsons disease assessed by judgment
of line orientation test: error analyses and practice effects. J Clin Exp Neuropsychol 2001;23.:592598.
15. Girotti FS, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinsons disease. Neurology
1988;51:14981502.
16. Livingston M, Hubel D. Segregation of form, color, movement, and depth: Anatomy, physiology, and perception.
Science 1988;240:740749.
17. Parker AJ, Cumming BG, Johnston EB, Hurlbert AC. Multiple cues for three-dimensional shape. In: Gazzaniga MS,
ed. The Cognitive Neurosciences. Cambridge, MA: MIT Press, 1985:351364.
18. Gulyas B, Roland PE. Binocular disparity discrimination in human cerebral cortex: functional anatomy by positron
emission tomography. Proc Natl Acad Sci USA 1994;91:12391243.
19. Ptito A, Zatorre RJ, Petrides M, Frey S, Alivisatos B, Evans AC. Localization and lateralization of stereoscopic pro-
cessing in the human brain. Neuroreport 1993;4:11551158.
20. Fortin A, Ptito A, Faubert J, Ptito M. Cortical areas mediating stereopsis in the human brain: a PET study. Neuroreport
2002;3:895898.
21. Perenin MT, Vighetto A. Optic ataxia: a specific disruption in visuomotor mechanisms. I. Different aspects of the
deficit in reaching for objects. Brain 1988;111(Pt 3):643647.
22. Bonfiglioli C, De Berti G, Nichelli P, Nicoletti R, Castiello U. Kinematic analysis of the reach to grasp movement in
Parkinsons and Huntingtons disease subjects. Neuropsychologia 1998;36:12031208.
23. Castiello U, Bennett K, Bonfiglioli C, Lim S, Peppard RF. The reach-to-grasp movement in Parkinsons disease: response
to a simultaneous perturbation of object position and object size. Exp Brain Res 1999;125:453462.
24. Fellows SJ, Noth J, Schwarz M. Precision grip and Parkinsons disease. Brain 1998;121:17711784.
25. Rearick MP, Stelmach GE, Leis B, Santello M. Coordination and control of forces during multifingered grasping in
Parkinsons disease. Exp Neurol 2002;177:428442.
26. Heilman KM. Neglect and related disorders. In: Heilman KM, ed. Clinical Neuropsychology. New York: Oxford Uni-
versity Press, 1979:268307.
27. Albert ML. A simple test of visual neglect. Neurology 1973;23:322326.
28. Gauthier L, Dehaut F, Joannette Y. The Bells Test: A quantitative and qualitative test for visual neglect. Int J Clin
Neuropsychool 1989;11:4954.
29. Mesulam M-M. Principles of Behavioral Neurology. Philadelphia: Davis, 1985.
30. Bradshaw JL, Nettleton NC, Nathan G, Wilson L. Bisecting rods and lines: effects of horizontal and vertical posture on
left-side underestimation by normal subjects. Neuropsychologia 1985;23:421425.
31. Scarisbrick DJ, Tweedy JR, Kuslansky G. Hand preference and performance effects on line bisection. Neuropsychologia
1987;25:695699.
32. Milner AD, Brechmann M, Pagliarini L. To halve and to halve not: an analysis of line bisection judgements in normal
subjects. Neuropsychologia 1992;30:515526.
33. Ishiai S, Sugishita M, Watabiki S, Nakayama T, Kotera M, Gono S. Improvement of left unilateral spatial neglect in a
line extension task. Neurology 1994;44:294298.
34. Carli M, Evenden JL, Robbins TW. Depletion of unilateral striatal dopamine impairs initiation of contralateral actions
and not sensory attention. Nature 1985;313:679682.
35. Marshall JF, Gotthelf T. Sensory inattention in rats with 6-hydroxydopamine-induced degeneration of ascending dopam-
inergic neurons: apomorphine-induced reversal of deficits. Exp Neurol l1979;65:398411.
36. Ljungberg T, Ungerstedt U. Sensory inattention produced by 6-hydroxydopamine-induced degeneration of ascending
dopamine neurons in the brain. Exp Neurol 1976;53:585600.
37. Fleet WS, Valenstein E, Watson RT, Heilman KM. Dopamine agonist therapy for neglect in humans. Neurology
1987;37:17651770.
38. Geminiani G, Bottini G, Sterzi R. Dopaminergic stimulation in unilateral neglect. J Neurol Neurosurg Psychiatry
1998;65:344347.
39. Villardita C, Smirni P, Zappal G. Visual neglect in Parkinson disease. Arch Neurol 1983;40:737739.
40. Gauthier L, Gautheir SG, Joannette Y. Visual neglect in left-, right-, and bilateral parkinsonians. J Clin Exp
Neuropsychol 1985;7:145 (abstract).
41. Starkstein S, R Leiguarda R, Gershanik O, Berthier M. Neuropsychological disturbances in hemiparkinsons disease.

Neurology 1987;37:17621764.
42. Ransmayr G, Schmidhuber-Eiler B, Karamath E. Visuoperception and visuospatial and visuorotational performance in
Parkinsons disease. J Neurol 1987;235:99101.
43. Lee AC, Harris JP, Atkinson E, Fowler MS. Evidence from a line bisection task for visuospatial neglect in left
hemiparkinsons disease. Vision Res 2001;41:26772686.
44. Ebersbach G, Trottenberg T, Hattig H, Schelosky L, Schrag A, Poewe W. Directional bias of initial visual exploration.
A symptom of neglect in Parkinsons disease. Brain 1996;119(Pt 1):7987.
45. Posner MI, Cohen Y, Rafal RD. Neural systems control of spatial orienting. Philos Trans R Soc Lond B Biol Sci
1982;298:187198.
46. Briand KA, Strallow D, Hening W, Poizner H, Sereno AB. Control of voluntary and reflexive saccades in Parkinsons
disease. Exp Brain Res 1999;129:3848.
47. Crawford T, Henderson L, Kennard C. Abnormalities of nonvisually guided eye movements in Parkinsons disease.
Brain 1989;112:15371586.
48. Crevits L, De Ridder K. Disturbed striatoprefrontal mediated visual behavior in moderate to severe Parkinsonian patients.
49. OSullivan EP, Shaunak LH, Hawken M, Crawford TJ, Kennard C. Abnormalities of predictive saccades in Parkinsons
disase. Neuroreport 1997;8:12091213.
50. Carl JB, Wurts RH. Asymmetry of saccadic control in patients with hemi-Parkinsons disease. Investigative Ophthal-
mology and Visual Science 1985;26:258.
51. Kitagawa M, Fukushima J, Tashiro K. Relationship between antisaccades and the clinical symptoms in Parkinsons
disease. Neurology 1994;44:22852289.
52. Wright MJ, Burns RJ, Geffen GM, Geffen LB. Covert orientation of visual attention in Parkinsons disease: an impair-
ment in the maintenance of attention. Neuropsychologia 1990;28:151159.
53. Yamada T, Izyuuinn M, Schulzer M, Hirayama K. Covert orienting attention in Parkinsons disease. J Neurol Neurosurg
Psychiatry 1990;53:593596.
54. Bennett KM, Waterman C, Scarpa M, Castiello U. Covert visuospatial attentional mechanisms in Parkinsons disease.
Brain 1995;118:153166.
55. Rafal RD, Posner MI, J.A. W, Friedrich FJ. Cognition and the basal ganglia. Separating mental and motor components
of performance in Parkinsons disease. Brain 1984;107:10831094.
56. Sharpe MH. Patients with early Parkinsons disease are not impaired on spatial orientating of attention. Cortex
1990;26:515524.
57. Filoteo JV, Delis DC, Salmon DP, Demadura T, Roman MJ, Shults CW. An examination of the nature of attentional
deficits in patients with Parkinsons disease: evidence from a spatial orienting task. J Int Neuropsychol Soc 1997;3
:337347.
58. Yamaguchi S, Kobayashi S. Contribution of the dopaminergic system to voluntary and automatic orienting of
visuospatial attention. J Neurosci 1998;18:18691878.
59. Briand KA, Hening W, Poizner H, Sereno AB. Automatic orienting in Parkinsons disease. Neuropsychologia
2001;39:12401249.
60. Desimone R, Schein SJ. Visual properties of neurons in area V4 of the macaque: sensitivity to stimulus form. J
Neurophysiol 1987;57:835868.
61. Shiller PH, Lee K. The role of the primate extrastriate area V4 in vision. Science 1991;251:12511253.
62. Frassinetti F, Nichelli P, di Pellegrino G. Selective horizontal dysmetropsia following prestriate lesion. Brain
1999;122(Pt 2):339350.
63. Milner AD, Harvey M. Distortion of size perception in visual spatial neglect. Curr Biol 1995;5:8589.
64. Harris JP, Atkinson EA, Lee AC, Nithi K, Fowler MS. Hemispace differences in the visual perception of size in left
hemiParkinsons disease. Neuropsychologia 2003;41:795807.
65. Lee AC, Harris JP, Atkinson EA, Fowler MS. Disruption of estimation of body-scaled aperture width in
Hemiparkinsons disease. Neuropsychologia 2001;39:10971104.
66. Baddeley A. Working Memory. London: Oxford University Press, 1986.
67. Smith EE, J. J. Neuroimaging analyses of human working memory. Proc Natl Acad Sci USA 1998;95:1206112068.
68. Courtney SM, Petit L, Maisog JM, Ungerleider LG, Haxby JV. An area specialized for spatial working memory in
human frontal cortex. Science 1998;279:13471351.
69. Milner B. Interhemispheric differences in the localization of psychological processes in man. Br Med Bull 1971;27:
272277.
70. Orsini A, Fragassi NA, Chiacchio L, Falanga AM, Cocchiaro C, Grossi D. Verbal and spatial memory span in patients
with extrapyramidal diseases. Percept Mot Skills 1987;65:555558.
71. Bradley VA, Welch JL, Dick DJ. Visuospatial working memory in Parkinsons disease. J Neurol Neurosurg Psychiatry
1989;52:12281235.
72. Postle BR, Jonides J, Smith EE, Corkin S, Growdon JH. Spatial, but not object, delayed response is impaired in early
Parkinsons disease. Neuropsychology 1997;11:171179.
73. Owen AM, Iddon JL, Hodges JR, Summers BA, Robbins TW. Spatial and non-spatial working memory at different
stages of Parkinsons disease. Neuropsychologia 1997;35:519532.
74. Owen AM, James M, Leigh PN, et al. Fronto-striatal cognitive deficits at different stages of Parkinsons disease. Brain
1992;115(Pt 6):17271751.
75. Owen AM, Beksinska M, James M, et al. Visuospatial memory deficits at different stages of Parkinsons disease.
Neuropsychologia 1993;31:627644.
76. Lewis SJ, Cools R, Robbins TW, Dove A, Barker RA, Owen AM. Using executive heterogeneity to explore the nature
of working memory deficits in Parkinsons disease. Neuropsychologia 2003;41:645654.
77. Brown RG, Marsden CD. Dual task performance and processing resources in normal subjects and patients with
Parkinsons disease. Brain 1991;114(Pt 1A):215-231.
78. Dalrymple-Alford JC, Kalders AS, Jones RD, Watson RW. A central executive deficit in patients with Parkinsons
disease. J Neurol Neurosurg Psychiatry 1994;57:336367.
79. Fournet N, Moreaud O, Rouliin JL, Naegele B, Pellat J. Working memory functioning in medicated Parkinsons disease
patients and the effect of withdrawal of dopaminergic medication. Neuropsychology 2000;14:247253.
80. Tamura I, Kikuchi S, Otsuki M, Kitagawa M, Tashiro K. Deficits of working memory during mental calculation in
patients with Parkinsons disease. J Neurol Sci 2003;209:1923.
81. Le Bras C, Pillon B, Damier P, Dubois B. At which steps of spatial working memory processing do striatofrontal
circuits intervene in humans? Neuropsychologia 1999;37:8390.
82. Simon SR, Meunier M, Piettre L, Berardi AM, Segebarth CM, Boussaoud D. Spatial attention and memory versus
motor preparation: premotor cortex involvement as revealed by fMRI. J Neurophysiol 2002;88:20472057.
83. Petrides M, Alivisatos B, Evans AC, Meyer E. Dissociation of human mid-dorsolateral from posterior dorsolateral
frontal cortex in memory processing. Proc Natl Acad Sci USA 1993;90:873877.
84. McCarthy G, Blamire AM, Puce A, et al. Functional magnetic resonance imaging of human prefrontal cortex activation
during a spatial working memory task. Proc Natl Acad Sci USA 1994;91:86908694.
85. Belger A, Puce A, Krystal JH, Gore JC, Goldman-Rakic P, McCarthy G. Dissociation of mnemonic and perceptual
processes during spatial and nonspatial working memory using fMRI. Hum Brain Mapp 1998;6:1432.
86. Smith ML, Milner B. The role of the right hippocampus in the recall of spatial location. Neuropsychologia 1981;19:
781793.
87. Pillon B, Ertle S, Deweer B, Sarazin M, Agid Y, Dubois B. Memory for spatial location is affected in Parkinsons
disease. Neuropsychologia 1996;34:7785.
88. Pillon B, Ertle S, Deweer B, Bonnet AM, Vidailhet M, Dubois B. Memory for spatial location in de novo parkinso-
nian patients. Neuropsychologia 1997;35:221228.
89. Pillon B, Deweer B, Vidailhet M, Bonnet AM, Hahn-Barma V, Dubois B. Is impaired memory for spatial location in
Parkinsons disease domain specific or dependent on strategic processes? Neuropsychologia 1998;36:19.
90. Wallesch CW, Karnath HO, Papagno C, Zimmermann P, Deuschl G, Lucking CH. Parkinsons disease patients
behaviour in a covered maze learning task. Neuropsychologia 1990;28:839849.
91. Kosslyn SM. Image and the Brain: The Resolution of the Imagery Debate. CAmbridge, MA: MIT Press, 1996.
92. Le Bihan D, Turner R, Zeffiro TA, Cuenod CA, Jezzard P, Bonnerot V. Activation of human primary visual cortex
during visual recall: a magnetic resonance imaging study. Proc Natl Acad Sci U S A 1993;90:1180211805.
93. Kosslyn SM, Thompson WL, Kim IJ, Alpert NM. Topographical representations of mental images in primary visual
cortex. Nature 1995;378:496498.
94. Cohen MS, Kosslyn SM, Breiter HC, et al. Changes in cortical activity during mental rotation. A mapping study using
functional MRI. Brain 1996;119(Pt 1):89100.
95. Jacobs DH, Shuren J, Bowers D, Heilman KM. Emotional facial imagery, perception, and expression in Parkinsons
disease. Neurology 1995;45:16961702.
96. Brown RG, Marsden CD. Visuospatial function in Parkinsons disease. Brain 1986;109(Pt 5):9871002.
97. Lee AC, Harris JP, Calvert JE. Impairments of mental rotation in Parkinsons disease. Neuropsychologia 1998;36:109
114.
98. Bowen B, Hoehn MM, Yahr MD. Parkinsonism: alteration in spatial orientation as determined by route walking task.
Neuropsychologia 1972;10:355361.
99. Buytenhuijs EL, Berger HJ, Van Spaendonck KP, Horstink MW, Borm GF, Cools AR. Memory and learning strategies
in patients with Parkinsons disease. Neuropsychologia 1994;32:335342.
100. Stepankova K, Ruzicka E. Object location learning and non-spatial working memory of patients with Parkinsons
disease may be preserved in real life situations. Physiol Res 1998;47:377384.
101. Montgomery P, Silverstein P, Wichmann R, Fleischaker K, Andberg M. Spatial updating in Parkinsons disease. Brain
Cogn 1993;23:113126.
102. Leplow B, Holl D, Zeng L, Herzog A, Behrens K, Mehdorn M. Spatial behaviour is driven by proximal cues even in
mildly impaired Parkinsons disease. Neuropsychologia 2002;40:14431455.
103. Olton DS, Samuelson RJ. Remmebrance of place passe: spatial memory in rats. J Exp Psychol Anim Behav Proc
1976;2:97116.
104. Morris RGM. Spatial localization does not require the presence of local cues. Learning and Motivation 1981;12:239260.
105. Proctor F, Riklan M, Cooper IS, Teuber H-L. Judgement of visual and postural vertical by parkinsnonian patients.
Neurology 1964;14:287293.
106. Danta G, Hilton R. Judgment of the visual vertical and horizontal in patients with Parkinsonism. Neurology 1975;25:
4347.
107. Della Sala S, Di Lorenzo G, Giordano A, Spinnler H. Is there a specific visuo-spatial impairment in Parkinsonians? J
108. Direnfeld LK, Albert ML, Volicer L, Langlais PJ, Marquis J, Kaplan E. Parkinsons disease. The possible relationship
of laterality to dementia and neurochemical findings. Arch Neurol 1984;41:935941.
109. Bentin S, Silverberg R, Gordon HW. Asymmetrical cognitive deterioration in demented and Parkinson patients. Cortex
1981;17:533543.
110. Huber SJ, Freidenberg DL, Shuttleworth EC, Paulson GW, Clapp LE. Neuropsychological similarities in lateralized
parkinsonism. Cortex 1989;25:461470.
111. Riklan M, Stellar S, Reynolds C. The relationship of memory and cognition in Parkinsons disease to lateralisation of
motor symptoms. J Neurol Neurosurg Psychiatry 1990;53:359360.
112. Pillon B, Dubois B, Cusimano G, Bonnet AM, Lhermitte F, Agid Y. Does cognitive impairment in Parkinsons disease
result from non-dopaminergic lesions? J Neurol Neurosurg Psychiatry 1989;52:201206.
113. Saint-Cyr JA, Trepanier LL, Kumar R, Lozano AM, Lang AE. Neuropsychological consequences of chronic bilateral
stimulation of the subthalamic nucleus in Parkinsons disease. Brain 2000;123(Pt 10):2091-108.
114. Rafal RD. Visually guided behavior. In: Litvan I, Agid Y, eds. Progressive Supranuclear Palsy: Clinical and Research
Approaches. New York: Oxford University Press, 1992:204222.
115. Ghika J, Tennis M, Growdon J, Hoffman E, Johnson K. Environment-driven responses in progressive supranuclear
palsy. J Neurol Sci 1995;130:104111.
116. Kimura J, Barnett HJ, Burkhart G. The psychological test pattern in progressive supranuclear palsy. Neuropsychologia
1981;19:301306.
117. Fisk JD, Goodale MA, Burkhart G, Barnett HJ. Progressive supranuclear palsy: the relationship between ocular motor
dysfunction and psychological test performance. Neurology 1982;32:698705.
118. Soliveri P, Monza D, Paridi D, et al. Cognitive and magnetic resonance imaging aspects of corticobasal degeneration
and progressive supranuclear palsy. Neurology 1999;53:502507.
119. Soliveri P, Monza D, Paridi D, et al. Neuropsychological follow up in patients with Parkinsons disease, striatonigral
degenration-type multisystem atrophy, and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry
2000;69:315318.
120. Esmonde T, Giles E, Gibson M, Hodges JR. Neuropsychological performance, disease severity, and depression in
progressive supranuclear palsy. J Neurol 1996;243:638643.
121. Warrington EK, James M. Visual object and space perception battery. Bury St. Edmonds, UK: Thames Valley Test Co.,
1991.
122. Posner MI, Rafal RD, Choate L, Vaughn J. Inhibition of return: Neural basis and function. Cogn Neuropsychol
1985;2:211228.
123. Rafal RD, Posner MI. Deficits in human visual spatial attention following thalamic lesions. Proc Natl Acad Sci USA
1987;84:73497353.
124. Kertzman C, Robinson DL, Litvan I. Effects of physostigmine on spatial attention in patients with progressive supra-
nuclear palsy. Arch Neurol 1990;47:13461350.
125. Schiller PH, True SD, Conway JL. Effects of frontal eye field and superior colliculus ablations on eye movements.
Science 1979;206:590592.
126. DAntona R, Baron J, Samson Y, et al. Subcortical dementia. Frontal cortex hypometabolism detected by positron
tomography in patients with progressive supranuclear palsy. Brain 1985;108 (Pt 3):785799.
127. Posner MI, Walker JA, Friedrich FJ, Rafal RD. Effects of parietal injury on covert orienting of attention. J Neurosci
1984;4:18631874.
128. Henik A, Rafal R, Rhodes D. Endogenously generated and vsually guided saccades after lesions of the human frontal
eye fields. Soc Neurosc Abstr 1991;17:803.
129. Rafal R, Henik A, Smith J. Exrageniculate contributions toreflex visual orienting in normla humans: A temporal
hemified advantage. J Cogn Neurosci 1991;3:323329.
130. Rafal R, Smith J, Krantz J, Cohen A, Brennan C. Extrageniculate vision in hemianopic humans: saccade inhibition by
signals in the blind field. Science 1990;250:118121.
131. Leiguarda R, Lees AJ, Merello M, Starkstein S, Marsden CD. The nature of apraxia in corticobasal degeneration. J
132. Blondel A, Eustache F, Schaeffer S, Marie RM, Lechevalier B, de la Sayette V. tude clinique et cognitive de lapraxie
dans latrophie cortico-basale. Un trouble slectif du systme de production. Rev Neurol (Paris) 1997;153:737747.
133. Jacobs DH, Adair JC, Macauley B, et al. Apraxia in corticobasal degeneration. Brain Cogn 1999;40:336354.
134. Merians A, Clark M, Poizner H, et al. Apraxia differs in corticobasal degeneration and left-parietal stroke: A case
study. Brain Cogn 1999;40(2):314335.
135. Otsuki M, Soma Y, Yoshimura N, Tsuji S. Slowly progressive limb-kinetic apraxia. Eur Neurol 1997;37:100103.
136. Moreaud O, Naegele B, Pellat J. The nature of apraxia in corticobasal degeneration: a case of melokinetic apraxia.
Neuropsychiatry Neuropsychol Behav Neurol 1996;9:288292.
137. Goldenberg G, Wimmer A, Auff E, Schnaberth G. Impairment of motor planning in patients with Parkinsons disease:
evidence from ideomotor apraxia testing. J Neurol Neurosurg Psychiatry 1986;49:12661272.
138. Watson RT, Fleet WS, Gonzalez-Rothi L, Heilman KM. Apraxia and the supplementary motor area. Arch Neurol
1986;43:787792.
139. Yamadori A, Osumi Y, Imamura T, Mitani Y. Persistent left unilateral apraxia and a disconnection theory. Behav
Neurol 1988;1:1122.
140. Marchetti C, Della Sala S. On crossed apraxia. Description of a right-handed apraxic patient with right supplementary
motor area damage. Cortex 1997;33:341354.
141. Pause M, Freund HJ. Role of the parietal cortex for sensorimotor transformation. Evidence from clinical observations.
Brain Behav Evol 1989;33:136140.
142. Freund HJ. The parietal lobe as a sensorimotor interface: a perspective from clinical and neuroimaging data. NeuroImage
2001;14(1 Pt 2):S142S146.
143. De Renzi E, Lucchelli F. Ideational apraxia. Brain 1988;111(Pt 5):11731185.
144. Barbieri C, De Renzi E. The executive and ideational components of apraxia. Cortex 1988;24(4):535534.
145. Peigneux P, Salmon E, Garraux G, et al. Neural and cognitive bases of upper limb apraxia in corticobasal degeneration.
Neurology 2001;57:12591268.
146. Leiguarda RC, Marsden CD. Limb apraxias: higher-order disorders of sensorimotor integration. Brain 2000;123(Pt 5):
860879.
147. Leiguarda R, Merello M, Balej J. Apraxia in corticobasal degeneration. Adv Neurol 2000;82.
148. Decety J, Perani D, Jeannerod M, et al. Mapping motor representations with positron emission tomography. Nature
1994;371:600602.
149. Bonda E, Petrides M, Frey S, Evans A. Neural correlates of mental transformations of the body-in-space. Proc Natl
Acad Sci USA 1995;92:1118011184.
150. Sirigu A, Daprati E, Pradat-Diehl P, Franck N, Jeannerod M. Perception of self-generated movement following left
parietal lesion. Brain 1999;122(Pt 10):18671874.
151. Wolpert DM, Goodbody SJ, Husain M. Maintaining internal representations: the role of the human superior parietal
lobe. Nat Neurosci 1998;1:529533.
152. Andersen RA, Snyder LH, Bradley DC, Xing J. Multimodal representation of space in the posterior parietal cortex and
its use in planning movements. Annu Rev Neurosci 1997;20:303330.
153. Rothi LJ, Ochipa C, Heilman KM. A cognitive neuropsychological model of limb praxis. In: Rothi LJ, Heilman KM,
eds. Apraxia: The neuropsychology of action. Hove, UK: Psychology, 1997:2950.
155. Rey GJ, Tomer R, Levin BE, Sanchez-Ramos J, Bowen BB, J.H. Psychiatric symptoms, atypical dementia, and left
visual field inattention in corticobasal ganglionic degeneration. Mov Disord 1995;10:106110.
156. Kleiner-Fisman G, Black SE, Lang AE. Neurodegenerative disease and the evolution of art: the effects of presumed
corticobasal degeneration in a professional artist. Mov Disord 2003;18:294302.
157. De Renzi E. Disorders of Space Exploration and Cognition. New York: Wiley, 1982.
158. Mendez MF. Corticobasal ganglionic degeneration with Balints syndrome. J Neuropsychiatry Clin Neurosci
2000;12:273275.
159. Leone M, Budriesi C, Molinari MA, Nichelli P. Progressive biparietal atrophy: A case report and a review of clinico-
pathological correlations of focal (lobar) atrophy. Neurol Sci 2002;23:117.
160. Mendez MF, Turner J, Gilmore GC, Remler B, Tomsak RL. Balints syndrome in Alzheimers disease: visuospatial
functions. Int J Neurosci 1990;54:339346.
161. Furey-Kurkjian MI, Pietrini P, Graff-Radford N, et al. Visual variant of Alzheimer disease: Distinctive
neurospychlogical features. Neuropsychology 1996;10:294300.
tion. Neurology 1999;53:19691974.
164. De Renzi E. Disorders of spatial orientation. In: Frederiks JAM, ed. Handbook of Clinical Neurology, Vol. 45: Clinical
Neuropsychology. Amsterdam: Elsevier Science, 1985:405422.
165. Goethals M, Santens P. Posterior cortical atrophy. Two case reports and a review of the literature. Clin Neurol Neurosurg
2001;103:115119.
166. Mendez MF. Visuospatial deficits with preserved reading ability in a patient with posterior cortical atrophy. Cortex
2001;37:535543.
167. Papagno C. Progressive impairment of constructional abilities: a visuospatial sketchpad deficit? Neuropsychologia
2002;40:18581867.
168. Suzuki K, Otsuka Y, Endo K, et al. Visuospatial deficits due to impaired visual attention: investigation of two cases of
slowly progressive visuospatial impairment. Cortex 2003;39:327341.
170. Gnanalingham KK, Byrne EJ, Thornton A. Clock-face drawing to differentiate Lewy body and Alzheimer type demen-
tia syndromes. Lancet 1996;347:696697.
171. Gnanalingham KK, Byrne EJ, Thornton A, Sambrook MA, Bannister P. Motor and cognitive function in Lewy body
dementia: comparison with Alzheimers and Parkinsons diseases. J Neurol Neurosurg Psychiatry 1997;62:243252.
172. Walker Z, Allen RL, Shergill S, Katona CL. Neuropsychological performance in Lewy body dementia and Alzheimers
disease. Br J Psychiatry 1997;170:156158 .
173. Shimomura T, Mori E, Yamashita H, et al. Cognitive loss in dementia with Lewy bodies and Alzheimer disease. Arch
Neurol 1998;55:15471552.
174. Mori E, Shimomura T, Fujimori M, et al. Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol
2000;57:489493.
175. Simard M, van Reekum R, Myran D. Visuospatial impairment in dementia with Lewy bodies and Alzheimers disease:
a process analysis approach. Int J Geriatr Psychiatry 2003;18:387391.
176. Manford M, Andermann F. Complex visual hallucinations. Clinical and neurobiological insights. Brain 1998;121(Pt
10):18191840.
177. Imamura T, Ishii K, Hirono N, et al. Visual hallucinations and regional cerebral metabolism in dementia with Lewy
bodies (DLB). Neuroreport 1999;10:19031907.
178. Ala TA, Hughes LF, Kyrouac GA, Ghobrial MW, Elble RJ. Pentagon copying is more impaired in dementia with Lewy
bodies than in Alzheimers disease. J Neurol Neurosurg Psychiatry 2001;70:483488.
179. Quinn N. Multiple system atrophythe nature of the beast. J Neurol Neurosurg Psychiatry 1989;Special Suppl:7889.
180. Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Auton Nerv
Syst 1998;74:189192.
Mov Disord 2003;18:467486.
183. Robbins TW, James M, Lange KW, Owen A, Quinn NP, Marsden CD. Cognitive performance in multiple system
atrophy. Brain 1992;115(Pt 1):271291.
184. Sahakian BJ, Morris RG, Evenden JL, et al. A comparative study of visuospatial memory and learning in Alzheimer-
type dementia and Parkinsons disease. Brain 1988;111(Pt 3):695718.
185. Tebartz van Elst L, Greenlee MW, Foley JM, Lucking CH. Contrast detection, discrimination and adaptation in patients
with Parkinsons disease and multiple system atrophy. Brain 1997;120(Pt 12):22192228.
186. Bodis-Wollner I. Visual deficits related to dopamine deficiency in experimental animals and Parkinsons disease pa-
tients. Trends Neurosci 1990;13:296302.
187. Haug BA, Kolle RU, Trenkwalder C, Oertel WH, Paulus W. Predominant affection of the blue cone pathway in
Parkinsons disease. Brain 1995;118(Pt 3):771778.
188. Djamgoz MB, Hankins MW, Hirano J, Archer SN. Neurobiology of retinal dopamine in relation to degenerative states
of the tissue. Vision Res 1997;37:35093529.
189. Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci 1982;298:199209.
190. Keith Berg W, D. B. The Tower of London spatial problem-solving task: enhancing clinical and research implementa-
tion. J Clin Exp Neuropsychol 2002;24:586604.
191. Goel V, Grafman J. Are the frontal lobes implicated in planning functions? Interpreting data from the Tower of
Hanoi. Neuropsychologia 1995;33:623642.
192. Saint-Cyr JA, Taylor AE, Lang AE. Procedural learning and neostriatal dysfunction in man. Brain 1988;111(Pt 4):
941959.
Role of Ocular Motor Assessment 235
15
Role of Ocular Motor Assessment in Diagnosis
and Research
R. John Leigh and David S. Zee
INTRODUCTION
The clinical evaluation of eye movements can contribute substantially to the diagnosis of parkin-
sonian disorders, provided the physician performs a proper examination and interprets the findings
by referring to a simple scheme of the neurobiology of eye movements (1). Further diagnostic infor-
mation can often be obtained by recording eye movements, which are more accessible to measure-
ment and analysis than limb movements or gait. A good part of the neurobiological substrate of eye
movements has been defined, which makes it possible to attribute disordered properties of eye move-
ments to dysfunction of specific neuronal populations or structures in the brain. In this chapter, first,
we review pertinent aspects of the ocular motor examination; second, we highlight some important
test paradigms and technical aspects of measuring eye movements; and third, we summarize disor-
ders of ocular motility reported with parkinsonian disorders and diseases affecting the basal ganglia.
CLINICAL EXAMINATION OF EYE MOVEMENTS IN PARKINSONISM

The systematic examination of eye movements is summarized in Table 1. The most useful part of
the examination concerns saccades, which are the rapid eye movements by which we voluntarily
move our line of sight (direction of gaze). Saccades are perhaps the best understood of all movements
both in terms of their dynamic properties and neurobiology (13). It is important to differentiate
between limited range of movement, especially upward, and speed of saccades, especially vertically.
Normal elderly subjects show limited upgaze (4), and this may be because of changes in the connec-
tive tissues of the orbit (5). Nonetheless, some normal elderly subjects make vertical saccades that
have normal velocities, within their restricted range of motion (6). Range of movement is conven-
tionally elicited as the patient attempts to follow the examiners moving finger, but this does not test
saccades. It is important to ask the patient to shift gaze on command between two stationary visual
targets, displaced horizontally or vertically, such as a pencil tip and the examiners nose. After each
verbal cue (e.g., look at the pencil; now look at my nose), note the time taken to initiate the saccade,
its speed, and whether it gets the eye on target, or whether further corrective saccades are needed. It
is also useful to ask parkinsonian patients to make saccades voluntarily at a rapid pace back and forth
between two stationary targets (e.g., a finger from the left and right hand of the examiner. Patients
with idiopathic Parkinsons disease (PD) often have difficulty making such self-generated sequences
and several saccades, rather than one, are needed for the eye to reach the target (see video 1 on
accompanying DVD).

235
236 Leigh and Zee
Table 1
Summary of Eye Movement Examination
Establishment of the range of ocular motility in horizontal and vertical planes
Fixation stability in central and eccentric gaze (looking for nystagmus or saccades that intrude on
steady fixation)
Horizontal and vertical saccades made voluntarily between two fixed visual targets (noting initiation
time, speed, and accuracy)
Horizontal and vertical pursuit of a smoothly moving target (looking for catch-up saccades)
Optokinetic nystagmus induced with horizontal or vertical motion of a hand-held drum or tape
Ocular alignment during fixation of a distant target, and vergence responses to smooth or stepping
motion of targets aligned in the patients sagittal plane
The vestibular ocular reflex in response to smooth sinusoidal, or sudden, head rotations in horizontal
and vertical planes (looking for corrective saccades that accompany or follow the head rotation)
Another important feature of many parkinsonian disorders is inappropriate saccades that intrude
on steady fixation; the most common are small square-wave jerks that are most easily appreciated
during ophthalmoscopy as to-and-fro movements of the fundus. Smooth pursuit is not usually help-
ful, because many elderly normal subjects and even some younger subjects may have impaired pur-
suit that requires catch-up saccades to keep the line of sight on the moving target. Optokinetic
stimulation at the bedside may be useful in some patients who have difficulty initiating voluntary
saccades (e.g., progressive supranuclear palsy [PSP]); vertical drum motion may induce tonic verti-
cal deviation of the eyes in affected individuals or evoke reflexive quick phases of nystagmus.
Vergence is also often impaired in normal elderly subjects, and identification of abnormalities may
require laboratory assessment.
A NOTE ON LABORATORY METHODS FOR STUDYING EYE MOVEMENTS

IN PARKINSONIAN DISORDERS
Perhaps the most important diagnostic contribution to be made by recording eye movements in
parkinsonian disorders concerns tests of vertical saccades (7,8). Reliable measurement of horizontal
or vertical saccades requires methods with adequate bandwidth (0150 Hz), sensitivity (0.1), and
linear range (30). DC-amplified electro-oculography (EOG) is adequate to signal horizontal eye
position and timing at the beginning and end of a saccade, but is unreliable for measuring vertical
movements. Infrared methods provide better bandwidth but inferior range to EOG, and also cannot
be used to measure vertical movements. The most reliable method is the magnetic search coil which,
in our experience, is well tolerated by frail and elderly subjects, and has the added advantage of being
calibrated independently of the patients voluntary range of movements (1). Fast frame-rate video-
based techniques are suitable for measuring dynamic properties of horizontal and vertical saccades
(9), but their calibration depends on the ability of the patient to look at visual targets, and this may be
impaired, for example, in PSP.
Saccades show consistent relationships between their size, speed, and duration (2,10). Thus, the
bigger the saccade, the greater its peak velocity and the longer it lasts. Examples of the main
sequence relationships between peak velocity, duration, and amplitude are provided from normal
subjects in Fig. 1; exponential or power-function equations have been used to describe these relation-
ships and define prediction intervals for normal subjects (2,10,11). Deviations of measured eye move-
ments from these relationships indicate either abnormal saccades, or nonsaccadic eye movements.
Thus, in Fig. 1, we also provide an example of abnormally slow vertical saccades from a patient
with PSP.
Fig. 1. Plots summarizing important dynamic properties of saccades. (A) Plot of peak velocity vs amplitude
of vertical saccades. Data points are saccades from 10 normal subjects. The data are fit with an exponential
equation; also plotted are the 5% and 95% prediction intervals. The + indicate vertical saccades from a patient
with PSP, which lie outside the prediction intervals for normals. (B) Plot of duration vs amplitude. The data
from 10 normal subjects are fit with a power equation. The + indicate vertical saccades from a patient with PSP,
which have greater duration than control subjects.
Aside from measurement of saccadic dynamics, substantial effort has been put into using saccades
as a behavioral index of motor programming in basal ganglia and associated cortical disorders (12).
Thus, although the frontal and parietal eye fields project directly to the brainstem centers, such as the
superior colliculus and pontine nuclei, a second pathway running through the basal ganglia plays an
important role, and comprises the caudate, substantia nigra par reticulata (SNpr), subthalamic nucleus,
and superior colliculus (Fig. 2). A simplified view of this basal ganglia pathway is that it is composed
of two serial, inhibitory links: a caudate-SNpr inhibition, which is only phasically active, and a SNpr-
collicular inhibition, which is tonically active (13). If frontal cortex causes caudate neurons to fire,
then the SNpr-collicular inhibition is removed and the superior colliculus is able to activate a sac-
cade. In addition, the subthalamic nucleus contains neurons that discharge in relation to saccades and
238 Leigh and Zee
Fig. 2. (A) Block diagram of the major structures that project to the brainstem saccade generator (premotor
burst neurons in PPRF and riMLF). Also shown are projections from cortical eye fields to superior colliculus.
FEF, frontal eye fields; SEF, supplementary eye fields; DLPC, dorsolateral prefrontal cortex; IML, intramedul-
lary lamina of thalamus; PEF, parietal eye fields (LIP); PPC, posterior parietal cortex; SNpr, substantia nigra,
pars reticulata.
excites (SNpr), which in turn inhibits the superior colliculus. Animal studies indicate that this path-
way appears important for programming of saccades to targets for which there is an expectation of
reward (14,15). The caudate nucleus also probably contributes to smooth pursuit (16).
For these reasons, studies of the effects of human diseases affecting basal ganglia have focused on
behaviors such as memory-guided or predictive saccades (Fig. 3). Memory-guided saccades are made
in darkness several seconds after a visual target has been flashed. Predictive saccades are made in
anticipation of a target appearance or jump. In the anti-saccade task, the subject is required to look in
the opposite direction (mirror image position) to a visual stimulus. Thus, a reflexive, visually guided
saccade must be inhibited and a saccade to an imagined target made instead (17). Such testing is still
mainly a research tool, but it has provided insights into the pathogenesis of parkinsonian disorders, as
we will mention in discussing each type of disorder.
Fig. 3. Schematic summary of stimulus paradigms that have been used to test saccades in Parkinsonian
disorders. (A) Simultaneous switching of fixation target off and visual target on (overlap paradigm). (B) Gap
paradigm, in which fixation target is switched off before visual target is switched on. (C) Memory target task.
The subject views the fixation target during the time that the visual target is flashed and after several seconds
(the memory period), the fixation light is switched off and the subject looks toward the remembered location
of the target. (D) The antisaccade task. The subject is required to look in the opposite direction when the visual
stimulus is presented. (E) Predictive task. Subject makes saccades to a target that jumps to a predictable loca-
tion with predictable timing.
240 Leigh and Zee
IDIOPATHIC PARKINSONS DISEASE (TABLE 2)

Clinical Findings in PD
Most patients with PD show relatively minor abnormalities at the bedside that may also occur in
healthy elderly subjects. For example, steady fixation may be disrupted by saccadic intrusions
(square-wave jerks) (1820), but these are also seen in some normal elderly subjects. Moderate
restriction of the range of upward gaze is common in elderly individuals (4), with or without par-
kinsonism, and has been attributed to changes in the orbital tissues (5). Similarly, smooth pursuit can
be impaired in PD but is also abnormal in some healthy normals (21). Convergence insufficiency is
common and sometimes symptomatic (22). Patients with PD often have lid lag. Patients with advanced
PD may show some slowing of vertical saccades, but PSP should always be considered in such cases.
A characteristic sign in PD is that hypometria becomes more marked when patients are asked to
rapidly perform self-paced refixations between two continuously visible targets (e.g., a finger of the
examiners right and left hand about 6080 apart; the normal horizontal ocular motor range is about
45 to either side) (video 1).
Laboratory Findings in PD
Saccades
Saccades in PD usually undershoot the target (i.e., they are hypometric), especially vertically
(20,21). Patients may show a stair-case of saccades to acquire the target (especially with remem-
bered targets); this fragmentation has been interpreted as a robust correction mechanism to com-
pensate for the underlying hypometria (23). It has been possible to investigate the pathogenesis of the
hypometria, which becomes more marked when patients are asked to make self-paced refixations
between two continuously visible targets. This phenomenon is not simply because of the persistence
of the visual targets, because saccades made in anticipation of the appearance of a target light at a
remembered location are also hypometric (24,25). Patients with PD have difficulty in generating
sequences of memory-guided saccades (2628), whereas saccades made reflexively to novel visual
stimuli are normal in size and promptly initiated (7). Furthermore, visually guided adaptation of
saccades is preserved whereas memory guided adaptation of saccades is impaired (29). Thus, it
appears that PD patients are unable to generate internally guided saccades to accurately shift gaze
(7,30). Despite this hypometria, patients can still shift their gaze with a series of saccades to the
location of a briefly flashed target; this indicates a retained ability to encode the location of objects in
extrapersonal space (20,24).
The reaction time (latency) of saccades made in response to nonpredictable target jumps may be
normal or mildly increased (20,30). During self-paced refixations between two visible targets,
intersaccadic intervals increase above the latency of responses to nonpredictable target jumps (30,31)
If the fixation light is turned out 100 msec before a target light appears (gap paradigmFig. 3) PD
patients are able to make short-latency (100130 ms) express saccades like normal subjects (7).
The pathophysiology of saccadic disorders in PD is not fully understood. One possible mechanism
is via the subthalamic nucleus (Fig. 2), which contains neurons that discharge in relation to saccades.
The subthalamic nucleus is hyperactive in PD, and excites the substantia nigra, pars reticulata (SNpr),
which in turn inhibits the superior colliculus. It may be that excess activity in SNpr in PD leads to a
defect in generation of the more voluntary, internally guided saccades such as those during prediction
and to memorized targets. Functional imaging studies have suggested that the basal ganglia are impor-
tant for processing of temporal information (32), which may be important for generating a regular series
of saccades. Furthermore, during predictive visuomanual tracking, there is an underactivity of sen-
sorimotor cortex, but increase in premotor areas, such as pre-SMA (supplementary motor area), which
may represent compensation or impaired suppression (33). Finally, PD also affects the dopaminergic
Table 2
Summary of Disordered Eye Movements in Some Basal Ganglia Disorders
Progressive Supranuclear Palsy (PSP)
Slow vertical saccades, especially down, with a preserved range of movement, may be the first sign of
the disorder; later, loss of vertical saccades and quick phases
Horizontal saccades become slow and hypometric
Disruption of steady gaze by horizontal saccadic intrusions (square-wave jerks)
Impaired smooth pursuit, vertically (reduced range) and horizontally (with catch-up saccades)
Smooth eye-head tracking may be relatively preserved, especially vertically
Preservation of slow phases of vestibular ocular reflex but quick phases are affected as saccades
Horizontal disconjugacy suggesting INO
Loss of convergence
Ultimately, all eye movements may be lost, but vestibular movements are the last to go
Eyelid disorders: apraxia of lid opening, lid lag, blepharospasm, inability to suppress a blink to a
bright light.
Parkinsons Disease
Fixation may be disrupted by square-wave jerks
Hypometria of horizontal and vertical saccades, especially when patients are asked to perform self-
paced refixations between two continuously visible targets
Normal saccadic velocity except in some advanced cases
Impaired smooth pursuit, horizontally and vertically, owing partly to inadequate catch-up saccades
Vestibular eye movements normal for natural head movements
Impaired convergence
Oculogyric crises
Lid lag
Huntingtons Disease
Difficulties initiating saccades (without an associated head thrust and blink)
Difficulties suppressing saccades to novel visual stimuli (especially during the antisaccade task)
Slow saccades, especially vertically, and in patients with early age of onset
Impairment of smooth pursuit
Preservation of VOR and gaze-holding
cells within the retina. PD patients have abnormalities of color vision and in detection of spatially and
temporally modulated gratings (34).
Smooth Pursuit
Mildly affected PD patients differ little from age-matched control subjects in their smooth-pursuit
performance (21,35). During tracking of a target moving in a predictable, sinusoidal pattern, eye
speed is less than target speed, leading to catch-up saccades (20,36). In addition, the catch-up sac-
cades are hypometric; thus, the cumulative tracking eye movement is less than that of the target (35).
Despite these impairments, the phase relationship between eye and target movement is normal,30
implying a normal predictive smooth tracking strategy. This is in contrast to saccadic tracking of
predictive target jumps which, as described earlier, is deficient.
Vestibular Responses
Both caloric and low-frequency rotational vestibular responses, in darkness, may be hypoactive in
patients with PD (37,38). However, at higher frequencies of head rotation, and particularly during
visual fixation, the vestibular ocular (VOR) reflex adequately compensates for head perturbations,
which accounts for the lack of complaint of oscillopsia in patients with PD.
242 Leigh and Zee
Effects of Disease Course and Treatment

Patients with advanced PD may show greater defects on more demanding tests, such as making
memory-guided saccades, and on the anti-saccade tasks (Fig. 3), which requires inhibiting a reflexive
saccade, and looking in the opposite direction to the target (its mirror location). In addition, patients
with advanced disease may show some slowing of vertical or horizontal saccades.
In general, L-dopa treatment of PD does not seem to improve the ocular motor deficits except for
improvement of saccadic accuracy (i.e., saccades become larger) (36,39). Some newly diagnosed
patients with idiopathic PD may show improved smooth pursuit after the institution of dopaminergic
therapy (39). Memory-guided saccades are reported to be impaired after pallidotomy for PD (40), but
improved with subthalamic nucleus stimulation (41), possibly by improving learning abilities in the
corticobasal ganglia network (42). Pallidotomy increases saccadic intrusions on steady fixation
(square-wave jerks) (43,44).
Toxic Parkinsonism
In patients with parkinsonism owing to methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tox-
icity, saccadic latency is shortened and saccadic accuracy improved by dopaminergic agents; in addi-
tion, reflex blepharospasm was improved (45). In monkeys that received MPTP, saccadic
abnormalities, including increased latency, increased duration, decreased rate of spontaneous sac-
cades, and inappropriate saccades, were all reversed by dopaminergic therapy (46,47).

Clinical Features
PSP is a degenerative disease of later life characterized by abnormal vertical saccades; the early
appearance of falls, usually within a year of onset, owing to disturbance of tone and posture; difficul-
ties with swallowing and speech; and mental slowing (48). Median survival time is about 6 yr. The
disturbance of eye movements is usually present early in the course, but occasionally develops late,
or is sometimes not noted by the patients physicians (49). Patient may complain of blurred vision,
double vision, or photophobia (48), and have often been fitted with several different spectacle refrac-
tions, without improvement. On direct questioning, it is usually possible to determine that these
visual complaints are a result of loss of the ability to voluntarily shift gaze in the vertical plane so
that, for example, patients cannot look down to see a plate of food, tie their shoes, or confidently
navigate going down the stairs.
The initial ocular motor deficit consists of slowing of vertical saccades and quick phases, either
down or up or both (see video 2 on accompanying DVD). Sometimes vertical saccades take a curved
or oblique trajectory (round the houses) (21,50). Vertical smooth pursuit is relatively preserved,
but of decreased gain (51). Larger targets may elicit greater responses (52), and could be used to
evaluate the range of eye movements in patients in whom neck stiffness makes testing of the VOR
technically difficult. Similarly, full-field optokinetic stimuli may induce responses that are useful
for analysis (11). Combined eye-head tracking may also be relatively spared. As the disease
progresses, the range of movements possible with vertical saccades and pursuit declines and eventu-
ally no voluntary vertical eye movements are possible. However, the VOR is preserved until late in
the disease (although a characteristic rigidity of the neck may make the vertical dolls head maneu-
ver difficult to elicit).
Horizontal eye movements also show characteristic changes: steady fixation is disrupted by square-
wave jerks (11,18,21), which are more common than in other parkinsonian disorders. Horizontal
saccades are initially hypometric but normal in speed (see video 3 on accompanying DVD) (53); as
the disease progresses, they also become slow. In some patients, the involvement of horizontal sac-
cades resembles internuclear ophthalmoplegia (INO), although vestibular stimulation may overcome
the limitation of adduction (54). Horizontal smooth pursuit appears impaired, in part, because of
square-wave jerks. Convergence eye movements are commonly impaired (55). Late in the disease,
the ocular motor deficit may progress to a complete ophthalmoplegia. Patients with absent quick
phases but intact vestibular eye movements may also show sustained deviation of the eyes in the orbit
during body rotation, and if the head is free to move it too may deviate opposite to the direction of
body rotation (56).
There are a variety of eyelid abnormalities in PSP: blepharospasm, lid-opening apraxia, eye-clos-
ing apraxia, lid retraction, and lid lag (21). Patients typically show an inability to suppress a blink to
a bright lighta visual Meyersons (glabella) sign (see video 4 on accompanying DVD) (57). A
single patient may have more than one of these abnormalities. Bells phenomenon is usually absent.
Laboratory Findings in PSP

Saccades
Reliable measurements of saccades in PSP have demonstrated that vertical saccades are slower
than horizontal saccades of similar size (21,58). For patients who are able to make only small sac-
cades, it is still possible to determine whether the movements are slowed using an appropriate statis-
tical approach (59). Vertical saccades are generated by burst neurons in the midbrain but horizontal
saccades are generated by burst neurons in the pons. Thus, the selective involvement of vertical
saccades in the early stage of PSP has indicated that the brunt of the disease initially falls on midbrain
burst neurons, or their local circuitry (superior colliculus and the adjacent central mesencephalic
reticular formation) (60,61).
The latency (reaction time) of horizontal saccades in PSP is prolonged in some patients, but others
retain the ability to make short-latency or express saccades (62). Patients with PSP also make
errors when they are required to look in the opposite direction to a suddenly appearing target (the
antisaccade taskFig. 3). Both the presence of express saccades and errors on the antisaccade task
suggest defects in frontal lobe function and, although neuropathological changes there are mild,
positron emission scanning indicates profound frontal hypometabolism (63).
Vestibular Eye Movements
Measurements of vestibular eye movements during horizontal rotation, either in darkness, or dur-
ing fixation of a stationary target, confirms that PSP patients show similar slow-phase responses to
normal subjects but quick phases are commonly impaired leading to tonic deviation of the eyes in the
contraversive direction in the oribit during rotation in the dark (51).
Smooth-Pursuit, Optokinetic, and Vergence Movements
Smooth pursuit is usually impaired in both horizontal and vertical planes (21). In the vertical
plane, no corrective catch-up saccades can be made. The combined impairment of vertical sac-
cades and pursuit constitutes voluntary gaze palsy. During large-field, vertical optokinetic stimula-
tion, PSP patients often show tonic deviation of the eyes in the direction of stripe motion, with small
or absent resetting quick phases (11). When PSP patients shift their fixation point between distant
and near targets, the vergence movement is slowed compared to control subjects (64).
EYE MOVEMENTS IN OTHER DISORDERS CAUSING PARKINSONIAN
SYNDROMES: DIFFERENTIATION FROM PSP (TABLE 3)
The clinical challenge often posed to neurologists is to diagnose parkinsonian patients with abnor-
mal eye movements. As noted above, most patients with PD have normal eye movements for their
age, whereas as most patients with PSP do not. In fact, a number of other parkinsonian disorders have
been reported to produce abnormal eye movements, and it is those disorders that we review in this
section, noting features that help to differentiate from PSP.
244 Leigh and Zee
Table 3
Comparison of Findings in Some Parkinsonian Syndromes
SWJ During Fixation Visually Guided Saccades Laboratory Testing of Saccades
PD Increased following Hypometric, when self-generated and Difficulty generating memorized
pallidotomy especially when instructed to generate sequences
successive saccades back and forth at a rapid Advanced cases make errors
pace; slow vertically in advanced casedes on antisaccade task
PSP Markedly increased Slow; hypometric; initiated with difficulty Increased errors on antisaccade task
MSA Increased in some Slow and hypometric in some patients
patients
CBGD Increased in some Hypometric and increased latency; deficit more Increased errors on antisaccade task
patients marked in the presence of a visual
background
HD May be increased Difficulty with initiation; may be slow and Markedly increased errors
hypometic on antisaccade task; impaired
predictive saccade tracking
Conditions that closely mimic PSP, causing slow vertical saccades, horizontal square-wave jerks,
dysphagia, and frequent falls, include multiple infarcts affecting the basal ganglia, internal capsule,
and midbrain (in the distribution of the perforating vessels arising from the proximal portions of the
posterior cerebral artery) (65), infiltrative processes such as lymphoma, and paraneoplastic syndromes
(66). Disorders causing the dorsal midbrain syndrome, such as tumor and hydrocephalus, can also
produce a clinical picture that has some similarities to PSP with vertical-gaze palsy.
Whipples disease can also closely mimic PSP, with vertical saccadic gaze palsy (67,68). In addi-
tion, there may be characteristic oculomasticatory myorhythmia a pendular vergence oscillation
with concurrent contractions of the masticatory muscles; occasionally the limb muscles also show
rhythmic contractions (69). Whipples disease can now be diagnosed using polymerase chain reac-
tion (PCR) analysis of involved tissues (70), and can be treated with antibiotics (71).
Pure akinesia is characterized by profound disturbances of speech, handwriting, and gait, so that,
for example, affected patients may suffer episodes during which they stand frozen for hours on end
(72). Tremor, limb rigidity, akinesia, dementia, or responsiveness to levodopa are absent. Such patients
may show slow and hypometric vertical saccades. The disorder may be a restricted form of PSP with a
longer, more benign course.
Cortical-basal degeneration (CBD) may lead to a defect in range of vertical eye movements but it
usually does not cause marked slowing of saccades; instead the defect is an increased saccadic reac-
tion time (latency), which is evident at the bedside (21,73). Hypometria of upward saccades may
occur early in the course, and should be differentiated from restricted upward range, which is present
in elderly normal subjects. Other occasional findings in CBD include some decrease in horizontal
saccade speed in the direction of the more affected limb, and increased distractibility during the
antisaccade paradigm (looking at, instead of way from, the visual target). The other features of this
degenerationfocal dystonia, ideomotor apraxia, alien hand syndrome, myoclonus, asymmetric aki-
netic-rigid syndrome with late onset of gait or balance disturbancesare more important in securing
the diagnosis (74,75).
Multiple system atrophy (MSA) causes a parkinsonian syndrome with marked autonomic find-
ings. Some patients show slowing of vertical saccades as well as hypometria (21,76), whereas other
have cerebellar eye movement findings, including downbeat nystagmus during positional testing (77),
impaired smooth ocular and eye-head pursuit.
Dementia with Lewy bodies, which causes parkinsonism and fluctuating dementia with florid visual
hallucinations, may be associated with a vertical-gaze paralysis (78,79), but systematic measurements
of vertical saccade are not yet available.
Other basal ganglia disorders that have been reported to show features similar to PSP include
idiopathic striopallidodentate calcification (Fahrs disease) (80), and autosomal dominant parkin-
sonism and dementia with pallido-ponto-nigral degeneration (81). Some patients with Huntingtons
disease (HD) may present with vertical saccadic palsy and axial rigidity; this condition is discussed
in a later section. Patients with the syndrome of amyotrophic lateral sclerosis (ALS), parkinsonism,
and dementia (Lytico-Bodig), which is encountered in the inhabitants of the islands of the South
Pacific Ocean, including Guam, may show more severe deficits than those with idiopathic PD, includ-
ing limitation of vertical gaze (82). A variant of ALS has been described, in which slow vertical sac-
cades, gaze-evoked nystagmus, and impaired pursuit were prominent (83). In the French West Indies,
a PSP-like syndrome thought to result from neurotoxic alkaloids is associated with ingestion of herbal
teas and fruits (84). Slow saccades, with a supranuclear gaze palsy, are also characteristic of
CreutzfeldtJakob disease but usually in both the horizontal and vertical planes (85). Periodic alter-
nating nystagmus, rebound nystagmus, and centripetal nystagmus (slow phases directed eccentri-
cally) on lateral gaze are also characteristic of this condition owing to cerebellar involvement (85,86).
DRUG-INDUCED PARKINSONISM AND OCULOGYRIC CRISIS

Drug intoxications, especially with phenothiazines such as the butyrophenones, may produce a
parkinsonian picture with slowing of saccades and an akinetic mutism picture. A distinct syndrome
is oculogyric crisis, which was once a common feature of postencephalitic parkinsonism, but is now
a side effect of drugs, especially neuroleptic agents (87). Oculogyric crises may also rarely be a
feature of Wilsons disease (88), and disorders of amino acid metabolism (aromatic L-amino acid decar-
boxylase deficiency) (89).
A typical oculogyric crisis is ushered in by feelings of fear or depression, which give rise to an
obsessive fixation on a thought. The eyes usually deviate upward, and sometimes laterally; they
rarely deviate downward. During the period of upward deviation, the movements of the eyes in the
upper field of gaze appear nearly normal. Affected patients have great difficulty in looking down,
except when they combine a blink and downward saccade. Thus, the ocular disorder may reflect an
imbalance of the vertical gaze-holding mechanism (the neural integrator). Anticholinergic drugs
promptly terminate the thought disorder and ocular deviation, a finding that has led to the suggestion
that the disorders of thought and eye movements are linked by a pharmacological imbalance common
to both (87). Delayed oculogyric crises have been described after striatocapsular infarction, and with
bilateral putaminal hemorrhage (90). Oculogyric crises are distinct from the brief upward ocular
deviations that occur in Tourette syndrome (91), Rett syndrome (92), children with benign paroxys-
mal tonic upgaze (93), and in many patients with tardive dyskinesia (94). In some patients with
tardive dyskinesias, however, the upward eye deviations are more sustained and also have the charac-
teristic neuropsychological syndrome of oculogyric crises (95). Episodic brief spells of tonic upgaze
have also been reported after bilateral lentiform lesions (96).
HUNTINGTONS DISEASE
Clinical Findings
HD results from a genetic defect of the IT15 gene (huntingtin) on chromosome 4, causing
increased CAG triplet repeat length. Disturbances of voluntary gaze are common in this disorder
(97100). Initiation of saccades may be difficult with prolonged latencies, especially when the sac-
246 Leigh and Zee
cade is made to command or in anticipation of a target that is moving in a predictable fashion. An

obligatory blink or head turn may be used to start the eye moving (101). Saccades may be slow in the
horizontal or vertical plane; this deficit can often be detected early in the disease if eye movements
are measured, but may not be evident clinically until late in the course. Longitudinal studies of sac-
cades have documented progressive slowing and prolongation of reaction time (102). Saccades may
be slower in patients who become symptomatic at an earlier age, and it has been suggested that such
individuals are more likely to have inherited the disease from their father (99).
Fixation is abnormal in some patients with HD because of saccadic intrusions (100). This defect of
steady fixation is particularly evident when patients view a textured background. Smooth pursuit
may also be impaired with decreased gain, but often is relatively spared compared with saccades. By
contrast, gaze holding and the VOR are spared. Late in the disease, rotational stimulation causes the
eyes to tonically deviate with few or no quick phases.
Despite the near-ubiquitous finding of abnormal eye movements in HD, some individuals who
have been studied at a presymptomatic point in their disease have shown normal eye movements
(97,103,104). Thus, routine testing of eye movements cannot be regarded as a reliable method for
determining which offspring of affected patients will go on to develop the disease. Some improve-
ment of the eye movement abnormalities in HD has been reported with sulpiride (105).
The paradoxical findings of difficulty in initiating voluntary saccades but with an excess of extrane-
ous saccades during attempted fixation has been further elucidated using special test stimuli (Fig. 3).
These have revealed an excessive distractibility in, for example, tasks in which patients are required to
look in the opposite direction to a suddenly appearing target (antisaccade task) (106). A second finding
is that saccades to visual stimuli are made at normal latency, whereas those made to command are
delayed. These findings can be related to the parallel pathways that control the various types of
saccadic responses. On the one hand, disease affecting either the frontal lobes or the caudate nucleus,
which inhibits the SNpr, may lead to difficulties in initiating voluntary saccades in tasks that require
learned or predictive behavior (107). On the other hand, HD also affects the SNpr (108). Since this
structure inhibits the superior colliculus (nigro-collicular projection), and so suppresses reflexive
saccades to visual stimuli, one might expect excessive distractibility during attempted fixation (107).
The slowing of saccades might reflect involvement of saccadic burst neurons (109) but at least some
pathologic evidence suggests that disturbance of prenuclear inputs, such as the superior colliculus or
frontal eye fields, is responsible (110).
Disorders to be considered in the differential diagnosis of HD include neuroacanthocytosis (111),
although abnormal eye movements have not been described as an important feature of this disorder.
Dentatorubropallidoluysian atrophy, also called the Haw River syndrome (112), is another CAG
triplet repeat disease (B37, chromosome 12) and is characterized by slow saccades but more myoclo-
nus and ataxia than in HD.
OTHER DISORDERS THAT MAY AFFECT THE BASAL GANGLION

DISORDERS AND MAY HAVE ABNORMAL EYE MOVEMENTS
Wilsons disease, hepatolenticular degeneration, is an autosomal recessive, inherited disorder of
copper metabolism. The defect is in a copper-transporting ATPase with the gene at q14.3 on chromo-
some 13. CT typically shows hypodense areas, and positron emission tomography (PET) scanning
indicates a decreased rate of glucose metabolism in the globus pallidum and putamen. The classic
clinical picture is a movement disorder with psychiatric symptoms and associated liver disease. The
KayserFleisher ring is typical in the posterior cornea in Descemets membrane, and some patients
may have a sunflower cataract. Ocular motor disorders in Wilsons disease include a distractibility of
gaze, with inability to voluntarily fix upon an object unless other, competing, visual stimuli are
removed (e.g., fixation of a solitary light in an otherwise dark room) (113). Slow vertical saccades
have also been reported in one patient with Wilsons disease (114), but are often normal. A lid-
opening apraxia has also been noted (115). Oculogyric crises may occur (88). The eye movements of
Wilsons disease, therefore, show some similarities to those described in HD and Alzheimers dis-
ease. The distractibility in both conditions may be owing to involvement of the inhibitory pathways
from the basal ganglia to the superior colliculus (Fig. 2).
Ataxia telangiectasia results from a defect on chromosome 11q. Characteristic eye signs include
an ocular motor apraxia with hypometria and increased latency, but normal velocity of saccades with
head thrusts (116119). Both vertical and horizontal saccades are affected. Other features are gaze-
evoked nystagmus, periodic alternating nystagmus, square-wave jerks, and unusual slow smooth-
pursuit-like movements that are used to change gaze voluntarily when saccades are difficult to
generate. F-Feto protein levels are usually dramatically elevated.
NiemannPick disease (NiemannPick type C [2S] disease), usually presents during adolescence
with intellectual impairment, ataxia, and dysarthria, and a selective slowing of vertical saccades (120
122). Other eye movements (including horizontal saccades) are normal. Diagonal saccades may show
a curved trajectory evident during the clinical examination. A bone marrow examination shows sea
blue histiocytes.
Caudate hemorrhage has been associated with ipsilateral gaze preference (123), consistent with
experimental dopamine depletion of this structure. Patients with bilateral lentiform nucleus lesions
show abnormalities of predictive and memory-guided saccades (both internally generated), but visu-
ally guided saccades and antisaccades (both triggered by a visual target) are normal (124). It has been
suggested that defects in the control of predictive smooth-pursuit eye movements are a feature of striatal
damage (125), consistent with demonstration of pursuit projections to the caudate nucleus (16).
Patients with Gilles de la Tourette syndrome may show abnormalities such as blepharospasm and
eye tics that include involuntary gaze deviations (91). Routine testing of saccades, fixation, and pur-
suit is normal, but patients show increased latency and decreased peak velocity of antisaccades, as
well as impaired sequencing of memory-guided saccades (126131). The lid abnormalities of Tourette
syndrome must be distinguished from benign eye movement tics, which children often outgrow
(132,133). Patients with LeschNyhan syndromea disorder of purine metabolismshow an impaired
ability to make voluntary saccades, errors on the antisaccade task, blepharospasm, and intermittent
gaze deviations similar to Tourette syndrome (134).
Patients with essential blepharospasm generally show normal eye movements (135), although
saccadic latencies may be increased in certain visually guided and memory-guided saccade tests
(136,137). Patients with spasmodic torticollis may show abnormalities of vestibular function includ-
ing the torsional VOR (138,139). Whether vestibular abnormalities are the cause or a secondary
effect of spasmodic torticollis has not been settled, but affected patients do show changes in their
perceptions of the visual vertical and straight ahead (140). Patients with tardive dyskinesia may dis-
play increased saccade distractibility (141). Patients with active Sydenhams chorea are reported to
show saccadic hypometria (142). Patients with essential tremor, which may sometimes be confused
with PD, have eye movement disorders suggestive of cerebellar dysfunction (impaired pursuit and
impaired modulation of the duration of vestibular responses by head orientation) (143).
PROSPECTS FOR EYE MOVEMENTS IN PARKINSONIAN

RESEARCH (TABLE 4)
At present, much is known about the neurobiology of eye movements, especially saccades, which
can be applied to understanding the pathogenesis of disturbed behavior in a range of movement
disorders. It can be expected that the trend of using novel paradigms (such as shown in Fig. 3) along
with functional imaging is likely to provide new insights. To the clinical movement disorder special-
ists, examination of eye movement remains a useful diagnostic tool that will likely become even
more important with basic science advances. As more movement disorder specialists incorporate a
systematic eye movement examination into their daily routine, not only will diagnostic accuracy
248 Leigh and Zee
Table 4
Major Issues for Eye Movement Research in Parkinsonian Syndromes
General significance:
Eye movements can contribute to a better understanding of the pathogenesis of parkinsonian disorders, and
conversely, the study of patients with parkinsonian disorders can contribute to a better understanding of how
the brain controls movement in general and eye movements in particular.
Many functions are accessible to bedside clinic testing.
Ease and reliability of eye movement measurement.
Eye movements, and the stimuli that drive them, are readily quantified.
Important aspects of the neurobiological substrate of eye movements have been defined.
Paradigms are readily available that can test brainstem functions as well as the role of eye move
ments in prediction, memory, learning, visual search, attention, and reward.
Specific issues that can be addressed by eye movement research

What is the substrate for frequent saccadic intrusions (square-wave jerks) in PSP and in PD following
pallidotomy?
What is the pathogenesis of selective slowing of vertical saccades early in the course of PSP, and what
accounts for the curved trajectories of saccades?
Why do patients with PSP smoothly track a large visual target better than a small one?
What is the role of the basal ganglia in generation of pursuit eye movements?
Why do PD patients have difficulty generating voluntary saccades between visible targets without an
external cue (such as an auditory prompt)?
What are the effects of deep brain stimulation on the full range of saccadic and pursuit dynamics?
Why do head thrusts and a blinks facilitate the generation of saccades in patients with HD?
What is the neurobiological basis for ocular motor tics?
What is the role of the basal ganglia in ocular motor learning?
increase, but there will be more insights into the pathophysiology of the ocular motor disturbances in
parkinsonian disorders and how they respond to treatment.
ACKNOWLEDGMENTS
Dr. Leigh is supported by the Office of Research and Development, Medical Research Service,
Department of Veterans Affairs; NIH grant EY06717; Evenor Armington Fund. Dr. Zee is support by
NIH grant EY01849 and the Robert M. and Annetta J. Coffelt endowment for PSP research.
VIDEO LEGENDS
Video 1: Voluntary saccades in Parkinsons disease. During the initial part of the clip, the patient
is verbally instructed to look between two visual targets (a pen and the camera); some mild hypometria
is evident. Subsequently, the patient is instructed to make self-generate saccades between two sta-
tionary targets about 6080 apart; hypometria becomes much more marked, as well as some delayed
in initiation.
Video 2: Vertical saccades in PSP. The patient is looking between two stationary targets about 40
apart in the vertical plane. The movements are slow, but carry the eyes to their targets. Their trajecto-
ries are slightly oblique or curved with a horizontal correction at the end (round the houses) (50).
Video 3: Horizontal saccades in PSP. The patient is looking between two stationary targets sepa-
rated about 60 in the horizontal plane. Horizontal saccades are faster than vertical saccades (Video 2),
but tend to be hypometric.
Video 4: Light-induced blink response in a patient with PSP. This was tested by flashing a pen-
light repetitively into one eye at 12 Hz, as he viewed a distant target with both eyes. Unlike normals,
or patients with PD, no habituation occurred.
REFERENCES
1. Leigh RJ, Zee DS. The neurology of eye movements. New York: Oxford University Press, 1999.
2. Becker W. Metrics. In: Wutz RH, Goldberg ME, eds. The Neurobiology of Saccadic Eye Movements. Amsterdam:
Elsevier, 1989: 1367.
3. Scudder CA, Kaneko CS, Fuchs AF. The brainstem burst generator for saccadic eye movements: a modern synthesis.
Exp Brain Res 2002; 142(4):439462.
4. Chamberlain W. Restriction of upward gaze with advancing age. Am J Ophthalmol 1971;71:341346.
5. Demer JL. Pivotal role of orbital connective tissues in binocular alignment and strabismus. Invest Ophthalmol Vis
Sci 2004;45(3):729738.
6. Huaman AG, Sharpe JA. Vertical saccades in senescence. Invest Ophthalmol Vis Sci 1993;34:25882595.
7. Vidailhet M, Rivaud S, Gouider-Khouja N, Bonnet A, Gaymard B, Agid Y, et al. Eye movements in parkinsonian
syndromes. Ann Neurol 1994;35:420426.
8. Bhidayasiri R, Riley DE, Somers JT, Lerner AJ, Buttner-Ennever JA, Leigh RJ. Pathophysiology of slow vertical
saccades in progressive supranuclear palsy. Neurology 2001;57(11):20702077.
9. DiScenna AO, Das VE, Zivotofsky AZ, Seidman SH, Leigh RJ. Evaluation of a video tracking device for measurement
of horizontal and vertical eye rotations during locomotion. J Neurosci Methods 1995;58:8994.
10. Lebedev S, Van Gelder P, Tsui WH. Square-root relation between main saccade parameters. Invest Ophthalmol Vis Sci
1996;37:27502758.
11. Garbutt S, Riley DE, Kumar AN, Han U, Harwood MR, Leigh RJ. Abnormalities of optokinetic nystagmus in progres-
sive supranuclear palsy, J Neurosurg Psychiatry 2004, in press.
12. Pierrot-Deseilligny C, Ploner CJ, Muri RM, Gaymard B, Rivaud-Pechoux S. Effects of cortical lesions on saccadic: eye
movements in humans. Ann N Y Acad Sci 2002;956:216229.
13. Hikosaka O, Takikawa Y, Kawagoe R. Role of the basal ganglia in the control of purposive saccadic eye movements.
Physiol Rev 2000;80(3):953978.
14. Itoh H, Nakahara H, Hikosaka O, Kawagoe R, Takikawa Y, Aihara K. Correlation of primate caudate neural activity
and saccade parameters in reward-oriented behavior. J Neurophysiol 2003;89:17741783.
15. Sato M, Hikosaka O. Role of primate substantia nigra pars reticulata in reward-oriented saccadic eye movement. J Neurosci
2002;22(6):23632373.
16. Cui D, Yan Y, Lynch J. Pursuit subregion of the frontal eye field projects to the caudate nucleus in monkeys. J Neurophysiol
2003;89:26782684.
17. Crawford TJ, Bennett D, Lekwuwa G, Shaunak S, Deakin JF. Cognition and the inhibitory control of saccades in
schizophrenia and Parkinsons disease. Prog Brain Res 2002;140:449466.
18. Rascol O, Sabatini U, Simonetta-Moreau M, Montastruc JL, Rascol A, Clanet M. Square wave jerks in Parkinsonian
syndromes. J Neurol Neurosurg Psychiatry 1991;54:599602.
19. OSullivan JD, Maruff P, Tyler P, Peppard RF, McNeill P, Currie J. Unilateral pallidotomy for Parkinsons disease
disrupts ocular fixation. J Clin Neurosci 2003;10(2):181185.
20. White OB, Saint-Cyr JA, Tomlinson RD, Sharpe J. Ocular motor deficits in Parkinsons disease. II: Control of saccadic
and smooth pursuit systems. Brain 1983;106:571587.
21. Rottach KG, Riley DE, DiScenna AO, Zivotofsky AZ, Leigh RJ. Dynamic properties of horizontal and vertical eye
movements in parkinsonian syndromes. Ann Neurol 1996;39:368377.
22. Repka MX, Claro MC, Loupe DN, Reich S. Ocular motility in Parkinsons disease. Pediatr Ophthalmol Strabismus
1996;33:144147.
23. Kimmig H, Haussmann K, Mergner T, Lucking CH. What is pathological with gaze shift fragmentation in Parkinsons
disease? J Neurol 2002;249(6):683692.
24. Crawford T, Goodrich S, Henderson L, Kennard C. Predictive responses in Parkinsons disease: Manual key presses
and saccadic eye movements to regular stimulus events. J Neurol Neurosurg Psychiatry 1989;52:10331042.
25. Lueck CJ, Crawford TJ, Henderson L, Van Gisbergen JA, Duysens J, Kennard C. Saccadic eye movements in Parkinsons
disease: II. Remembered saccades - towards a unified hypothesis? Quart J Exp Psychol 1992;45A:211233.
26. Nakamura T, Bronstein AM, Lueck CJ, Marsden CD, Rudge P. Vestibular, cervical and visual remembered saccades in
Parkinsons disease. Brain 1994;117:14231432.
27. Vermersch AI, Rivaud S, Vidailhet M, Bonnet A, Gaymard B, Agid Y, et al. Sequences of memory-guided saccades in
Parkinsons disease. Ann Neurol 1994;35:487490.
28. Kimmig H, Haussmann K, Mergner T, Lucking CH. What is pathological with gaze shift fragmentation in Parkinsons
disease? J Neurol 2002;249(6):683692.
250 Leigh and Zee
29. MacAskill MR, Anderson TJ, Jones RD. Saccadic adaptation in neurological disorders. Prog Brain Res 2002;140:
417431.
30. Bronstein AM, Kennard C. Predictive ocular motor control in Parkinsons disease. Brain 1985;108:925940.
31. Ventre J, Zee DS, Papageorgiou H, Reich S. Abnormalities of predictive saccades in hemi-parkinsons disease. Brain
1992;115:11471165.
32. Nenadic I, Gaser C, Volz H, Rammsayer T, Hager F, Sauer H. Processing of temporal information and the basal gan-
glia: new evidence from fMRI. Exp Brain Res 2003;148:238246.
33. Turner R, Grafton S, McIntosh A, DeLong M, Hoffman J. The functional anatomy of parkinsonian bradykinesia.
Neuroimage 2003;19:163179.
34. Djamgoz M, Hankins M, Hirano J, Archer S. Neurobiology of retinal dopamine in relation to degenerative states of the
tissue. Vision Res 1997;37:35093529. 1997.
35. Waterston JA, Barnes GR, Grealy MA, Collins S. Abnormalities of smooth eye and head movement control in
Parkinsons disease. Ann Neurology 1996;39:749760.
36. Rascol O, Clanet M, Montastruc JL, Simonetta M, Soulier-Esteve MJ, Doyon B, et al. Abnormal ocular movements in
Parkinsons disease. Evidence for involvement of dopaminergic systems. Brain 1989;112:11931214.
37. White OW, Saint-Cyr JA, Sharpe JA. Ocular motor deficits in Parkinsons disease. I. The horizontal vestibulo-ocular
reflex and its regulation. Brain 1983;106:555570.
38. Reichert WH, Doolittle J, McDowell FH. Vestibular dysfunction in Parkinsons disease. Neurology 1982;32:11331138.
39. Gibson JM, Pimlott R, Kennard C. Ocular motor and manual tracking in Parkinsons disease and the effect of treatment.
40. Blekher T, Siemers E, Abel LA, Yee RD. Eye movements in Parkinsons disease: before and after pallidotomy. Invest
Ophthalmol Vis Sci 2000;41(8):21772183.
41. Rivaud-Pechoux S, Vermersch AI, Gaymard B, Ploner CJ, Bejjani BP, Damier P, et al. Improvement of memory guided
saccades in parkinsonian patients by high frequency subthalamic nucleus stimulation. J Neurol Neurosurg Psychiatry
2000;68(3):381384.
42. Carbon M, Ghilardi M, Feigin A, Fukuda M, Silvestri G, Mentis M, et al. Learning networks in health and Parkinsons
disease: reproducibility and treatment effects. Hum Brain Mapp 2003;19:197211.
43. OSullivan JD, Maruff P, Tyler P, Peppard RF, McNeill P, Currie J. Unilateral pallidotomy for Parkinsons disease
disrupts ocular fixation. J Clin Neurosci 2003;10(2):181185.
44. Averbuch-Heller L, Stahl JS, Hlavin ML, Leigh RJ. Square wave jerks induced by pallidotomy in parkinsonian patients.
Neurology 1999;52:185188.
45. Hotson JR, Langston EB, Langston JW. Saccade responses to dopamine in human MTPT-induced parkinsonism. Ann
Neurol 1986;20:456463.
46. Schultz W, Romo R, Scarnati E, Sundstrom E, Jonsson G, Studer A. Saccadic reaction times, eye-arm coordination and
spontaneous eye movements in normal and MTPT-treated monkeys. Exp Brain Res 1989;78:253267.
47. Brooks BA, Fuchs AF, Finochio D. Saccadic eye movement deficits in the MTPT monkey model of Parkinsons dis-
ease. Brain Res 1986;383:402407.
48. Nath U, Ben-Shlomo Y, Thomson R, Lees A, Burn D. Clinical features and natural history of progressive supranuclear
palsy. A clinical cohort study. Neurology 2003;60:910916.
1985;17:337343.
50. Quinn N. The round the houses sign in progressive supranuclear palsy. Ann Neurol 2003;40:951.
51. Das V, Leigh R. Visual-vestibular interaction in progressive supranuclear palsy. Vision Res 2000;40:20772081.
52. Seemungal B, Faldon M, Revesz T, Lees A, Zee D, Bronstein A. Influence of target size on vertical gaze palsy in a
pathologically proven case of progressive supranuclear palsy. Mov Disord 2003;18:818822.
54. Mastaglia FL, Grainger KMR. Internuclear ophthalmoplegia in progressive supranuclear palsy. J Neurol Sci
1975;25:303308.
55. Kitthaweesin K, Riley DE, Leigh RJ. Vergence disorders in progressive supranuclear palsy. Ann N Y Acad Sci
2002;956:504507.
56. Jenkyn LR, Walsh DB, Walsh BT, Culver CM, Reeves AG. The nuchocephalic reflex. J Neurosurg Psychiatry
1975;38:561566.
57. Kuniyoshi S, Riley DE, Zee DS, Reich SG, Whitney C, Leigh RJ. Distinguishing progressive supranuclear palsy from
other forms of Parkinsons disease: evaluation of new signs. Ann N Y Acad Sci 2002;956:484486.
59. Garbutt S, Harwood M, Kumar A, Han Y, Leigh R. Evaluating small eye movements in patients with saccadic palsies.
Ann NY Acad Soc 2003;1004:337346.
60. Bhidayasiri R, Plant GT, Leigh RJ. A hypothetical scheme for the brainstem control of vertical gaze. Neurology
2000;54(10):19851993.
62. Pierrot-Deseilligny C, Rivaud S, Fournier E, Agid Y. Lateral visually-guided saccades in progressive supranuclear
palsy. Brain 1989;112:471487.
63. Goffinet AM, DeVolder AG, Gillian C, Rectem D, Bol A, Michel C et al. Positron tomography demonstrates frontal
lobe hypometabolism in progressive supranuclear palsy. Ann Neurol 1989;25:131139.
64. Kitthaweesin K, Riley DE, Leigh RJ. Vergence disorders in progressive supranuclear palsy. Ann N Y Acad Sci
2002;956:504507.
65. Moses HI, Zee DS. Multi-infarct PSP. Neurology 1987;37:1819.
66. Bhidayasiri R, Plant GT, Leigh RJ. A hypothetical scheme for the brainstem control of vertical gaze. Neurology
2000;54(10):19851993.
67. Averbuch-Heller L, Paulson G, Daroff R, Leigh R. Whipples disease mimicking progressive supranuclear palsy: the
diagnostic value of eye movement recording. J Neurol Neurosurg Psychiatry 1999;66:532535.
68. Knox DL, Green WR, Troncosa JC, Yardley JH, Hsu J, Zee DS. Cerebral ocular Whipples disease: a 62 year-old
odyssey from death to diagnosis. Neurology 1995;45:617-625.
69. Schwartz MA, Selhorst JB, Ochs AL, Beck RW, Campbell WW, Harris JK, et al. Oculomasticatory myorhythmia: a
unique movement disorder occurring in Whipples disease. Ann Neurol 1986;20:677683.
70. Lowsky R, Archer GL, Fyles G, Minden M, Curtis J, Messner H, et al. Diagnosis of Whipples disease by molecular
analysis of peripheral blood. N Engl J Med 1994;331:13431346.
71. Fleming JL, Wiesner RH, Shorter RG. Whipples disease: clinical, biochemical, and histopathological features and
assessment of treatment in 29 patients. Mayo Clin Proc 1988;63:539551.
72. Riley DE, Fogt N, Leigh RJ. The syndrome of pure akinesia and its relationship to progressive supranuclear palsy.
Neurology 1994;44:10251029.
73. Vidailhet M, Rivaud-Pechoux S. Eye movement disorders in corticobasal degeneration. Adv Neurol 2000;82:161167.
74. Riley DE, Lang AE, Lewis A, Resch L, Ashby P, Hornykiewicz O et al. Cortical-basal ganglionic degeneration. Neu-
rology 1990;40:12031212.
75. Gibb WRG, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112:11711192.
77. Bertholon P, Bronstein A, Davies R, Rudge P, Thilo K. Positional down beating nystagmus in 50 patients: cerebellar
disorders and possible anterior semicircular canalithiasis. J Neurol Neurosurg Psychiatry 2002;72:366372.
78. Brett F, Henson C, Staunton H. Familial diffuse Lewy body disease, eye movement abnormalities, and distribution of
pathology. Arch Neurol 2003;59:464467.
79. de Bruin VM, Lees AJ, Daniel SE. Diffuse Lewy body disease presenting with supranuclear gaze palsy, parkinsonism,
and dementia: a case report. Mov Disord 1992;7:355358.
80. Saver JL, Liu GT, Charness ME. Idiopathic striopallidodentate calcification with prominent supranuclear abnormality
of eye movement. J Neuro-ophthalmology 1994;14:2933.
81. Wszolek ZK, Pfeiffer RF, Bhatt MH, Schelper RL, Cordes M, Snow BJ, et al. Rapidly progressive autosomal dominant
parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol 1992;32:312320.
82. Lepore FE, Steele JC, Cox TA, Tillson G, Calne DB, Duvoisin RC, et al. Supranuclear disturbances of ocular motility
in Lytico-Bodig. Neurology 1988;38:18491853.
83. Averbuch-Heller L, Helmchen C, Horn AKE, Leigh RJ, Bttner-Ennever JA. Slow vertical saccades in motor neuron
disease: correlation of structure and function. Ann Neurol 1998;44:641648.
84. Caparros-Lefebvre D, Sergeant N, Lees A, Camuzat A, Daniel S, Lannuzel A, et al. Guadeloupean parkinsonism: a
cluster of progressive supranuclear palsy-like tauopathy. Brain 2002;125:801811.
85. Grant MP, Cohen M, Petersen RB, Halmagyi GM, McDougall A, Tusa RJ, et al. Abnormal eye movements in
CreutzfeldtJakob disease. Ann Neurology 1993;34:192197.
86. Helmchen C, Bttner U. Centripetal nystagmus in a case of CreutzfeldtJakob disease. Neuro-ophthalmology
1995;15:187192.
87. Leigh RJ, Foley JM, Remler BF, Civil RH. Oculogyric crisis: a syndrome of thought disorder and ocular deviation. Ann
Neurol 1987;22:1317.
88. Lees A, Kim Y, Lyoo C. Oculogyric crisis as an initial manifestation of Wilsons disease. Neurology 1999;52:17141715.
89. Swoboda K, Hyland K, Goldstein D, Kuban K, Arnold L, Holmes C, et al. Clinical and therapeutic observations in
aromatic L-amino decarboxylase deficiency. Neurology 1999;53:12051211.
90. Liu GT, Carrazana EJ, Macklis JD, Mikati MA. Delayed oculogyric crises associated with striatocapsular infarction.
J Clin Neuro-ophthalmol 1991;11:198201.
252 Leigh and Zee
91. Frankel M, Cummings JL. Neuro-ophthalmic abnormalities in Tourettes syndrome. Functional and anatomical impli-
cations. Neurology 1984;34:359361.
92. FitzGerald PM, Jankovic J, Glaze DG, Schultz R, Percy AK. Extrapyramidal involvement in Retts syndrome. Neurol-
ogy 1990;40:293295.
93. Hoyt CS, Mousel DK. Transient supranuclear disturbances of gaze in healthy neonates. Am J Ophthalmol 1980;89:
708713.
94. FitzGerald PM, Jankovic J. Tardive oculogyric crisis. Neurology 1989;39:14341437.
95. Sachdev P. Tardive and chronically recurrent oculogyric crises. Mov Disord 1993;8:9397.
96. Kim JS, Kim HK, Im JH, Lee MC. Oculogryic crisis and abnormal magnetic resonance imaging signals in bilateral
lentiform nuclei. Mov Disord 1996;11:756758.
97. Collewijn H, Went LN, Tamminga EP, Vegter-Van der Vlis M. Oculomotor defects in patients with Huntingtons
disease and their offspring. J Neurol Sci 1988;86:307320.
98. Lasker AG, Zee DS. Ocular motor abnormalities in Huntingtons disease. Vision Res 1997;37:3639-3645.
99. Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS. Saccades in Huntingtons disease: initiation defects and
distractability. Neurology 1987;37:364370.
100. Leigh RJ, Newman SA, Folstein SE, Lasker AG, Jensen BA. Abnormal ocular motor control in Huntingtons disease.
Neurology 1983;33:12681275.
101. Zangemeister WH, Mueller-Jensen A. The coordination of gaze movements in Huntingtons disease. Neuro-ophthal-
mology 1985;5:193206.
102. Rubin AJ, King WM, Reinbold KA, Shoulson I. Quantitative longitudinal assessment of saccades in Huntingtons
disease. J Clin Neuro-opthalmol 1993;13:5966.
103. Kirkwood SC, Siemers E, Bond C, Conneally PM, Christian JC, Foroud T. Confirmation of subtle motor changes
among presymptomatic carriers of the Huntington disease gene. Arch Neurol 2000;57(7):10401044.
104. Rothlind JC, Brandt J, Zee D, Codori AM, Folstein S. Verbal memory and oculomotor control are unimpaired in
asymptomatic adults with the genetic marker for Huntingtons disease. Arch Neurol 1993;50:799802.
105. Reveley MA, Dursun SM, Andrews H. Improvement of abnormal saccadic eye movements in Huntingtons disease by
sulpiride: a case study. Journal of Psychopharmacology 1994;8:262265.
106. Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS. Saccades in Huntingtons disease: initiation defects and distract-
ibility. Neurology 1987;37:364370.
107. Hikosaka O, Takikawa Y, Kawagoe R. Role of the basal ganglia in the control of purposive saccadic eye movements.
Physiol Rev 2000;80(3):953978.
108. Oyanagi K, Takeda S, Takahashi H, Ohama E, Ikuta F. A quantitative investigation of the substantia nigra in
Huntingtons disease. Ann Neurol 1989;26:1319.
109. Koeppen AH. The nucleus pontis centralis caudalis in Huntingtons disease. J Neurol Sci 1989;91:129141.
110. Leigh RJ, Parhad IM, Clark AW, Buettner-Ennever JA, Folstein SE. Brainstem findings in Huntingtons disease. J Neurol
Sci 1985;71:247256.
111. Rinne JO, Daniel SE, Scaravilli F, Pires M, Harding AE, Marsden CD. The neuropathological features of
neuroacanthocytosis. Mov Disord 1994;9:297304.
112. Burke JR, Wingfield MS, Lewis KE, Roses AD, Lee JE, Hulette C, et al. The haw river syndrome: dentatorubro-
pallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 1994;7:521524.
113. Lennox G, Jones R. Gaze distractibility in Wilsons disease. Ann Neurol 1989;25:415417.
114. Kirkham TH, Kamin DF. Slow saccadic eye movements in Wilsons disease. J Neurol Neurosurg Psychiatry
1974;37:191194.
115. Keane JR. Lid-opening apraxia in Wilsons disease. J Clin Neuro-ophthalmol 1988;8:3133.
116. Lewis RF. Ocular motor apraxia and ataxia-telangiectasia. Arch Neurol 2001;58(8):1312.
117. Lewis RF, Crawford TO. Ocular motor abnormalities in ataxia telangiectasia. Neurology 1998;50(Suppl).
118. Lewis RF, Crawford TO. Slow target-directed eye movements in ataxia-telangiectasia. Invest Ophthalmol Vis Sci
2002;43(3):686691.
119. Stell R, Bronstein AM, Plant GT, Harding AE. Ataxia telangiectasia: a reappraisal of the ocular motor features and their
value in the diagnosis of atypical cases. Mov Disord 1989;4:320329.
120. Rottach KG, von Maydell RD, Das VE, Zivotofsky AZ, DiScenna AO, Gordon JL, et al. Evidence for independent feed-
back control of horizontal and vertical saccades from NiemannPick type C disease. Vision Res 1997;37:36273638.
121. Garbutt S, Harris CM. Abnormal vertical optokinetic nystagmus in infants and children. Br J Ophthalmol
2000;84(5):451455.
122. Higgins JJ, Patterson MC, Dambrosia JM, Pikus AT, Pentchev PG, Sato S, et al. A clinical staging classification for
type C NiemannPick disease. Neurology 1992;42:22862290.
123. Stein RW, Kase CS, Hier DB, Caplan LR, Mohr JP. Caudate hemorrhage. Neurology 1984;34:15491554.
124. Vermersch AI, RM M, Rivaud S, Vidailhet M, Gaymard B, Agid Y, et al. Saccade disturbances after bilateral lentiform
nucleus lesions in humans. J Neurol Neurosurg Psychiatry 1996;60:179184.
125. Lekwuwa GU, Barnes GR. Cerebral control of eye movements. II. Timing of anticipatory eye movements, predictive
pursuit and phase errors in focal cerebral lesions. Brain 1996;119:491505.
126. Dursun SM, Burke JG, Reveley MA. Antisaccade eye movement abnormalities in Tourette syndrome: evidence for
cortico-striatal network dysfunction? J Psychopharmacol 2000;14(1):3739.
127. LeVasseur AL, Flanagan JR, Riopelle RJ, Munoz DP. Control of volitional and reflexive saccades in Tourettes syn-
drome. Brain 2001;124(Pt 10):20452058.
128. Mostofsky SH, Lasker AG, Singer HS, Denckla MB, Zee DS. Oculomotor abnormalities in boys with Tourette syn-
drome with and without ADHD. J Am Acad Child Adolesc Psychiatry 2001;40(12):14641472.
129. Munoz DP, Le Vasseur AL, Flanagan JR. Control of volitional and reflexive saccades in Tourettes syndrome. Prog
Brain Res 2002;140:467481.
130. Narita AS, Shawkat FS, Lask B, Taylor DS, Harris CM. Eye movement abnormalities in a case of Tourette syndrome.
Dev Med Child Neurol 1997;39:270273.
131. Straube A, Mennicken J-B, Riedel M, Eggert T, Mller N. Saccades in Gilles de la Tourettes syndrome. Movement
Disorders 1997;12:536546.
132. Binyon S, Prendergast M. Eye-movement tics in children. Dev Med Child Neurol 1991;33:343355.
133. Shawkat FS, Harris CM, Jacobs M, Taylor D, Brett EM. Eye movement tics. Brit J Ophthalmol 1992;76:697699.
134. Jinnah HA, Lewis RF, Visser JE, Eddey GE, Barabas G, Harris JC. Ocular motor dysfunction in LeschNyhan disease.
Pediatr Neurol 2001;24(3):200204.
135. Demer JL, Holds JB, Hovis LA. Ocular movements in essential blepharospasm. Am J Ophthalmol 1990;110:674682.
136. Aramideh M, Bour LJ, Koelman JHTM, Speelman JD, Ongerboer de Visser BW. Abnormal eye movements in ble-
pharospasm and involuntary levator palpebrae inhibition. Brain 1994;117:14571474.
137. Bollen E, Van Exel E, van der Velde EA, Buytels P, Bastiaanse J, van Dijk JG. Saccadic eye movements in idiopathic
blepharospasm. Movement Disorders 1996;11:678682.
138. Averbuch-Heller L, Rottach KG, Zivotofsky AZ, Suarez JI, Pettee AD, Remler BF et al. Torsional eye movements in
patients with skew deviation and spasmodic torticollis: responses to static and dynamic head roll. Neurology
1997;48:506514.
139. Stell R, Bronstein AM, Marsden CD. Vestibulo-ocular abnormalites in spasmodic torticollis before and after botulinum
toxin injections. J Neurol Neurosurg Psychiatry 1989;52:5762.
140. Anastasopoulos D, Nasios G, Psilas K, Mergner T, Maurer C, Lcking C-H. What is straight ahead to a patient with
torticollis? Brain 1998;121:91101.
141. Thaker GK, Nguyen JA, Tamminga CA. Increased saccadic distractibility in tardive dyskinesia: functional evidence for
subcortical GABA dysfunction. Biol Psychiatry 1989;25:4959.
142. Cardosa F, Eduardo C, Silva AP, Mota CCC. Chorea in fifty consecutive patients with rheumatic fever. Mov Disord
1997;12:701703.
143. Helmchen C, Hagenow A, Miesner J, Sprenger A, Rambold H, Wenzelburger R et al. Eye movement abnormalities in
essential tremor may indicate cerebellar dysfunction. Brain 2003;126:13191392.
Speech and Language Disturbances 255
16
Characterizing and Assessing Speech and Language
Disturbances
Carol Frattali and Joseph R. Duffy
INTRODUCTION
Speech and language disturbances in atypical parkinsonian disorders often present as initial symp-
toms or prominent neurobehavioral sequelae that worsen as the disease progresses. These disorders,
even in their early stages, can have profound effects on communicative functioning and, by exten-
sion, psychosocial well-being. In the face of neurodegenerative disease, the downward course of the
ability to communicate mirrors a loss considered elemental to the human condition; it unavoidably
robs the individual of a primary mode of expression of thoughts and ideas and, in its most severe
form, basic needs.
We draw a distinction between speech and language for purposes of clarity throughout this chap-
ter. These terms, sometimes used interchangeably or in combination by clinicians and researchers,
can be defined and distinguished in a hierarchical representational framework (1):
Language represents high-order cortico-cortical and cortical-subcortical network activity as a component
of cognitive-linguistic processes. These processes represent thoughts, feelings, and emotions that gener-
ate intent to communicate. They are next converted to verbal symbols that follow psycholinguistic rules
(e.g., phonology, morphology, syntax, semantics, pragmatics) as ordered meaningfully by propositional
elements (units of meaning). Language processes can be divided broadly as those that link thought (mean-
ing) to word forms (lexical-semantic) and those that sequence words and word endings to convey relation-
ships among words (syntactic) (2). In its disordered state, a breakdown of language, either at
lexical-semantic or syntactic process levels, is called aphasia.
Speech represents cortical-subcortical and brain stem activity via neuromuscular and central and periph-
eral nervous system activity involving two processes: motor speech programming and neuromuscular
execution. In motor speech programming, selection and organization of sensorimotor plans activate the
speech musculature at appropriate coarticulated times, durations, and intensities. During speech produc-
tion, the neuromuscular transmissions that involve respiration, phonation, resonation, articulation, and
prosody generate muscle contractions and finely coordinated movements of oral/motor structures that
generate an identifiable acoustic signal. In their disordered states, breakdowns of motor speech program-
ming and related neuromuscular activity are known as apraxia (nonverbal orofacial or buccofacial apraxia,
apraxia of speech) and dysarthria respectively.
Overview of Neuroanatomical Correlates

If approached from the perspective of classical neuroanatomical correlates, damage to portions of
the auditory and visual association areas of the cortex can result in comprehension deficits of the
spoken or written word. Damage to Wernickes area (Brodmann area 22), in the posterior portion of

255
256 Frattali and Duffy
the superior temporal gyrus of the dominant hemisphere, can result in a type of aphasia generally
called Wernickes aphasia. Wernickes aphasia is marked by reduced comprehension and fluent but
often paragrammatic verbal output characterized by word or nonword substitutions (paraphasias)
sometimes to the extent of producing fluent streams of non-English or neologistic jargon. In contrast,
damage to Brocas area (Brodmann areas 4445), in the third convolution or inferior gyrus of the
frontal lobe of the dominant hemisphere can result in a type of aphasia generally called Brocas
aphasia. Brocas aphasia, in contrast to Wernickes aphasia, is marked by relatively spared compre-
hension but sparse, effortful, nonfluent, and agrammatic verbal output. Along the parameters of flu-
ency, comprehension, repetition, and naming, other classic aphasia syndromes have been identified
including conduction, transcortical motor, transcortical sensory, and global aphasia.
The nondominant hemisphere is also increasingly implicated in its role in language functions,
particularly for global and thematic processing of narratives, pragmatics (relation between language
behavior and context in which it is used or interpreted), and prosody (elements of speech melody,
rate, stress, juncture, and duration) of language, and inferencing, coherence, and topic maintenance
during discourse processing and production (3,4).
Skilled motor programs for control of the larynx, lips, mouth, respiratory system, and other acces-
sory muscles of articulation are thought to be initiated from Brocas area. Damage to this area, or
within other parts of the left hemispheres network of structures involved in the planning and pro-
gramming of speech, results in apraxia of speech. Once these programs are activated via the premotor
zone of Brocas area, thus mediating orofacial and speech praxis, the facial and laryngeal regions of
the motor cortex (bilaterally) activate the speech musculature for actual emission of sound. The neu-
ral substrates of neuromuscular execution originate in the primary motor cortex (Brodmann area 4)
with pathways descending either directly or indirectly via the pyramidal or extrapyramidal tracts.
The pyramidal tract consists of upper motoneurons in the cerebral cortex with axons coursing through
the pyramidal tract in the medulla and terminating on anterior horn cells or interneurons in the spinal
cord. The pyramidal tract is composed of the corticospinal tract and the corticobulbar tract that influ-
ences cranial nerve activity. Types of dysarthria that could result (e.g., spastic dysarthria) would have
features of spasticity, increased muscle stretch reflexes, and clonus. In contrast, damage to lower
motoneurons from spinal and cranial nerves results in loss of voluntary and reflex responses of
muscles. The result would be hypotonia and absence of muscle stretch reflexes. Paralysis and atrophy
would occur, with the early stages of atrophy resulting in fibrillations and fasciculations. Dysarthrias
with damage to lower motoneurons would have characteristics of flaccidity (e.g., flaccid dysarthria)
(5). Other pathways that, if interrupted, would result in dysarthria, include extrapyramidal (coursing
through structures of the basal ganglia) and cerebellar motor pathways, which could result in hyper-
kinetic or hypokinetic components following extrapyramidal damage, or ataxic dysarthria following
cerebellar damage (see Appendix A for descriptions of aphasia syndromes, apraxias, and dysarthria
types; Appendix B for case descriptions and test stimuli used for audio samples of speech and lan-
guage disorders that accompany this chapter).
With advances in neuroimaging techniques, a dynamic systems rather than localization view of
speech and language functions is being adopted. Neuroimaging findings have shown that language
processing extends beyond the classical perisylvian region containing Brocas and Wernickes areas
and depends on many neural sites linked as systems. For example, both left temporal and prefrontal/
premotor cortices have been found to be activated by language processing, and do so selectively.
Neuroimaging studies have also shown that structures in the basal ganglia, thalamus, and supplemen-
tary motor area are engaged in language processing (6). Adding to the evidence of functional connec-
tivity, a recent study suggests that the anatomical and functional organization of the human auditory
cortical system points to multiple, parallel, hierarchically organized processing pathways involving
temporal, parietal, and frontal cortices (7). Computational mapping methods, which can combine
probabilistic maps of cytoarchitectonically defined regions with functional imaging data, hold prom-
ise for further elucidating brain region specialization. For example, Horwitz et al. (8). found that BA
45, not BA 44, is activated by oral or signed language production, implicating BA 45 as the part of
Brocas area that is fundamental to the modality-independent aspects of language generation.
Overview of Clinical Assessment Procedures

In order to clinically assess or scientifically examine aspects of speech and language, the clinician
or researcher employs a battery of instrumental and behavioral tests or experimental tasks that tap
both isolated and integrated components of speech and language. This approach is intended to deter-
mine relative strengths and weaknesses necessary for differential diagnosis, and to assess the conse-
quential effects of specific disturbances on functional communication in daily life contexts. Therefore,
a clinical battery is best composed of diagnostic instruments that measure the fine-grained features of
speech or language, and functional measures of communication that address speech or language as an
integrative construct in the context of daily life activities. In line with contemporary models of health
and disability that encompass both biophysical and psychosocial aspects of medical intervention
(e.g., World Health Organization International Classification of Functioning, Disability and Health;
see ref. 9). Clinicians and researchers are also extending clinical measurement to aspects of general
wellness or quality of life in order to determine the effect of an impairment or activity limitation on
social participation, autonomy, and self-worth.
Specific to language, behavioral measurement (online automated tasks that capture aspects of
processing or production as they occur in real time; standardized paper-and-pencil tests) typically
includes assessment of aspects of spontaneous speech, comprehension of oral and written language,
repetition of words and phrases of increasing length, naming of objects and actions, and writing.
Assessment of these parameters allows differential diagnosis of aphasia, either as a classical syn-
drome or as a constellation of deficits that point to specific neuropathological processes.
Assessment of speech typically is conducted via a combination of perceptual, acoustic, and physi-
ologic methods (1). Perceptual methods are based primarily on auditory-perceptual attributes that allow
clinical differential diagnosis. Acoustic methods contribute to acoustic quantification and description of
clinically perceived impaired speech and confirm perceptual judgments of, for example, slow speech
rate, breathy or tremulous voice quality, vocal pitch and loudness variations, hypernasal resonance,
and imprecise articulation. Their ability to make visible and quantify the speech signal can be used as
baseline data or as an index of stability or change. Physiologic methods focus on characterizing the
movements of speech structures and respiratory function, muscle contractions that generate move-
ment, temporal parameters and relationships among central and peripheral neural activity and biome-
chanical activity, and temporal relationships among active CNS (central nervous system) structures
during the planning and execution of speech (for comprehensive reviews of assessment methods, see
ref. 1 for motor speech disorders; refs. 10 and 11 for aphasia and related neurologic language disor-
ders; refs. 4 and 12 for right-hemisphere communication disorders; ref. 13 for functional communica-
tion and psychosocial consequences of neurologic communication disorders).
Our purposes here are to characterize the atypical Parkinsonian disorders of corticobasal degen-
eration (CBD), progressive supranuclear palsy (PSP), multiple systems atrophy (MSA), and demen-
tia with Lewy Body disease (DLB) from the perspectives of speech and language. For each diagnostic
group, we: (a) describe the neuroanatomical correlates of speech and language disorders, (b) identify
their clinically common and differentiating features on the bases of clinical assessment and clinical
research findings, and (c) offer some clinical management suggestions. We end by suggesting some
directions for future research. Table 1 abstracts the common and distinctive features of speech and
language disturbances across diagnostic groups.
258
Table 1
Common and Differentiating Features of Speech and Language by Diagnostic Group
Feature CBD PSP MSA Dementia with Lewy Bodies
Speech
Oral/motor Presence of nonverbal orofacial apraxia or Nonverbal orofacial Rare Rare
programming (praxis) apraxia of speech is commonly reported. apraxia or apraxia
Apraxia of speech often presents concurrently of speech is atypical.
with orofacial apraxia, whereas orofacial
apraxia may occur singly.
Neuromuscular Dysarthria is commonly reported Dysarthria is commonly reported Dysarthria is very common, Dysarthria (hypokinetic)
Execution with primarily hypokinetic and spastic features. with primarily hypokinetic and with hypokinetic probably common, but not
Dysarthria severity has not been found spastic components. Ataxic and predominating in MSA-P, early in course of disease.
to correlate with disease duration. hyperkinetic features are less and ataxic predominating
common. in MSA-C. Spastic,
hyperkinetic, and flaccid
types may also occur.
Language Aphasia present in approximately one third to Classic aphasias are atypical. Aphasia not expected. Aphasia is uncommon/
one half of cases, of mild to moderate severity, Dynamic aphasia is a common Dementia, when present, rare as an isolated or
and characterized primarily by anomic or non- presenting feature. Slowed can affect dominant deficit.
fluent features. Yes/no reversals may be present. information processing, reduced communication ability. Semantic deficits often
present but embedded
Predominantly receptive aphasic disturbances verbal fluency, and word retrieval within other
are atypical. deficit may also be present. cognitive impairments
(e.g., visuoperceptual,
working memory and
attention deficits,
fluctuating attention).
Frattali and Duffy
CBD, a rare neurodegenerative multisystem disorder of insidious onset, is typically described and
characterized by its asymmetric motor signs of limb function abnormalities. We report on the nature,
frequency, and severity of speech and language disturbances (see Chapters 1821).
Neuroanatomical Correlates
A striking feature of CBD is the asymmetry with which the disease presents. Its progressive nature
eventually involves extensive and bilateral damage to cortical and basal ganglionic structures. Both the
asymmetry and involvement of cerebral cortex and basal ganglia influence motor speech and language
disturbances, which increase in severity as the disease progresses. A structural magnetic resonance
imaging (MRI) study of 25 patients with CBD (14) found that this series of cases presented almost
exclusively with asymmetric posterior frontal and parietal atrophy, which explains the prevalence of
motor speech and language disorders owing to perisylvian area involvement. In addition, postmortem
studies of basal ganglia abnormalities explain a prevalent finding of hypokinetic features of dysarthria
resulting from damage to the extrapyramidal tract (the reader is referred to Chapter 4 for further informa-
tion regarding neuroanatomical correlates of CBD, PSP, MSA, and Dementia with Lewy bodies).
Speech Disturbances
Dysarthria in CBD is commonly reported (1518), but with variable dysarthria types including
hypokinetic and spastic features primarily and a wide frequency range from 29% to 93%. In their
comprehensive review of the literature, Lehman Blake et al. (18) found descriptions of speech or
language characteristics in 60 of 66 papers characterizing the features of CBD, representing 457
cases. Across these studies, motor speech disorders were identified in 55% of the cases, with dysar-
thria reported in 42% of the cases, nonverbal oral apraxia reported in 4% of the cases, and apraxia of
speech reported in 3.9% of the cases.
Among group studies, Riley et al. (15) documented the presence of dysarthria in about half of their
15 cases followed. Wenning and colleagues (16) found dysarthria in 29% of their sample during the
first visit (on average 3 [1.9] yr after onset of symptoms, and 75% of their sample during the last
visit (on average 6.1 [2.0] after onset of symptoms). In the Wenning et al. study, speech abnormali-
ties were variably described as slurred (n = 9), dysphonic (n = 5), mute (n = 5), aphonic (n = 4),
unintelligible (n = 4), echolalic (i.e., compulsive and unsolicited complete or partial repetition of
others utterances) (n = 2), or palilalic (i.e., compulsive word and phase repetitions with increased
rate usually during spontaneous speech) (n = 1), suggesting that identification of speech characteris-
tics also extended to language abnormalities (i.e., echolalia, and possibly mutism). Frattali and Sonies
(17) found dysarthria in 13 (93%) of their sample of 14 cases, therefore documenting dysarthria as a
prominent feature of CBD, even in the relatively early phases of disease progression (mean disease
duration = 3.5 yr). Using the dysarthria classifications of Darley, Aronson, and Brown (19), dysar-
thria varied in both type and severity. Of the 13 cases, the majority had mild symptoms, with 7 patients
presenting with mild symptoms, 5 with moderate symptoms, and only 1 case with severe symptoms.
Five patients (35.7%) had hypokinetic dysarthria, three patients (21.4%) had mixed dysarthria with
predominant hypokinetic features, two patients (14.3%) had mixed dysarthria with predominant
hyperkinetic features, two patients (14.3%) had mixed dysarthria with predominant spastic fea-
tures, and one patient (7.1%) had spastic dysarthria. It should be noted that 57% of this clinical
sample displayed hypokinetic features of dysarthriafeatures that characterize the dysarthria of
patients with parkinsonism resulting from extrapyramidal damage. This finding provides one expla-
nation for the misdiagnoses of CBD for Parkinsons disease (PD), particularly in early stages. Type
or severity of dysarthria did not correlate with duration of disease. Apraxia was also prevalent in this
sample, which was assessed in 13 patients. Of this sample, six patients (46%) had orofacial apraxia
and five patients (38%) had combined orofacial apraxia and apraxia of speech. Of interest was that
none of the patients had apraxia of speech in the absence of orofacial apraxia, but orofacial apraxia
presented singly in nearly 50% of this clinical sample. In the most severe cases of oral apraxia, two
patients (15.3%) could not voluntarily open their mouths, pucker their lips, or even volitionally per-
form activities automatic to oral movements (e.g., taking pills, drinking, or eating). The severity of
orofacial apraxia for these patients resulted in mechanical interference during their modified barium
swallow study procedures. When instructed to look straight ahead, hold bolus in mouth momentarily,
and swallow, both patients unintentionally opened their mouths with subsequent loss of bolus from
the oral cavity, commenting, I tried as hard as I could, or My mouth would not cooperate.
Lehman Blake et al. (18), in their study of 13 autopsy-confirmed cases of CBD, found dysarthria
and apraxia of speech in 31% and 38% of their sample, respectively. Of the patients with apraxia of
speech, two exhibited nonverbal oral apraxia. Of the patients with dysarthria, dysarthria type was
typically mixed, with either spastic or hypokinetic features present in all cases. Lehman Blake and
colleagues further found that speech and/or language difficulties were either the first sign, or among
the first signs of CBD in 6 (46%) of the 13 patients.
In another study of dysarthria and orofacial apraxia in CBD (20), 9 of the 10 patients followed
were mildly dysarthric on the bases of results from administration of the Frenchay Dysarthria As-
sessment (21). Severity of dysarthria, as assessed by an intelligibility score, correlated with global
severity but not with duration of disease. Voluntary movement of the tongue and lips were impaired
in all patients. Orofacial apraxia was present in the same nine patients. The apraxia scores, however,
did not correlate with the severity of dysarthria, suggesting independent underlying mechanisms. The
study concluded that the presence of dysarthria and orofacial apraxia is more frequent in CBD than
usually reported.
One study used discriminant analysis to sensitively characterize the variability of dysarthria in
20 patients with atypical parkinsonism (22), resulting in classifications among the three types of
hypokinetic, spastic, or ataxic dysarthria for the seven patients with CBD.
An atypical example of a patient with CBD who presented with isolated speech deficits for several
years before other symptoms emerged is found in the literature. Bergeron et al. (23) described an
unusual presentation in a case with an isolated speech disturbance for 5 yr before developing the
more typical features of CBD. The most severe neuroanatomical changes were observed in the left
motor cortex and adjacent Brocas area.
Language Disturbances
Aphasia, though included in accounts of the clinical syndrome of CBD, has neither been well
described in the literature nor sufficiently studied to determine its clinical frequency, behavioral
features, and neuropathological correlates (24). For example, Rinne et al. (25) reported language distur-
bances to be uncommon in CBD whereas Wenning et al. (16) reported one-third of their 14 patients to
have aphasia.
Because of their suspected underreporting in the literature, Frattali et al. (26) attempted to system-
atically identify and characterize the language deficits of CBD. Based on performance on the West-
ern Aphasia Battery (WAB) (27) and related language and cognitive measures, 53% of the15 patients
studied had identifiable aphasia syndromes, including anomic, Brocas, and transcortical motor
aphasias. WAB aphasia quotients (100 being normal) ranged from 56.3 to 89.8 (mean = 87.2 12.2)
suggesting the presence of mildly to moderately severe aphasia among the cases studied. As aphasia
quotients decreased, indicating increasing severity, aphasia classifications changed on an index of
fluency, from fluent anomic to nonfluent Brocas or transcortical motor aphasia. None of the patients
with aphasia showed predominant receptive aphasic disturbances, suggesting a predominance of fron-
tal involvement. Corroborating these findings, Lehman Blake et al. (18) found aphasia to be present
in 7 (54%) of the 13 patients with autopsy-confirmed CBD studied, with aphasia type most often
characterized as nonfluent (i.e., agrammatic, telegraphic, reduced phrase length) or anomic.
Recently, a unique behavioral feature of language disturbance, termed yes/no reversals, has been
described in CBD among other neurodegenerative diseases (28). For this phenomenon, a patient
verbalizes or gestures yes when meaning no, or vice versa, when responding to queries during
social discourse. Though not a distinguishable feature of CBD, the prospective arm of this study
found its presence in 11 of 34 patients (32%) or nearly one-third of those with CBD (i.e., met the
modified diagnostic criteria of Lang et al., ref. 29). Of those who presented with yes/no reversals and
for whom MRI data were available (N = 10), 7 had left-hemisphere involvement, suggesting a promi-
nent role of the left hemisphere in this lexically related cognitive sign. Although the phenomenon
was dissociated from features of aphasia, correlations of yes/no reversals with frontal lobe functions
suggested that higher-order mental disruptions (i.e., mental flexibility and inhibitory control) inter-
acting with motor programming disruptions were associated with the phenomenon.
Consistent with the findings of unusual case presentations depending on lesion topography in
CBD (23), an atypical case of progressive sensory aphasia resulting from CBD is found in the litera-
ture (30). This patient showed progressive sensory aphasia as an initial symptom, then developed
total aphasia within 6 yr and finally severe dementia. Neuropathological correlates were found in
the cerebral cortex, with the superior and transverse temporal gyri most severely affected, and subse-
quently in the inferior frontal gyrus. Degeneration of the subcortical gray matter was most severe in
the substantia nigra, and it was moderate to mild in the ventral part of the thalamus, globus pallidus,
and striatum. A subsequent survey of 28 pathologically evaluated cases of CBD revealed two similar
cases, both of which began with progressive aphasia and presented cortical degeneration in the supe-
rior temporal gyrus. Also in the literature is a case report of a patient with CBD whose initial symp-
tom was progressive nonfluent aphasia, with the distribution of her cortical lesion at autopsy
accentuated in the frontal language-related area (31). In summary, progressive aphasia, either fluent
or nonfluent, should be considered among the initial symptoms in CBD.
Clinical Management
The likelihood that speech and language disorders will become prominent features in CBD is high,
with the late-stage results severely compromising interpersonal communication. Given this profile,
periods of speech-language treatment regimens for the purposes of maintaining functional communi-
cation are warranted. Intervention should be tailored to the various stages of decline, beginning with
instruction of compensatory strategies (e.g., pacing and overarticulation to improve speech intelli-
gibility, instruction of communication partners to rephrase questions requiring simpler or shorter
responses, increasing the salience and structure of context during interactions, and reducing ambi-
ent noise in the patients environments to minimize distractions), proceeding to use of augmentative
communication systems (e.g., picture boards, portable voice amplifiers) tailored to the functional use
of the patient, and use of multimodality cues to enhance communication (e.g., say it, show it, draw it,
point it out). In late stages, the speech-language pathologist can serve as a facilitator to determine
what residual communication skills can be used by the patient and can tailor these skills to allow
communication of strong preferences or basic need.

PSP is a multisystem neurodegenerative disease that commonly presents with dysarthria among
its early features. Using the Litvan et al. criteria (32), probable PSP is diagnosed on the bases of
parkinsonism with age at onset over 40 yr, supranuclear vertical gaze palsy, postural instability in the
first year of illness, late mild dementia, and poor or absent response to L-dopa, in the absence of other
diseases that could explain the signs and symptoms.
PSP is differentiated neuropathologically from CBD by its limited cortical pathology, less com-
mon white matter pathology, and more common distribution of tract degeneration affecting the corti-
cospinal tract (33). In a recent review of 24 cases (14), MRI studies demonstrated symmetrical
cerebral atrophy in 19 patients (79.2%), midbrain atrophy in 22 cases (91.7%) (accounting for the
atypical hyperextended head positioning found in this clinical population), and a slight increase in
signal intensity in the periaqueductal region (consistent with cell loss and gliosis) in 16 patients
(66.7%). Because of progressive and selective neuronal loss in the subcortical gray nuclei and
brainstem, the neural pathways controlling oral sensorimotor function are affected in PSP.
Speech Disturbances
Sonies (34) conducted a systematic investigation of speech in 22 patients with a confirmed diag-
nosis of PSP. The patients, (12 males, 10 females) ranged in age from 52 to 77 yr with a mean
duration of illness of 41.14 mo. Seventeen patients (71%) were found to have one or more abnormal
speech symptoms. The most common symptom was imprecise articulation evident in 50% of the
patients. In frequency, this symptom was followed by reduced ability to sustain phonation and re-
duced voice volume in eight patients (36.4%), hypernasality in seven patients (31.8%), slowed rate of
speaking in five patients (22.7%), hoarseness, reduced variation in intonation (monotone), and slow
alternating motion rate in four patients (18.2%), rapid rate of speech and strained/strangled voice
quality in three patients (13.6%), aphonia in three patients (13.6%), and harsh voice quality, unintel-
ligible speech, and uncontrolled vocal bursts in two patients (9.1%). Sonies reported that these char-
acteristics can be categorized into both hypokinetic and hyperkinetic classifications of dysarthria,
with many combined characteristics suggesting mixed dysarthrias in this study sample. Also sug-
gested among the characteristics reported are features of spastic and ataxic dysarthrias.
Kluin et al. (35) also found a high frequency of dysarthria in PSP, consisting of prominent
hypokinetic and spastic components with less prominent ataxic components. In the 14 patients stud-
ied, all had hypokinetic and spastic components of dysarthria. Nine patients had ataxic components.
When compared with neuropathological findings, the severity of hypokinetic features correlated sig-
nificantly with the degree of neuronal loss and gliosis in the substantia nigra pars compacta and pars
reticulata, but not in the subthalamic nucleus, striatum, or globus pallidus. The severity of spastic and
ataxic components did not correlate significantly with neuropathological changes in the frontal cortex
or cerebellum. In an earlier study of 44 patients with PSP (36), all were found to have dysarthria with
variable degrees of spasticity, hypokinesia, and ataxia. Twenty-eight patients had all three compo-
nents, and 16 patients had only two components. Twenty-two patients (50%) had predominantly spas-
tic components, 15 (34%) had predominantly hypokinetic components, and 6 (14%) had predominantly
ataxic components. Stuttering also occurred in nine patient (20%) and palilalia in five (11%). The
finding of mixed dysarthria with a combination of spastic, hypokinetic, and ataxic components was
considered important to diagnosis and coincided with the neuropathologic changes found in PSP.
Consistent with the findings of Kluin et al. (35), Auzou et al. (22) found that the seven patients
with PSP all had hypokinetic dysarthria. Also noted were the speech abnormalities of palilalia and
repetitive speech phenomena in case studies (37,38).
Among atypical presentations, a case study of a patient with atypical PSP reports the presence of
progressive apraxia of speech and nonverbal oral apraxia, along with progressive nonfluent aphasia
(39). This patient showed progressive changes reflecting left- greater than right-cerebral-hemisphere
dysfunction with a more widespread cortical pathology than is typical of PSP, found at autopsy.
Though classical language disturbances are uncommon in PSP, dynamic aphasia can be a common
presenting symptom (see Appendix A for description). For example, a study of three cases found
presenting symptoms as difficulty with language output (40). Behavioral testing showed consider-
able impairment on a range of single-word tasks requiring active initiation and search strategies
(letter and category fluency, sentence completion), and on a test of narrative language production. In
contrast, naming from pictures and verbal descriptions, as well as word and sentence comprehension,
were largely intact. Esmonde et al. concluded that selective involvement of cognitive processes criti-
cal for planning and initiating language output may occur in some patients with PSP. This presenta-
tion resembles the phenomenon of verbal adynamia or dynamic aphasia seen in patients with frontal
lobe damage. The deficit is thought to reflect frontal deafferentation secondary to interruption of
frontostriatal feedback loops.
As mentioned above, a case study of a patient with atypical PSP also reported the presence of
progressive nonfluent aphasia and subsequent dementia (39). SPECT (single photon emission com-
puted tomography) scans showed progressive changes reflecting left > right cerebral hemisphere
dysfunction with hypoperfusion in the left temporal > frontal > parietal cortex. Neuropathological
examination revealed findings characteristics of PSP but with more widespread cortical pathology.
Thus, PSP can present clinically as an atypical dementing syndrome dominated by progressive
nonfluent aphasia and apraxia of speech.
Among characteristic language or related cognitive features of PSP, Bak and Hodges (41) include
general slowness of information processing, deficits in focused and divided attention, impaired ini-
tiation (a symptom of dynamic aphasia), grossly reduced verbal fluency, and memory impairment
affecting active recall (41) Word retrieval deficit has also been reported by Gurd and Hodges (42).
Two cases of PSP demonstrated word-finding difficulties associated with pervasive problems in word
retrieval. The deficit was also found to be less amenable to cue facilitation than that found in word
retrieval deficits associated with PD. Reduced frontal perfusion was found in one of the two cases.
Clinical Management
As in the management of other progressive neurological diseases, educating communication part-
ners to facilitate interactions, and offering compensatory strategies to maintain functional communi-
cation over time, which changes in need and method as the disease progresses, become important
aspects of clinical intervention. For those PSP patients with dynamic aphasia, it is helpful for com-
munication partners to explicitly lead the patient into conversations by asking direct questions that
are weighted toward the concrete and personal rather than abstract, and to increase the salience of
context during interactions. If processing is slowed, it is helpful to allow extra time (without interrup-
tion) for the patient to process and respond. Verifying receipt of the message conveyed before pro-
ceeding in an interaction is also helpful.
For dysarthria, clinical interventions can include the use of pacing methods to slow rate of speech,
and the use of pausing, chunking streams of speech into units, and, in severe, cases, a one-word-at-a-
time approach. If hypophonia is present, frequent cues to increase loudness, and use of voice ampli-
fiers and other augmentative communication devices/systems may be warranted as tailored to the
abilities of the patient.

MSA is an uncommon, sporadic (nonfamilial), and distinct neurodegenerative condition that is
characterized by varying combinations of parkinsonism, cerebellar ataxia, spasticity, and autonomic
dysfunction (43). Its onset is usually in the sixth to seventh decade, with a duration range of 118 yr
and median survival of about 9 yr (44,45). Recognizing MSA as distinct from PD is important be-
cause prognosis, counseling, and treatment of the communication problems of people with PD and
MSA differ.
MSA is a plural disorder, with three previously recognized subtypes that include ShyDrager
syndrome, sporadic olivopontocerebellar atrophy (OPCA), and striatonigral degeneration. A recent
consensus statement on MSA (45) recommended replacing these subtype designations with MSA-P
if parkinsonian features predominate, and MSA-C if cerebellar features predominate. Because the
literature contains references to both subtyping schemes, both will be used here when applicable.
The range of neuroanatomic involvement in MSA includes neuronal loss and gliosis in the basal
ganglia (neostriatum), substantia nigra, cerebellum, inferior olives, middle cerebellar peduncles, basis
pontine nuclei, intermediolateral and anterior horn cells, and corticospinal tracts. Some investigations
have reported cerebral atrophy, especially in the frontal lobes (4649). In light of the motor speech
disorders that can occur, it is reasonable to assume that the corticobulbar tracts can also be involved.
The predominant loci of nerve cell loss vary across the MSA subtypes, but with overlap, and they are
associated with the prominent but overlapping clinical features, including speech and language find-
ings. Thus, in striatonigral degeneration (MSA-P) nerve cell loss and gliosis predominate in the neo-
striatum and substantia nigra; parkinsonian features, including hypokinetic dysarthria, are prominent
and beneficial response to levodopa is limited because striatal neurons containing dopamine receptors
are lost. In OPCA (MSA-C), there may be prominent involvement of the cerebellum, explaining clini-
cal cerebellar features, including ataxic dysarthria. In ShyDrager syndrome, early and prominent dy-
sautonomia (including orthostatic hypotension, incontinence, reduced respiration, and impotence)
stems from loss of preganglionic sympathetic neurons in the intermediolateral horns; because the sub-
stantia nigra, striatum, cerebellum, and corticospinal tracts are also affected, parkinsonism (possibly
including hypokinetic dysarthria) with suboptimal response to levodopa, ataxia (possibly including
ataxic dysarthria), and spasticity (possibly including spastic dysarthria) may also be evident (50,51).
Speech Disturbances
A review of clinical studies suggest that apraxia of speech (AOS) is rarely, if ever, associated with
MSA. For example, in Duffys (1) review of etiologies for 107 quasirandomly selected cases with
AOS, in which 16% of the cases had degenerative neurologic disease, no patient had a diagnosis of
MSA or any of its subtypes. And, in a review of 61 patients with AOS associated with degenerative
neurologic disease, in only 1 patient was MSA (vs PSP) considered a diagnostic possibility (52).
Relatedly, Leiguardia et al. (53) found no evidence of limb, nonverbal oral or respiratory apraxia in 10
patients with MSA.
In contrast, dysarthria is common, sometimes occurring in 100% of patients in series unselected for
dysarthria (54). It tends to emerge relatively early (median onset within the first 2 yr) in the course of the
disease, generally earlier than in PD, and on average the dysarthrias of MSA are believed to be more
severe than in PD (5557). Mller et al. (55) reported severe (i.e., unintelligible) speech impairment in
60% of their 15 MSA patients at the time of their last clinic visit (a median of 5 mo before death).
The types of dysarthria generally correlate with other neuromotor signs of MSA, and the dysar-
thria type is most often mixed. MSA, including each of its subtypes, accounted for about 8% of all
mixed dysarthrias attributable to degenerative neurologic disease in a series of patients reviewed by
Duffy (1). Kluin et al. (54) evaluated 46 patients with MSA, unselected for type of speech disorder.
All had dysarthria with combinations of hypokinetic, ataxic, and spastic types. Seventy percent had
all three types, 28% had two types, and one patient had only ataxic dysarthria. The hypokinetic
component predominated in 48%, the ataxic component in 35%, and the spastic component in 11%.
The presence in MSA of dysarthria types other than hypokinetic is important to differential diagno-
sis. For example, because untreated PD is associated only with hypokinetic dysarthria, recognizing
another dysarthria type or a mixed dysarthria can help distinguish PD from MSA or other degenera-
tive neurologic diseases.
The most comprehensive study of dysarthria in a MSA subtype is that by Linebaugh (58), who
reviewed 80 cases with a diagnosis of ShyDrager syndrome seen at the Mayo Clinic over a 14-yr
period. Forty-four percent had dysarthria, 43% ataxic dysarthria, 31% hypokinetic dysarthria, and
26% mixed dysarthrias. The mixed dysarthrias included hypokinetic-ataxic, ataxic-spastic, and spas-
tic-ataxic-hypokinetic.
The dysarthrias associated with OPCA (MSA-C) have received little study. Gilman and Kluin
(59) examined three patients with OPCA who had clinical signs of cerebellar involvement plus
corticobulbar findings suggestive of spasticity (e.g., pseudobulbar affect, active gag reflex, slow facial
movements). The primary speech findings were consistent with mixed ataxic-spastic dysarthria, but
some had stridor, which would suggest a flaccid component. Hartman and ONeill (60) discussed a
man with a clinical diagnosis of OPCA whose predominant deviant speech characteristics were con-
sistent with a mixed flaccidspastic dysarthria (stuttering-like dysfluencies were also apparent, pos-
sibly reflecting a reemergence of developmental stuttering.). Palatal myoclonus, technically a
hyperkinetic dysarthria if apparent in speech, has been noted as variably present in OPCA (61). Because
features of parkinsonism can occur in OPCA, hypokinetic dysarthria should also be expected in some
cases. It thus appears that a variety of dysarthria types are possible. Considering the areas of the
motor system that are commonly affected, ataxic, spastic, hypokinetic, and flaccid dysarthria, singly
or in combination, are the common expected types.
The dysarthrias associated with striatonigral degeneration (MSA-P) have not been studied system-
atically, but dysarthria is probably common. Hypokinetic dysarthria is the most common expected type,
but hyperkinetic and perhaps spastic dysarthria would seem possible based on the common loci of
pathology.
Stridor can be present in as many as one-third of people with MSA (44). It can be associated with
severe upper-airway obstruction and death, and nasal continuous positive airway pressure or tracheo-
stomy is often recommended to treat it. It is manifest as excessive snoring and sleep apnea, and
sometimes is evident as audible inspiration just before speech is initiated, or at phrase boundaries
during ongoing speech. Inhalatory stridor associated with various combinations of spastic, ataxic,
and hypokinetic dysarthria is probably uncommon in degenerative diseases other than MSA. The
cause of the stridor is some matter of debate. It is commonly thought to reflect abductor laryngeal
paresis or paralysis, particularly in the posterior cricoarytenoid muscles with pathology in the nucleus
ambiguous (62), but more recent evidence suggests that laryngeal dystonia may be the cause (63,64).
Relatedly, cervical and limb dystonia are not uncommon in untreated patients with MSA-P, and
levodopa-induced neck and face dystonia can also occur (65).
To our knowledge, aphasia has not been reported and, in fact, focal aphasia is considered one
exclusionary criterion for MSA diagnosis (45). Dementia is considered to be a variably evident defi-
cit (61), perhaps present to a mildmoderate degree in about one-fifth of patients (44). When present,
nonaphasic cognitive deficits can influence an affected individuals communication abilities.
Clinical Management
In MSA, management efforts focus primarily on the dysarthrias. Their emphasis may be on: (a)
improving physiologic support for speech to improve speech intelligibility, (b) compensatory strate-
gies to improve the intelligibility or comprehensibility of speech, or (c) developing alternative or
augmentative means of communication. In general, such approaches are effective in improving com-
munication ability (see ref. 66, for a review of data on treatment effectiveness). Such management is
often staged during the course of the disease, with early efforts aimed at improving speech or main-
taining intelligibility, and later efforts aimed at developing augmentative or alternative means of
communication. If the dysarthria is hypokinetic or predominantly hypokinetic, the patient may ben-
efit from Lee Silverman Voice Treatment (LSVT), a program involving vigorous vocal exercise that
has been shown to be effective for the dysarthria associated with PD (see ref. 67, for a comprehensive
review). If individuals undergo tracheotomy for stridor/sleep apnea, a number of prosthetic devices
are available to permit vocalization or the generation of artificial voice.

DLB is a clinically identifiable dementing illness that often includes parkinsonian features (68).
The average ages at onset is 75 yr, and mean survival is about 3.5 yr, with a range of 120 yr (69).
The central feature of DLB is progressively disabling dementia, but its core features, of which two
out of three are necessary for a probable diagnosis, include fluctuating cognition, visual hallucina-
tions, and motor signs of parkinsonism. Additional problems that may support the diagnosis include
falls, syncope, loss of consciousness, delusions and hallucinations (auditory, olfactory, tactile), and
sensitivity to neuroleptic medications (70). At its end stage profound dementia and parkinsonism
may be present (70). Speech and language deficits may be present in DLB but they do not contribute
to differential diagnosis of the condition.
The neuropathology of DLB is complex. This brief discussion will emphasize the loci of pathol-
ogy because of their direct relevance to clinical features, particularly speech and language deficits.
Pathologic abnormalities are found in the neocortex, limbic cortex, subcortical nuclei, and
brainstem, but brainstem or cortical Lewy bodies (LBs) are the only features that must be present for
a pathologic diagnosis (70). Spongioform changes and some pathologic features of Alzheimers dis-
ease (AD) may also be present. Limbic and neocortical LBs are logically related to neuropsychiatric
and cognitive signs and symptoms. LBs in spinal cord sympathetic neurons and dorsal vagal nuclei
may be linked to autonomic failure and dysphagia (and some aspects of dysarthria), respectively
(69,70).
On neuroimaging, in contrast to findings in AD, people with DLB have relative preservation of
medial temporal structures, including the hippocampus. In comparison to AD, DLB is associated
with greater occipital hypoperfusion and greater compromise in the nigrostriatal pathways (69).
Speech Disturbances
Mller et al. (55) examined the evolution of dysarthria and dysphagia in 14 patients with patho-
logically confirmed DLB. Dysarthria was present in 72%. Dysarthria and dysphagia onset were not
early in DLB (median onset was 42 and 43 mo, respectively), but were typically earlier than in PD.
Dysarthria was said to be predominantly hypophonic/monotonous in 70%. Severe speech impairment
at the last clinical visit (~ 5 mo before death) was present in 29%. McKeith et al. (70) note that motor
features of parkinsonism are typically mild but can include hypophonic speech. In general,
hypokinetic dysarthria is the primary and perhaps only neurologic motor speech disturbance expected
in DLB.
Language impairments, particularly aphasia, are not among the signs or symptoms included in
clinical criteria for the diagnosis of DLB, and only infrequently are they mentioned in case descrip-
tions. Only one single case study (71) has documented primary progressive aphasia as the initial
presentation (and only sign for 6 yr) in a patient who eventually developed visual hallucinations and
parkinsonism; the pathology was that of DLB and AD. A few additional case descriptions have made
reference to the presence of aphasia, or signs suggestive of aphasia, such as difficulty with word
recall and retrieval and sentence completion (72,73), but the language deficits in each case were
vaguely described and appeared to be part of widespread cognitive and personality changes.
Deficits within the language domain probably are not uncommon but they likely are most often
embedded within a constellation of other cognitive impairments. For example, in a study of people
with AD and DLB, matched in age and severity of cognitive impairment, Lambon Ralph et al. (74)
found both groups to have semantic memory deficits as reflected in a graded naming test, picture
naming, spoken word to picture matching, semantic association, a category sorting test, and a word
and letter fluency test. In comparison to the AD group, the DLB group had more severe semantic
deficits for pictures than words, as well as visuoperceptual deficits. The authors concluded that patients
with DLB have a generalized dementia that affects many different domains of performance, including
semantic abilities.
Although impairment of cognitive functions in DLB appears broad, cognitive reaction time, atten-
tion, fluctuations of attention, working memory, and (particularly) visuoperceptive abilities are often
noteworthy and, on average, are more impaired in DLB than AD (7578). McKeith et al. (70) note
that prominent memory impairment may not be evident early in DLB, but that with disease progression
deficits in memory, language, and other cognitive skills frequently overlap with those seen in AD.
Clinical Management
If hypokinetic dysarthria is present, and cognitive deficits not severe, LSVT may help improve
loudness and intelligibility. Otherwise listener and speaker strategies must be considered to maxi-
mize comprehensibility (e.g., amplifier, pacing board, reduce noise, intelligibility breakdown repair
strategies). If visuoperceptual deficits are prominent, increased emphasis is placed on the verbal (and
other nonvisual) modality to enhance comprehension. It is important to work with significant others
to identify strategies to maximize communication (e.g., how best to provide verbal input, how best to
ask or make confirmatory statements to clarify needs and wants). With the exception of the complica-
tion of visuoperceptual deficits, these strategies would probably be common to those often used for
people with AD.
DIRECTIONS FOR FUTURE RESEARCH

Directions for future research point strongly toward the need to develop both specific and com-
bined behavioral, pharmacotherapeutic, or neurostimulation interventions that might slow, arrest, or
even reverse the progression of the speech and language manifestations of atypical parkinsonian
disorders (see Table 2 for summary). For example, cholinergic stimulation using centrally active
cholinesterase inhibitors may be beneficial in improving cognitive or linguistic performance in the
early stages of disease progression. Transcranial magnetic stimulation (TMS) can also be used to
investigate the excitability of motor cortices in neurodegenerative diseases, thus providing important
information having pathophysiological and clinical relevance. For example, TMS can be used to
study the effects of drugs and surgery thus introducing the possibility of monitoring the action of
treatment of movement disorders (including dysarthria) on cortical excitability (79). As medical treat-
ments become available for atypical parkinsonian conditions, their effects on speech and language
abilities need to be established. Relative to motor speech abilities, for example, medical interventions
that may improve limb motor deficits may or may not have a positive effect on speech.
The epidemiology of speech and language disorders must also evolve to a more accurate science.
This calls for the development of explicit clinical diagnostic criteria for sensitively and differentially
characterizing the features of these disorders and the relative influence of each on communication
ability. Currently, comparisons across natural history studies suffer from variability in their assess-
ment methods and descriptions of the various features that constitute dysarthria, apraxia, or aphasia.
A second limitation across studies is small sample size. Therefore, multi-institution studies, using
consistent and agreed-upon taxonomies in characterizing speech and language functions, and consis-
tent methods in assessing these functions, could increase our understanding of the pathogeneses of
these diseases. A solid foundation for such a taxonomy for speech functions has already been estab-
lished by the extensive work of Darley, Aronson, and Brown (19); any effort to develop explicit
criteria for differentiating the dysarthrias should begin with their seminal work.
The efficacy of various approaches to management of communication disorders, including how
approaches to management may be influenced by some of the unique characteristics of these diseases
(e.g., limb apraxia, visual deficits, deficits of attention) will need to be determined. Also to be deter-
mined are the best way to stage management during the course of these conditions. For example,
when should management attempt to improve impairment (e.g., LSVT) vs work to compensate for
deficits?
Of future interest will also be the combined effects of disease progression and aging, with a nor-
mative databank created against which to compare various dimensions of performance. These com-
parisons may help to parse out the effects of the disease thus increasing clinical management
precision. Neuroimaging studies should investigate the effects of neuronal loss from the perspective
of studying neural networks and functional connectivity. The methods of probabilistic computational
mapping and structural equation modeling will assist with hypothesis-driven studies that can eluci-
268
Table 2
Summary of Future Research Directions
Study Type Example
Drug Effect Cholinergic stimulation to improve cognitive and linguistic skills in the early stages of disease progression.
Neurostimulation TMS to investigate the effects of surgery and drugs on cortical excitability and their relationship to changes in speech.
Medical Intervention Nerve growth implantation and relative effects on motor speech abilities.
Epidemiology Development of explicit clinical diagnostic criteria and an agreed-upon taxonomy for characterizing speech and language disor-
ders.
Treatment Efficacy Conventional and new behavioral approaches to speech or language management as influenced by unique disease characteristics
(e.g., limb apraxia, visual deficits, attention deficit).
Natural History Development of normative databank to determined combined effects of disease progression and aging.
Neuroimaging Investigations of the effects of neuronal loss from the perspective of functional connectivity, and their relationships with spe-
cific speech and language disturbances.
Genetic Identification of gene abnormalities to assist in early diagnosis and increase the effectiveness of preventive therapies. Establish
the relationships between specific genetic findings and speech and language manifestations.
Frattali and Duffy
date links between neural breakdowns and behavioral effects (8). Finally genetic studies designed to
identify gene abnormalities may assist in reducing the incidence and prevalence of atypical parkinso-
nian disorders and can assist in their early diagnosis and increase the effectiveness of preventive
therapies.
ACKNOWLEDGMENTS
The authors would like to thank Yun Kyeong Kang for expert assistance in manuscript and audio
samples preparation.
REFERENCES
1. Duffy JR. Motor Speech Disorders: Substrates, Differential Diagnosis, and Management. St. Louis: Mosby, 1995.
2. Mesulam M-M. Principles of Behavioral and Cognitive Neurology. New York: Oxford University Press, 2000.
3. Beeman M, Chiarello C, eds. Right Hemisphere Language Comprehension: Perspectives from Cognitive Neuroscience.
Erlbaum: Mahwah, NJ, 1998.
4. Tompkins CA. Right Hemisphere Communication Disorders: Theory and Management. San Diego: Singular, 1995.
5. Gilman S, Newman SW, Manter JT, Gatz AJ. Essentials of clinical neuroanatomy and neurophysiology. 6 ed. Philadel-
phia: F.A. Davis Company, 1996.
6. Damasio A, Damasio H. Aphasia and the neural basis of language. In: Mesulam M-M, ed. Principles of Behavioral and
Cognitive Neurology. New York: Oxford University Press, 2000:294315.
7. Scott S, Johnsrude J. The neuroanatomical and functional organization of speech perception. TRENDS in Neurosciences
2003;26(2):100107.
8. Horwitz B, Amunts K, Bhattacharyya R, et al., Activation of Brocas area during the production of spoken and signed
language: a combined cytoarchitectonic mapping and PET analysis. Neuropsychologia 2003;41(14):18681876.
9. World Health Organization, International Classification of Functioning, Disability and Health (ICF). Geneva, Switzer-
land: WHO, 2001.
10. LaPointe LL, ed. Aphasia and Related Neurogenic Language Disorder, 3rd ed., New York: Thieme, is still in press.
11. Davis G. Aphasiology: Disorders and Clinical Practice. Boston: Allyn & Bacon, 2000.
12. Myers PS. Right Hemisphere Damage: Disorders of Communication and Cognition. 1999, San Diego: Singular, 1999.
13. Worrall LW, Frattali C, eds. Neurogenic Communication Disorders: A Functional Approach. New York: Thieme, 2000.
14. Savoiardo M, Grisoli M, Girotti F. Magnetic resonance imaging in CBD, related atypical parkinsonian disorders, and
dementias. In: Litvan I, Goetz C, Lang AE, eds. Advance in Neurology, Corticobasal Degeneration and Related Disor-
ders, vol. 82. Philadelphia: Lippincott Williams & Wilkins, 2000:197208.
15. Riley DE, Lang AE, Lewis A, et al., Cortical-basal ganglionic degeneration. Neurology 1990;40:12031212.
16. Wenning G, Litvan I, Jankovic J, et al. Natural history and survival of 14 patients with autopsy-confirmed corticobasal
degeneration. J Neurol Neurosurg Psychiatry 1998;64:184189.
17. Frattali CM, Sonies BC. Speech and swallowing disturbances in corticobasal degeneration. In: Litvan I, Goetz CG,
Lang AE, eds. Advances in Neurology, Corticobasal Degeneration and Related Disorders, vol. 82. Philadelphia:
Lippincott Williamas & Wilkins, 2000:153160.
18. Lehman Blake M, Duffy JR, Boeve BF, et al., Speech and language disorders associated with corticalbasal degenera-
tion. J Med Speech Lang Pathol 2003;11:131146.
19. Darley FL, Aronson AE, Brown JR. Motor Speech Disorders. Philadelphia: Saunders, 1975.
20. Ozsancak C, Auzou P, Hannequin D. Dysarthria and orofacial apraxia in cortical degeneration. Mov Disord
2000;15(5):905910.
21. Enderby P. Frenchay Dysarthria Assessment. San Diego: College-Hill, 1986.
22. Auzou P, Ozsancak C, Jan M, et al., Evaluation of motor speech function to diagnose different types of dysarthria. Rev
Neurol (Paris) 2000;156(1):4752.
23. Bergeron C, Pollanen M, Weyer L, et al. Unusual clinical presentations of cortical basal ganglionic degeneration. Ann
Neurol 1996;40(6):893900.
24. Black SE. Aphasia in corticobasal degeneration. In: Litvan I, Goetz CG, Lang AE, eds. Corticobasal degeneration and
related disorders. Philadelphia: Lippincott Williams & Wilkins, 2000:123133.
25. Rinne J, Lee M, P. Thompson PD, Marsden C. Corticobasal degeneration. A Clinical study of 36 cases. Brain
1994;117:11831196.
26. Frattali CM, Grafman J, Patronas N, Makhlouf MS, Litvan I. Language disturbances in corticobasal degeneration.
Neurology 2000;54(4)990992.
27. Kertesz A. Western Aphasia Battery. Test Manual. San Antonio, TX: Psychological Corporation, 1982.
28. Frattali CM, Duffy JR, Litvan I, et al., Yes/no reversals as neurobehavioral sequela: a disorder of language, praxis or
inhibitory control? Eur J Neurol 2003;10:103106.
29. Lang AE, Riley DE, BergeronC. Cortical-basal ganglionic degeneration. In: Calne DB, ed. Neurodegenerative Dis-
eases. Philadelphia: Saunders, 1994:877894.
30. Ikeda K, Akiyama H, Iritana S, et al. Corticobasal degeneration with primary progressive aphasia and accentuated
cortical lesion in superior temporal gyrus: Case report and review. Acta Neuropathol 1996;92(5):534539.
31. Mimura M, Oda T, Tsuchiya K, et al. Corticobasal degeneration presenting with nonfluent primary progressive apha-
sia: A clinicopathological study. J Neurol Sci 2001;183:1926.
32. Litvan I, Agid Y, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy
(SteeleRichardsonOlszewski syndrome). Neurology 1996:46:922930.
33. Dickson DW, Liu WK, Rsiezak-Reding H, Yen SH. Neuropathologic and molecular considerations. In: Litvan I, Goetz
CG, Lang AE, eds. Advances in Neurology, Corticobasal Degeneration and Related Disorders, vol. 82. Philadelphia:
Lippincott Williams & Wilkins, 2000:927.
34. Sonies B. Swallowing and speech disturbances. In: Litvan I, Agid Y, eds. Progressive Supranuclear Palsy: Clinical and
Research Approaches. New York: Oxford University Press, 1992:240253.
35. Kluin KJ, Gilman S, Foster NL, et al. Neuropathological correlates of dysarthria in progressive supranuclear palsy.
Arch Neurol 2001;58:265269.
36. Kluin KJ, Foster NL, Berent S, Gilman S. Perceptual analysis of speech disorders in progressive supranuclear palsy.
Neurology 1993;43:563566.
37. Benke T, Butterworth B. Palilalia and repetitive speech: Two case studies. Brain Lang 2001;78:6281.
38. Benke T, Hohenstein C, Poewe W, Butterworth B. Repetitive speech phenomena in Parkinsons disease. J Neurol
Neurosurg Psychiatry 2000:63:319325.
39. Boeve B, Dickenson D, Duffy JR, et al. Progressive nonfluent aphasia and subsequent aphasic dementia associated
with atypical progressive supranuclear palsy pathology. Eur Neurol 2003;49(2):7278.
40. Esmonde T, Giles E, Xuereb J, Hodges J. Progressive supranuclear palsy presenting with dynamic aphasia. J Neurol
41. Bak TH, Hodges JR. The neuropsychology of progressive supranuclear palsy. Neurocase, 1998;4:8994.
42. Gurd JM, Hodges JR. Word-retrieval in two cases of progressive supranuclear palsy. Behav Neurol 1997;10:3141.
43. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology, Consensus
statement on the definition of orthostatic hypotention, pure autonomic failure, and multiple system atrophy. Neurology
1996;46(5):1470.
44. Bower JH. Multiple system atrophy. In: Adler CH Ahlskog JE, eds. Parkinsons Disease and Movement Disorders:
Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana, 2000.
1999;163:9498.
46. Konagaya M, Konagaya Y, Sakai M, et al. Progressive cerebral atrophy in multiple system atrophy. J Neurol Sci
2002;195:123127.
47. Naka H, Ohshita T, Maruta Y, et al. Characteristic MRI findings in multiple system atrophy: comparison of the three
subtypes. Neuroradiology 2002;44:204209.
48. Su M, Yoshida Y, Hirata, Y, et al. Primary involvement of the motor area in association with the nigrostriatal pathway
in multiple system atrophy: neuropathological and morphometric evaluations. Acta Neuropathol 2001;101:5764.
49. Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese
patients. Brain 2002;125:10701083.
50. Dewey RB. Clinical features of Parkinsons disease. In: Adler CH, Ahlskog JE, eds. Parkinsons Disease and Move-
ment Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, NJ: Humana Press, 2000.
51. Fahn S, Przedborski S. Parkinsonism. In: Rowland L, ed. Merritts Neurology, Philadelphia: Lippincott Williams &
Wilkins, 2000.
52. Duffy JR. Progressive apraxia of speech: A retrospective study. Paper presented at the Conference on Motor Speech.
Williamsburg, VA, 2002.
53. Leiguardia RC, Pramstaller PP, Merello M, et al. Apraxia in Parkinsons disease, progressive supranuclear palsy, mul-
tiple system atrophy and neuroleptic-induced parkinsonism. Brain 1997;120:7590.
54. Kluin K, Gilman S, Lohman M, Junck L. Characteristics of the dysarthria of multiple system atrophy. Arch Neurol
1996;53:545548.
55. Mller J, Wenning GK, Verny M, et al. Progression of dysarthria and dysphasia in postmortem-confirmed parkinsonian
disorders. Arch Neurol 2001;58:259264.
56. Quinn N. Multiple system atrophy: the nature of the beast [review]. J Neurol Neurosurg Psychiatry 1989;52(Suppl):
7889.
57. Wenning G, Ben-Shlomo Y, Hughes A, et al. What clinical features are most useful to distinguish definite multiple
atrophy from Parkinsons disease? J Neurol Neurosurg Psychiatry 2000;68:434440.
58. Linebaugh CW. The dysarthria of ShyDrager syndrome. J Speech Hear Disord 1979;44:5560.
59. Gilman, S. and D. Kluin, Perceptual analysis of speech disorders in Friedreich disease and olivopontocerebellar atro-
phy. In: Bloedel JR, Dichgans J, Precht W, eds. Cerebellar Functions, New York: Springer-Verlag, 1984.
60. Hartman DE, ONeil BP. Progressive dysfluency, dysphagia, dysarthria: a case of olivopontocerebellar atrophy. In:
Yorkston KM, Beukelman DR, eds. Recent Advances in Dysarthria. Boston: College-Hill, 1989.
61. Duvoisin RC. The olivopontocerebellar atrophies. In: Marsden CD, Fahn S, eds. Movement Disorders 2. Boston:
Butterworth, 1987.
62. Bannister R, Gibson W, Michael L, Oppenheimer DR. Laryngeal abductor paralysis in multiple system atrophy; a
report on three necropsied cases, with observations on the laryngeal muscles and the nuclei ambigui. Brain
1981;104:351368.
63. Benarroche EE, Schmeichel AM, Parisi JE. Preservation of branchiomotor neurons of the nucleus ambiguus in multiple
system atrophy. Neurology 2003;60:115117.
64. Isono S, Shiba K, Yamaguchi M, et al. Pathogenesis of laryngeal narrowing in patients with multiple system atrophy. J
Physiol 2001;536:237249.
65. Boesch S, Wenning GK, Ransmayr G, Poewe W. Dystonia in multiple system atrophy. J Neurol Neurosurg Psychiatry
2002;72:300303.
66. Yorkston KM. Treatment efficacy: dysarthria. J Speech Hear Res 1996;39:S46S57.
67. Fox CM, Morrison CE, Ramig LO, Sapir S. Current perspectives on the Lee Silverman Voice Treatment (LSVT) for
individuals with idiopathic Parkinson disease. Am J Speech Lang Pathol 2002;11:111123.
68. Small S, Mayeux R. Alzheimer disease and related dementias. In: Rowland LP, ed. Merritts Neurology. Philadelphia:
Lippincott Williams & Wilkins, 2000.
2001;16:S12S18.
70. McKeith I, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathological diagnosis of dementia
with Lewy bodies (DLB); report of the consortium on DLB international workshop. Neurology 1996;47:11131124.
71. Caselli R, Beach TG, Sue LI, et al., Progressive aphasia with Lewy bodies. Dement Geriatr Cogn Disord 2002;14:5558.
72. Galvin JE, Lee SL, Perry A, et al., Familial dementia with Lewy bodies: clinicopathologic analysis of two kindreds.
Neurology 2002;59:10791082.
73. Tsuang DW, Dalan AM, Eugenio CJ, et al., Familial dementia with Lewy bodies: a clinical and neuropathological study
of 2 families. Arch Neurol 2002;59:11621630.
74. Lambon Ralph MA, Powell J, Howard D, et al., Semantic memory is impaired in both dementia with Lewy bodies and
dementia of Alzheimers type: a comparative neuropsychological study and literature review. J Neurol Neurosurg Psy-
chiatry 2001;70:149156.
75. Ballard C, OBrien J, Gray A, et al., Attention and fluctuating attention in patients with dementia with Lewy bodies and
Alzheimer disease. Arch Neurol 2001;58:997982.
76. Calderon J, Perry RJ, Erzinclioglu SW, et al., Perception, attention, and working memory are disproportionately impaired
in dementia with Lewy bodies compared to Alzheimers disease. J Neurol Neurosurg Psychiatry 2001;70:157164.
77. Galasko D. Lewy bodies and dementia. Curr Neurol Neurosci Rep 2001;1:435441.
78. Mori E, Shimomura T, Fujimori M, et al., Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol
2000;57:489493.
79. Priori A, Berardelli A. Transcranial brain stimulation in movement disorders. In: . Pascual-Leone A, Davey NJ, Rothwell
J, Wassermann EM, Puri BK, eds. Handbook of Transcranial Magnetic Stimulation. London, Arnold, 2002.
80. Gernsbacher MA. Handbook of Psycholinguistics. San Diego: Academic, 1994.
81. Damasio H, Damasio AR. Lesion Analysis in Neuropsychology. New York: Oxford University Press, 1989.
82. Alexander MP. Disorders of language after frontal lobe injury: Evidence for the neural mechanisms of assembling
language. In: Stuss DT, Knight RT, eds. Principles of Frontal Lobe Function. New York: Oxford University Press,
2002:159167.
83. Luria A. The working brain. New York: Basic Books, 1973.
84. Luria AR, Tsevkosva LS. Towards the mechanism of dynamic aphasia. Acta Neurol Psychiatrica Belg 1967;67:
10451067.
85. Tognolo G, Vignolo LA. Brain lesions associated with oral apraxia in stroke patients: A clinico-neuroradiological
investigation with the CT scan. Neuropsychologia 1980;18(3):257272.
86. Helm-Estabrooks N. Test of oral and limb apraxia, normed edition. Chicago: Riverside, 1992.
87. Darley F, Aronson AE, Brown JR. Differential diagnostic patterns of dysarthria. J Speech Hear Res 1969;12:246269.
88. Benson DF. Aphasia, alexia, and agraphia. New York: Churchill Livingstone, 1979.
Appendix A
Descriptions of Classic Aphasia Syndromesb, Apraxias, and Dysarthria Types 272
Type of Speech
or Language Disturbance Classical Neuroanatomical Correlates Clinical Features
Aphasias:
Brocas Primarily posterior aspects of the third frontal convolution Major disturbance in speech production with sparse, halting speech,
and adjacent inferior aspects of the precentral gyrus of the often misarticulated, frequently missing function words (articles,
dominant hemisphere (80). conjunctions, pronouns, prepositions, auxiliary verbs) and bound
morphemesi (80). Connected speech is often described as telegraphic or
agrammatic, with relatively spared auditory comprehension (11). Verbal
problems often reflect a concomitant apraxia of speech. Repetition of
spoken words and phrases and confrontation naming are also impaired.
Writing is impaired with written errors resembling verbal production
errors qualitatively. Reading comprehension is deficient to a degree that
generally parallels auditory comprehension.
Wernickes Posterior portion of the superior temporal gryus and Major disturbance in auditory comprehension, fluent speech with dis-
possible adjacent cortex of the dominant hemisphere (80). turbances of the sounds and structures of words (phonemic, morphologi-
cal and semantic paraphasias, including neologisms) (80). Often
described as press of speech (must often be stopped as conversation is
continuous). Defective repetition of words and phrases, both reading and
writing are usually disturbed.
Global Large portion of the perisylvian association cortex in Disruption of all language-processing components (80). Some patients
distribution of middle cerebral artery of the dominant may speak noncommunicatively with verbal stereotypes (e.g., dee, dee,
hemisphere (80). dee, down the hatch), although they may be alert and aware of their sur-
roundings, and often express feeling and thoughts through facial, vocal,
and manual gestures (11).
Anomic Wide range of lesion patterns, both focal and diffuse. Disturbance in the production of single words, most marked for common
Linked to large left-hemisphere lesions or focal lesions nouns and variable comprehension problems (80). Presence of fluent,
of connections between the left temporal and parietal grammatically coherent utterances weakened in communicative power by
cortex (81). Also inferior parietal lobe lesions (80). a word retrieval deficit. Utterances are vacuous with indefinite nouns and
pronouns filling in for substantive words.
Transcortical Motor Continual debate, however, lesion localization thought to Disturbance of spontaneous speech similar to Brocas aphasia
be mid- and upper premotor cortex around or including with relatively preserved repetition (80). Verbal output is
the supplementary motor area. Disruptions of white matter nonfluent with relatively spared visual and auditory comprehension.
tracts deep to Brocas area (80). Lesions also described
Frattali and Duffy
in the left lateral frontal lobe, variably anterior and

superior to Brocas area (82).
Transcortical Sensory Associated with lesions of the left inferior parieto-temporo- Disturbance in single-word comprehension with relatively intact
occipital area, however localization remains controversial repetition (80). Also, fluent verbal output with poorer auditory
(81). Also, disruptions of white matter tracts connecting and visual comprehension. Echolalia (patient repeats a question
parietal lobe to temporal lobe or in portions of the inferior instead of answering it) is prominent feature of this syndrome.
parietal lobe (80).
Conduction Lesion in the arcuate fasciculus and/or cortico-cortical Disturbance of repetition and spontaneous phonemic
connections between temporal and frontal lobes (80). Also, paraphasias (80). No significant difficulty in comprehension
damage to the insula, contiguous auditory cortex, and of normal conversation.
underlying white matter of the left hemisphere (81).
Dynamic aphasia Frontal deafferentation secondary to interruption of Cardinal features of reduction in spontaneous speech with lack
frontostriatal feedback loops (40).Lesions in dorsolateral of initiation, limitations in the amount and range of narrative expression,
(BA 8, 9, 10, 46), with particular emphasis on posterior and loss of verbal fluency. Articulation and speech motor programming
portion of the second frontal convolution. remain intact, however language is impoverished with decreases in proposi-
Speech and Language Disturbances
tions and length and complexity of response. Singly described as a distur-

bance of complex, open-ended sentence assembly (8284).
Apraxias:
Orofacial Frontal and central (rolandic) opercula, adjacent portions Disturbances in purposeful, learned movement of the oral/respiratory
or Buccofacial Apraxia of the first temporal convolution, and the anterior portion structures despite intact strength of the peripheral speech musculature
of the insula (85). (1,86).
Apraxia of Speech Brodmann area 44 or third frontal convolution (Brocas An articulatory disorder marked by difficulty in programming
area), premotor and supplementary motor areas of the the positioning of the speech muscles and sequencing the muscle
frontal lobe of dominant hemisphere. Also the parietal lobe movements for volitional production of phonemes (1).
somatosensory cortex and supramarginal gyrus play a role
in motor speech planning and programming. The insula has
also been implicated (1).
Dysarthrias:
Flaccid Damage to lower motor neurons or motor units of cranial Weakness and hypotonia are the underlying neuromuscular deficits
or spinal nerves that innervate speech muscles (1). that explain most of the speech characteristics (1). Most deviant
features (listed in order from most to least severe) include hypernasalitya,
imprecise consonants, breathinessa, monopitch, nasal emissiona, audible
inspirationa, harsh voice quality, short phrasesa, and monoloudness (87).
Spastic Damage to the direct (pyramidal) and indirect (extra- Salient effects of upper motor neuron lesions on speech movements
pyramidal and cerebellar) activation pathways (upper include spasticity, weakness, reduced range of movement, and slowness
motor neurons) bilaterally (1). of movement (1). Most deviant features encountered (in order from
273
Appendix A (continued)
Type of Speech 274
or Language Disturbance Classical Neuroanatomical Correlates Clinical Features
least to most severe) are imprecise consonantsa, monopitch, reduced
prosodic stress, harshnessa, monoloudness, low pitcha, slow ratea,
hypernasality, strained-strangled quality, short phrasesa, distorted vowels,
pitch breaksa, breathy voice, excess and equal prosodic stress (87).
Hyperkinetic Usually associated with dysfunction of the basal ganglia Characteristics can be manifest in the respiratory, phonatory,
control circuit, but may also be related to involvement resonatory, and articulatory levels of speech, and prosody is often
of the cerebellar control circuit or other portions of the prominently affected. Deviant speech characteristics reflect the effects
extrapyramidal system (1). on speech of abnormal rhythmic or irregular and unpredictable, rapid or
slow involuntary movements (1). Most deviant features encountered (listed
in order from most to least severe) are imprecise consonants, prolonged
intervalsa, variable ratea, monopitch, harsh voice quality, inappropriate
silencesa, distorted vowels, excess loudness variationsa, prolonged
phonemesa, monoloudness, short phrases, irregular articulatory break-
downs, excess and equal stress, hypernasality, reduced stress, strained-
strangled quality, sudden forced inspiration or expirationa, voice
stoppagesa, transient breathinessa (87).
Hypokinetic Damage to basal ganglia control circuit (1). Characteristics are most evidence in voice, articulation, and prosody. The
effects of rigidity, reduced force and range of movement, and slow
individual and sometimes fast repetitive movements seem to account for many
of its deviant speech characteristics (1). Most deviant features encountered
(listed in order from most to least severe) are monopitcha, reduced stressa,
monoloudnessa, imprecise consonants, inappropriate silencesa, short rushes
of speecha, harsh voice quality, breathy voice, low pitch, variable ratea,
increased rate in segmentsa, increase of rate overalla, repeated phonemesa (87).
Ataxic Damage to the cerebellar control circuit, most frequently Deficits are most evident in articulation and prosody. Incoordination
to the lateral hemispheres or vermis (1). and reduced muscle tone appear responsible for the slowness of movement
and inaccuracy in the force, range, timing, and direction of speech move
ments (1). Most deviant features encountered (listed from most to least
severe) are imprecise consonants, excess and equal stressa, irregular
articulatory breakdownsa, distorted vowelsa, harsh voice quality, prolonged
phonemesa, prolonged intervals, monopitch, monoloudness, slow rate,
excess loudness variationsa, and voice tremor (87).
aTend to be distinctive features or more severely impaired than in any other single dysarthria (1).
Frattali and Duffy
bClassifiable in only about half of the cases of aphasia seen routinely in a clinical practice (88). Advances in neuroimaging technologies reduce the utility of clinical assessment
for lesion localization.

Appendix B
Case Descriptions and Text Stimuli Used to Elicit Audio-Recorded Speech and Language Samples
Speech or Language
Case no. Age Gender Medical Diagnosis Disturbances Notes
Speech Disturbances
1 65 F Indeterminate Spastic dysarthria 2-yr history of progressive speech and swallowing difficulty
corticobulbar
dysfuncion
2 57 M Olivopontocerebellar atrophy Ataxic dysarthria 1.5-yr history of progressive incoordination and speech difficulty
3 73 M Multiple System Atrophy hypokinetic dysarthria 10-yr history of nonspeech signs and symptoms of MSA. 2-yr history of
progessive speech difficulty.
4 75 M Corticobasal Degeneration Apraxia of speech; 2.5-yr history of progressive speech disturbance; evidence of only equivocal
mixed hypolinetic- aphasia.
spastic and possible
ataxic aysarthria
Speech and Language Disturbances
5 70 M Progressive Supranuclear Palsy Hypokinetic dysarthria Prominent characteristic of excessive rate of speech.
6 63 F Corticobasal Degeneration Brocas aphasia and Characteristics of language deficit include agrammatism and repetition
co-occurring apraxia deficit.
of speech
7 38 F Primary Progressive Aphasia; Anomic aphasia Characteristics of language deficit include fluent verbal output with vacuous
possible CBD content, impaired confrontation naming of objects, and impaired auditory
comprehension.
8 72 F Corticobasal Degeneration Nonfluent aphasia close Characteristics of language deficit include nonfluent verbal output, dysnomia,
in features to transcortical impaired auditory comprehension for sequential commands, and
motor aphasia, with perserveration, with relatively spared repetition.
co-occurring mixed
dysarthria
9 58 F Corticobasal Degeneration Tangential discourse with Characteristics of languate deficits include semantic paraphasia and
impaired topic maintenance, perservation.
with co-occurring features
of fluent aphasia
10 68 F Corticobasal Degeneration Dynamic aphasia Characteristics of language include reduced initiation, low propositionality,
reduced verbal fluency, and yes/no reversals.
Picture description used for Case no. 4 was the Cookie Theft Scene from the Boston Diagnostic Aphasia Examination; all other picture descriptions were elicited from the Picnic
275
Scene from the Western Aphasia Battery. (Case numbers are linked to .wav files on accompanying DVD.)
TEST STIMULI FOR AUDIOTAPED SAMPLES
Grandfather Passage
You wish to know all about your grandfather. Well, he is nearly 93 years old, yet he still
thinks as swiftly as ever. He dresses himself in an old black frock coat, usually several buttons
missing. A long beard clings to his chin, giving those who observe him a pronounced feeling of
the utmost respect. Twice each day he plays skillfully and with zest upon a small organ. Except
in the winter when the snow or ice prevents, he slowly takes a short walk in the open air each
day. We have often urged him to walk more and smoke less, but he always answers, Banana
Oil! Grandfather likes to be modern in his language.
Test Stimuli used for Picture descriptions:
Source: Cookie Theft Picture from Boston Diagnostic Aphasia Exam in The Assessment of Aphasia and
related Disorders (second edition) by Goodglass, H & Kaplan, E., 1983, Philadelphia: Lea & Febiger. Repro-
duced with permission.
Source: Picnic scene picture from Western Aphasia Battery by Kertesz, A., 1982, by The Psychological
Corporation, a Harcourt Assessment Company. Reproduced with permission. All rights reserved.
Quality of Life in Atypical Parkinsonian Disorders 277
17
Quality of Life Assessment in Atypical Parkinsonian
Disorders
Anette Schrag and Caroline E. Selai
INTRODUCTION
Assessing the health-related quality of life (Hr-QoL) of patients with atypical parkinsonism disor-
ders is important yet no validated measures are currently available. The atypical parkinsonian disor-
ders are chronic progressive conditions, which not only shorten life expectancy but affect many
aspects of patients and their carers lives. No curative treatment for these disorders is available, and
management of these patients largely has to concentrate on amelioration of symptoms, such as falls,
immobility, autonomic features or dysphagia, activities of daily living and (in)dependence, and pa-
tients social and emotional well-being; in short, the improvement of patients quality of life. Assess-
ment of patients with atypical parkinsonism has concentrated on objective measures such as mortality
and clinical evaluation of impairment and physical functioning, supplemented by laboratory test re-
sults. However, a large literature shows that patients own assessments of their health, their prefer-
ences, and their views regarding health often differ significantly from physicians objective
assessments (1). Where possible, treatment decisions should focus on health outcomes of value to the
individual patient.
Scales to measure Hr-QoL, fully psychometrically tested and validated, are now used in a number
of clinical and research contexts. Some types of Hr-QoL scale yield information that, combined with
economic data, can be used to assess the cost benefit of health interventions and to inform decisions
about the allocation of scarce health care resources. There are currently no validated measures to
assess Hr-QoL in patients with atypical Parkinsonian disorders.
This chapter starts with a general overview of some of the conceptual and methodological issues
relating to the measurement of subjective health assessment and Hr-QoL. Section two gives an over-
view of Hr-QoL instruments that have been used in Parkinsons disease (PD) and the impact of PD on
Hr-QoL. The third section addresses what is known about the Hr-QoL of patients with atypical par-
kinsonism, in particular multiple system atrophy (MSA) and progressive supranculear palsy (PSP).
The chapter concludes with some comments about future research in this area.
HEALTH-RELATED QUALITY OF LIFE: CONCEPTUAL

AND METHODOLOGICAL ISSUES
What Is Quality of Life?
Although the definition of this somewhat elusive term is still occasionally discussed in the litera-
ture, there is general consensus on some fundamental points. First, although the phrases quality of

277
278 Schrag and Selai
life, health-related quality of life, and health status are used somewhat interchangeably, there is
broad agreement that, in the medical context, Hr-QoL should be regarded as a multidimensional
construct (2), comprising physical, psychological, and social well-being. Within these three broad
dimensions, most Hr-QoL scales have items on physical health and functioning, activities of daily
living, mental health (e.g., perceived stigma, anxiety, depression), social activities, family relation-
ships, and cognitive functioning. Because of these multiple factors, it has been argued that although
it may be helpful to derive a summary index of Hr-QoL, the different aspects of Hr-QoL as measured
by the scale domains should also be presented separately in order to better understand the precise
impact of interventions (3).
Second, since quality of life is highly subjective, any appraisal of Hr-QoL should rely, where
possible, on the perception of the individual patient. Many groups of patients cannot, however, assess
their own Hr-QoL, e.g., those with severe dementia, and there is a growing literature on the use of
proxy ratings.
Third, no quality of life instrument can comprehensively cover all aspects of Hr-QoL. Although
some scales attempt to comprehensively assess all aspects of Hr-QoL, such instruments are often
lengthy and burdensome and so are not feasible in clinical practice, particularly where patients have
disabling conditions. Therefore, most measures focus on a limited number of specific aspects of
Hr-QoL. The choice of instrument will be determined by the precise aim of the study.
Finally, in order to provide meaningful data for research and clinical practice, Hr-QoL measures
need to be carefully developed and validated and there is now a large literature on the validation and
psychometric properties that need to be demonstrated before the scientific community will accept
that an instrument has been shown to be appropriately validated. Before considering psychometric
testing in more detail, it is useful to consider next why Hr-QoL might be measured.
Why Assess Health-Related Quality of Life?

Though Hr-QoL measures have been developed for a number of reasons, two basic aspects of
health care underlie most of the questions that Hr-QoL appraisals set out to answer: outcome of
treatment and cost. As discussed above, Hr-QoL has emerged as an important outcome that incorpo-
rates patients views of their health. Also, since no country in the world can afford to do all that it is
technically possible to do to improve the health of its citizens, the need has arisen for some system of
setting priorities. The assessment of the Hr-QoL of patients with atypical parkinsonian disorders will
become increasingly important if and when new drug treatments and other therapies for these disor-
ders are developed. Trials will need to address the benefit of therapeutic interventions and measure
change of symptoms in relation to Hr-QoL.
HEALTH-RELATED QUALITY OF LIFE MEASURES: DEVELOPMENT

AND VALIDATION
All clinical assessment measures need to be shown to be valid and reliable. In addition, self-com-
pleted measures for patients with a disabling disease need to be short and feasible. Instrument devel-
opers must test the psychometric properties of a new instrument, which is a labor-intensive exercise,
involving a series of studies to obtain data on the performance of the measure in different situations.
For a comprehensive review of the statistical procedures, see Streiner and Norman (4). In brief, valid-
ity is how well the instrument measures what it purports to measure. There are various statistical
procedures for testing different aspects of an instruments validity. The terminology is somewhat
confusing but Streiner and Norman provide a useful guide to the various types (e.g., face validity,
construct validity, criterion validity, concurrent validity, and predictive validity). Reliability assesses
whether the same measurement can be obtained on other occasions and concerns the amount of error
inherent in any measurement. Two basic tests are the internal consistency of a test, measured by
coefficient alpha, and testretest reliability where scores taken on two occasions are compared. Sensi-
tivity or responsiveness to change is concerned with how sensitive the measure is to detecting clini-
cally relevant changes in Hr-QoL. This is important for monitoring benefits of treatment. Newer meth-
ods that allow further improvement of scales include Rasch analysis and Item Response Theory, a
discussion of which is beyond the scope of this chapter.
This psychometric testing has not uniformly been conducted with all instruments, particularly
older instruments.
Types of Hr-QoL Measures

There is no gold standard for measuring Hr-QoL and there is a wide range of instruments avail-
able, or in development. The categories of Hr-QoL measures have been comprehensively reviewed
elsewhere (5). In brief, generic instruments cover a broad range of Hr-QoL domains in a single
instrument. Their chief advantage is in facilitating comparisons among different disease groups. Dis-
ease-specific instruments reduce patient burden by including only relevant items for a particular
illness but their main disadvantage is the lack of comparability of results with those from other dis-
ease groups. Health profiles provide separate scores for each of the dimensions of Hr-QoL, whereas
a health index, a type of generic instrument, gives a single summary score, usually from 0 (death) to
1 (perfect health). A further category, developed within the economic tradition, is that of utility mea-
sures, which are based on preferences for health states. Preference weighted measures are required
when the focus is on society as a whole and the societal allocation of scarce resources. The choice of
measure will depend upon the goal of the study.
Preference-Based Outcome Measures

Preference-based outcome measures are a particular type of measure used in economic analyses,
such as cost-utility analyses. Cost-utility analysis is a technique that uses the quality adjusted life
year (QALY) as an outcome measure. For its calculation, the QALY requires well-being or Hr-QoL
to be expressed as a single index score. The three most commonly used preference measurement
techniques are visual analog scales, time trade-off, and standard gamble. A review of the literature on
the use of Hr-QoL life data in economic studies is beyond the scope of this chapter, but interested
readers can consult a series of chapters on this topic in ref. 6. As treatments for atypical parkinsonisan
disorders become available, they will undoubtedly be subject to economic appraisal and robust, pro-
spectively collected Hr-QOL data will be important for the calculation of QALYs and for other eco-
nomic analyses.
Which Outcome Measure to Use?

The choice of instrument depends on the purpose of the study. A common recommendation is to
include both disease-specific and generic measures in an investigation. The generic measure facili-
tates comparisons of the target group with the normal population and/or other patient groups whereas
the disease-specific instrument provides more sensitivity and is therefore usually more responsive to
change in health status. If pharmaco-economic evaluation or a comparison of two or more treatment
options is the aim of the study, incorporation of an additional utility measure is recommended. In
atypical parkinsonism no disease-specific instruments are available to date but disease-specific instru-
ments for MSA and PSP are currently being developed.
HEALTH-RELATED QUALITY OF LIFE IN PARKINSONS DISEASE

Health-Related Quality of Life Instruments Used in Parkinsons Disease
A number of studies have assessed Hr-QoL in idiopathic PD. The authors of the first of these
studies used generic instruments including the Sickness Impact Profile (SIP) (7), the Nottingham
Health Profile (NHP) (8), the Medical Outcomes Short Form (SF 36) (9), and EQ-5D (10). These
measures were shown to be valid to varying degrees. However, the older instruments, such as the SIP
and the NHP have been criticized for their content and their psychometric properties. For example,
the NHP is skewed toward the severe end of disability and worse functional status and is therefore
less likely to capture subtle changes in early stages of disease. The questions in the SIP have been felt
to be offensive to patients by some (11), and the SF 36 may have limited feasibility and validity in
patients with parkinsonism (12). However, the SF 36, a widely used Hr-QoL instrument, which has
been translated in several languages and been validated for use in many cultures, enables compari-
sons across cultures and disease groups. The EQ-5D has also been shown to be valid in patients with PD
(12), and its brevity of five questions and a visual analog scale is an advantage in disabled patients. In
addition, its summary index yields a utility score that can be used in pharmaco-economic analyses.
The EQ-5D has also been translation into many languages.
More recently, PD-specific Hr-QoL measures have been developed. Table 1 briefly describes
the PD-specific Hr-QoL measures, showing the scale domains. All of the PD-specific instruments
have been shown to have good psychometric properties, but only the Parkinsons Disease Ques-
tionnaire (PDQ 39; ref. 13) and the Parkinsons Disease Quality of Life Questionnaire (PDQL; ref.
14) have been validated by researchers independent of the developers (15). The PDQ 39 is the most
widely used Hr-QoL instrument in Parkinsons disease. It has been translated in several languages,
and has been shown to be valid, reliable and sensitive to change. An abbreviated format, the PDQ 8,
which has been shown to have comparable validity (16), is also available. Although PDQ 39 has been
validated in some cultures, including Britain, the United States, Spain, France, China, and Japan, its
validity in other cultures needs to be established. The PDQL is similar to the PDQ 39 in content and
format, but includes some questions that are missing in the PDQ 39, e.g., on sexuality. It has been
validated in The Netherlands and Britain, but it has not been translated into other languages and no
validation studies in other cultures are currently available. Its psychometric properties are less well
tested than those of the PDQ 39 and some issues such as self-care, role functions, and close relation-
ships are not addressed (15).
The Parkinsons Impact Scale (PIMS) was developed to identify the major problems in patients
lives in a clinical setting. It is based on consensus rather than testing in a patient sample and its
content validity has been criticized (15). However, it is the only instrument that distinguishes between
on and off periods and has been reported to be valid, reliable, and sensitive to change (17). The
Parkinsons Disease Quality of Life Scale (PDQUALIF) includes questions on fatigue and driving
ability, concentrates on the nonmotor symptoms of Parkinsons disease, and has more emphasis on
social functioning than other scales (18). The Parkinsons Disease Symptom Inventory (PDSI; ref.
19) has a larger number of questions (51 items) and asks patients to indicate the frequency as well as
the distress caused by each item. There is also a German questionnaire, the ParkinsonLebensqualitt
(PQL), which has been psychometrically tested in a German population (20). The differences between
some of these scales are discussed in an excellent review by Marinus et al. (15).
Finally, a number of measures that assess only the psychosocial aspects of Hr-QoL, excluding
items relating to physical impairment, have recently been developed and validated (21,22). The choice
of instrument in each setting will be guided by the differences between the content of the question-
naires, published data on the psychometric testing, and, if relevant to the study, the availability of
translations and cultural adaptation. For specific interventions different aspects of Hr-QoL will be
important and as no instrument can be both completely comprehensive and feasible, the selection of
the instrument will be based on the particular aim of the study. As discussed above, whereas generic
instruments can be used in patients with Parkinsons disease, PD-specific instruments are likely to be
more valid, sensitive, and responsive to change.
Table 1
Disease-Specific Hr-QoL Measures Developed for Parkinsons Disease
PD-Specific Measure Number of Items Domains of Hr-QoL Covered by Scale Reference
Parkinson Disease Questionnaire 39 mobility, activities of daily living, emotional well-being, stigma, Peto et al. 1995 (13)
39-item version (PDQ-39) social support, cognition, communications, bodily discomfort
Parkinson Disease Questionnaire 8 mobility, activities of daily living, emotional well-being, stigma, Peto et al. 1998 (16)
8-item version (PDQ-8) social support, cognition, communications, bodily discomfort
Parkinson Disease Quality of Life 37 Parkinsonian symptoms, systemic symptoms, emotional functioning, De Boer et al. 1996 (14)
Questionnaire (PDQL) social functioning
Parkinsons Impact Scale (PIMS) 10 Work, finance, leisure, safety, travel, self, feel, family, friend, Schulzer et al. 2002 (17)
Quality of Life in Atypical Parkinsonian Disorders
sexuality; differentiates between on- and off-states

Parkinsons Disease Quality of Life 33 Social/role function, self-image/sexuality, sleep, outlook, physical Welsh et al. 2003 (18)
Scale (PDQUALIF) function, independence, urinary function, global HrQoL
Parkinsons Disease Symptom 51 Frequency and distress of symptoms; further analysis on scoring Hogan et al. 1999 (19)
Inventory (PDSI) ongoing
Fragebogen Parkinson 44 Depression, physical achievement, leisure, concentration, social Van den Berg, 1998 (20)
LebensQualitt (PLQ) integration, insecurity, restlessness, activity limitation, anxiety
281
THE IMPACT OF PARKINSONISM ON HEALTH-RELATED QUALITY

OF LIFE
Parkinsons Disease
The only parkinsonian disorder that has been assessed in detail with regard to Hr-Qol is PD.
Studies on Hr-QoL of patients with PD have improved our understanding of subjectively experienced
difficulties associated with this disease, and we now have a clearer understanding of what aspects of
Hr-QoL are most important to patients with PD. A full review of the expanding Hr-QoL literature in
PD is beyond the scope of this chapter. However, it has consistently been found that all areas of
Hr-QoL are affected by PD, not merely the physical impairment or functioning (23,25,26). The
main areas of impairment in PD are in physical functioning, emotional reactions, social isolation, and
energy. Other domains of impairment of Hr-QoL in PD, include bodily discomfort/pain, self-image,
cognitive function, communication, sleep, role function, and sexual function (23,2527). It has also
become clear that in PD, it is not primarily disease severity and presence of the symptoms of PD that
determine Hr-QoL, but the disability associated with these symptoms and, more than any other fac-
tor, the presence and severity of depression (24,25,28). Further symptoms, which have also been
found to be highly relevant to Hr-QoL of patients with PD, are postural instability and falls, impaired
cognition, and insomnia. Other factors, including motor complications of treatment, may also be
associated with poorer Hr-QoL in subgroups of patients, but this association is no longer significant
once other important factors such as depression and disability due to parkinsonism are accounted for.
Potentially Important Quality-of-Life Issues in Atypical Parkinsonian Disorders

A wide range of symptoms are likely to be associated with impaired Hr-QoL in atypical parkinso-
nian disorders, including the cardinal features of parkinsonism, nonmotor symptoms such as sexual
and autonomic dysfunction, postural instability and falls, cognitive impairment, and visual distur-
bances.
Some analogies can usefully be drawn from Hr-QoL studies in PD. The degree of disability in atypi-
cal parkinsonism is at least as great as in PD and depression occurs in all atypical parkinsonian disor-
ders (29,30). It is therefore likely that these factors are also important in atypical parkinsonian
disorders. However, these are likely not to be the only difficulties encountered by patients with atypi-
cal parkinsonism in whom, frequently, many systems are affected. The impact of features such as
greater autonomic dysfunction, higher rate of falls, behavioral changes, or cognitive impairment, will
depend on the type of atypical parkinsonism. In addition, the shortened life expectancy, greater dis-
ability, lack of response to treatment, associated nonmotor features, cognitive impairment, and
behavioral disturbances in atypical parkinsonian disorders will all impact on patients subjective
evaluation of their Hr-QoL. On the other hand, symptoms that occur less frequently in atypical par-
kinsonism than in PD, such as tremor, hallucinations, dyskinesias, and motor fluctuations, are likely
to be of lesser importance to the Hr-QoL in patients with atypical parkinsonian disorders.
All of these symptoms may lead to increased dependence on others, a diminished sense of autonomy
and self-image (31), impairment of role functioning, emotional disturbances, fear of social stigma asso-
ciated with physical symptoms, and impairment of social functioning. Table 2 gives examples of
features of atypical parkinsonism, domains of Hr-QoL, which can be affected, and demographic and
psycho-social variables, which may influence Hr-QoL in patients with atypical parkinsonism.
Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP)
We have recently undertaken in-depth interviews with patients with MSA and PSP and their car-
ers, and conducted a large survey on issues relevant to patients with atypical parkinsonian disorders,
with the aim of developing disease-specific Hr-QoL questionnaires for patients with MSA and PSP.
There was considerable overlap in reported areas of health-related quality of life issues relevant to
patients with PSP and MSA, but also some differences.
Table 2
Examples of Factors Relevant to Hr-Qol in Atypical Parkinsonian Disorders
Domains of HR-QoL That May Be Affected Features of Atypical Parkinsonian Disorders Demographic Variables Psychosocial Variables
Physical function, e.g., mobility, bodily Motor symptoms Age Personal, e.g., coping
discomfort, bladder problems strategies, personal attitudes,
expectation of optimism
Activites of daily living, e.g., self-care, Speech impairment Gender Social and environmental,
communication, difficulties eating, reading e.g., social support, health care
difficulties resource circumstances, e.g., family
or in nursing home
Psychological, e.g., stigma, self-image, Autonomic dysfunction Socioeconomic class
depression, isolation, fear of future
Social, e.g., family life, social interaction, Visual impairment Area of residence
dependence on others
Quality of Life in Atypical Parkinsonian Disorders
Role functioning, e.g., emotional, physical Sexual dysfunction

Insomnia
Cognitive impairment, including bradyphrenia,
executive dysfunction, retrieval difficulties,
apraxia, neglect
Affect, e.g., depression, anxiety
Behavioral disturbances, e.g., apathy,
disinhibition
283
The main presentations of MSA, which include autonomic dysfunction and cerebellar symptoms
in addition to parkinsonism, were reflected in our preliminary Hr-QoL interviews. Patients with MSA
reported difficulties with bladder and autonomic dysfunction among their most common and severe
problems, which were not reported as commonly by patients with PSP, or those with PD (32). Lack of
coordination, which was also more commonly reported in MSA patients than in PSP patients, is
likely to reflect not only parkinsonism but also cerebellar dysfunction, which also results in diffi-
culty walking and balance problems. The reported items transferring from lying down to sitting
or difficulty standing up without support may reflect orthostatic hypotension in addition to bradyki-
nesia. Other issues more often rated as important by patients with MSA such as worrying about the
family, worrying about the future, or change of role within the family may reflect the younger
age group affected by MSA. Although these issues can also be important to patients with PSP, other
items were rated as more important by patients with PSP.
Problems commonly reported in PSP but rare in Parkinsons disease or MSA include early pos-
tural impairment and falls, visual impairment owing to supranuclear gaze palsy, eyelid apraxia or
photophobia, clinically relevant cognitive impairment, personality change, swallowing difficulties,
and speech disturbances (33). In addition, patients with PSP may develop neuropsychiatric complica-
tions, including apathy, inhibition, and depression (29,30). From the patients point of view, these
issues are also particular problems, although apathy and personality change were less problematic
from the patients than from the carers point of view (34).
In patients with MSA as well as PSP, difficulties beyond those of physical and mental symptoms
of the disease were rated as important. Patients in both groups not only reported difficulties in daily
activities but patients with MSA reported being anxious and worried about the future, had experi-
enced loss of self-esteem and confidence, felt ignored or that nobody could understand their difficul-
ties. Patients with PSP reported difficulties in showing their emotions, frustration and isolation,
difficulties in communication, and worrying about others reactions. Without doubt, the impact on
the emotional and social aspects of Hr-QoL goes beyond that of physical impairment and disability in
both disorders.
Other Parkinsonian Disorders

For other atypical parkinsonism such as corticobasal degeneration there are currently no data avail-
able on Hr-QoL. However, it is likely that, as in the other atypical parkinsonian disorders, there is
considerable overlap of Hr-QoL issues, but that some features specific to this syndrome are also
particularly relevant to their Hr-QoL, e.g., loss of hand function owing to alien limb, and impairment
of activities of daily living because of apraxia. Other features important to PSP or MSA, such as
bladder dysfunction or visual disturbances, are likely to have less impact in this patient group.
CARER BURDEN
It is not only the lives of patients that are severely affected by the chronic progressive disease
course, by decreased life expectancy, and by the multiple consequences of atypical parkinsonian
disorders; the lives of each family member and, particularly their carers, are also affected. It is likely
that atypical parkinsonian disorders affect carers physical functioning (e.g., caring affecting the
carers own health), emotional well-being (e.g., response to change in role, feelings of hopelessness
and depression), and social functioning (limitations on social life), but no studies to date have
assessed the different aspects of caregiver burden in these disorders. However, one study investi-
gated the correlates and determinants of carer burden in PSP (35). In this study, the impact of PSP on
carers increased with advancing disease severity and disability. Interestingly, this was most pro-
nounced in the first 18 mo after diagnosis, but carer burden plateaued after this initial increase. The
presence of affective and behavioral problems such as depression and aggression was associated with
greater carer burden, and women reported greater carer burden then men, even when disease severity
and behavioral disturbances were accounted for. The overall degree of carer burden appeared similar
to that reported in carers of patients with Alzheimers disease.
CONCLUSION
The assessment of Hr-QoL in patients with atypical parkinsonian disorders is important for clini-
cal research, surveys, and clinical trials. Since there is no cure, the management and current treatment
of these chronic, disabling disorders is aimed at improving patients subjective Hr-QoL. The impact
of these disorders on an individual is complex, comprising multiple aspects of physical, cognitive,
emotional, and social functioning. The patients rating of their own Hr-QoL may vary considerably
from their physicians assessment. The valid and reliable assessment of patient-rated health status
and Hr-QoL will become even more relevant as treatments for these disorders become available and
the benefits of treatment need to be rigorously assessed. Generic Hr-QoL instruments can be used,
but their validity and feasibility in patients with atypical parkinsonism is not known. PD-specific
Hr-QoL instruments, although incorporating a number of features of relevance to atypical parkin-
sonism, have not been validated in any of the atypical parkinsonian disorders and are likely to lack
some of the salient features. The particular manifestations of each of the atypical parkinsonian disor-
ders, e.g., the specific cognitive impairments in PSP or the autonomic features in MSA together with
the features of parkinsonism, are not adequately reflected in any of these instruments. Hr-QoL instru-
ments specifically for patients with MSA and PSP and for their carers are currently being developed.
FUTURE RESEARCH
Little information is available on the impact of atypical parkinsonism on specific domains of
Hr-QoL. Our starting point must be to ask the patients what factors are most important to their
Hr-QoL. It is anticipated that, analogous to the clinical presentations, some aspects of Hr-QoL,
such as mobility, will be common to all of these disorders, whereas specific aspects will be associ-
ated with particular disorders, e.g., bladder function in patients with MSA. Identifying the most
important aspect of Hr-QoL in these disorders, from the patients perspective, will assist in the man-
agement of these patients and will inform debate about the provision of health care resources. Finally,
but perhaps most importantly, if and when symptomatic treatments for these disorders become
available, their efficacy and relevance can be assessed by arguably the most important outcome
measure: the effect on patients Hr-QoL as rated by the patients themselves.
MAJOR QUESTIONS FOR FUTURE RESEARCH

What aspects of Hr-QOL are important in atypical parkinsonian disorders, as judged by the patients them-
selves?
Which instruments are most useful to assess Hr-QoL in atypical parkinsonian disorders?
Which areas of Hr-QoL are most affected in each of the atypical parkinsonian disorders and what are the
implications for the allocation of health care resources?
Which demographic, clinical, and environmental factors have the greatest influence on patientss subjec-
tive Hr-QoL?
What is the effect of potential symptomatic treatments for atypical parkinsonian disorders on patients
Hr-QoL as rated by the patients themselves?
REFERENCES
1. Slevin ML, Plant H, Lynch D, Drinkwater J, Gregory WM. Who should measure quality of life, the doctor or the
patient? Br J Cancer 1988;57:109112.
2. Spilker B, Revicki DA. Taxonomy of quality of life. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in
Clinical Trials, 2nd ed. Philadelphia: Lippincott-Raven, 1996:2531.
3. McDowell I, Newell C. Measuring Health: A Guide to Rating Scales and Questionnaires. New York: Oxford University
Press, 1987.
4. Streiner,DL, Norman GR. Health Measurement Scales: A Practical Guide to Their Development and Use, 2nd ed.
Oxford: Oxford Medical Publications, 1995.
5. Brooks RG. Health Status Measurement: A Perspective on Change. Philadelphia: Macmillan, 1995.
6. Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials, 2nd ed. Philadelphia: Lippincott-Raven,
1996.
7. Bergner M, Bobbitt RA, Carter WB, et al. The Sickness Impact Profile: development and final revision of a health
status measure. Med Care 1981;19:787805.
8. Hunt SM, McEwen J, McKenna SP. Measuring health stats: a new tool for clinicians and epidemiologists. J Royal Coll
Gen Pract 1985;35:185188.
9. Ware JE, Sherbourne CD. The MOS 36-item short form health survey (SF 36). I. Conceptual framework and item
selection. Med Care 1992;30:473483.
10. EuroQoL Group. EuroQoL: a new facility for the measurement of health-related quality of life. Health Policy
1990;16:199208.
11. Mitchell JD, OBrien MR. Quality of life in motor neurone diseasetowards a more practical assessment tool? J Neurol
Neurosurg Psychiatry. 2003;74:287288.
12. Schrag A, Selai C, Jahanshahi M, Quinn NP. The EQ-5Da generic quality of life measureis a useful instrument to
measure quality of life in patients with Parkinsons disease. J Neurol Neurosurg Psychiatry 2000;69:6773
13. Peto V, Jenkinson C, Fitzpatrick R, Greenhall R. The development and validation of a short measure of functioning
and well being for individuals with Parkinsons disease. Qual Life Res 1995;4:241248.
14. de Boer AG, Wijker W, Speelman JD, de Haes JC . Quality of life in patients with Parkinsons disease: development of
a questionnaire. J Neurol Neurosurg Psychiatry 1996;61:7074.
15. Marinus J, Ramaker C, van Hilten JJ, Stiggelbout AM. Health related quality of life in Parkinsons disease: a system-
atic review of disease specific instruments. J Neurol Neurosurg Psychiatry 2002;72:241248.
16. Peto V, Jenkinson C, Fitzpatrick R. PDQ-39: a review of the development, validation and application of a Parkinsons
disease quality of life questionnaire and its associated measures. J Neurol 1998;245(Suppl 1):S10S14.
17. Schulzer M, Mak E, Calne SM. The psychometric properties of the Parkinsons Impact Scale (PIMS) as a measure of
quality of life in Parkinsons disease. Parkinsonism Relat Disord 2003;9:291294.
18. Welsh M, McDermott MP, Holloway RG, Plumb S, Pfeiffer R, Hubble J, The Parkinson Study Group development and
testing of the Parkinsons Disease Quality of Life Scale. Mov Disord 2003;18:637645.
19. Hogan T, Grimaldi R, Dingemanse J, Martin M, Lyons K, Koller W. The Parkinsons disease symptom inventory
(PDSI): a comprehensive and sensitive instrument to measure disease symptoms and treatment side-effects. Parkin-
sonism Relat Disord 1999;5:9398.
20. Van den Berg M. Leben mit Parkinson: Entwicklung und psychometrische Testung des Fragenbogens PLQ. Neurol
Rehabil 1998;4:221226.
21. Marinus J, Visser M, Martinez-Martin P, van Hilten JJ, Stiggelbout AM. Questionnaire for patients with Parkinsons
disease: the SCOPA-PS. J Clin Epidemiol 2003;56:6167.
22. Spliethoff-Kamminga NGA, Zwinderman AH, Springer MP, Roos RAC. Psychosocial problems in Parkinsons dis-
ease: evaluation of a disease-specific questionnaire. Mov Disord 2003;18: 503509.
23. Schrag A, Jahanshahi M, Quinn N. How does Parkinsons disease affect quality of life? A comparison with quality of
life in the general population. Mov Disord 2000;15:11121118.
24. Schrag A, Jahanshahi M, Quinn N.What contributes to quality of life in patients with Parkinsons disease? J Neurol
25. Karlsen KH, Larsen JP, Tandberg E, Maland JG. Quality of life measurements in patients with Parkinsons disease: a
community-based study. Eur J Neurol 1998;5:443450.
26. Kuopio AM, Marttila RJ, Helenius H, Toivonen M, Rinne UK. The quality of life in Parkinsons disease. Mov Disord
2000;15:216223.
27. Damiano AM, McGrath MM, Willian MK, et al. Evaluation of a measurement strategy for Parkinsons disease: assess-
ing patient health-related quality of life. Qual Life Res 2000;9:87100.
28. Global Parkinsons Disease Survey Steering Committee. Factors impacting on quality of life in Parkinsons disease:
results from an international survey. Mov Disord 2002;17:6067.
ogy 1996;47:11841189.
30. Aarsland D, Litvan I, Larsen JP. Neuropsychiatric symptoms of patients with progressive supranuclear palsy and
Parkinsons disease. J Neuropsychiatry Clin Neurosci 2001;13:4249.
31. Fitzsimmons B, Bunting LK. Parkinsons diseasequality of life issues. Nurs Clin North Am 1993;28:807818
32. Fitzpatrick R, Peto V, Jenkinson C, Greenhall R, Hyman N. Health-related quality of life in Parkinsons disease: a
study of outpatient clinic attenders. Mov Disord 1997;12:916922.
nuclear palsy: a clinical cohort study. Neurology 2003;60:910916.
34. Schrag A, Selai D, Davis J, Lees A, Jahanshahi M, Quinn N. Health-related quality of life in patients with progressive
supranuclear palsy (PSP). Mov Disord 2003;18:14641469.
35. Uttl B, Santacruz P, Litvan I, Grafman J. Caregiving in progressive supranuclear palsy. Neurology 1998;51:13031309.
PSP 287
18
Irene Litvan
INTRODUCTION
Progressive supranuclear palsy (PSP) is the most common atypical neurodegenerative parkinso-
nian disorder (1,2). It was first described as a discrete clinicopathological entity by Steele et al. (3) in
1964 (Fig. 1), but there are several previous clinical descriptions of patients who may have had this
disease (see Chapter 2). Clinically, PSP typically presents at middle-to-late age with progressive
unexplained prominent postural instability with falls, supranuclear vertical gaze palsy, pseudobulbar
palsy, levodopa-unresponsive parkinsonism, and frontal cognitive disturbances (35). Neuropath-
ologically, PSP is characterized by the presence of neurofibrillary tangles in neurons and glia in
specific basal ganglia and brainstem areas (6) (Fig.2). Neurofibrillary tangles are abnormal aggre-
gates of tau protein that are also the main pathologic feature in corticobasal degeneration (CBD),
Picks disease, frontotemporal dementia with parkinsonism associated to chromosome 17 abnormali-
ties (FTDP-17), and Alzheimers disease (AD). Hence, as all these disorders, PSP is considered a
tauopathy (see also Chapter 4).
CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

The most important features that characterize and differentiate PSP from other disorders are pre-
sented in Table 1 and described in more detail in the subheading that follows.
Postural Instability and Falls

Postural instability manifested as nonexplained and unexpected falls or tendency to falls is the
most frequent symptom presentation in PSP (714). In the National Institutes of Neurological Disor-
ders and Stroke (NINDS) study (10), 96% of 24 PSP patients had gait disorder and postural instabil-
ity (83% history of falls) at the first visit to a specialized neurology center, which generally occurred
33.5 yr after symptom onset. Falls usually occur backward in PSP, but they can occur in any direc-
tion (7,10) (described by a patient in the video-PSP). The presence of nonexplained and unexpected
falls within the first year of symptom onset is in fact one of the required criteria for the diagnosis of
PSP when using the NINDSSociety for PSP (SPSP) diagnostic criteria (Table 2). PSP is the most
likely diagnosis when unexplained postural instability and falls occur within the first year of symp-
tom onset, but after that, multiple system atrophy (MSA) is equally possible. When postural instabil-
ity and falls are the only features of the disease and an abnormal response to the postural reflex may
be the only abnormality in patients examination, diagnostic problems are frequent.

287
288 Litvan
Fig. 1. (Left) Neurologist J. Clifford Richardson (19091986) realized that a set of patients evaluated since
1955 in Toronto had an unusual combination of symptoms that seemed to correspond to a disease he was
unaware of. (Middle) pathologist Jerry Olszewski (19131964) described in detail the pathological findings of
seven cases that came to autopsy. (Right) John C. Steele (1934) joined the neurology residency in 1961 and
investigated with Dr. Richardson the clinical features and progression of these patients during the following 2
yr. From Progressive Supranuclear Palsy: Clinical and Research Approaches, edited by Irene Litvan and Yves
Agid, copyright 1992 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.
Fig. 2. Pattern of lesions found in the nine cases reported by Prof. Olszewski in 1963 and published in
Archives of Neurology in 1964 (3), with permission.
PSP 289
Table 1
Comparison of Features of Various Atypical Parkinsonian Neurodegenerative Disorders
CBD
Lateralized Dementia
Characteristics PSP MSA Phenotype Phenotype DLB
Progression Rapid Rapid Rapid Rapid Rapid
Postural Instability/Falls Initial Early Present (late Late usually Early
unless limbs
are initially
affected)
Parkinsonism Symmetric/Axial Asymmetric/Distal Asymmetric Bilateral Asymmetric
Distal /Distal
Levodopa response Initial? Absent 1/3 of cases Absent Absent? Variable
Cognitive disturbances Early/Frontal Frontal Mild Lateralizeda Early/Frontal Early/Frontal
(Severe) (Severe) (Severe)/Cortical
Psychiatric disturbances Apathy, Depression Depression Apathy Hallucinations,

disinhibition Delusions
Myoclonus Absent Distal Present Present Present
Dystonia Axial Axial (antecollis) Asymmetric Bilateral? Late
(retrocollis) Limbs
Contracture Late Late Early Late? Late?
Saccades latency Normal Normal Impaired ? ?
vertical and
horizontal
Saccades speed Slow vertical Normal Normal ? ?
horizontal
Pyramidal signs Late (Bilateral) Present (Bilateral) Unilateral Bilateral Late,
( Bilateral bilateral
Cerebellar signs Absent in limbs, Present Absent Absent Absent
but wide gait
Dysautonomia Absent Initial, severe Absent Absent Present
Gait Ataxic Ataxic Apraxic/ Small-step Apraxic/
(wide-step) small-step small-step
aLateralizedcognitive disturbances: sensory or visual neglect, ideomotor apraxia, aphasia, or alien limb syndrome. Cortical
disturbances: memory, aphasia, apraxia, and agnosia. PSP, progressive supranuclear palsy; MSA, multiple system atrophy;
CBD, corticobasal degeneration; DLB, dementia with Lewy bodies.
Diagnostic certainty only increases with the appearance of telltale signs. Instability and falls in
MSA are usually present when patients already exhibit autonomic disturbances. Early instability or
falls may also rarely develop early in patients with CBD when symptoms initially occur in lower
extremities, but examination shows unilateral features (15). Falls are not an early feature in
Parkinsons disease (PD), but they may occur early in dementia with Lewy bodies (DLB) and usually
associate to cognitive disturbances.
290 Litvan
Table 2
Revised NINDSSPSP Consensus Criteria for Clinical Diagnosis
Definite PSP: Clinically probable or possible PSP and histologically typical PSP
Clinically Definite PSP
Step 1 Mandatory Inclusion Criteria:
1. Gradually progressive disorder with onset at age 40 or later and
2. Vertical supranuclear ophthalmoparesis (either moderate to severe upward or any downward
gaze abnormalities) and
3. Prominent postural instability with falls (or tendency to falls) in the first year of symptom onset
Clinically Probable PSP
Step 1 Mandatory Inclusion Criteria:
1. Gradually progressive disorder with onset at age 40 or later and either:
2a. Vertical supranuclear ophthalmoparesis (either moderate to severe upward- or any downward-
gaze abnormalities) or
2b. Slowing of vertical saccades and prominent postural instability with falls (or tendency to falls) in
the first year of symptom onset
For Both Clinically Definite and Clinically Probable PSP
Step 2 Mandatory Exclusion Criteria:
1. History compatible with encephalitis lethargica
2. Alien hand syndrome, cortical sensory deficits, focal frontal or temporoparietal atrophy
3. Hallucinations or delusions unrelated to dopaminergic therapy
4. Cortical dementia of Alzheimers type (severe amnesia and aphasia or agnosia,
NINCDSADRDA criteria)
5. Prominent cerebellar symptomatology or unexplained dysautonomia (early, prominent inconti
nence, impotence, or symptomatic postural hypotension)
6. Severe asymmetry of parkinsonian signs (bradykinesia)
7. Neuroradiologic evidence of relevant structural abnormality (basal ganglia or brainstem infarcts,
lobar atrophy)
8. Whipples disease, confirmed by polymerase chain reaction, if indicated
Clinically Possible PSP
To be defined
Ocular Motor Abnormalities

Supranuclear vertical gaze palsy allows the diagnosis of PSP to be made and distinguishes it from
all other related disorders such as CBD, MSA, PD, and DLB (see video-PSP and Chapter 15). How-
ever, vertical supranuclear gaze palsy is rarely (8%) present at symptom onset; it usually takes 34 yr
for it to develop (10). Vertical supranuclear gaze palsy, moderate or severe postural instability, and
falls during the first year after onset of symptoms classified the NINDS sample with 9% error using
logistic regression analysis (16). Although supranuclear gaze palsy is key in diagnosing PSP, it may
occasionally be present in patients with DLB, arteriosclerotic pseudoparkinsonism, MSA,
CreutzfeldtJakob disease, Whipples disease, or CBD.
Symptom progression is usually very helpful to differentiate these disorders. Whereas in PSP the
vertical supranuclear gaze palsy precedes the development of the horizontal gaze palsy, in CBD the
supranuclear gaze palsy, when present, usually affects both horizontal and vertical gaze and is usu-
ally preceded by ocular motor apraxia (see video-oculomotor apraxia Chapter 1). Both downward-
and upward-gaze palsy can be observed in PSP, but the upward-gaze palsy needs to be differentiated
from the limitation of upward gaze observed in elderly patients.
PSP 291
Slowing of vertical saccades (rapid eye movement between two stimuli not letting the eyeball
movement be seen) usually precedes the development of the supranuclear vertical gaze palsy and
allows an earlier diagnosis of the disease (4) (see video-slowing of saccades Chapter 1). In fact,
marked slowing of vertical saccades should point toward the diagnosis of PSP. The saccades in CBD
may have an increased latency but normal speed, and are similarly affected in the vertical and hori-
zontal plane, whereas in MSA, the saccades have normal speed and latency. Similarly, note that the
vertical saccades of elders with upward-gaze limitation are of normal speed.
Blink rate usually becomes profoundly sparse in PSP, although often diminished in PD and MSA.
The combination of rare blinking, facial dystonia, and gaze abnormalities leads to the development of
a particular staring and nonblinking faces. Eyelid apraxia (a difficulty or slowness with opening or
closing the eyelids accompanied by compensatory elevation of the eyebrows and frontalis overactivity
giving a furrowed brow) or blepharospasm (a forceful contraction of orbicularis oculi squeezing the
eyes shut and making the eyebrows descend) are also features observed in PSP (14,17,18), but they
hardly help in the diagnosis as they may be observed in other parkinsonian disorders (i.e., CBD).
Behavioral and Cognitive Frontal Features

Florid frontal lobe symptomatology (impaired abstract thought, decreased verbal fluency) includ-
ing motor perseveration and frontal behavioral disturbances, primarily apathy, but also disinhibition,
depression, and anxiety, usually manifests at early stages in PSP, whereas it is typically less evident
or manifests later in the other parkinsonian disorders (1925). Apathy, but not depression, is fre-
quently observed in patients with PSP and may be the initial symptom (24). Almost all PSP patients
examined neuropsychologically demonstrate an early and prominent executive dysfunction that includes
difficulty with planning, problem solving, concept formation, and social cognition. Moreover, execu-
tive dysfunction may be the presenting symptom in some PSP patients and is a frequent feature
throughout the disease.
In PD and MSA, in contrast to PSP, frontal lobe features are usually mild, and revealed only on
detailed neuropsychological testing (26). Because patients with PSP usually exhibit early frontal lobe
cognitive and/or behavioral disturbances, they occasionally are confused with patients with Picks
disease or AD. However in PSP, cortical dementia is rare or only mild.
Extrapyramidal Signs
PSP patients usually exhibit axial more than limb muscle involvement (10,27) (see video-PSP). In
the NINDS study, at the first visit to a specialized neurology center, 88% had bilateral bradykinesia;
63% a predominant akinetic-rigid disease course, and 63% axial rigidity (10). An absent, poor, or
waning response to levodopa is a characteristic feature defining the atypical parkinsonian disorders
(see Chapter 1) and is a feature of PSP. For practical purposes, all PD patients have a good or excel-
lent response to dopaminergic agents given in appropriate doses for an adequate period of time. If
they do not respond, they almost certainly do not have PD. A few PSP patients show a moderate
transient response from dopaminergic agents, but most do not. Indeed, this may be because many
PSP patients have little or no limb parkinsonism to respond to. In addition, PSP patients uncommonly
develop levodopa-induced involuntary movements and if they do, they usually develop dystonia (i.e.,
blepharospasm). The disproportionate retrocollis that used to be thought of as characteristic of PSP is
infrequently observed, but other types of dystonia such as oromandibular, blepharospasm, and more
rarely limb dystonia, have been reported (18). In those cases dopaminergic medication should be
cautiously reduced or discontinued to rule out the possibility of treatment-induced symptoms.
Speech, Swallowing, and Other Neurological Features

Patients with PSP may also present prominent early, or severe, speech and swallowing difficulties,
but these features may also be present in CBD. PSP patients classically have a hypokinetic-spastic
292 Litvan
dysarthria (see video-PSP, and also Chapter 16). Speech perseveration, where whole words or phrases
are repeated, and anomia, but not true aphasia may be observed in PSP.
Swallowing disturbances occur early in PSP. PD rarely causes early dysphagia, and even later in
the disease, severe dysphagia is more common in PSP and MSA. Severe early sialorrhoea may be
observed in PSP, but is rarely observed early in PD. Drooling of saliva and the voluntary down-gaze
palsy causing food to fall from the fork may lead to the reported sloppy tie or shirt sign.
Even at early stages of the disease, PSP patients may have difficulty judging the amount of food
they can swallow and tend to take oversize mouthfuls or overstuff their mouths when eating (see
video-PSP). This type of change in eating behavior is infrequent in patients with other atypical par-
kinsonian disorders or PD.
Pyramidal signs, usually bilateral, are features that present later in PSP than in MSA or CBD.
About one-third of patients with PSP and one-half of those with MSA and CBD develop pyramidal
signs. In these disorders, it may be hard to differentiate a Babinski sign from a striatal toe owing to
dystonia.
Early or late insomnia and difficulties in maintaining sleep have all been reported in this disorder,
but REM sleep behavioral abnormalities are infrequently reported. Sleep disturbances are thought to
be a result of abnormalities in sleep patterns and in motor function.
In general, symptoms and signs apparent early in the course of PSP progress steadily. Most PSP
patients eventually require a wheelchair and a feeding tube, and speech may become unintelligible,
palilalic, or mute. Goetz et al. reported that these three milestones (wheelchair, unintelligible speech,
and feeding tube) occur rapidly in PSP and can be monitored with standardized rating scales (28). In
their study, 88% of the sample (50 patients) met at least one of the three milestones, but the need for
nasogastric tube was never the first. The median time from symptom onset to the first key motor
impairment was 48 mo; gait disturbances occurred at a median symptom duration of 57 mo, and
unintelligible speech at 71 mo. As a composite end point, speech and gait accounted for 98% of this
sample first key motor impairment. These indices could be used as outcome measures in clinical
trials to assess how interventions alter anticipated disease progression (29).
DIAGNOSTIC DIFFICULTIES AND DIAGNOSTIC ACCURACY

In the tertiary referral setting, the diagnosis of a patient consulting with a history of early falls and
visual disturbances can be obvious, however, the diagnosis of PSP may be challenging at early dis-
ease stages when the clinician is not familiar with the condition or does not have a high index of
suspicion. This is particularly true since, as discussed, individual clinical features of PSP may occur
in other parkinsonian or dementia disorders, and telltale signs may present in midstages of the dis-
ease. It can be particularly difficult to distinguish PSP from PD during the first 23 yr from symptom
onset if patients with PSP do not yet clearly exhibit postural instability or ophthalmoplegia, and when
they may still show a levodopa response. This presentation is infrequent, but the presence of only
axial or additional symmetric limb signs at onset should raise suspicion that the diagnosis of PD may
be incorrect. Patients with PD, DLB, or CBD usually have asymmetric signs. In patients with isolated
asymmetric parkinsonism that does not respond to levodopa, the development of increased latency of
horizontal saccades, ideomotor apraxia, cortical sensory signs, visual neglect, severe dystonia, or
myoclonus should suggest a diagnosis of CBD. In the presence of severe autonomic signs (e.g.,
impotence, incontinence, syncope, or presyncope) or cerebellar disturbances with normal cognition
and behavior, MSA should be considered. However, one should recognize that urinary symptoms,
rarely incontinence but not retention, can also occur in PSP.
Neuropathologic and clinical criteria for the diagnosis of PSP have been standardized and vali-
dated and are widely accepted (4,6,30). Both possible and probable NINDSSPSP criteria were shown
to have a high specificity and positive predictive value in an independent study sample (30). Such
specific criteria are ideal for genetic studies, clinical drug trials, and analytic epidemiologic studies.
Because of their high specificity, the probable NINDSSPSP criteria was renamed as clinically defi-
PSP 293
nite and the possible NINDSSPSP as clinically probable criteria (Table 2). Criteria for clinically
possible PSP are being developed and will require validation. The newly developed possible criteria
should have a higher sensitivity but will still maintain relatively preserved specificity so it could be
used for descriptive epidemiologic studies as well as clinical practice.
In addition to the difficulty in diagnosing PSP because of nonspecific features, PSP may infre-
quently be associated with unusual traits. There are reports of neuropathologically confirmed cases
of PSP without ophthalmoplegia or with dementia or akinesia as the only presenting symptoms, or
with unilateral dystonia and apraxia or with motor aphasia and speech apraxia (3135). One should
consider that PSP is an unlikely diagnosis when symptoms develop before age 40 or last longer than
20 yr, because none of these characteristics have been reported in neuropathologically confirmed
cases of PSP.
EPIDEMIOLOGIC ASPECTS
The incidence of PSP is closer to 10% of PD (36), making it much more common than previously
recognized. Early crude incidence rates of PSP ranged from 0.3 to 0.4 per 100,000 per year (37), but
an incidence study of PSP and all types of parkinsonism in Olmsted County, Minnesota, from 1976 to
1990 (1,36) found a crude incidence rate for PSP of 1.1 per 100,000 per year, which increased from
1.7 cases per 100,000 per year at age 5059 years to 14.7 per 100,000 per year at ages 8099 yr (1).
It is thought that these figures are higher because of better methodological case finding and increased
recognition of the disorder by neurologists and non-neurologists (1). Similarly, the earlier underesti-
mated prevalence of 1.39 per 100,000 (38) has been found to be 6.06.4/100,000 in two population-
based prevalence studies using currently accepted diagnostic criteria for PSP conducted in the United
Kingdom (2,39).
The natural history of PSP, as evaluated by surveying a large sample of caregivers of living and
deceased patients with PSP (12) and by retrospectively evaluating the medical records of a small
sample of autopsy-confirmed cases (40), found that onset of falls during the first year, early dysph-
agia, and incontinence predicted a shorter survival time. Similar predictors of survival were identi-
fied in a recently published record-based study of 187 PSP patients of which 33% were examined by
the investigators, but none of those who died during follow-up underwent autopsy confirmation (14).
These investigators found that classification as probable PSP according to the NINDSSPSP criteria
was associated with a poorer survival. In particular, they found that onset of falls, speech problems,
or diplopia within 1 yr and swallowing problems within 2 yr, were associated with a worse prognosis.
NEUROPATHOLOGY
Neuropathologically, PSP is characterized by abundant neurofibrillary tangles and/or neuropil
threads particularly in the striatum, pallidum, subthalamic nucleus, substantia nigra, oculomotor com-
plex, periaqueductal gray, superior colliculi, basis pontis, dentate nucleus, and prefrontal cortex (see
Fig. 2). Neuronal loss and gliosis are variable (see Chapter 4) (6,41). Pathological tau in PSP is
composed of aggregated four-repeat (E10+) isoforms that accumulate as abnormal filamentous lesions
in cells and glia in subcortical and cortical areas (42,43). In the normal adult human brain, there are six
different tau isoforms with different microtubule-binding domains and the ratio of tau isoforms with
three- (3-R) and four-repeat (4-R) microtubule binding domains is 1:1. In AD, there is amyloid depo-
sition and the six tau isoforms aggregate mainly in neurons, but the 1:1 ratio is maintained. By con-
trast, in PSP and CBD, there is no amyloid deposition and tau aggregates in neurons and glia mainly
as a 4-R isoform, altering the 3-R:4-R ratio (6,4446).
Neurochemical studies indicate that the degenerative process in PSP involves dopaminergic neu-
rons that innervate the striatum and form the nigrostriatal dopamine system, as well as cholinergic
and GABAergic efferent neurons in the striatum and other basal ganglionic and brain stem nuclei,
thereby explaining the lack or transient nature of the levodopa response (4751).
294 Litvan
Fig. 3. Hypothesized pathways to neurodegeneration in PSP. Genetic, toxins, oxidative injury, and inflam-
mation are thought to contribute to neurodegeneration in this disease.
ETIOPATHOGENESIS
The cause of PSP is unknown but it is hypothesized that genetic and/or environmental factors
contribute to its development (52,53) (Fig. 3). Environmental and genetic factors have also been
linked to other neurodegenerative disorders.
Genetic
PSP is associated with a specific form of the tau gene (H1 tau haplotype) (5,54,55) (see Chapters
5 and 9). However, since the H1/H1 genotype is present in approx 90% of patients with this disorder,
and also in approx 60% of healthy Caucasians, it is unclear whether inheritance of the H1/H1 tau
genotype represents a predisposition to develop PSP (requiring other environmental or genetic factors),
or whether a relatively rare mutation with low penetrance (rather than an inherited susceptibility vari-
ant) could contribute to the abnormal tau aggregation present in this disorder.
CBD is also associated with the inheritance of the H1 haplotype (54,55). The observation that
coding and splice-site mutations in the tau gene cause FTDP-17 demonstrates that tau dysfunction is
sufficient to induce neurodegeneration (44,5658). The parallels between FTDP-17 and PSP/CBD
also include the fact that there are FTDP-17 patients with defined tau mutations (e.g., P-301, N279K)
who share many clinical and pathologic features with PSP and CBD (5961) such as selective depo-
sition of 4-R tau. However, because highly penetrant tau mutations are not found in PSP and CBD, it
is likely that other genetic or environmental factors contribute to the development of these disorders.
Litvan et al. recently showed in a pilot study that H1 haplotype dosage does not influence age of
onset, severity, or survival of PSP patients (5) in contrast to what is observed with ApoEJ4 in AD. It
is likely that differential environmental or genetic factors may lead to different cell vulnerability,
phenotypes, and rate of disease progression observed in PSP patients. Whether the rarely reported
familial cases of PSP (62,63) are owing to unidentified FTDP-17 mutations or they are a result of
non-tau mutated genes, is currently the subject of investigation.
PSP 295
Oxidative Injury
Several laboratories have suggested that mitochondrial abnormalities (6466) and lipid
peroxidation may play a role in the neurodegeneration occurring in PSP (6771). Albers et al. mea-
sured tissue malondialdehyde (MDA) levels in the subthalamic nucleus and cerebellum from brain
tissue of 11 PSP and 11 age-matched control cases using sensitive HPLC techniques, and found a
significant MDA increase in the subthalamic nucleus, but not in the cerebellum, of the PSP patients
(69). Significant increases (+36%) were also found in tissue MDA levels in the superior frontal cor-
tex of 14 PSP patients as compared with controls, and significant decreases (39%) were also found
in the F-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio (70). Increased oxida-
tion has been also found in the substantia nigra of PSP patients. These findings suggest that lipid
peroxidation may explain regionally specific neurodegeneration in PSP. Further, Odetti et al. (71)
showed that lipoperoxidation is selectively involved in PSP and hypothesized that intraneuronal ac-
cumulation of toxic aldehydes may hamper tau degradation leading to abnormal aggregation. It is
likely that irrespective of the primary cause of PSP, the onset of oxidative stress is a common mecha-
nism by which neuronal death occurs, and one that contributes to disease progression.
Inflammation
Inflammation is thought to play a role in the etiopathogenesis of PSP because of strong evidence
that in PSP there is activated glia (7276) and that there may be augmented complement activation in
the brain (higher CSF levels of C4 in PSP compared to controls and PD) (77). Moreover, active glial
involvement in PSP is as (or more) severe than that found in AD (54). Inflammation has also been
demonstrated in other neurodegenerative disorders. In AD, activation of the complement cascade and
accumulation and activation of microglia (78,79) have also been reported. Although there is limited
information about a decreased inflammatory reaction after treatment with antiinflammatory medica-
tion in autopsy-confirmed AD cases (79,80), several epidemiologic studies have shown that anti-
inflammatory agents may delay the onset and slow the progression of AD (8183).
Environmental/Occupational Factors
Only a few case-control studies have been conducted in PSP and the findings reported have lim-
ited value because of the small sample size of the studies. Two case-control studies from the same
institution resulted in conflicting conclusions on the role of education as a risk factor for PSP (38,84).
The authors attributed this disparity to methodologic differences in control selection (84). The possi-
bility that lower educational attainment may be a proxy for poor early-life nutrition or exposure to
neurotoxic substances or that alternatively, subtle cognitive changes of PSP begin early in life so as
to impair intellectual or educational motivation, have been hypothesized (84). Davis et al. found that
cases of PSP had a significantly higher educational level than controls in two of three categories
tested (odds ratio [OR] 3.1 for completing high school, and 2.9 for completing college, p < 0.05) (38),
whereas Golbe et al. found that patients with PSP were less likely to have completed at least 12 yr of
school (OR = 0.35) (84).
On the other hand, recent studies in the French West Indies suggest that environmental factors
may be relevant for developing PSP. Caparros-Lefebvre et al. (85) reported an unusually high
frequency of patients with an atypical parkinsonian syndrome (postural instability with early falls,
L-dopa unresponsiveness, prominent frontal lobe dysfunction, and pseudo-bulbar palsy) over the past
5 yr in the French West Indies. This new focus of atypical parkinsonism has been linked to exposure
to tropical plants containing mitochondrial complex I inhibitors (quinolines [TIQ], acetogenins,
rotenoids). In an initial case-control study, Caparros-Lefebvre et al. (86) reported an association with
consumption of tropical fruits (pawpaw) or herbal teas (boldo) in 31 patients with PSP and 30 patients
with atypical parkinsonism compared to controls (OR = 4.35). More recently, the authors reported
that from 220 patients consecutively evaluated at the Guadeloupe University Hospital, they found 58
296 Litvan
with probable PSP, 96 with undetermined parkinsonism, 50 with PD, 15 with ALS and parkinsonism,
and 1 with probable MSA. This cluster of cases seem to have a tauopathy closely related to PSP.
Neuropathological examination of three patients who died and were homozygous for the H1 tau
haplotype showed an accumulation of four-repeat tau proteins predominating in the midbrain (85).
There is evidence that TIQs are potentially neurotoxic (87,88). Injections of TIQs have caused par-
kinsonism in mice (8991) and in primates (9294). In addition, cellular studies showed that TIQs
exert a direct toxicity to dopaminergic neurons through inhibition of complex I enzymes, a mitochon-
drial mechanism similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or roten-
one exposure (95,96). It is unlikely that PSP patients seen in the United States or Europe are past
consumers of the tropical fruits and herbal teas that have been linked to PSP in Guadeloupe. How-
ever, TIQs have been found in foods that are common in the Western diet, specifically, in cheese,
milk, eggs, cocoa, and bananas (97,98). Although the amounts of TIQs in these foods vary, they may
accumulate in the brain over many years (97). There have also been reports of other toxins causing
atypical parkinsonism. There is some evidence of an environmental effect in LyticoBodig disease
(99) and ecological correlations support the cycad hypothesis (100,101).
Environmental exposure to organic solvents has also been reported in patients with PSP (102,103).
Petroleum waste ingestion has been linked to parkinsonism in a 20-yr-old man (104). N-Hexane has
been shown to induce parkinsonism in rats (105), and was linked to parkinsonism in a 49-yr-old
Italian leather worker (106). Although PSP patients were not found to have an association with any
occupation or toxin exposure in the two previous case-control studies (38,84), these studies were not
powered to test this hypothesis.
A possible role for traumatic brain injury (TBI) as a risk factor in the development of 4R-
tauopathies such as PSP is supported by several observations. First, it is well known that repetitive
TBI induces the formation of neurofibrillary tangles (107), which are found in PSP. Second, post-
traumatic parkinsonism may occur following cumulative head trauma in contact sports and infre-
quently after a single severe closed head injury (108,109). However, it is unclear whether TBI should
be considered a risk factor in the pathogenesis of PD (110). Third, several epidemiologic studies have
demonstrated that TBI is a risk factor for developing another tauopathy, AD (111113), although
controversy exists over the extent to which TBI and genetics contribute to the development of AD. A
recent large cross-sectional multicenter study of first-degree relatives of AD patients suggest that the
influence of TBI on developing AD is greater among persons lacking APOE-J4 compared with those
having one or two J4 alleles (113). These findings were confirmed in a retrospective study that evalu-
ated two autopsy-confirmed cohorts of patients with AD with known APOE-J4 genotype (114). On
the other hand, two recent large European prospective clinical epidemiologic studies suggest that a
history of TBI, with or without an association with APOEJ4, is not a risk factor for developing AD
(115,116), although major or many TBIs may increase the risk of cognitive decline (117). Finally, a
large number of experimental animal studies support the role of TBI in the onset or progression of
AD. Regrettably, a previous epidemiologic study in PSP had limited power to study this issue but
note that it found high ORs for boxing (4.0), TBI with loss of consciousness (2.4), and TBI with
memory loss (1.8), although none of them reach statistical significance (38).
Davis et al. found that heavy coffee drinking (>5 cups/d) and cigarette smoking were inversely
associated with PSP, but that the results of their case-control study were statistically insignificant
(38). Vanacore et al. found no difference in tobacco use between PSP cases and controls (118). The
number of cases in both PSP studies, however, was small (50,55). Risk factors that occur with low
frequency in the population may not be detected, thus resulting in type II error. These findings con-
trast with those in PD. An analysis from the Honolulu-Asia Aging Study based on a large sample size
suggest that midlife coffee consumption is significantly inversely associated with PD independent of
the effect of tobacco use (119). Similarly, a significant inverse association between heavy coffee
drinking (>5 cups/d) before or at age 40 yr and PD (120) and that tobacco use is inversely associated
with PD, has been tested in several studies (121).
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The role of hypertension (HTN) in PSP remains controversial. Dubinsky and Jankovic proposed a
vascular etiology for some of the cases diagnosed as clinical PSP (122). They found that 19/58 PSP
patients (32.8%) had radiological evidence of cortical, subcortical, or brainstem strokes, compared
with 25/426 (5.9%) of PD patients (p < 0.001). The same group of investigators (123) found that 30/
128 (23.3%) of PSP patients satisfied the criteria for vascular PSP. However, there have been few
autopsy-confirmed cases of exclusively vascular PSP. Frequently, PSP associates with strokes or
other neurodegenerative diseases (124). Two studies looked at the presence of presymptomatic HTN
in patients with PSP (125,126). Ghika et al. excluded clear-cut cases of vascular parkinsonism by
omitting cases with obvious multilacunar state on computed tomography (CT) or magnetic resonance
imaging (MRI), severe hypertensive leukoencephalopathy, Binswanger disease, pseudo-PSP owing
to small vessel disease, and vascular dementia. They found that the prevalence of presymptomatic
HTN in patients with clinically diagnosed PSP was 34/42 (81%). Because the vascular cases were
excluded, they proposed that HTN may be the first symptom of PSP, arising from degeneration of
adrenergic nuclei in the brainstem. However, Fabbrini et al. (125), and a previous case-control study
conducted by Davis et al. (38), found no increased frequency of HTN in PSP patients. Further studies
are needed to evaluate whether HTN is simply acting as a risk factor for vascular parkinsonism.
Whether the factors discussed provide a clue for the pathogenesis of 4R-tauopathies, are appli-
cable to a possible protective mechanism, or whether the epidemiologic data support the notion that
different risks factors may be associated with different groups of neurodegenerative disorders, needs
to be further investigated. Although the literature on PSP is definitely limited, it is reasonable to
consider that there may be different risk factors for PSP than for the other neurodegenerative parkin-
sonian disorders.
NOSOLOGY
PSP and CBD have much in common from a clinical, pathologic, and genetic perspective
(16,44,45). Besides both being sporadic 4-R tauopathies, they both may present with frontal cogni-
tive disturbances, parkinsonism not responding to levodopa therapy, ocular motor, and speech and
swallowing disturbances (16,127). The similarities between PSP and CBD have led investigators to
question whether the two disorders are distinct nosologic entities or different phenotypes of the same
disorder (128). Recently validated neuropathologic diagnostic criteria (129) emphasize the presence of
tau-immunoreactive lesions in neurons, glia, and cell processes in these disorders and also provide
good differentiation between PSP and CBD (129). For further details on the discussion of the nosology
of PSP and its relationship with CBD and other disorders, the reader is remitted to Chapters 8 and 9.
LABORATORY
There are no laboratory markers for the diagnosis of PSP but ocular motor studies, electrophysi-
ological studies, MRI, magnetic resonance spectroscopy, and positron emission tomography (PET)
scans may be helpful to support the diagnosis or exclude other disorders. In general the sensitivity
and specificity of these techniques in distinguishing patients with clinically equivocal or early PSP
from other conditions has not been assessed. For this reason this techniques are not yet considered
standard diagnostic tools in PSP. The availability and cost of some of these tools also limits their use
to research settings for the foreseeable future.
Ocular Motor Studies

Electrooculographic recording may help distinguish PSP patients from other parkinsonian disor-
ders at an early stage (130). There is slight or no saccade impairment in PD and MSA patients with
parkinsonism (i.e., those with no cerebellar signs). PSP patients have decreased horizontal saccade
amplitude and velocity but normal latency, whereas opposite results are observed in CBD patients.
The antisaccade task (looking in the direction opposite to a visual stimulus), which correlates well
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with frontal lobe dysfunction, is reported to be markedly impaired in patients with PSP, although it
may also be impaired in patients with AD. A pilot study suggest that longitudinal electrooculographic
studies may help distinguish patients with PSP from those with CBD (131). For further details on the
role of electrooculographic studies in the diagnosis of PSP, see Chapter 15.
Neuroimaging
Structural Imaging Changes
CT, as well as MRI, may at some stage in the disease show definite atrophy of the midbrain and of
the region around the third ventricle in more than half of PSP patients (132135) (Figs. 4 A,B).
Thinning of the quadrigeminal plate, particularly in its superior part, better seen in sagittal MRI
sections, has been shown to support a diagnosis of PSP (Fig. 4C). Minimal signal abnormalities in the
periaqueductal region could also be seen in proton density MRI (Fig. 4D). Although CT or MRI of
the brain are generally of little help in establishing the diagnosis of PSP, they can aid in ruling out
other diagnoses (e.g., CBD when asymmetric atrophy may be present in the parietal area, or MSA
when there may be atrophy of the pons, middle cerebellar peduncles, and cerebellum or altered signal
intensity in the putamen; it may also be used to rule out multiinfarct states, hydrocephalus, or tumors).
See also Chapter 25 for further details on the role of MRI studies in the diagnosis of PSP.
Functional Imaging
Magnetic resonance spectroscopy imaging detects different patterns of cortical and subcortical
involvement in PSP, CBD, and PD. PSP patients, compared with controls, have reduced NA/Cre in
the brainstem, centrum semiovale, frontal and precentral cortex, and reduced NA/Cho in the lenti-
form nucleus. On the other hand, CBD patients, compared with control subjects, have reduced NA/
Cre in the centrum semiovale, and reduced NA/Cho in the lentiform nucleus and parietal cortex.
Although significant group differences can be found using this technique, magnetic resonance spec-
troscopy is not helpful to differentiate between individual patients.
18F-Fluorodeoxyglucose PET scans and 123IMPsingle photon emission computed tomography
(SPECT) blood flow studies have both shown marked reduction in frontal and striatal metabolism in
PSP. Frontal hypometabolism in PSP is secondary to deafferentation and cortical pathology. How-
ever, this finding is not specific to PSP. PET measures of striatal dopamine D2 receptor density using
76Br-bromospiperone, or 11C-raclopride are also significantly reduced in most PSP patients, but again,
these findings are not specific to PSP. Hypometabolism of glucose in the frontal cortex, and decreased
18F-fluorodopa uptake in the presynaptic nigrostriatal dopaminergic system (with similar reduction in
both putamen and caudate) have also been shown by PET in PSP patients. See Chapters 26 and 27 for
further details on the role of functional neuroimaging studies in the diagnosis of PSP.
Behavioral and Neuropsychological Evaluations
When evaluated with a series of neuropsychological tests that included the Wisconsin Card Sort-
ing Test, Trail Making Tests, Tower of Hanoi, fluency test, the Similarity and Picture Arrangement
subtests of the WAISR (Wechsler Adult Intelligence ScaleRevised), motor series of Luria, or imi-
tation behavior, almost all PSP patients examined demonstrate an early and prominent difficulty
executive dysfunction (19,20,22,23,26,136) Similarly, the use of the Neuropsychiatric Inventory
helps identify the apathy these patients usually manifest (24). Identification of these deficits is help-
ful for the diagnosis and for the management of these patients. A lack of benefit from levodopa
therapy and the presence of severe frontal cognitive and/or behavioral deficits help support the diag-
nosis of PSP and differentiate this disorder from related disorders as shown in Fig. 5. Consideration
of both, patients response to levodopa and identified deficits in neuropsychological testing not only
improves clinicians diagnostic accuracy but helps us manage these two important aspects of the
disease. See Chapters 1114 for details on the role of neuropsychological studies in the diagnosis of
this patient population.
PSP 299
Fig. 4. MRI abnormalities in PSP. Midbrain atrophy (A,C), dilation of third ventricle (B), and an increased
signal intensity in the periaqueduct gray matter in T2 (D) are the changes typically observed in PSP. Midbrain
atrophy measured by an anteroposterior (AP) diameter equal or less than 13.4 mm (135) or an AP diameter
equal or less than 17 mm in addition to dilation of third ventricle (132) have been proposed as radiologic
features that help distinguish PSP from related parkinsonian disorders, particularly PD and MSA.
Neurophysiological Studies
PSP patients have both slowed movement and information processing. Their cognitive slowness
can be evaluated with complex reaction time tasks or with cognitive evoked potentials. Event-related
brain potentials recorded while PSP patients perform an Oddball task show a normal N1 component
but dramatically increased latencies and decreased amplitudes of the P2 and P300 components (137).
The remarkably delayed latencies found in PSP have not been reported in any other type of dementia.
These findings are different from those reported in CBD (138,139).
Polysomnographic studies show a diminished total sleep time, an increase in awakenings, and
progressive loss of REM sleep. These disturbances can be attributed to degeneration of brainstem
structures crucial to generate normal sleep patterns, such as the pontine tegmentum, characteristi-
cally involved in PSP.
300 Litvan
Fig. 5. Levodopa responsiveness and cognitive patterns. A lack of response to levodopa and a severe execu-
tive dysfunction supports the diagnosis of PSP.
Brainstem auditory evoked potentials are normal in PSP, however other neurophysiological mea-
sures of brainstem function are abnormal, reflecting the widespread pathological alteration in the
pons and mesencephalon in these patients. Whereas the blink reflex to an electrical stimulus is nor-
mal, there is an absence of the orbicularis oculi response in patients with PSP exhibiting a mentalis
response to electrical stimulation of the median nerve. This finding differentiates PSP patients from
those with PD, MSA, and CBD, all of them presenting simultaneous responses of the orbicularis
oculi and mentalis muscles after median nerve electrical stimulation (140). The startle response in
which brainstem circuits are also implicated has been found to be markedly altered in PSP, but gen-
erally normal in PD and MSA. Valls-Sole et al. recently developed a functional method for studying
the startle circuit consisting of the administration of the startling stimulus with a go signal in a reac-
tion time task paradigm (140). The rapid habituation to the motor response that normally follows the
delivery of a startling stimulus and that markedly limits the practical value of this test in the labora-
tory is dramatically reduced in this manner (114).
Urinary incontinence is not infrequent in PSP and anal sphincter electromyogram (EMG) has been
found abnormal in about 40% of patients, with findings indicative of denervation (141). Similar
findings are encountered in MSA but not in PD. See Chapter 24 for further details on the role of
electrophysiological studies in the diagnosis of this patient population.
MANAGEMENT
General Considerations
At present there are no effective therapies that could slow or completely resolve patients symp-
toms, however, state-of-the-art management should include the palliative treatment of patientss
symptoms at the different stages of the disease, as well as providing education and support to the patient
and their caregivers. In our clinical experience, both contribute to the improvement of the quality of life
of patients and caregivers and help delay institutionalization. Informed patients are usually eager to
participate in research and should be provided with the latest information.
Neurotransmitter Replacement
Neurotransmitter replacement therapeutic approaches have thus far failed in PSP because of the
widespread involvement of dopaminergic and non-dopaminergic neurotransmitter systems
PSP 301
(GABAergic striatal interneurons, cholinoceptive striatal interneurons, cholinergic brainstem, and

opioid striatal neurons) (142). Case studies and our clinical experience show no significant improve-
ment with levodopa. Similar findings are observed in double-blind placebo-controlled studies with
dopamine agonists (e.g., bromocriptine, pergolide including newer dopaminergic agonists such as
ropinirole or pramipexole) (143,144). Although dopaminergic replacement therapies are usually only
transiently and/or mildly effective, they should be tried when patients have parkinsonism since lack
of sustained and/or marked benefit from levodopa therapy effectively rules out PD, and may also
support the diagnosis of PSP (or other atypical parkinsonism). Future studies should evaluate the
effects of selective D1 agonists since D1 receptors are relatively preserved in PSP.
Several randomized, double-blind controlled trials using cholinergic agents (physostigmine; RS-86;
donepezil) showed similar mild or no efficacy (145148). However, as PSP patients mental status and
gait may worsen on anticholinergic drugs, these drugs should generally be avoided unless needed to
treat particular symptoms (142). Despite reported noradrenergic deficits in PSP (149), these agents
failed to benefit patients. Although PSP patients were reported to have some minor improvement in
motor performance after the administration of idazoxan (150), they failed to respond to efaroxan, a
more potent noradrenergic agent (151).
Palliative Measures
The combination of frontal lobe-type disturbances (impulsivity, unawareness, disinhibition) and
postural instability may result in significant difficulty in the management of patients with PSP who,
misjudging their disability, are exposed to a higher than necessary risk of falling. Palliative thera-
peutic approaches used in practice are listed in Table 3 and rehabilitation approaches are detailed
in Chapter 29. Future studies should systematically evaluate whether symptomatic palliative thera-
pies (e.g., speech therapy, physical therapy) improve the quality of life or survival of PSP patients (e.g.,
by preventing aspiration).
A small number of PSP patients have been subjected to pallidotomy, without significant benefit.
At present, there is no evidence that pallidotomy or any other surgical procedure helps PSP patients.
Future Therapies
The development of biologic therapies for PSP requires additional pathogenetic studies. Recently
developed four-repeat tau-transgenic animal models resembling PSP will likely accelerate efforts to
discover more effective therapies (see Chapter 5). Given the recent progress that has been made in
understanding the significance of tau in the development of neurodegeneration, it would seem likely
that the most promising approaches are those that aim at preventing the abnormal aggregation of
microtubule-associated protein tau. Future drug design should explore the use of agents that prevent
tau aggregation such as oligonucleotides or peptide nucleic acids that inhibit the splicing of tau E10
or the translation of E10+ mRNA, and thus the generation of four-repeat tau isoforms, (152). Alterna-
tively, microtubule stabilizers such as Taxol derivatives may turn out to be promising therapeutic
approaches.
Additional potential biologic therapeutic targets include free radical scavengers, enhancers of cell
metabolism, and anti-inflammatory agents (nonsteroidals) that cross the blood brain barrier. Agents
that could block microglial activation such as minocyclin may prove to be of therapeutic value.
Similarly, because in PSP the principal neuronal types affected are dopaminergic, cholinergic, and
GABAergic, neurotrophic factors that promote the growth, survival, and differentiation of these cells
or small molecules having nerve growthlike activity may end up being beneficial. However, poten-
tially useful proteins, such as growth factors, cannot be administered systemically or in the ventricles
since they have peripheral and central side effects and do not cross the blood brain barrier. Moreover,
high levels of growth factors in the cerebrospinal fluid (CSF) can lead to side effects associated with
circulating growth factors. On the other hand direct intraparenchymal administration of proteins into
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Table 3
Management Approach: Palliative Treatments
Feature Palliative Approach
Gait Instability/Falls Physical therapy, weighted walkers
Speech disturbances Speech therapy, communication devices
Dysphagia Thickeners, percutaneus
endoscopic grastostomy (PEG)
Blepharospasm, levator Botulinum toxin (except antecollis)
inhibition and other dystonias
Tearing, light sensitivity Natural tears, dark glasses
Depression Antidepressants; support therapy
Emotional incontinence Antidepressants
Drooling Anticholinergics (use cautiously!)
Patient and family support Social services; support therapy; lay
associations: (caregiver burden) Society
for PSP, Inc. Suite 515, Woodholme
Medical Building, 1838 Greene Tree
Road, Baltimore, MD 21208,
http://www.psp.org/);
and the PSP (Europe) Association (The
Old Rectory, Wappenhan, Towcester
NN12 8SQ, UK,
http://www.ion.ucl.ac.uk/~hmorris/
contact.htm)
the lenticular nuclei by acute and/or chronic infusions may provide a means of delivery. Preliminary
results of a double-blind, placebo-controlled pilot study in a single patient using a chronic
intraparenchymal administration of GDNF/placebo (one side each) by convection-enhanced delivery
recently conducted at the NINDS did not seem as promising as expected (personal communication).
Alternative approaches to chronically deliver therapeutic growth factors that might slow down or halt
the degeneration process in PSP include the administration of therapeutic genes to the disease-affected
regions of the brain. Newly developed transgenic tau animal models will allow us to explore these
alternatives as well as whether the administration of viral vectors by convection-enhanced delivery may
improve the spread of vector particles in the brain resulting in more uniform transgene expression.
CONCLUSION AND FUTURE DIRECTIONS

Knowledgeable physicians can easily diagnose PSP when the disease presents with its classical
features, but at early disease stages or when it presents with atypical features, the hunted biologic
markers are expected to be of assistance. Palliative treatment rather than neurotransmitter replace-
ment therapies are being used in clinical practice, whereas coordinated research efforts to find the
cause and cure for this devastating disease remain crucial (Box). It is conceivable that therapeutic
strategies aimed at limiting free radical production, oxidative stress, inflammation, and/or tau aggre-
gation, may slow the advance of PSP. The availability of recently developed four-repeat tau-animal
models resembling PSP will likely accelerate the translation of research from bench to bedside. It is
hoped that as a result of these efforts, investigators will identify biologic markers to diagnose PSP at
earlier stages and will develop biologic therapies that could prevent the abnormal aggregation of tau
and prolong neuronal survival, which in turn will slow or stop the disease progression.
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LEGEND TO VIDEOTAPE
PSP: Brief history and exam of a patient with the disorder. Falls, speech and visual disturbances
are the major problems reported. Severe limitation in the range of ocular motor movements affects
voluntary gaze, saccades, and OKNs. Motor disturbances affect axial (gait, neck) more than limb
muscles (tapping). There is an impaired postural reflex with the backward pull test. The patient would
have fallen, unless aided by the examiner.
FUTURE RESEARCH DIRECTIONS FOR PSP

Continue the search for:
Diagnostic criteria for possible PSP that will increase the sensitivity in the diagnosis of this disease.
Biologic markers of the disease that will improve the diagnostic accuracy.
Cause(s) for PSP (case-control and genetic studies) that will help in turn to find appropriate biologic
therapies.
Improved transgenic animal models of the disease that will help to test therapies.
Refined biologic therapies that will slow or stop disease progression.
REFERENCES
1. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple
system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49(5):12841288.
2. Schrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive supranuclear palsy and multiple system atrophy: a
cross-sectional study. Lancet 1999;354(9192):17711775.
4. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of
progressive supranuclear palsy (SteeleRichardsonOlszewski syndrome): report of the NINDSSPSP international
workshop. Neurology 1996;47(1):19.
5. Houlden H, Baker M, Morris HR, MacDonald N, Pickering-Brown S, Adamson J, et al. Corticobasal degeneration and
progressive supranuclear palsy share a common tau haplotype. Neurology 2001;56(12):17021706.
6. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, et al. Preliminary NINDS neuropathologic criteria
for SteeleRichardsonOlszewski syndrome (progressive supranuclear palsy). Neurology 1994;44(11):20152019.
sive supranuclear palsy). Neurology 1986;36(7):10051008.
8. Walsh JS, Welch HG, Larson EB. Survival of outpatients with Alzheimer-type dementia. Ann Intern Med
1990;113(6):429-434.
9. Tolosa E, Valldeoriola F, Marti MJ. Clinical diagnosis and diagnostic criteria of progressive supranuclear palsy (Steele
RichardsonOlszewski syndrome). J Neural Transm Suppl 1994;42:1531.
10. Litvan I, Mangone CA, McKee A, Verny M, Parsa A, Jellinger K, et al. Natural history of progressive supranuclear
palsy (SteeleRichardsonOlszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol
Neurosurg Psychiatry 1996;60(6):615620.
11. Verny M, Jellinger KA, Hauw JJ, Bancher C, Litvan I, Agid Y. Progressive supranuclear palsy: a clinicopathological
study of 21 cases. Acta Neuropathol 1996;91(4):427431.
12. Santacruz P, Uttl B, Litvan I, Grafman J. Progressive supranuclear palsy: a survey of the disease course. Neurology
1998;50(6):1637-1647.
13. Wenning GK, Ebersbach G, Verny M, Chaudhuri KR, Jellinger K, McKee A, et al. Progression of falls in postmortem-
confirmed parkinsonian disorders. Mov Disord 1999;14(6):947-950.
nuclear palsy: A clinical cohort study. Neurology 2003;60(6):910916.
15. Litvan I, Grimes DA, Lang AE, Jankovic J, McKee A, Verny M, et al. Clinical features differentiating patients with
postmortem confirmed progressive supranuclear palsy and corticobasal degeneration. J Neurol 1999;246 Suppl 2:II1II5.
16. Litvan I, Campbell G, Mangone CA, Verny M, McKee A, Chaudhuri KR, et al. Which clinical features differentiate
progressive supranuclear palsy (SteeleRichardsonOlszewski syndrome) from related disorders? A clinicopathologi-
cal study. Brain 1997;120(Pt 1):6574.
17. Collins SJ, Ahlskog JE, Parisi JE, Maraganore DM. Progressive supranuclear palsy: neuropathologically based diag-
nostic clinical criteria. J Neurol Neurosurg Psychiatry 1995;58(2):167173.
18. Barclay CL, Lang AE. Dystonia in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1997;62(4):352356.
19. Pillon B, Dubois B, Lhermitte F, Agid Y. Heterogeneity of cognitive impairment in progressive supranuclear palsy,
Parkinsons disease, and Alzheimers disease. Neurology 1986;36(9):11791185.
304 Litvan
20. Grafman J, Litvan I, Gomez C, Chase TN. Frontal lobe function in progressive supranuclear palsy. Arch Neurol
1990;47(5):553558.
21. Grafman J, Weingartner H, Newhouse PA, Thompson K, Lalonde F, Litvan I, et al. Implicit learning in patients with
Alzheimers disease. Pharmacopsychiatry 1990;23(2):94101.
22. Pillon B, Dubois B, Ploska A, Agid Y. Severity and specificity of cognitive impairment in Alzheimers, Huntingtons,
and Parkinsons diseases and progressive supranuclear palsy. Neurology 1991;41(5):634643.
23. Pillon B, Deweer B, Michon A, Malapani C, Agid Y, Dubois B. Are explicit memory disorders of progressive supra-
nuclear palsy related to damage to striatofrontal circuits? Comparison with Alzheimers, Parkinsons, and Huntingtons
diseases. Neurology 1994;44(7):12641270.
ogy 1996;47(5):11841189.
hypokinetic movement disorders. Arch Neurol 1998;55(10):13131319.
26. Robbins TW, James M, Owen AM, Lange KW, Lees AJ, Leigh PN, et al. Cognitive deficits in progressive supranuclear
palsy, Parkinsons disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction. J Neurol Neurosurg
Psychiatry 1994;57(1):7988.
27. Verny M, Duyckaerts C, Agid Y, Hauw JJ. The significance of cortical pathology in progressive supranuclear palsy.
Clinico-pathological data in 10 cases. Brain 1996;119(Pt 4):11231136.
28. Goetz CG, Leurgans S, Lang AE, Litvan I. Progression of gait, speech and swallowing deficits in progressive supra-
nuclear palsy. Neurology 2003;60(6):917922.
29. Siderowf A, Quinn NP. Progressive supranuclear palsy: setting the scene for therapeutic trials. Neurology
2003;60(6):892893.
30. Lopez OL, Litvan I, Catt KE, Stowe R, Klunk W, Kaufer DI, et al. Accuracy of four clinical diagnostic criteria for the
diagnosis of neurodegenerative dementias. Neurology 1999;53(6):12921299.
1985;17(4):337343.
32. Matsuo H, Takashima H, Kishikawa M, Kinoshita I, Mori M, Tsujihata M, et al. Pure akinesia: an atypical manifesta-
tion of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1991;54(5):397400.
33. Daniel SE, de Bruin VM, Lees AJ. The clinical and pathological spectrum of SteeleRichardsonOlszewski syndrome
(progressive supranuclear palsy): a reappraisal. Brain 1995;118(Pt 3):759770.
34. Bergeron C, Pollanen MS, Weyer L, Lang AE. Cortical degeneration in progressive supranuclear palsy. A comparison
with cortical-basal ganglionic degeneration. J Neuropathol Exp Neurol 1997;56(6):726734.
35. Boeve B, Dickson D, Duffy J, Bartleson J, Trenerry M, Petersen R. Progressive nonfluent aphasia and subsequent
aphasic dementia associated with atypical progressive supranuclear palsy pathology. Eur Neurol 2003;49(2):7278.
36. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County,
Minnesota, 19761990. Neurology 1999;52(6):12141220.
37. Mastaglia FL, Grainger K, Kee F, Sadka M, Lefroy R. Progressive supranuclear palsy (the SteeleRicharsonOlszewski
syndrome) clinical and electrophysiological observations in eleven cases. Proc Aust Assoc Neurol 1973;10:3544.
38. Davis PH, Golbe LI, Duvoisin RC, Schoenberg BS. Risk factors for progressive supranuclear palsy. Neurology
1988;38(10):15461552.
39. Nath U, Ben-Shlomo Y, Thomson RG, Morris HR, Wood NW, Lees AJ, et al. The prevalence of progressive supra-
nuclear palsy (SteeleRichardsonOlszewski syndrome) in the UK. Brain 2001;124(Pt 7):14381449.
40. Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C, et al. Consensus statement on the diagnosis of
multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res
1998;8(6):359362.
41. Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian DS, et al. Validity and reliability of the preliminary
NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol
1996;55(1):97105.
42. Mailliot C, Sergeant N, Bussiere T, Caillet-Boudin ML, Delacourte A, Buee L. Phosphorylation of specific sets of tau
isoforms reflects different neurofibrillary degeneration processes. FEBS Lett 1998;433(3):201204.
43. Buee L, Delacourte A. Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration,
FTDP-17 and Picks disease. Brain Pathol 1999;9(4):681693.
44. Goedert M, Crowther RA, Spillantini MG. Tau mutations cause frontotemporal dementias. Neuron 1998;21(5):955958.
45. Sergeant N, Wattez A, Delacourte A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal
degeneration: tau pathologies with exclusively exon 10 isoforms. J Neurochem 1999;72(3):12431249.
46. Chambers CB, Lee JM, Troncoso JC, Reich S, Muma NA. Overexpression of four-repeat tau mRNA isoforms in pro-
gressive supranuclear palsy but not in Alzheimers disease. Ann Neurol 1999;46(3):325332.
47. Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, R LH, Hauw JJ, et al. Dopaminergic and cholinergic lesions in progres-
sive supranuclear palsy. Ann Neurol 1985;18(5):523529.
PSP 305
48. Agid Y, Javoy-Agid F, Ruberg M, Pillon B, Dubois B, Duyckaerts C, et al. Progressive supranuclear palsy:
anatomoclinical and biochemical considerations. Adv Neurol 1987;45:191206.
49. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in
Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci U S A 1987;84(16):59765980.
50. Javoy-Agid F. Cholinergic and peptidergic systems in PSP. J Neural Transm Suppl 1994;42:205218.
51. Kasashima S, Oda Y. Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive
supranuclear palsy and corticobasal degeneration. Acta Neuropathol (Berl) 2003;105(2):117124.
52. Frattali CM, Grafman J, Patronas N, Makhlouf F, Litvan I. Language disturbances in corticobasal degeneration. Neu-
rology 2000;54(4):990992.
53. Golbe L. Progressive supranuclear palsy in the molecular age. Lancet 2000;356:870871.
54. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, et al. Association of an extended haplotype in the
tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8(4):711715.
55. Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati C, et al. Corticobasal degeneration shares a common
genetic background with progressive supranuclear palsy. Ann Neurol 2000;47(3):374377.
56. DSouza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, et al. Missense and silent tau gene mutations cause
frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regu-
latory elements. Proc Natl Acad Sci USA 1999;96(10):55985603.
57. Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VM, et al. A distinct familial presenile dementia
with a novel missense mutation in the tau gene. Neuroreport 1999;10(3):497501.
58. Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, et al. 5' splice site mutations in tau associated with the
inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem
1999;274(21):1513415143.
59. Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, et al. A clinical pathological comparison of three
families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain 1999;122(Pt 4):741756.
61. van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M, de Koning I, et al. Phenotypic variation in hereditary
frontotemporal dementia with tau mutations. Ann Neurol 1999;46(4):617626.
62. Rojo A, Pernaute RS, Fontan A, Ruiz PG, Honnorat J, Lynch T, et al. Clinical genetics of familial progressive supra-
nuclear palsy. Brain 1999;122(Pt 7):12331245.
63. Morris HR, Katzenschlager R, Janssen JC, Brown JM, Ozansoy M, Quinn N, et al. Sequence analysis of tau in familial
and sporadic progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2002;72(3):388390.
64. Swerdlow RH, Golbe LI, Parks JK, Cassarino DS, Binder DR, Grawey AE, et al. Mitochondrial dysfunction in
cybrid lines expressing mitochondrial genes from patients with progressive supranuclear palsy. J Neurochem
2000;75(4):1681-1684.
65. Albers DS, Beal MF. Mitochondrial dysfunction in progressive supranuclear palsy. Neurochem Int 2002;40(6):559564.
66. Di Monte DA, Harati Y, Jankovic J, Sandy MS, Jewell SA, Langston JW. Muscle mitochondrial ATP production in
progressive supranuclear palsy. J Neurochem 1994;62(4):16311634.
67. Jenner P, Dexter DT, Sian J, Schapira AH, Marsden CD. Oxidative stress as a cause of nigral cell death in Parkinsons
disease and incidental Lewy body disease. The Royal Kings and Queens Parkinsons Disease Research Group. Ann
Neurol 1992;32(Suppl):S82S87.
68. Jenner P. Oxidative stress in Parkinsons disease and other neurodegenerative disorders. Pathol Biol (Paris)
1996;44(1):5764.
69. Albers DS, Augood SJ, Martin DM, Standaert DG, Vonsattel JP, Beal MF. Evidence for oxidative stress in the subtha-
lamic nucleus in progressive supranuclear palsy. J Neurochem 1999;73(2):881884.
70. Albers DS, Augood SJ, Park LC, Browne SE, Martin DM, Adamson J, et al. Frontal lobe dysfunction in progressive
supranuclear palsy: evidence for oxidative stress and mitochondrial impairment. J Neurochem 2000;74(2):878881.
71. Odetti P, Garibaldi S, Norese R, Angelini G, Marinelli L, Valentini S, et al. Lipoperoxidation is selectively involved in
progressive supranuclear palsy. J Neuropathol Exp Neurol 2000;59(5):393397.
72. Ferrer I, Blanco R, Carmona M, Puig B. Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein
kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II
(CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies. J Neural Transm
2001;108(12):13971415.
73. Ferrer I, Blanco R, Carmona M, Ribera R, Goutan E, Puig B, et al. Phosphorylated map kinase (ERK1, ERK2) expres-
sion is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerabil-
ity and cell death, in Alzheimer disease, Picks disease, progressive supranuclear palsy and corticobasal degeneration.
Brain Pathol 2001;11(2):144158.
74. Drache B, Diehl GE, Beyreuther K, Perlmutter LS, Konig G. Bcl-xl-specific antibody labels activated microglia asso-
ciated with Alzheimers disease and other pathological states. J Neurosci Res 1997;47(1):98108.
306 Litvan
75. Lippa CF, Flanders KC, Kim ES, Croul S. TGF-beta receptors-I and -II immunoexpression in Alzheimers disease: a
comparison with aging and progressive supranuclear palsy. Neurobiol Aging 1998;19(6):527533.
76. Lippa CF, Smith TW, Flanders KC. Transforming growth factor-beta: neuronal and glial expression in CNS degenera-
tive diseases. Neurodegeneration 1995;4(4):425432.
77. Uchihara T, Mitani K, Mori H, Kondo H, Yamada M, Ikeda K. Abnormal cytoskeletal pathology peculiar to corticobasal
degeneration is different from that of Alzheimers disease or progressive supranuclear palsy. Acta Neuropathol (Berl)
1994;88(4):379383.
78. McGeer PL, Rogers J. Anti-inflammatory agents as a therapeutic approach to Alzheimers disease. Neurology
1992;42(2):447449.
79. Halliday G, Robinson SR, Shepherd C, Kril J. Alzheimers disease and inflammation: a review of cellular and therapeu-
tic mechanisms. Clin Exp Pharmacol Physiol 2000;27(12):18.
80. Mackenzie IR. Anti-inflammatory drugs and Alzheimer-type pathology in aging. Neurology 2000;54(3):732734.
81. Arima K, Murayama S, Oyanagi S, Akashi T, Inose T. Presenile dementia with progressive supranuclear palsy tangles
and Pick bodies: an unusual degenerative disorder involving the cerebral cortex, cerebral nuclei, and brain stem nuclei.
Acta Neuropathol (Berl) 1992;84(2):128134.
82. Imran MB, Kawashima R, Awata S, Sato K, Kinomura S, Ono S, et al. Parametric mapping of cerebral blood flow
deficits in Alzheimers disease: a SPECT study using HMPAO and image standardization technique. J Nucl Med
1999;40(2):244249.
83. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for
Alzheimers disease: a review of 17 epidemiologic studies. Neurology 1996;47(2):425432.
84. Golbe LI, Rubin RS, Cody RP, Belsh JM, Duvoisin RC, Grosmann C, et al. Follow-up study of risk factors in progres-
sive supranuclear palsy. Neurology 1996;47(1):148154.
85. Caparros-Lefebvre D, Sergeant N, Lees A, Camuzat A, Daniel S, Lannuzel A, et al. Guadeloupean parkinsonism: a
cluster of progressive supranuclear palsy-like tauopathy. Brain 2002;125(Pt 4):801811.
of tropical plants: a case-control study. Caribbean Parkinsonism Study Group. Lancet 1999;354(9175):281286.
87. Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, et al. 7-(4-[4-(2,3-Dichlorophenyl)-1-
piperazinyl]butyloxy)-3,4-dihydro-2(1H)-qui nolinone (OPC-14597), a new putative antipsychotic drug with both pr-
esynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol
Exp Ther 1995;274(1):329336.
88. Soto-Otero R, Mendez-Alvarez E, Hermida-Ameijeiras A, Munoz-Patino AM, Labandeira-Garcia JL. Autoxidation
and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the
pathogenesis of Parkinsons disease. J Neurochem 2000;74(4):16051612.
89. Kotake Y, Tasaki Y, Makino Yea. 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel
endogenous amine in mouse brain and parkinsonian CSF. J Neurochem 1995;65:26332638.
90. Kawai H, Makino Y, Hirobe M, Ohta S. Novel Endogenous 1,2,3,4-tetrahydroisoquinoline derivative: uptake by dopam-
ine transporter and activity to induce parkinsonism. J Neurochem 1998;70:745751.
91. Tasaki Y, Makino Y, Ohta S, Hirobe M. 1-Methyl-1,2,3,4-tetrahydroisoquioline, decreasing in 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine-treated mouse, prevents parkinsonims-like behavior abnormalities. J Neurochemi
1991;57:19401943.
92. Kotake T, Yoshida M, Ogawa Mea. Chronic Administration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline, an endog-
enous amine in the brain, induces parkinsonism in a primate. Neuroscience Letters 1996;217:6971.
93. Nagatsu T, Yoshida M. An edogenous substance of the brain, tetrahydroisoquinoline, produces parkinsonism in pri-
mates with decreased dopamine, tyrosine hydroxylase and biopterin in the nigrostriatal regions. Neurosci Lett.
1988;87:178182.
94. Yoshida M, Niwa T, Nagatsu T. Parkinsonism in monkeys produced by chronic administration of an endogenous sub-
stance of the brain, tetrahydroisoquinolone: the behavioral and biochemical changes. Neuroscie Lett. 1990;119:109113.
95. Lannuzel A, Michel PP, Abaul MJ, Caparros-Lefebvre D, Ruberg M. Neurotoxic effects of alkaloids from Annona
muricata (sour-sop) on dopaminergic neurons: potential role in etiology of atypical parkinsonism in French West Indies.
Mov Disord 2000;13(Suppl 3):28 [Abstract].
96. Friedrich MJ. Pesticide study aids Parkinson research. JAMA 1999;282:2200.
97. Makino Y, Ohta S, Tachikawa O, Hirobe M. Presence of Tetrahydroisoquinoline and 1-Methyl-Tetrahydro-Isoquinoline
in Foods: Compounds Related to Parkinsons Disease. Life Sciences 1988;43:373378.
98. Niwa T, Takeda N, Sasaoka T, Kaneda T, hashizume Y, Yoshizumi H, Tatematsu A, et al. Detection of
tetrahydroisoquinoline in parkinsonian brain as an endogenous amine by use of gas chromatography-mass spectrom-
etry. J Chromatogr 1989;491:397403.
99. Spencer PS, Kisby GE, Ross SM, Roy DN, Hugon J, Ludolph AC, et al. Guam ALS-PDC: possible causes. Science
1993;262(5135):825826.
100. Zhang ZX, Anderson DW, Mantel N, Roman GC. Motor neuron disease on Guam: geographic and familial occurrence,
195685. Acta Neurol Scand 1996;94(1):5159.
PSP 307
101. Zhang ZX, Anderson DW, Mantel N. Geographic patterns of parkinsonism-dementia complex on Guam, 1956 through
1985. Arch Neurol 1990;47(10):10691074.
102. McCrank E. PSP risk factors. Neurology 1990;40(10):1637.
103. McCrank E, Rabheru K. Four cases of progressive supranuclear palsy in patients exposed to organic solvents. Can J
Psychiatry 1989;34(9):934936.
104. Tetrud J, Langston J, Irwin I, Snow B. Parkinsonism caused by petroleum waste ingestion. Neurology 1994;44:
10511054.
105. Pezzoli G, Ricciardi S, Masotto C, Mariani CB, Carenzi A. n-Hexane induces parkinsonism in rodents. Brain Res
1990;531(1-2):355357.
106. Pezzoli G, Barbieri S, Ferrante C, Zecchinelli A, Foa V. Parkinsonism due to n-hexane exposure [letter]. Lancet
1989;2(8667):874.
107. Geddes JF, Vowles GH, Nicoll JA, Revesz T. Neuronal cytoskeletal changes are an early consequence of repetitive
head injury. Acta Neuropathol (Berl) 1999;98:171178.
108. Bhatt M, Desai J, Mankodi A, Elias M, Wadia N. Posttraumatic akinetic-rigid syndrome resembling Parkinsons dis-
ease: a report on three patients. Mov Disord 2000;15(2):313317.
109. Goetz CG, Pappert EJ. Trauma and movement disorders. Neurol Clin 1992;10(4):907919.
correlates of dementia with Lewy bodies. Neurology 1999;53(6):12841291.
111. OMeara ES, Kukull WA, Sheppard L, Bowen JD, McCormick WC, Teri L, et al. Head injury and risk of Alzheimers
disease by apolipoprotein E genotype. Am J Epidemiol 1997;146:373384.
112. Nemetz PN, Leibson C, Naessens JM, Beard M, Kokmen E, Annegers JF, et al. Traumatic brain injury and time to onset
of Alzheimers disease: a population-based study. Am J Epidemiol 1999;149:3240.
113. Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H, et al. Head injury and the risk of AD in the MIRAGE
114. Kofler M, Muller J, Wenning GK, Reggiani L, Hollosi P, Bosch S, et al. The auditory startle reaction in parkinsonian
disorders. Mov Disord 2001;16(1):6271.
115. Mehta KM, Ott A, Kalmijn S, Slooter AJ, vanDuijn CM, Hofman A, et al. Head trauma and risk of dementia and
Alzheimers disease: the Rotterdam Study. Neurology 1999;53:19591962.
116. Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, et al. Rates and risk factors for dementia and
Alzheimers disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work
Groups. European Studies of Dementia. Neurology 1999;52:7884.
117. Luukinen H, Viramo P, Koski K, Laippala P, Kivela SL. Head injuries and cognitive decline among older adultsa
population-based study. Neurology 1999;52:557562.
118. Vanacore N, Bonifati V, Fabbrini G, Colosimo C, Marconi R, Nicholl D, et al. Smoking habits in multiple system
atrophy and progressive supranuclear palsy. European Study Group on Atypical Parkinsonisms. Neurology
2000;54(1):114119.
119. Fujii C, Harado S, Ohkoshi N, Hayashi A, Yoshizawa K. Cross-cultural traits for personality of patients with Parkinsons
disease in Japan. Am J Med Genet 2000;96:13.
120. Nefzger M, Quadfasel F, Karl V. A retrospective study of smoking in parkinsons disease. Am J Epidemiol
1968;88:149158.
121. Morens D, Grandinetti A, Reed D, White L, Ross G. Cigarette smoking and protection from Parkinsons disease: false
association or etiologic clue? Neurology 1995;45:10411051.
122. Dubinsky RM, Jankovic J. Progressive supranuclear palsy and a multi-infarct state. Neurology 1987;37(4):570576.
123. Winikates J, Jankovic J. Vascular progressive supranuclear palsy. J Neural Transm Suppl 1994;42:189201.
124. Gearing M, Olson DA, Watts RL, Mirra SS. Progressive supranuclear palsy: neuropathologic and clinical heterogene-
ity. Neurology 1994;44(6):10151024.
125. Fabbrini G, Vanacore N, Bonifati V, Colosimo C, Meco G. Presymptomatic hypertension in progressive supranuclear
palsy. Study Group on Atypical Parkinsonisms [letter]. Arch Neurol 1998;55(8):11531155.
126. Ghika J, Bogousslavsky J. Presymptomatic hypertension is a major feature in the diagnosis of progressive supranuclear
palsy. Arch Neurol 1997;54(9):11041108.
127. Litvan I, Agid Y, Jankovic J, Goetz C, Brandel JP, Lai EC, et al. Accuracy of clinical criteria for the diagnosis of
progressive supranuclear palsy (SteeleRichardsonOlszewski syndrome). Neurology 1996;46(4):922930.
128. Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and
frontotemporal dementia. Ann Neurol 2003;54(Suppl 5):S15S19.
129. Boeve BF, Maraganore DM, Parisi JE, Ivnik RJ, Westmoreland BF, Dickson DW, et al. Corticobasal degeneration and
frontotemporal dementia presentations in a kindred with nonspecific histopathology. Dement Geriatr Cogn Disord
2002;13(2):8090.
130. Vidailhet M, Rivaud S, Gouider-Khouja N, Pillon B, Bonnet AM, Gaymard B, et al. Eye movements in parkinsonian
syndromes. Ann Neurol 1994;35(4):420426.
308 Litvan
131. Rivaud-Pechoux S, Vidailhet M, Gallouedec G, Litvan I, Gaymard B, Pierrot-Deseilligny C. Longitudinal ocular motor
study in corticobasal degeneration and progressive supranuclear palsy. Neurology 2000;54(5):10291032.
132. Schrag A, Good CD, Miszkiel K, Morris HR, Mathias CJ, Lees AJ, et al. Differentiation of atypical parkinsonian
syndromes with routine MRI. Neurology 2000;54(3):697702.
disease, MSA, PSP, and CBD. J Neural Transm 2003;110(2):151169.
134. Savoiardo M. Differential diagnosis of Parkinsons disease and atypical parkinsonian disorders by magnetic resonance
imaging. Neurol Sci 2003;24(Suppl 1):S35S37.
135. Warmuth-Metz M, Naumann M, Csoti I, Solymosi L. Measurement of the midbrain diameter on routine magnetic
resonance imaging: a simple and accurate method of differentiating between Parkinson disease and progressive supra-
nuclear palsy. Arch Neurol 2001;58(7):10761079.
136. Pillon B, Dubois B, Agid Y. Testing cognition may contribute to the diagnosis of movement disorders. Neurology
1996;46:329334.
137. Johnson R, Jr., Litvan I, Grafman J. Progressive supranuclear palsy: altered sensory processing leads to degraded
cognition. Neurology 1991;41(8):12571262.
138. Takeda M, Tachibana H, Okuda B, Kawabata K, Sugita M. Electrophysiological comparison between corticobasal
degeneration and progressive supranuclear palsy. Clin Neurol Neurosurg 1998;100(2):9498.
139. Okuda B, Tachibana H, Takeda M, Kawabata K, Sugita M. Asymmetric changes in somatosensory evoked potentials
correlate with limb apraxia in corticobasal degeneration. Acta Neurol Scand 1998;97(6):409412.
140. Valls-Sole J. Neurophysiological characterization of parkinsonian syndromes. Neurophysiol Clin 2000;30(6):352367.
141. Valldeoriola F, Valls-Sole J, Tolosa ES, Marti MJ. Striated anal sphincter denervation in patients with progressive
supranuclear palsy. Mov Disord 1995;10(5):550555.
142. Litvan I, Blesa R, Clark K, Nichelli P, Atack JR, Mouradian MM, et al. Pharmacological evaluation of the cholinergic
system in progressive supranuclear palsy. Ann Neurol 1994;36(1):5561.
143. Kompoliti K, Goetz CG, Litvan I, Jellinger K, Verny M. Pharmacological therapy in progressive supranuclear palsy.
Arch Neurol 1998;55(8):10991102.
144. Weiner WJ, Minagar A, Shulman LM. Pramipexole in progressive supranuclear palsy. Neurology 1999;52(4):873874.
145. Litvan I, Gomez C, Atack JR, Gillespie M, Kask AM, Mouradian MM, et al. Physostigmine treatment of progressive
supranuclear palsy. Ann Neurol 1989;26(3):404407.
and movement in PSP despite effects on sleep. Neurology 1989;39(2 Pt 1):257261.
147. Frattali CM, Sonies BC, Chi-Fishman G, Litvan I. Effects of physostigmine on swallowing and oral motor functions in
patients with progressive supranuclear palsy: a pilot study. Dysphagia 1999;14(3):165168.
patients with progressive supranuclear palsy. Neurology 2001;57(3):467473.
149. Pascual J, Berciano J, Gonzalez AM, Grijalba B, Figols J, Pazos A. Autoradiographic demonstration of loss of alpha 2-
adrenoceptors in progressive supranuclear palsy: preliminary report. J Neurol Sci 1993;114(2):165169.
150. Ghika J, Tennis M, Hoffman E, Schoenfeld D, Growdon J. Idazoxan treatment in progressive supranuclear palsy.
Neurology 1991;41(7):986991.
151. Rascol O, Sieradzan K, Peyro-Saint-Paul H, Thalamas C, Brefel-Courbon C, Senard JM, et al. Efaroxan, an alpha-2
antagonist, in the treatment of progressive supranuclear palsy. Mov Disord 1998;13(4):673676.
152. Litvan I, Dickson DW, Buttner-Ennever JA, Delacourte A, Hutton M, Dubois B, et al. Research goals in progressive
supranuclear palsy. First International Brainstorming Conference on PSP. Mov Disord 2000;15(3):446458.
153. Steele JC. Introduction. In: Litvan I, Agid A, eds. Progressive Supranuclear Palsy: Clinical and Research Aspects. New
York: Oxford University Press, 1992:314.
Corticobasal Degeneration 309
19
The Syndrome and the Disease
Bradley F. Boeve
INTRODUCTION
In 1967, Rebeiz, Kolodny, and Richardson described three patients with a progressive asymmetric
akinetic-rigid syndrome and apraxia and labeled these cases as corticodentatonigral degeneration
with neuronal achromasia (1,2). Additional reports on this disorder were almost nonexistent until
the early 1990s. Over the past 10 yr, interest in this disorder has increased markedly. The nomencla-
ture has also undergone evolution. The core clinical features that have been considered characteristic
of the disorder include progressive asymmetric rigidity and apraxia, with other findings suggesting
additional cortical (e.g., alien limb phenomena, cortical sensory loss, myoclonus, mirror movements)
and basal ganglionic (e.g., bradykinesia, dystonia, tremor) dysfunction.
The characteristic findings at autopsy have been asymmetric cortical atrophy, which is typically
maximal in the frontoparietal regions, basal ganglia degeneration, and nigral degeneration. Micro-
scopically, swollen neurons that do not stain with conventional hematoxylin/eosin (so-called bal-
looned, achromatic neurons) are found in the cortex. Abnormal accumulations of the
microtubule-associated tau protein are found in both neurons and glia.
In this chapter, the concepts and data relating to the corticobasal syndrome and corticobasal
degeneration as presented in a recent review (3) are expanded.
NOMENCLATURE
The terminology relating to corticobasal degeneration (CBD) has been confusing. The following
terms have been used: corticodentatonigral degeneration with neuronal achromasia (1,2),
corticonigral degeneration (CND) (4), cortical-basal ganglionic degeneration (CBGD) (5),
corticobasal ganglionic degeneration (CBGD) (6), and corticobasal degeneration (CBD) (7). Analy-
ses from several academic centers have shown that the constellation of clinical features originally
considered characteristic of this disorder can be seen in several non-CBD disorders, leading others to
suggest syndromic terms such as corticobasal syndrome (3), corticobasal degeneration syndrome
(8), Pick complex (9), progressive asymmetric rigidity and apraxia (PARA) syndrome (10), and asym-
metric cortical degeneration syndromeperceptual-motor type (11). Consensus on the terminology
has not been established. In this review, the term corticobasal syndrome (and abbreviation CBS) will
be used to characterize the constellation of clinical features initially considered characteristic of
corticobasal degeneration, and the term corticobasal degeneration (and abbreviation CBD) will be
used for the histopathologic disorder.

309
310 Boeve
DEMOGRAPHICS AND EPIDEMIOLOGY

Like many other neurodegenerative disorders, symptoms usually begin insidiously in the sixth to
eighth decade and gradually progress over 315 yr until death. Males and females are equally affected.
A defining characteristic of the CBS is asymmetric limb findings, but there does not appear to be any
predilection to the right or left side. A relatively high frequency of coexisting autoimmune diseases
was noted in one series (12). This is a sporadic disorder, although there are rare reports of a similarly
affected relative (13).
The incidence and prevalence of the CBS and CBD are not known. Bower et al. did not identify
any case of CBS or CBD in their analysis of parkinsonism in Olmsted County, Minnesota (14).
However, in a review of the autopsy records of the Mayo Clinic from 1970 to 2000, two residents of
Olmsted County, Minnesota, were found to have CBD pathology, with one exhibiting the CBS and
the other exhibiting dementia of the Alzheimer type (B. Boeve, unpublished data). As of 2003, we are
following 11 patients with the CBS in the Mayo Alzheimers Disease Research Center who reside in
the state of Minnesota. Considering there are approx 5 million residents in the state, a minimum
prevalence estimate is at least 2 per million (B. Boeve, unpublished data). The rarity of the CBS and
CBD will make more definitive incidence and prevalence estimates difficult.
CLINICAL FEATURES OF THE CORTICOBASAL SYNDROME

Details regarding the specific clinical features of the CBS can be found in several sources
(3,5,10,12,1517).
Progressive Asymmetric Rigidity and Apraxia

The core clinical features are progressive asymmetric rigidity and apraxia. Symptoms typically
begin in one limb, with no apparent predilection for the right or left side. Patients describe their limb
as clumsy, incoordinated, or stiff. On examination the limb is mildly to severely rigid, and
sometimes adopts a dystonic posture. Features of both rigidity (i.e., velocity-independent increased
tone) and spasticity (i.e., velocity-dependent increased tone) can be present in the affected limbs.
Alternating motion rates are markedly reduced. The affected limb often becomes profoundly apraxic.
Initially, the clumsiness and breakdown of complex coordinated movements may represent limb-
kinetic apraxia. However, this is difficult to completely distinguish from the effects of basal ganglia
dysfunction including rigidity, bradykinesia, and dystonia. Later, clear features of ideomotor apraxia
develop with the inability to correctly perform or imitate gestures and simple activities. When asked
to perform these activities or gestures with an involved hand, patients often glare at the limb in
question and visibly struggle. With time, the limb becomes completely useless, and other limbs become
similarly affected. Typically, progressive asymmetric rigidity and apraxia is present in one of the upper
limbs for at least 2 yr, then either the ipsilateral lower limb or contralateral upper limb becomes
involved, eventually leading to severe generalized disability several years later. Less commonly, a
lower limb is affected first, or progression occurs rapidly over many months.
Apraxia and rigidity have undegone further study. Leiguarda et al. evaluated buccofacial, ideomo-
tor, and ideational praxis in 10 patients with the CBS (18). Their findings suggested that ideomotor
apraxia was the most common type of apraxia in the CBS, and likely reflected dysfunction of the
supplementary motor area. Those who had coexisting ideational apraxia correlated with global cog-
nitive impairment, which suggested additional parietal or more diffuse cortical dysfunction (18).
Caselli et al. compared detailed kinematic data in several patients with the CBS, including one case
who had CBD at autopsy and another who had Alzheimers disease (AD) (19). Severe abnormalities
in temporal and spatial control, motor programming, and intermanual symmetry were present regard-
less of the presence or absence of dementia or specific histology (19). Boeve et al. studied two sib-
lings with a familial neurodegenerative disorder associated with nonspecific histopathology, in which
one brother exhibited the CBS during life whereas the other had classic frontotemporal dementia
(FTD) features (20). The case with the CBS features had no significant degenerative changes in the
basal ganglia and substantia nigra, suggesting that extrapyramidal dysfunction can exist in the
absence of appreciable pathology in the nigrostriatal system (20). Hence, additional clinical, radio-
logic, and pathologic studies are necessary to better define the anatomic substrates underlying apraxia
and rigidity in the CBS.
Alien Limb Phenomenon
The alien limb phenomenon is an intriguing feature in the CBS. Patients often describe their affected
limb as alien, uncontrollable, or having a mind of its own, and often label the limb as it when
describing the limbs behavior. The movements are spontaneous and minimally affected by mental
effort, sometimes requiring restraint by the contralateral limb. This phenomenon often lasts a few
months to a few years before progressive rigidity or dystonia supercedes.
There has been debate as to what constitutes true alien behavior from pseudoathetosis owing to
cortical sensory loss to simple levitation of a limb (2125). This phenomenon likely relates to pathol-
ogy in the supplementary motor area and the efferent/afferent connections.
Cortical Sensory Loss
Cortical sensory loss is often manifested symptomatically as numbness or tingling. Impaired
joint position sense, impaired two-point discrimination, agraphasthesia, and astereognosis in the set-
ting of intact primary sensory modalities are all evidence of cortical sensory loss. This likely relates
to pathology in somotosensory cortex thalamus.
Myoclonus
Myoclonus, if present, usually begins distally in one upper limb and may spread proximally. The
frequency and amplitude of myoclonic jerks typically increase with tactile stimulation (i.e., stimulus-
sensitive myoclonus) and action (i.e., action myoclonus). Recent electrophysiologic studies suggest
that the myoclonus in this disorder results from enhanced direct sensory input to cortical motor areas.
Typically, a peripheral stimulus inducing myoclonic jerks is not associated with an enhanced soma-
tosensory evoked potential (SSEP) and the latency from stimulus to jerk is brief, just sufficient to
have reached the cortex and returned to the periphery (i.e., ~ 40 ms in the upper limb). These features
are distinct from most other forms of cortical reflex myoclonus (which is associated with enlarged
SSEPs and a longer stimulus-to-jerk latency) (26,27).
Mirror Movements
Mirror movements are present if the opposite limb involuntary performs the same activity as the
one being examined. Mirror movements are often suppressible, but when the individual is distracted
and rechallenged with the same maneuver several minutes later, they will recur. Patients also fre-
quently demonstrate overflow movements on the same side of the body, whereby attempted move-
ment in an arm or leg causes additional movement in the ipsilateral limb, including elevation,
mirroring, etc. Mirror movements have been associated with the alien hand syndrome (28), although
many patients have them without alien limb features. Mirror movements are often found on examina-
tion but are rarely symptomatic.
Dystonia
Dystonic posturing of a limb is a common early manifestation, usually affecting one upper limb.
Frequently, the posturing of the hand takes on a fisted appearance, although hyperextension of one
or more fingers may occur. Initially, dystonia may only be evident during walking or reaching. In
those with symptoms beginning in a lower limb, the foot is often tonically inverted, and ambulation
is severely limited. Pain often but not always accompanies dystonia. The fisted hand sign may
represent one of the most specific clinical features for underlying CBD in the CBS (Rippon et al.,
unpublished data).
312 Boeve
Tremor
Tremor is another common presenting feature, and patients typically describe the affected extrem-
ity as jerky. A postural and action tremor often evolves to a more jerky tremor and then to myoclo-
nus. Unlike the tremor of Parkinsons disease (PD), which is most prominent at rest and dampens
with action, the tremor is amplified with activity and minimal at rest. A classical 4- to 6-Hz parkinso-
nian rest tremor is rarely, if ever, evident in this disorder.
Lack of Levodopa Response

There are no published cases in which a significant and sustained clinical improvement has occurred
with levodopa therapy (29). Many regard the lack of objective improvement during therapy with at
least 750 mg of daily levodopa (divided doses, on an empty stomach) as a diagnostic feature of the
disorder (realizing that other akinetic-rigid syndromes fail to respond to levodopa as well).
Dementia
Clinically significant dementia is not a typical early finding in patients with the CBS, but impair-
ment in one or more cognitive domains is often present. However, it should be emphasized that the
absence of early clinically significant dementia relates largely to the application of diagnostic criteria
that have attempted to exclude other disorders such as AD and Lewy body dementia. In fact, as
discussed below, although the pathology of CBD may be the most common cause of the CBS, some
studies have found that it presents more commonly as a dementia syndrome (30).
Yes/No Reversals
A very intriguing feature in the CBS (as well as other disorders) is the tendency for patients to
shake their head and respond yes when they actually mean no, and vice versa (31). Whereas
some patients and relatives describe this phenomenon spontaneously, this often requires specific
questioning by the clinician. Relatives and friends of affected patients tend to repeat their questions,
or ask do you really mean yes or no? and thus this issue can significantly affect communication in
some patients. This phenomenon is likely due to frontosubcortical dysfunction, in which mental flex-
ibility and inhibitory control is impaired (31).
Focal or Lateralized Cognitive Features

Aphasia (which is typically nonfluent) (32), ideomotor apraxia, hemineglect, etc., are lateralized
cognitive features that are as frequent as the motor features. Apraxia of speech and/or nonverbal oral
apraxia are quite common; in fact, one published case presented with speech apraxia and did not
develop other typical features until at least 5 yr later (33). Although rarely symptomatic, patients
often demonstrate constructional dyspraxia on drawing tasks, particularly if the parietal lobe of the
nondominant hemisphere is sufficiently affected. Other nondominant parietal lobe findings such as
hemineglect and poor spatial orientation can also occur, which often are symptomatic in activities of
daily living. Apraxic agraphia may result if the homologous region of the dominant hemisphere is
dysfunctional. The lack of these findings being noted in the CBD literature probably stems from
clinicians not including assessment of visuospatial/visuoperceptual functioning and neglect (11,16).
Neuropsychiatric Features
Depression, obsessive-compulsive symptomatology, and frontal behavioral disturbances can
occur in the CBS syndrome (34,35). Visual hallucinations and delusions are very rare. The presence
of visual hallucinations in the setting of cognitive impairment and/or parkinsonism may therefore
favor a diagnosis of Lewy body disease rather than CBD (36,37).
Ocular Motor Apraxia

Ocular motor apraxia occurs to some degree in almost every patient (17). This includes difficulty
initiating saccades and voluntary gaze, but pursuit and optokinetic nystagmus are typically preserved.
In contrast to patients with progressive supranuclear palsy (PSP), those with the CBS have normal
speed and amplitude of the saccades. On the other hand, eventually patients may develop supra-
nuclear gaze paresis that can be indistinguishable from that seen in PSP. Eyelid opening/closing
apraxia is also frequent.
Other Findings
Several other less specific findings may also occur. Frontal release signs, hypokinetic dysarthria,
asymmetric hyperreflexia, and/or extensor toe responses also occur with some frequency. Postural
instability is very common later in the disease and may be related to gait apraxia, bilateral lowerlimb
parkinsonian, dystonia, or less frequently vestibular involvement. If balance problems are present at
an early stage, they are usually secondary to lower-limb involvement at onset. Appendicular ataxia,
chorea, and blepharospasm are infrequent manifestations. Dysphagia begins insidiously in the later
stages of the disease in contrast to what usually occurs in PSP, and as in that disorder eventually leads
to aspiration pneumonia and death in most instances.
DIAGNOSTIC CRITERIA
Four sets of clinical diagnostic criteria have been published (3,5,38,39) (Tables 1-4). The criteria
by Maraganore et al., Lang et al., and Kumar et al. are similar to other sets of criteria (e.g., AD, ref.
40, PSP, ref. 41; etc.) in which those clinical features that are thought to best predict underlying CBD
are listed and qualified. Yet, several investigators have shown considerable clinicopathologic hetero-
geneity in patients clinically suspected to have CBD (4244). The criteria proposed by Boeve et al.
takes this heterogeneity into account and lists the clinical features for the syndrome, which is con-
ceptually similar to the syndromes of frontotemporal dementia, progressive nonfluent aphasia, and
semantic dementia (45). None of these sets of criteria have been rigorously validated, and refinements
are likely to be necessary.
Consensus was reached for the neuropathologic criteria for the diagnosis of CBD (46). The core
features are listed in Table 5. A critical point is that appropriate staining techniques (i.e., Gallyas
silver staining, immunocytochemistry with tau, and phospho-neurofilament or F-B-crystallin), should
be performed in appropriate cases, particularly in those with dementia and/or parkinsonism where no
significant Alzheimer or Lewy body pathology is found. More details on the neuropathologic find-
ings in CBD are discussed below.
FINDINGS ON ANCILLARY TESTING

Many of the diagnostic studies available for evaluating brain disease have been studied in the CBS
and CBD, and like so many other facets of the syndrome and the disorder, the findings are difficult to
interpret. Most of the literature on the laboratory, neuropsychologic, electrophysiologic, and radio-
logic findings in CBD have involved patients with clinically diagnosed CBD (i.e., the CBS) but
without pathologic confirmation. Since a considerable proportion of patients with the CBS (approx
50% in one seriessee subheading Diagnostic Accuracy) have a non-CBD disorder underlying their
symptoms, one must view the findings described below consistent with the CBS but as yet unproven
for the disorder of CBD.
Laboratory Findings
Routine blood, urine, and cerebrospinal fluid (CSF) tests are typically normal. Recent studies
indicate that the tau haplotype in CBD is similar to that in PSP (47). Elevation of tau in the CSF has
also been identified in CBD patients (48). Whether the tau haplotype or CSF tau level improves
antemortem diagnostic accuracy requires further study.
314 Boeve
Table 1
Clinical Diagnosis of Corticobasal Degeneration: Criteria of Maraganore et al.
Clinically Possible CBD:
No identifiable cause (e.g., tumor, infarct), at least three of the following:
Progressive course
Asymmetric distribution PARA syndrome
Rigidity
Apraxia
Clinically Probable CBD:
All four of clinically possible criteria, no identifiable cause, at least two of the following:
Focal or asymmetric appendicular dystonia
Focal or asymmetric appendicular myoclonus
Focal or asymmetric appendicular postural/action tremor
Lack of levodopa response
Clinically Definite CBD:
Meets criteria for clinically probable CBD, at least one of the following:
Alien limb phenomenon
Cortical sensory loss
Mirror movements
Supportive findings:
Asymmetric amplitude on EEG
Focal or asymmetric frontoparietal atrophy on CT or MRI
Focal or asymmetric frontoparietal basal ganglia hypoperfusion on SPECT
Focal or asymmetric frontoparietal basal ganglia hypometabolism on PET
From ref. 38.
Table 2
Clinical Diagnosis of Corticobasal Degeneration: Criteria of Lang et al.
Inclusion criteria:
Rigidity plus one cortical sign (apraxia, cortical sensory loss, or alien limb
phenomenon)
or
Asymmetric rigidity, dystonia, and focal reflex myoclonus
Qualifications of clinical features:
Rigidity: easily detectable without reinforcement
Apraxia: more than simple use of limb as object; clear absence of cognitive or
motor deficit sufficient to explain disturbance
Cortical sensory loss: preserved primary sensation; asymmetric
Alien limb phenomenon: more than simple levitation
Dystonia: focal in limb; present at rest at onset
Myoclonus: reflex myoclonus spreads beyond stimulated digits
Exclusion criteria:
Early dementia
Early vertical-gaze palsy
Rest tremor
Severe autonomic disturbances
Sustained responsiveness to levodopa
Lesions on imaging studies indicating another pathologic process is responsible
From ref. 5.
Table 3
Clinical Diagnosis of Corticobasal Degeneration: Criteria of Kumar et al.
Core features:
Chronic progressive course
Asymmetric at onset (includes speech dyspraxia, dysphasia)
Presence of:
Higher cortical dysfunction (apraxia, cortical sensory loss, or alien limb) and
Movement disorders (akinetic-rigid syndrome resistant to levodopa, and limb
dystonia or spontaneous and reflex focal myoclonus)
Qualifications of clinical features:
Same as criteria of Lang et al.
Exclusion criteria:
Same as criteria of Lang et al.
From ref. 39.
Table 4
Proposed Criteria for the Diagnosis of the Corticobasal Syndrome
Core Features:
Insidious onset and progressive course
No identifiable cause (e.g., tumor, infarct)
Cortical dysfunction as reflected by at least one of the following:
focal or asymmetric ideomotor apraxia
alien limb phenomenon
cortical sensory loss
visual or sensory hemineglect
constructional apraxia
focal or asymmetric myoclonus
apraxia of speech/nonfluent aphasia
Extrapyramidal dysfunction as reflected by at least one of the following:
Focal or asymmetric appendicular rigidity lacking prominent and sustained
levodopa response
Focal or asymmetric appendicular dystonia
Supportive Investigations:
Variable degrees of focal or lateralized cognitive dysfunction, with relative
preservation of learning and memory, on neuropsychometric testing
Focal or asymmetric atrophy on CT or MRI, typically maximal
in parietofrontal cortex
Focal or asymmetric hypoperfusion on SPECT and hypometabolism on PET,
typically maximal in parietofrontal cortex basal ganglia thalamus
From ref. 3.
316 Boeve
Table 5
Office of Rare Diseases Neuropathologic Criteria for the Diagnosis of Corticobasal Degeneration
Core Features:
Focal cortical neuronal loss, most often in frontal, parietal, and/or temporal regions
Substantia nigra neuronal loss
Gallyas/tau-positive neuronal and glial lesions, especially astrocytic plaques and threads, in both white
matter and gray matter, most often in superior frontal gyrus, superior parietal gyrus, pre- and
postcentral gyri, and striatum
Supportive Features:
Cortical atrophy, often with superficial spongiosis
Ballooned neurons, usually numerous in atrophic cortices
Tau-positive oligodendroglial coiled bodies
Adapted from ref. 46.
Neuropsychological Findings
Neuropsychometric testing typically shows impairment in those domains subserved by frontal/
frontostriatal and parietal cognitive networks: attention/concentration, executive functions, verbal
fluency, praxis, and visuospatial functioning (49,50). The profile of impairment depends in part on
which cerebral hemisphere is maximally affected. Performance on tests of learning and memory
tends to be mildly impaired if impaired at all. Alternative diagnoses, particularly AD, should be
considered if performance on delayed recall and recognition measures are markedly abnormal.
It should be noted that the few published reports on the neuropsychological findings in CBD have
involved clinically but not pathologically diagnosed cases, thus these patients had the CBS and may
or may not have had underlying CBD. Since the diagnosis of CBS is based on the constellation of
clinical features, which reflects the topography of dysfunction in the frontostriatal and parietal neural
networks, the findings on neuropsychological testing should mirror this topography. Thus, the neu-
ropsychological findings noted above should be considered typical of the CBS but not be considered
diagnostic of underlying CBD.
Electrophysiologic Findings
Findings on electroencephalography (EEG) have varied from normal to marked dysrhythmic and
delta slowing (51,52). Asymmetric amplitudes of background alpha activity and sleep spindles have
been reported in the CBS (20).
The electrophysiologic aspects of myoclonus in cases of presumed CBD have been discussed in
detail elsewhere (26,27), including the short reflex latency and reduced inhibition following mag-
netic stimulation over the cortex (53). Although there is at least one case of pathologically proven
CBD who had a longer latency more typical of cortical reflex myoclonus, other cases of CBS with a
long latency form of reflex myoclonus that have been studied have demonstrated other pathologies at
postmortem (e.g., Picks disease, AD, and motor neuron inclusion body dementia). In contrast, to
date, the few cases coming to autopsy in which the short latency form was present in life have had the
pathology of CBD (3). These findings may be the most specific antemortem predictor of underlying
CBD identified thus far; however, many more cases need to be studied with clinical, electrophysi-
ological, and pathological correlation.
Magnetic Resonance Imaging Findings

The purpose of performing a computed tomography (CT) or magnetic resonance imaging (MRI)
scan of the brain is to exclude a structural lesion such as a tumor, abscess, hematoma, or infarct. In
the absence of these lesions, some findings can be supportive of the diagnosis of CBS, such as asym-
metric cortical atrophy, especially frontoparietal, with the more prominent atrophy existing contralat-
eral to the side most severely affected clinically (5459) (Fig. 1). The lateral ventricle in the
maximally affected cerebral hemisphere can also be slightly larger than opposite one. Asymmetric
atrophy in the cerebral peduncles may be present (5) (Fig. 2). Other reported MRI findings in the
CBS include atrophy of the middle or posterior segment of the corpus callosum (60) (Fig. 3),
hyperintense signal changes lateral to the putamen (54,56,61) (Fig. 4), atrophy of the putamen (61),
and subtle hyperintense subcortical signal changes in motor somatosensory cortex (62,63) (Fig. 5).
These are often subtle findings and their presence or absence should not alter the clinical diagnosis of
the CBS. Importantly, the majority of cases in which these MRI findings were identified have not had
CBD verified postmortem. In the only series of patients with the CBS associated with CBD pathol-
ogy, CBS associated with non-CBD pathology, and CBD pathology associated with non-CBS clini-
cal features, none of these MRI findings were found to be adequately sensitive or specific for CBDthe
disease (64).
Progressive parietal frontal atrophy (Fig. 6) and thinning of the middle and posterior portion of
the corpus callosum (Fig. 7) often occurs on serial MRI scans in patients with the CBS. Some patients
present with a focal cortical degeneration syndrome such as frontotemporal dementia (Fig. 8), pro-
gressive aphasia, or posterior cortical atrophy (Fig. 9) and subsequently develop CBS findings.
We have also observed several atypical MRI findings in the CBS and CBD. Focal hyperintense
subcortical signal changes can evolve (Figs. 1012). The hazy or hyperintense signal changes may
reflect gliosis and/or secondary demyelination. Some patients have minimal cortical atrophy, and
despite unequivocal clinical progression, progressive atrophy is difficult to appreciate, although ven-
tricular dilatation may be evident (Fig. 13). Increased signal along the parietofrontal cortical ribbon
can be seen in patients with CreutzfeldtJakob disease who present with the CBS (Fig. 14).
Functional Neuroimaging Findings

Asymmetric hypoperfusion on single photon emission computed tomography (SPECT) and asym-
metric hypometabolism on positron emission tomography (PET) involving the parietofrontal cortex
basal ganglia have been reported (6571) (Fig. 15). Imaging of the nigrostriatal dopamine system
typically demonstrates a reduction of striatal tracer uptake greater contralateral to the clinically most
affected side. Unlike PD, uptake in the caudate is generally reduced to the same extent as in the
putamen. However, these findings are not specific for CBDthe disease (72).
In summary, although the electrophysiologic findings in myoclonus and association of a specific
tau haplotype and increased CSF tau are promising, there are no antemortem features or biologic
markers identified to date that definitively distinguishes CBD from the CBD mimickers.
NEUROPATHOLOGIC FINDINGS
Consensus criteria for the pathologic diagnosis of CBD have recently been published (46) (Table 5).
Macroscopic
Asymmetric parietofrontal or frontotemporal cortical atrophy (Fig. 16), and pallor of the substan-
tia nigra, are the typical macroscopic pathologic findings. Some individuals with typical clinical and
microscopic findings do not have appreciable cortical atrophy, however.
Microscopic
Neuronal loss, gliosis, and superficial spongiosus are prominent in the maximally affected cortical
gyri. Immunocytochemistry with tau as well as phosphorylated neurofilament or FB-crystallin is
imperitive when characterizing cases with possible CBD. The pathologic features of CBDthe dis-
ease include tau-positive (tau+) astrocytic plaques and tau+ threadlike lesions in gray and white
318 Boeve
Fig.1. Coronal T1-weighted (A) and axial FLAIR (B) MR images in a patient with the corticobasal syn-
drome. Note the asymmetric parietal cortical atrophy, more evident in the right hemisphere in this patient.
Fig. 2. Axial FLAIR MR image in a patient with the corticobasal syndrome, showing asymmetric atrophy of
the cerebral peduncles.
Fig. 3. Midsagittal T1-weighted MR image in a patient with the corticobasal syndrome, showing thinning of
the corpus callosum where the projections between the parietal cortices traverse.
Fig. 4. Axial FLAIR MR image in a patient with the corticobasal syndrome, demonstrating the rare finding
of increased signal lateral to the putamen.
320 Boeve
Fig. 5. Axial FLAIR MR images of three patients with the corticobasal syndrome, showing subtle, hazy
increased signal in the subcortical posterior frontal/parietal white matter. The signal changes are asymmetric in
B and C, but quite symmetric in A despite strikingly asymmetric clinical findings in all three patients.
Fig. 6. Serial axial FLAIR MR images in a patient with the corticobasal syndrome. By age 61 (images in
column C), she had also developed features of the Balints syndrome.
Fig. 7. Serial midsagittal MR images in a patient with the corticobasal syndrome. Note the progressive
thinning of the posterior aspect of the corpus callosum (but sparing the splenium) and mild ventricular dilata-
tion. The decreased signal along the mesial frontal region in B reflects evolving atrophy in this region.
Fig. 8. Serial axial FLAIR MR images in a patient with features of frontotemporal dementia at age 79 (A),
which then evolves to include nonfluent aphasia at age 81 (B) and corticobasal syndrome findings at age 82 (C).
matter, most often in superior frontal gyrus, superior parietal gyrus, pre- and postcentral gyri, and
striatum (Fig. 17). Tau+ oligodendroglial coiled bodies are also common (Fig. 18). While achro-
matic, ballooned neurons that are immunoreactive to phosphorylated neurofilament or FB-crystallin
are typically present in CBD (Fig. 19), their absence does not preclude the diagnosis of CBD if the
appropriate tau+ lesions are present. These criteria have been validated (Litvan et al., in preparation).
These pathological features are indistinguishable from those in frontotemporal dementia and par-
kinsonism linked to chromosome 17 (FTDP-17) (46). Thus, knowledge about the family history and
molecular genetics is necessary to adequately classify cases with CBD-type pathology.
322 Boeve
Fig. 9. Sagittal T1-weighted (A), axial FLAIR (B), and coronal T1-weighted (C) MR images in a patient
who presented with the posterior cortical atrophy syndrome (i.e., Balints syndrome, Gerstmanns syndrome,
etc.) and subsequently developed classic corticobasal syndrome features.
Fig. 10. Axial FLAIR MR images in a patient with the corticobasal syndrome, showing focal increased
signal in the left posterior frontal white matter. Autopsy revealed corticobasal degeneration with significant
tau-positive glial pathology in this region.
Fig. 11. Axial FLAIR MR images in a patient with the corticobasal syndrome, showing focal increased
signal in the right frontal > parietal white matter. Autopsy revealed corticobasal degeneration with significant
tau-positive glial pathology in this region.
Fig. 12. Serial axial FLAIR MR images in a patient with the corticobasal syndrome, showing progressive
focal increased signal evolving in the periventricular and subcortical white matter of the left parietal region.
Fig. 13. Serial coronal T1-weighted images in a patient with the corticobasal syndrome at age 62 (A) and age
65 (B). Despite striking progression in her asymmetric CBS findings, note the rather mild and minimally pro-
gressive cerebral cortical atrophy over the frontal convexities. Mild progressive ventricular dilatation is evi-
dent, but the hippocampi do not appear significantly atrophic. This patient had progressive supranuclear palsy
at autopsy.
324 Boeve
Fig. 14. Axial FLAIR MR images in two patients with the corticobasal syndrome. The patient in A has had
a 3-yr course and is still alive, whereas the patient in B died after a 14-mo course. Note the striking increased
signal along the cortical ribbon in the posterior frontal/parietal regions in both patients. Autopsy in patient B
revealed CreutzfeldtJakob disease.
Fig. 15. Coronal single photon emission computed tomography (SPECT) images in a patient with the
corticobasal syndrome. Note the hypoperfusion in the right frontoparietal > temporal cortex as well as basal
ganglia and thalamus. Autopsy confirmed corticobasal degeneration in this patient.
CLINICAL FEATURES OF CORTICOBASAL DEGENERATION:

THE DISEASE
There are few reports in which the clinical features in pathologically proven CBD have been
characterized. Caselli et al. found subtle differences in kinematic abnormalities in a pathologically
proven case of CBD compared to a patient with CBS who had AD pathology (19). The speech and
language abnormalities associated with pathologically confirmed CBD have recently been described
(73). Symptoms and signs of speech or language dysfunction were among the presenting features in
over half of the patients in this series. Among these 13 cases, the features included dysarthria (n = 4;
hypokinetic, spastic, ataxic, and mixed forms), apraxia of speech (n = 5), and aphasia (n = 7; fluent,
nonfluent, and mixed forms). Hence, speech and language dysfunction is common in CBD, and the
findings include variable degrees of dysarthria, apraxia of speech, and aphasia (73).
Fig. 16. Photograph of the brain of a patient with corticobasal degeneration who had exhibited classic
corticobasal syndrome features antemortem. Note the cortical atrophy is maximal in the posterior frontal and
parietal region. Courtesy Joseph E. Parisi, MD, Mayo Clinic, Rochester, Minnesota.
Fig. 17. Photomicrograph of parietal cortex with tau immunocytochemistry (20) in a patient with
corticobasal degeneration. Note the tau-positive threads and clusters of tau-positive astrocytes (astrocytic
plaques) typical of CBD. Courtesy Joseph E. Parisi, MD, Mayo Clinic, Rochester, Minnesota.
326 Boeve
Fig. 18. Photomicrograph of subcortical frontal white matter with tau immunocytochemistry (x60) in a patient
with corticobasal degeneration. Note the coiled or comma-shaped appearance of the inclusion characteristic of an
oligodendroglial coiled body. Courtesy Joseph E. Parisi, MD, Mayo Clinic, Rochester, Minnesota.
Fig. 19. Photomicrograph of parietal cortex with phosphorylated-neurofilament immunocytochemistry (60)

in a patient with corticobasal degeneration. Note the intense staining in a ballooned neuron typical of CBD.
Courtesy Joseph E. Parisi, MD, Mayo Clinic, Rochester, Minnesota.
Table 6
Pathologic Diagnoses in 36 Consecutive Autopsied Cases
at the Mayo Clinic With the Corticobasal Syndrome
Diagnosis No. of cases
Corticobasal degeneration 18
Progressive supranuclear palsy 6
Alzheimers disease 4
CreutzfeldtJakob disease 3
Nonspecific degenerative changes 3
Picks disease 1
Combined Alzheimers disease/Picks disease 1
Table 7
Clinical Diagnoses in 32 Consecutive Autopsied Cases
at the Mayo Clinic With Pathologically Proven CBD
Initial Clinical Diagnosis Final Clinical Diagnosis
10 Corticobasal degeneration 18 Corticobasal degeneration
6 Atypical Parkinsons disease 7 Progressive supranuclear palsy
6 Dementia/Alzheimers disease 4 Primary progressive aphasia
4 Primary progressive aphasia 1 Alzheimers disease
2 Progressive supranuclear palsy 1 Dementia with Lewy bodies
1 Dementia with Lewy bodies 1 MarchiafavaBignami disease
1 MarchiafavaBignami disease
1 Multiple sclerosis
1 Stroke
The disorder of CBD can also present as several clinical syndromes. In addition to the CBS, the
reported focal/asymmetric cortical degeneration syndromes associated with CBD pathology include
frontotemporal dementia (7477), a progressive aphasia syndrome (fluent and nonfluent subtypes)
(7681), and posterior cortical atrophy (with some or all features of the Balints syndrome) (82).
Some patients have been diagnosed antemortem as probable AD (30, 77). In fact, dementia was the
most common presentation of CBD in one series (30). Many patients have had clinical findings
indistinguishible from PSP (44,8388). One patient presented with apraxia of speech and subse-
quently developed more typical CBD features (33). Another presented with obsessive-compulsive
features and visual inattention (89). Hence, from the clinicopathologic perspective, CBD is a hetero-
geneous disorder.
CLINICOPATHOLOGIC HETEROGENEITY
Although the early literature on CBD suggested it was a distinct clinicopathologic entity, numer-
ous case reports and small series clearly indicates considerable clinicopathologic heterogeneity in the
CBS and CBDthe disease. An updated review of this heterogeneity from one institution (43,90) is
shown in Tables 6 and 7. Thus, the following disorders can underlie the CBS: CBD, AD, Picks
disease, PSP, dementia lacking distinctive histopathology, and CreutzfeldtJakob disease (43), as well
as dementia with Lewy bodies (91), motor neuron inclusion body dementia (92), and neurofilament
inclusion body dementia (93). As noted above, CBD can present clinically as the CBS, dementia (not
otherwise specified), primary progressive aphasia, frontotemporal dementia, posterior cortical atro-
328 Boeve
Fig. 20. Note the close syndrome-topography association for each syndrome, but the variable associated
histopathologies for each syndrome. Darker lines signify associations that occur more frequently. Abbreviations:
CBD, corticobasal degeneration; CJD, Creutzfeldt-Jacob disease; DLB, dementia with Lewy bodies; DLDH,
dementia lacking distinctive histopathology; MND Inclusion Dem, motor neuron disease inclusion dementia;
NIBD, neurofilament inclusion body dementia; PSP, progressive supranuclear palsy. Adapted from ref. 99.
phy, and progressive speech apraxia. Some patients often present with one of these focal cortical
degeneration syndromes and subsequently develop features overlapping with one or more syndromes
(8,9). Hence, it is now clear that in the CBSlike in the other focal/asymmetric cortical degeneration
syndromes (11,94,95)the clinical presentation and progression of symptoms reflect the topographic
distribution of histopathology more so than the specific underlying disease. Furthermore, CBD has a
variable pattern of cerebral cortical pathology, and the topographic distribution of pathology dictates
the clinical presentation. A summary of the clinicopathologic correlations in the focal/asymmetric
cortical degeneration syndromes is shown in Fig. 20. As therapies are developed that specifically
target amyloid, tau, prion protein, synuclein, etc., pathophysiology, particularly if any such therapies
have toxic side effects, improving the diagnostic accuracy of patients with the CBS and other focal/
asymmetric cortical degeneration syndromes will become increasingly important.
DIAGNOSTIC ACCURACY
The clinicopathologic heterogeneity in CBS and CBD has led to relatively poor sensitivity and
specificity for the diagnosis of CBD. As shown in Tables 6 and 7, among 36 consecutive patients
with clinically suspected CBD (i.e., the CBS) who underwent autopsy, only half were found to have
underlying CBD (specificity of the CBS for CBD = 50%). Furthermore, among 32 patients with
pathologically proven CBD, only 18 exhibited the CBS (sensitivity of the CBS for CBD = 56%).
Other investigators found high sensitivity but low specificity in the clinical diagnosis of CBD (96).
This poor sensitivity and specificity has clearly stymied research in this area. However, if one views
the disorders as they relate to the putative dysfunctional protein, the specificity of the CBS for the
tauopathies (considering AD as an amyloidopathy for this calculation) is 69%. Since some therapies
that affect tau pathophysiology may have efficacy for any of the tauopathies, delineation of the spe-
cific histopathologic disorder may not be as important determining whether patients have a tauopathy
underlying their symptoms. Clearly, biomarkers that are more sensitive and specific for CBD as well
as the other tauopathies are needed.
PATHOPHYSIOLOGY
Several lines of evidence point toward dysfunction in microtubule-associated tau as a primary
factor in the pathogenesis of CBD. The inclusions in glia and neurons are immunoreactive to tau (46).
The pathology of CBD has been associated with mutations in tau (97). Transgenic mice with the
P301L mutation have exhibited clinical and neuropathologic findings similar to humans (98).
Hyperphosphorylation of tau disrupts binding to microtubules. Further characterization of the cas-
cade of events involved in tau dysfunction and neurodegeneration will be critical to ultimately develop
therapy.
MANAGEMENT
Since no therapy yet exists for CBD that affects the neurodegenerative process, management must
be tailored toward symptoms. Pharmacotherapy directed toward parkinsonism has been disappoint-
ing (29). Levodopa, dopamine agonists, and baclofen tend to have little effect on rigidity, spasticity,
bradykinesia, or tremor. However, levodopa should be titrated upward as tolerated to at least 750 mg
per day in divided doses on an empty stomach to provide an adequate trial. Some patients have noted
significant improvement in parkinsonism but this rarely persists beyond several months. In those
who do improve dramatically with levodopa therapy, one must question whether CBD is the underly-
ing disorder, as levodopa-refractory parkinsonism is considered by many to be a characteristic fea-
ture of the CBS and CBD. Anticholinergic agents rarely improve dystonia, and their use is limited by
side effects. Botulinum toxin can alleviate pain owing to focal dystonia. Central pain has been rare,
but some patients have responded to gabapentin. Tremor may respond initially to propranolol or
primidone, but their effects wane with progression of the disorder. Clonazepam and/or gabapentin
may reduce myoclonus in some cases. Although intuitively one would not consider any of the cho-
linesterase inhibitors to be beneficial in this disorder, we have seen rare cases who note improvement
in psychomotor speed, concentration, and problem-solving abilities with donepezil, rivastigmine, or
galantamine. Vitamin E and other antioxidant agents have been tried in hopes of delaying progres-
sion of the disorder, but there is no evidence yet supporting a disease-altering effect.
Because of the poor response to pharmacotherapy, the mainstay of management is therefore physi-
cal, occupational, and speech therapies. A home assessment by an occupational therapist can aid in
determining which changes could be made to facilitate functional independence (e.g., replacing rotating
doorknobs with handles; attaching specially formed pads around the handles of eating utensils and
toothbrushes; purchasing clothing with velcro instead of buttons or laces, etc.). Passive range of
motion (ROM) exercises minimize development of contractures, and all caregivers should be instructed
to provide passive ROM exercises daily. In those who develop dystonic flexion of the hand muscula-
ture to form a fisted hand, the fingernails can become imbedded in the palmar tissue leading to
cellulitis and even osteomyelitis of the hand. One can avoid this by clipping the fingernails periodi-
cally, and by placing a rolled-up washcloth or hand towel in the palm of the hand. All patients expe-
rience gait impairment at some point during their illness. A walker with handbrakes can improve
ambulation for some patients. Wheelchair and handicap priviledges are warranted in essentially every
patient. Use of a bedside commode is also worthwhile. Apraxia is often the most debilitating feature of
the disorder, and this feature can complicate ones ability to operate a wheelchair or motorized
scooter. However, many patients are able to learn to operate these devices and use them effectively
330 Boeve
for months or years. We have seen a few patients whose useless hand was made useful by employ-
ing constraint-induced movement therapy. Some third-party payers have denied coverage for these
devices and therapies, which is very unfortunate as any element of functional improvement and inde-
pendence is important for these patients. Speech therapy and communication devices can optimize
communication when dysarthria, apraxia of speech, or aphasia is present. Therapists also counsel
patients and families on swallowing maneuvers and food additives to minimize aspiration when dys-
phagia occurs. Feeding gastrostomy should be discussed with all patients, although many decide not
to undergo this procedure.
Some patients with the CBS develop elements of other focal cortical degeneration syndromes,
such that features of frontotemporal dementia (FTD), primary progressive aphasia (PPA), posterior
cortical atrophy (PCA), or some combination of these can evolve. Also, patients who present with
one of these syndromes can develop features of the CBS. Management of many of these non-CBS
syndromes is discussed elsewhere (99).
Other treatable comorbid illnesses must also be considered, most notably infections (e.g., pneu-
monia and urinary tract infections), psychiatric disorders, and sleep disorders. Although psychotic
features rarely occur in the CBS, depression evolves in essentially every patient, likely owing in part
to the preserved insight that is also characteristic of the disorder. Sleep disorders such as obstructive
sleep apnea, central sleep apnea, restless legs syndrome, periodic limb movement disorder, etc. occur
with some frequency in the CBS, and treatment can improve quality of life (100). REM sleep behav-
ior disorder is very rare in the CBS; in fact if it is present, one must suspect some contribution of
synucleinopathy pathology (101). Despite the difficulties of manipulating the headgear as part of
nasal continuous positive airway pressure (CPAP) therapy owing to the limb apraxia, CPAP therapy
for obstructive sleep apnea can be tolerated and used effectively in many patients. Patients and
caregivers eventually require assistance in maintaining optimal care, which can be provided either
through home health care or in a skilled nursing facility.
FUTURE DIRECTIONS
Clearly, with the CBS being no more than 60% sensitive and specific for CBDthe disease, further
research in improving the antemortem diagnosis of CBD is necessary. No consensus yet exists for the
diagnosis of the CBS. Further characterization of the natural history of patients with the CBS involv-
ing serial assessments of clinical, laboratory, neuropsychologic, and radiologic features is very impor-
tant, as this information will be necessary to design future drug trials, particularly if agents active against
tau pathophysiology are developed. Debate continues regarding whether CBD and PSP are variants
of the same pathophysiologic process or distinctly separate disorders, and this warrants clarification.
Additional studies on the rare kindreds with the clinical features of CBS (20,102) and/or pathologic
features of CBD (13), whether associated with mutations in tau (i.e., FTDP-17) or not, may offer key
insights as other genes impacting tau pathophysiology have yet to be identified. Finally, patients and
their families should be encouraged to access sources of information and support as well as partici-
pate in research.
MAJOR ISSUES TO BE STUDIED IN THE FUTURE:

Establish consensus criteria for the diagnosis of the CBS.
Identify which clinical, laboratory, neuropsychologic, and neuroradiologic features are most predictive of
underlying CBD in the CBS.
Characterize the natural history of clinical, laboratory, neuropsychologic, and neuroradiologic findings in
patients with the CBS to design future drug trials.
Determine if CBD and PSP are distinct disorders or variants of the same pathophysiologic process.
Identify kindreds with familial CBS and/or CBD.
Identify genetic mechanisms involved in CBS and CBD pathogenesis.
WEBSITES
Caregivers Guide to Cortical Basal Ganglionic Degeneration (CBGD)
http://www.tornadodesign.com/cbgd/
NINDS Corticobasal Degeneration Information Page
http://www.ninds.nih.gov/health_and_medical/disorders/cortico_doc.htm
WEMOVE - Corticobasal Degeneration
http://www.wemove.org/cbd.html
Parkinsons Institute on Corticobasal Degeneration
http://www.parkinsonsinstitute.org/movement_disorders/corticobasal.html
ACKNOWLEDGMENTS
Supported by grants AG06786, AG16574, and AG17216 from the National Institute on Aging.
This author thanks his many colleagues for their ongoing support and collaborations in CBD
research, and particularly extends his appreciation to the patients and their families for participating
in research on CBD.
REFERENCES
1. Rebeiz J, Kolodny E, Richardson E. Corticodentatonigral degeneration with neuronal achromasia: a progressive disor-
der of late adult life. Trans Am Neurol Assoc 1967;92:2326.
2. Rebeiz J, Kolodny E, Richardson E. Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol
1968;18:2033.
3. Boeve B, Lang A, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and fron-
totemporal dementia. Ann Neurol 2003;54:S15S19.
4. Lippa C, Smith T, Fontneau N. Corticonigral degeneration with neuronal achromasia: a clinicopathologic study of two
cases. J Neurol Sci 1990;98:301310.
5. Lang A, Riley D, Bergeron C. Cortical-basal ganglionic degeneration. In: Calne D, ed. Neurodegenerative Diseases.
Philadelphia: Saunders, 1994:877894.
6. Riley D, Lang A. Corticobasal ganglionic degeneration (CBGD): further observations in six additional cases. Neurol-
ogy 1988;38(Supp 1):360.
7. Gibb W, Luthert P, Marsden C. Corticobasal degeneration. Brain 1989;112:11711192.
aphasia and frontotemporal dementia. Neurology 2000;55(9):13681375.
9. Kertesz A, Davidson W, Munoz D. Clinical and pathological overlap between frontotemporal dementia, primary progres-
sive aphasia and corticobasal degeneration: the Pick complex. Dement Geriatr Cogn Disord 1999;10(Suppl 1):4649.
10. Boeve B. Corticobasal Degeneration. In: Adler C, Ahlskog J, eds. Parkinsons Disease and Movement Disorders: Diag-
nosis and Treatment Guidelines for the Practicing Physician. Totawa, NJ: Humana, 2000:253261.
11. Caselli R. Focal and asymmetric cortical degeneration syndromes. The Neurologist 1995;1:119.
12. Riley D, Lang A, Lewis A, Resch L, Ashby P, Hornykiewicz O, et al. Cortical-basal ganglionic degeneration. Neurol-
ogy 1990;40:12031212.
13. Boeve B, Parisi J, Dickson D, Baker M, Hutton M, Wszolek Z, et al. Familial dementia/parkinsonism/motor neuron
disease with corticobasal degeneration pathology but absence of a tau mutation. Neurobiol Aging 2002;23:S269.
14. Bower J, Maraganore D, McDonnell S, Rocca W. Incidence and distribution of parkinsonism in Olmsted County,
Minnesota, 1976-1990. Neurology 1999;52:12141220.
15. Rinne J, Lee M, Thompson P, Marsden C. Corticobasal degeneration: a clinical study of 36 cases. Brain 1994;117:
11831196.
16. Wenning G, Litvan I, Jankovic J, Granata R, Mangone C, McKee A, et al. Natural history and survival of 14 patients with
corticobasal degeneration confirmed at postmortem examination. J Neurol Neurosurg Psychiatry 1998;64:184189.
17. Litvan I, Goetz C, Lang A, eds. Corticobasal Degeneration and Related Disorders. Phildelphia: Lippincott, Williams &
Wilkins, 2000.
18. Leiguarda R, Lees A, Merello M, Starkstein S, Marsden C. The nature of apraxia in corticobasal degeneration. J Neurol
332 Boeve
19. Caselli R, Stelmach G, Caviness J, Timmann D, Royer T, Boeve B, et al. A kinematic study of progressive apraxia with
and without dementia. Mov Disord 1999;14:276287.
20. Boeve BF, Maraganore DM, Parisi JE, Ivnik RJ, Westmoreland BF, Dickson DW, et al. Corticobasal degeneration and
frontotemporal dementia presentations in a kindred with nonspecific histopathology. Dem Geriatr Cog Disord
2002;13(2):8090.
21. Ball J, Lantos P, Jackson M, Marsden C, Scadding J, Rossor M. Alien hand sign in association with Alzheimers
histopathology. J Neurol Neurosurg Psychiatry 1993;56:10201023.
22. Doody R, Jankovic J. The alien hand and related signs. J Neurol Neurosurg Psychiatry 1992;55:806810.
23. Feinberg T, Schindler R, Flanagan N, Haber L. Two alien hand syndromes. Neurology 1992;42:1924.
24. Gasquoine P. Alien hand sign. J Clin Exp Neuropsychol 1993;15:653667.
25. Goldberg G, Bloom K. The alien hand sign: localization, lateralization and recovery. Am J Phys Med & Rehabil
1990;69:228238.
26. Thompson P, Day B, Rothwell J, Brown P, Britton T, Marsden C. The myoclonus in corticobasal degeneration: evi-
dence for two forms of cortical reflex myoclonus. Brain 1994;117:11971207.
27. Thompson PD, Shibasaki H. Myoclonus in corticobasal degeneration and other neurodegenerations. Adv Neurol
2000;82:6981.
28. Gottlieb D, Robb K, Day B. Mirror movements in the alien hand syndrome. Am J Phys Med Rehabil 1992;71:297300.
29. Kompoliti K, Goetz C, Boeve B, Maraganore D, Ahlskog J, Marsden C, et al. Clinical presentation and pharmacologi-
cal therapy in corticobasal degeneration. Arch Neurol 1998;55:957961.
tion. Neurology 1999;53(9):19691974.
31. Frattali C, Duffy J, Litvan I, Patsalides A, Grafman J. Yes/no reversals as neurobehavioral sequela: a disorder of
language, praxis, or inhibitory control? Eur J Neurol 2003;10:103106.
32. Frattali CM, Grafman J, Patronas N, Makhlouf F, Litvan I. Language disturbances in corticobasal degeneration. Neu-
rology. 2000;54(4):990992.
33. Lang A. Cortical basal ganglionic degeneration presenting with progressive loss of speech output and orofacial dys-
praxia. J Neurol Neurosurg Psychiatry 1992;55:1101.
34. Litvan I, Cummings J, Mega M. Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiat
1998;65:717721.
35. Cummings J, Litvan I. Neuropsychiatric aspects of corticobasal degeneration. In: Litvan I, Goetz C, Lang A, eds.
Corticobasal Degeneration and Related Disorders. Philadelphia: Lippincott Williams & Wilkins, 2000, 147152.
36. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. Consensus guidelines for the clinical
and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international work-
shop. Neurology 1996;47(5):11131124.
37. Geda Y, Boeve B, Parisi J, Dickson D, Maraganore D, Ahlskog J, et al. Neuropsychiatric features in 20 cases of
pathologically-diagnosed corticobasal degeneration. Mov Disord 2000;15(Suppl 3):229.
38. Maraganore D, Ahlskog J, Petersen R. Progressive asymmetric rigidity with apraxia: a distinct clinical entity [abstract].
Mov Disord 1992;7(Supp 1):80.
39. Kumar R, Bergeron C, Pollanen M, Lang A. Cortical-basal ganglionic degeneration. In: Jankovic J, Tolosa E, eds.
Parkinsons Disease and Movement Disorders, 3rd ed. Baltimore: Williams & Wilkins, 1998:297316.
40. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimers disease:
report of the NINCDSADRDA work group under the auspices of the Department of Health and Human Services Task
Force on Alzheimers disease. Neurology 1984;34:939944.
RichardsonOlszewski syndrome): report of the NINDSSPSP International Workshop. Neurology 1996;47:19.
42. Movement Disorders Symposium on Cortical-Basal Ganglionic Degeneration and Other Asymmetric Cortical Degen-
eration Syndromes. Mov Disord 1996;11:346357.
43. Boeve BF, Maraganore DM, Parisi JE, Ahlskog JE, Graff-Radford N, Caselli RJ, et al. Pathologic heterogeneity in
clinically diagnosed corticobasal degeneration. Neurology 1999;53(4):795800.
44. Schneider J, Watts R, Gearing M, Brewer R, Mirra S. Corticobasal degeneration: neuropathologic and clinical hetero-
geneity. Neurology 1997;48:959969.
45. Neary D, Snowden J, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus
on clinical diagnostic criteria. Neurology 1998;51:15461554.
46. Dickson D, Bergeron C, Chin S, Duyckaerts C, Horoupian D, Ikeda K, et al. Office of Rare Diseases neuropathologic
criteria for corticobasal degeneration. J Neuropathol Exp Neurol 2002;61:935946.
47. Houlden H, Baker M, Morris H, MacDonald N, Pickering-Brown S, Adamson J, et al. Corticobasal degeneration and
progressive supranuclear palsy share a common tau haplotype. Neurology 2001;56:17021706.
48. Urakami K, Wada K, Arai H, Sasaki H, Kanai M, Shoji M, et al. Diagnostic significance of tau protein in cerebrospinal
fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J Neurol Sci 2001;183:9598.
49. Pillon B, Blin J, Vidailhet M, Deweer B, Sirigu A, Dubois B, et al. The neuropsychological pattern of corticobasal degen-
eration: comparison with progressive supranuclear palsy and Alzheimers disease. Neurology 1995;45:14771483.
50. Massman P, Kreiter K, Jankovic J, Doody R. Neuropsychological functioning in cortical-basal ganglionic degenera-
tion: differentiation from Alzheimers disease. Neurology 1996;46:720726.
51. Westmoreland B, Boeve B, Maraganore D, Ahlskog J. The EEG in cortical-basal ganglionic degeneration. Mov Disord
1996;11:352.
52. Westmoreland B, Boeve B, Parisi J, Dickson D, Maraganore D, Ahlskog J, et al. Electroencephalographic findings in
clinically- and/or pathologically-diagnosed corticobasal degeneration. Mov Disord 2000;15(Suppl 3):229.
53. Strafella A, Ashby P, Lang A. Reflex myoclonus in cortical-basal ganglionic degeneration involves a transcortical
pathway. Mov Disord 1997;12:360369.
54. Hauser RA, Murtaugh FR, Akhter K, Gold M, Olanow CW. Magnetic resonance imaging of corticobasal degeneration.
J Neuroimaging 1996;6(4):222226.
55. Ballan G, Tison F, Dousset V, Vidailhet M, Agid Y, Henry P. Study of cortical atrophy with magnetic resonance
imaging in corticobasal degeneration. Rev Neurolog 1998;154(3):224227.
56. Frasson E, Moretto G, Beltramello A, Smania N, Pampanin M, Stegagno C, et al. Neuropsychological and neuroimaging
correlates in corticobasal degeneration. Ital J Neurol Sci 1998;19(5):321328.
57. Soliveri P, Monza D, Paridi D, Radice D, Grisoli M, Testa D, et al. Cognitive and magnetic resonance imaging aspects
of corticobasal degeneration and progressive supranuclear palsy. Neurology 1999;53(3):502507.
dementias. Adv Neurol 2000;82:197208.
60. Yamauchi H, Fukuyama H, Nagahama Y, Katsumi Y, Dong Y, Hayashi T, et al. Atrophy of the corpus callosum,
cortical hypometabolism, and cognitive impairment in corticobasal degeneration. Arch Neurol 1998;55(5):609614.
61. Macia F, Yekhlef F, Ballan G, Delmer O, Tison F. T2-hyperintense lateral rim and hypointense putamen are typical but
not exclusive of multiple system atrophy. Arch Neurol 2001;58:10241026.
62. Winkelmann J, Auer DP, Lechner C, Elbel G, Trenkwalder C. Magnetic resonance imaging findings in corticobasal
degeneration. Mov Disord 1999;14(4):669673.
63. Doi T, Iwasa K, Makifuchi T, Takamori M. White matter hyperintensities on MRI in a patient with corticobasal degen-
eration. Acta Neurol Scand 1999;99(3):199201.
64. Josephs K, Tang-Wai D, Boeve B, Knopman D, Dickson D, Parisi J, et al. Clinicopathologic and imaging correlates in
corticobasal degeneration. Neurology 2002;58:A132.
65. Sawle G, Brooks D, Marsden C, Frackowiak R. Corticobasal degeneration: a unique pattern of regional cortical
oxygen hypometabolism and striatal fluorodopa uptake demonstrated by positron emission tomography. Brain 1991;
114:541556.
66. Blin J, Vidailhet M-J, Pillon B, Dubois B, Feve J-R, Agid Y. Corticobasal degeneration: decreased and asymmetrical
glucose consumption as studied with PET. Mov Disord 1992;4:348354.
67. Brooks DJ. Functional imaging studies in corticobasal degeneration. Adv Neurol 2000;82:209215.
68. Okuda B, Tachibana H, Kawabata K, Takeda M, Sugita M. Comparison of brain perfusion in corticobasal degeneration
and Alzheimers disease. Dem Geriatr Cog Disord 2001;12(3):226231.
69. Pirker W, Asenbaum S, Bencsits G, Prayer D, Gerschlager W, Deecke L, et al. beta-CIT SPECT in multiple system
atrophy, progressive supranuclear palsy, and corticobasal degeneration. Mov Disord 2000;15(6):11581167.
70. Okuda B, Tachibana H, Kawabata K, Takeda M, Sugita M. Cerebral blood flow in corticobasal degeneration and
progressive supranuclear palsy. Alz Dis Assoc Disord 2000;14(1):4652.
71. Zhang L, Murata Y, Ishida R, Saitoh Y, Mizusawa H, Shibuya H. Differentiating between progressive supranuclear
palsy and corticobasal degeneration by brain perfusion SPET. Nucl Med Commun 2001;22(7):767772.
72. Hauser M, Mullan B, Boeve B, Maraganore D, Ahlskog J, Parisi J, et al. SPECT findings in clinically- and/or patho-
logically-diagnosed corticobasal degeneration. Mov Disord 2000;15(Suppl 3):221.
73. Lehman M, Duffy J, Boeve B, Parisi J, Dickson D, Maraganore D, et al. Speech and language disorders associated with
corticobasal degeneration. J Med Speech Lang Dis 2003;11:131146.
74. Lerner A, Friedland R, Riley D, Whitehouse P, Lanska D, Vick N, et al. Dementia with pathological findings of corti-
cal-basal ganglionic degeneration. Ann Neurol 1992;32:271.
75. Lennox G, Jackson M, Lowe J. Corticobasal degeneration manifesting as a frontal lobe dementia. Ann Neurol
1994;36:273274.
76. Boeve B, Maraganore D, Parisi J, Ahlskog J, Graff-Radford N, Muenter M, et al. Clinical heterogeneity in patients with
pathologically diagnosed cortical-basal ganglionic degeneration. Mov Disord 1996;11:351352.
77. Boeve B, Parisi J, Maraganore D, Ahlskog J, Caselli R, Graff-Radford N, et al. Clinicopathologic heterogeneity in
clinically- and/or pathologically-diagnosed cortical-basal ganglionic degeneration. J Neurol Sci 1997;150:S109S110.
78. Lippa C, Cohen R, Smith T, Drachman D. Primary progressive aphasia with focal neuronal achromasia. Neurology
1991;41:882886.
334 Boeve
79. Arima K, Uesugi H, Fujita I, Sakurai Y, Oyanagi S, Andoh S, et al. Corticonigral degeneration with neuronal achroma-
sia presenting with primary progressive aphasia: ultrastructural and immunocytochemical studies. J Neurol Sci
1994;127:186197.
80. Ikeda K, Akiyama H, Iritani S, Kase K, Arai T, Niizato K, et al. Corticobasal degeneration with primary progressive
aphasia and accentuated cortical lesion in superior temporal gyrus: case report and review. Acta Neuropathol
1996;92:534539.
81. Sakurai Y, Hashida H, Uesugi H, Arima K, Murayama S, Bando M, et al. A clinical profile of corticobasal degeneration
presenting as primary progressive aphasia. European Neurology 1996;36(3):134137.
82. Tang-Wai D, Josephs K, Boeve B, Dickson D, Parisi J, Petersen R. Pathologically confirmed corticobasal degeneration
presenting with visuospatial dysfunction. Neurology 2003;61:11341135.
83. Boeve B, Maraganore D, Parisi J, Ahlskog J, Muenter M, Graff-Radford N, et al. Disorders mimicking the classical
clinical syndrome of cortical-basal ganglionic degeneration: report of nine cases. Movement Disorders 1996;11:351.
84. Davis P, Bergeron C, McLachlan D. Atypical presentation of progressive supranuclear palsy. Ann Neurol 1985;
17:337343.
85. Ford B, Fahn S. 60-year-old woman with parkinsonism and unilateral dystonia. Mov Disord 1996;11:355356.
86. Gearing M, Olson D, Watts R, Mirra S. Progressive supranuclear palsy: neuropathologic and clinical heterogeneity.
Neurology 1994;44:10151024.
87. Saint-Hilaire M-H, Handler J, McKee A, Feldman R. Clinical overlap between corticobasal ganglionic degeneration
and progressive supranuclear palsy. Mov Disord 1996;11:356.
88. Scully R, Mark E, McNeely W, McNeely B. Case records of the Massachusetts General Hospital (Case 46-1993). N Engl
J Med 1993;329:15601567.
89. Rey GJ, Tomer R, Levin BE, Sanchez-Ramos J, Bowen B, Bruce JH. Psychiatric symptoms, atypical dementia, and left
visual field inattention in corticobasal ganglionic degeneration. Mov Disord 1995;10(1):106110.
90. Boeve B, Parisi J, Dickson D, Maraganore D, Ahlskog J, Graff-Radford N, et al. Demographic and clinical findings in
20 cases of pathologically-diagnosed corticobasal degeneration. Mov Disord 2000;15(Suppl 3):228.
91. Horoupian D, Wasserstein P. Alzheimers disease pathology in motor cortex in dementia with Lewy bodies clinically
mimicking corticobasal degeneration. Acta Neuropathol 1999;98:317322.
92. Grimes DA, Bergeron CB, Lang AE. Motor neuron disease-inclusion dementia presenting as cortical-basal ganglionic
degeneration. Mov Disord 1999;14(4):674680.
93. Josephs K, Holton J, Rossor M, Braendgaard H, Ozawa T, Fox N, et al. Neurofilament inclusion body disease: a new
proteinopathy? Brain 2003;126:22912303.
94. Caselli RJ. Asymmetric cortical degeneration syndromes. Curr Opin Neurol 1996;9(4):276280.
95. Caselli R. Asymmetric cortical degeneration syndromes: clinicopathologic considerations. Mov Disord 1996;11:347348.
96. Litvan I, Agid Y, Goetz C, et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathological
97. Reed L, Wszolek Z, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22:89107.
98. Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, et al. Neurofibrillary tangles, amyotro-
phy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 2000;25(4):402405.
99. Boeve B. Diagnosis and management of the non-alzheimer dementias. In: Noseworthy JW, ed. Neurologic Therapeu-
tics. London: Martin Dunitz, 2003:28262854.
100. Boeve B, Silber M. Sleep disorders and dementia and related degenerative disorders. In: Carney PR, Berry RB, Geyer
J, eds. Sleep Medicine. Philadelphia: Lippincott Williams & Wilkins, 2003, in press.
101. Boeve B, Silber M, Ferman T, Lucas J, Parisi J. Association of REM sleep behavior disorder and neurodegenerative
disease may reflect an underlying synucleinopathy. Mov Disord 2001;16:622630.
Multiple System Atrophy 335
20
Felix Geser and Gregor K. Wenning
INTRODUCTION
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized clinically
by various combinations of parkinsonian, autonomic, cerebellar, or pyramidal symptoms and signs and
pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several brain and spinal cord
structures. The term MSA was introduced in 1969, however cases of MSA were previously reported
under the rubrics of striatonigral degeneration, olivopontocerebellar atrophy, ShyDrager syndrome
and idiopathic orthostatic hypotension. In the late 1990s, F-synuclein immunostaining was recog-
nized as most sensitive marker of inclusion pathology in MSA: because of these advances in molecu-
lar pathogenesis, MSA has been firmly established as F-synucleinopathy along with Parkinsons
disease (PD) and dementia with Lewy bodies. Recent epidemiological surveys have shown that MSA
is not a rare disorder (~5 cases per 100,000 population), and that misdiagnosis, especially with PD, is
still common due to variable clinical presentations of MSA. However, the clinical picture of MSA in
its full-blown form is distinctive. The patient is hypomimic with orofacial and anterior neck dystonia
resulting in a grinning smile akin to risus sardonicus and sometimes disproportionate antecollis.
The voice is often markedly impaired with a characteristic quivering high-pitched dysarthria. The
motor disorder of MSA is often mixed with parkinsonism, cerebellar ataxia, limb dystonia, myoclo-
nus, and pyramidal features occurring at the same time. However, akinesia and rigidity are the pre-
dominating features in 80% of patients, and cerebellar ataxia within the remaining 20%. According
to the predominant motor presentation, MSA patients may be labeled as parkinsonian or cerebellar
variant (MSA-P, MSA-C). The diagnosis of MSA is largely based on clinical expertise, and this is
well illustrated by the consensus diagnostic criteria, which comprise clinical features only (divided
into four domains including autonomic dysfunction, parkinsonism, cerebellar dysfunction, and corti-
cospinal tract dysfunction). Nevertheless, several autonomic function, imaging, neurophysiological,
and biochemical studies have been proposed in the last decade to help in the differential diagnosis of
MSA. No drug treatment consistently benefits patients with this disease. Indeed, parkinsonism often
shows a poor or unsustained response to chronic levodopa therapy, however, one-third of the patients
may show a moderate-to-good dopaminergic response initially. There is no effective drug treatment
for cerebellar ataxia. On the other hand, features of autonomic failure such as orthostatic hypoten-
sion, urinary retention or incontinence, constipation, and impotence, may often be relieved if recog-
nized by the treating physician. Novel symptomatic and neuroprotective therapies are urgently
required.

335
336 Geser and Wenning
EPIDEMIOLOGY
Descriptive Epidemiology
There are only a few descriptive epidemiological studies on MSA. Bower and colleagues reported
the incidence of MSA over a 14-yr period in Olmsted County, Minnesota. Nine incident cases of
MSA were identified, none of which had an onset before the age of 50 yr. The reported crude inci-
dence rate was 0.6 cases per 100,000 population per year; when the age band >50 yr was examined,
the estimate rose to 3 cases per 100,000 population (1).
Estimates of the prevalence of MSA (per 100,000 in the population) in five studies were 1.9 (2),
4.4 (3), 2.3 (4), 4.9 (5) andin individuals over 65 yr310 (6). The last three studies did not specifi-
cally address the prevalence of MSA, the primary aim of the work being to assess the prevalence of
PD. In the Western Europe population, estimated on the basis of Bowers study (1), 81.5% of the
cases are concentrated in the 60- to 79-yr age band, whereas only 9.8% and 8.7% fall within the 50-
to 59-yr and >80-yr age bands, respectively. These figures indicate a prevalence of MSA that is quite
similar to that of other well-known neurological conditions such as Huntingtons disease, myotonic
dystrophy, and motor neuron disease.
Analytical Epidemiology
So far no single environmental factor has been clearly established as conferring increased or reduced
risks to develop MSA. Only one case-control study, based on 60 MSA cases and 60 controls, has been
published to date (7). This study revealed a higher risk of disease onset associated with occupational
exposure to organic solvents, plastic monomers and additives, pesticides, and metals. Moreover, a
higher frequency of symptoms and neurological diseases has been observed in first relatives of MSA
cases than in controls. This last finding points to a genetic predisposition to neurological diseases,
though no family of MSA cases has yet been reported in the literature. A review of consecutive
medical records of 100 patients who satisfied the diagnostic Consensus criteria for MSA (8) showed
that 11 patients had a notable history of heavy exposure to environmental toxins including malathion,
diazinon, formaldehyde, n-hexane, benzene, methyl isobutyl ketone, and pesticides (9). Despite its
methodical limits, this study implicates environmental factors in the pathogenesis of MSA. Smoking
was less common among MSA patients compared to controls according to a cross-sectional study
(10). Prospective case-control studies are needed to clarify whether smoking is a protective factor
against MSA.
CLINICAL DIAGNOSTIC CRITERIA

Clinical diagnostic criteria for MSA were first proposed by Quinn in 1989 (11) and later slightly
modified in 1994 (12). According to this schema, patients are classified as either striatonigral degen-
eration (SND) or olivopontocerebellar atrophy (OPCA) type MSA depending on the predominance
of parkinsonism or cerebellar ataxia. There are three levels of diagnostic probability: possible, prob-
able, and definite. Patients with sporadic adult-onset poorly levodopa-responsive parkinsonism ful-
fill criteria for possible SND. The presence of other atypical features such as severe autonomic failure,
cerebellar or pyramidal signs, or a pathological sphincter electromyogram (EMG) is required for a
diagnosis of probable SND. Patients with sporadic late-onset predominant cerebellar ataxia with
additional mild parkinsonism or pyramidal signs are considered possible OPCA-type MSA. This
may result in confusion since some patients with possible OPCA may also qualify for probable SND
provided predominant cerebellar ataxia is accompanied by parkinsonian features. A diagnosis of
probable OPCA-type MSA requires the additional presence of severe autonomic failure or a patho-
logical sphincter EMG. A definite diagnosis rests on neuropathological confirmation. Predominant
SND- or OPCA-type presentations may be distinguished from pure types on the basis of associated
cerebellar (predominant SND) or parkinsonian features (predominant OPCA). Since some degree of
autonomic failure is present in almost all SND- and OPCA-type MSA patients (13,14) a further
autonomic subtype (ShyDrager syndrome) was not considered useful (15). A number of exclu-
sion criteria were also proposed: onset should be age 30 yr or more, and in order to exclude inherited
adult-onset ataxias there should be no family history of MSA.
The validity of Quinns criteria was evaluated in a clinicopathologic study by Litvan and cowork-
ers. This study revealed the criteria for the diagnosis of MSA proposed by Quinn present a subopti-
mal specificity (79% for possible MSA and 97% for probable MSA, at the first visit), a low sensitivity
(53% for possible MSA and 44% for probable MSA, at the first visit), and a predictive value of 30%
for possible MSA and 68% for probable MSA (16). Because of the suboptimal diagnostic accuracy of
Quinns criteria, in 1998 an International Consensus Conference promoted by the American Acad-
emy of Neurology was convened to develop new and optimized criteria for a clinical diagnosis of
MSA (Table 1) (8). The Consensus criteria are now widely used for a clinical diagnosis of MSA.
These criteria specify three diagnostic categories of increasing certainty: possible, probable, and
definite. The diagnosis of possible and probable MSA are based on the presence of clinical features
listed in Table 1. In addition, exclusion criteria have to be considered. A definite diagnosis requires a
typical neuropathological lesion pattern as well as deposition of F-synuclein-positive glial cytoplas-
mic inclusions.
A subsequent study analyzed the agreement between Quinns criteria and Consensus criteria in a
clinical series of 45 MSA patients. Concordance was moderate for possible MSA and substantial for
probable MSA (17). Moreover, four cases with probable (n = 2) or possible (n = 2) MSA according to
Quinns criteria were unclassifiable according to the Consensus criteria.
A recent retrospective evaluation of the Consensus criteria on pathologically proven cases showed
excellent positive predictive values (PPVs) for both possible (93%) and probable MSA (100%) at the
first clinic visit; however, sensitivity for probable MSA was poor especially in early stages of the
disease (16% at the first clinic visit) (18). Interestingly, the Consensus criteria and Quinns criteria
had similar PPVs. Whether the Consensus criteria will improve recognition of MSA patients espe-
cially in early disease stages needs to be investigated by prospective surveys with neuropathological
confirmation in as many cases as possible.
ONSET AND PROGRESSION

MSA usually manifests in middle age (the median age of onset is 53), affects both sexes, and
progresses relentlessly with a mean survival of 69 yr (13,19,20). MSA patients may present with
akinetic-rigid parkinsonism that usually responds poorly to levodopa. This has been identified as the
most important early clinical discriminator of MSA and PD (11,2123), although a subgroup of MSA
patients may show a good or, rarely, excellent, but usually short-lived, response to levodopa (2426).
Progressive ataxia, mainly involving gait, may also be the presenting feature of MSA (27,28). A
cerebellar presentation of MSA appears to be more common than the parkinsonian variant in Japan
compared to Western countries (29). Autonomic failure with symptomatic orthostatic hypotension
and/or urogenital and gastrointestinal disturbance may accompany the motor disorder in up to 50% of
patients at disease onset (20). Besides the poor response to levodopa, and the additional presence of
pyramidal or cerebellar signs or autonomic failure as major diagnostic clues, certain other features
(red flags) such as orofacial dystonia, stridor, or disproportionate antecollis (Fig. 1) may raise
suspicion of MSA (11) (Table 2). Red flags often are early warning signs of MSA (30).
MSA is a progressive disease characterized by the gradual accumulation of disability reflecting
involvement of the systems initially unaffected. Thus, patients who present initially with extrapyra-
midal features commonly progress to develop autonomic disturbances, cerebellar disorders, or both
(see video of an advanced MSA-P patient showing marked akinesia and rigidity as well as cerebellar
incoordination, particularly of lower limbs). Conversely, patients who begin with symptoms of cerebel-
lar dysfunction often progress to develop extrapyramidal or autonomic disorders, or both. Patients whose
Table 1
MSA Consensus Criteria 338
A. Nomenclature of clinical domains, features (disease characteristics) and criteria (defining features or composite of features) used in the diagnosis of MSA
Domain Criterion Feature
Autonomic and urinary dysfunction Orthostatic fall in blood pressure Orthostatic hypotension (by 20 mmHg systolic or 10 mmHg diastolic)
(by 30 mmHg systolic or 15 mmHg diastolic)
or
persistent urinary incontinence with erectile Urinary incontinence or incomplete bladder emptying
dysfunction in men
or both
Parkinsonism Bradykinesia plus Bradykinesia (progressive reduction in speed and amplitude
rigidity of voluntary movements during repetitive actions)
or
postural instability Rigidity
or
tremor Postural instability (loss of primary postural reflexes)
Tremor (postural, resting, or both)
Cerebellar dysfunction Gait ataxia plus Gait ataxia (wide-based stance with irregular steps)
ataxic dysarthria
or
limb ataxia Ataxic dysarthria
or
sustained gaze-evoked nystagmus Limb ataxia
Sustained gaze-evoked nystagmus
Corticospinal tract dysfunction No defining features Extensor plantar responses with hyperreflexia
B. Diagnostic categories of MSA
Possible MSA-P Criterion for parkinsonism plus two features from separate other domains. A poor levodopa response qualifies already
as one feature, hence only one additional feature is required.
Possible MSA-C Criterion for cerebellar dysfunction plus two features from separate other domains.
Probable MSA-P Criterion for autonomic failure/urinary dysfunction plus poorly levodopa-responsive parkinsonism.
Probable MSA-C Criterion for autonomic failure/urinary dysfunction plus cerebellar dysfunction.
Definite MSA Pathological confirmation: high density of F-synuclein-positive GCIs associated with degenerative changes in the
nigrostriatal (SND and olivopontocerebellar pathways (OPCA).
Modified from ref. 8.
Geser and Wenning
Reproduced with kind permission from Whitehouse Publishing: Wenning and Geser, Diagnosis and treatment of multiple system atrophy: an update.
ACNR 2004;3(6):510.
Fig. 1. Disproportionate antecollis of a patient with MSA-P.
symptoms initially are autonomic may later develop cerebellar, extrapyramidal, or both types of
disorders. In a recent large study on 230 cases carried out in Japan, MSA-P patients had more rapid
functional deterioration than MSA-C patients, but showed similar survival (29).
INVESTIGATIONS
The diagnosis of MSA still rests on the clinical history and neurological examination. Attempts
have been made, however, to improve diagnostic accuracy through analysis of cerebrospinal fluid
(CSF) and serum biomarkers, autonomic function tests, structural and functional neuroimaging and
neurophysiological techniques.
Table 2
Red Flags: Warning Features of MSAa
Motor Red Flags Definition
Orofacial dystonia Atypical spontaneous or L-dopa-induced dystonia predominantly affecting
orofacial muscles, occasionally resembling risus sardonicus of cephalic tetanus.
Pisa syndrome Subacute axial dystonia with a severe tonic lateral flexion of the trunk, head, and
neck (contracted and hypertrophic paravertebral muscles may be present).
Disproportionate antecollis Chin-on-chest, neck can only with difficulty be passively and forcibly extended
to its normal position. Despite severe chronic neck flexion, flexion elsewhere is
minor.
Jerky tremor Irregular (jerky) postural or action tremor of the hands and/or fingers.
Dysarthria Atypical quivering, irregular, severely hypophonic or slurring high-pitched
dysarthria, which tends to develop earlier, be more severe, and be associated
with more marked dysphagia compared to PD.
Nonmotor Red Flags
Abnormal respiration Nocturnal (harsh or strained, high-pitched inspiratory sounds) or diurnal inspira
tory stridor, involuntary deep inspiratory sighs/gasps, sleep apnea (arrest of
breathing for 10 s), and excessive snoring (increase from premorbid level, or
newly arising).
REM sleep behavior disorder Intermittent loss of muscle atonia and appearance of elaborate motor activity
(striking out with arms in sleep often with talking/shouting) associated with
dream mentation.
Cold hands/feet Coldness and color change (purple/blue) of extremities not resulting from drugs
with blanching on pressure and poor circulatory return.
Raynauds phenomenon Painful white finger, which may be provoked by ergot drugs.
Emotional incontinence Crying inappropriately without sadness or laughing inappropriately without mirth.
aExcluding cardinal diagnostic features of MSA such as orthostatic hypotension, urinary incontinence/retention, levodopa-
unresponsive parkinsonism, cerebellar (ataxia) and pyramidal signs. Also excluding nonspecific features suggesting atypical
parkinsonism such as rapid progression or early instability and falls.
Reproduced with kind permission from John Wiley & Sons, Inc.: Wenning et al., Multiple system atrophy: an update. Mov
Disord 2003;18(suppl 6):3442.
CSF Analysis
Studies have attempted to identify biomarkers in the CSF to achieve early and accurate diagnosis,
as well as to monitor response to treatment. Proteins in the CSF, including glial fibrillary acidic
protein (GFAP) and neurofilament (NFL) protein have been studied. No difference was found in CSF
concentrations of GFAP between patients with PD and MSA, but high concentrations of NFL seem to
differentiate atypical parkinsonian disorders from PD (31). Furthermore, CSF-NFL and levodopa
tests combined with discriminant analysis may contribute even better to the differential diagnosis of
parkinsonian syndromes (32). Whereas the CSF-NFL and levodopa tests predicted 79 and 85% cor-
rect diagnoses (PD or non-PD [MSA and progressive supranuclear palsyPSP]) respectively, the
combined test predicted 90% correct diagnoses.
Hormonal Testing
In vivo studies in MSA, which involved testing of the endocrine component of the central auto-
nomic nervous systems (the hypothalamopituitary axis) with a variety of challenge procedures, pro-
vided evidence of impaired humoral responses of the anterior and the posterior part of the pituitary
gland with impaired secretion of adrenocorticotropic hormone (ACTH) (33), growth hormone (34),
and vasopressin/ADH (35). Although these observations can be made in virtually all advanced patients,
their prevalence during the early course of MSA is unknown.
There is an ongoing debate about the diagnostic value of the growth hormone (GH) response to
clonidine (CGH-test), a neuropharmacological assessment of central adrenoceptor function, in PD
and MSA. Clonidine is a centrally active F2-adrenoceptor agonist that lowers blood pressure pre-
dominantly by reducing CNS (central nervous system) sympathetic outflow. In an early study, there
was no increase in GH levels after clonidine in patients with MSA compared to those with PD or pure
autonomic failure (36). Kimber and colleagues confirmed a normal serum GH increase in response to
clonidine in 14 PD patients (without autonomic failure) and in 19 patients with pure autonomic failure,
whereas there was no GH rise in 31 patients with MSA (34). However, these findings have been chal-
lenged subsequently (37). More studies in well-defined patient cohorts are needed before the clonidine
challenge test can be recommended as a helpful diagnostic test in patients with suspected MSA.
Autonomic Function Tests

Autonomic function tests are a mandatory part of the diagnostic process and clinical follow-up in
patients with MSA. Findings of severe autonomic failure early in the course of the disease make the
diagnosis of MSA more likely, although the specificity in comparison to other neurodegenerative
disorders is unknown in a single patient. Pathological results of autonomic function tests may account
for a considerable number of symptoms in MSA patients and should prompt specific therapeutic steps
to improve quality of life and prevent secondary complications like injuries owing to hypotension-
induced falls or ascending urinary infections.
Cardiovascular Function
A history of postural faintness or other evidence of orthostatic hypotension, e.g., neck ache on
rising in the morning or posturally related changes of visual perception, should be sought in all patients
in whom MSA is suspected. After taking a comprehensive history, testing of cardiovascular function
should be performed. According the consensus statement of the American Autonomic Society and
the American Academy of Neurology on the definition of orthostatic hypotension, pure autonomic
failure, and MSA, a drop in systolic blood pressure (BP) of 20 mm Hg or more, or in diastolic BP of
10 mmHg or more, compared with baseline is defined as orthostatic hypotension (OH) and must lead
to more specific assessment (38). This is based on continuous noninvasive measurement of blood
pressure and heart rate during tilt table testing (3941). Although abnormal cardiovascular test re-
sults may provide evidence of sympathetic and/or parasympathetic failure, they do not differentiate
autonomic failure associated with PD vs MSA (42).
In MSA, cardiovascular dysregulation appears to be caused by central rather than peripheral auto-
nomic failure. During supine rest noradrenaline levels (representing postganglionic sympathethic
efferent activity) are normal (43), and there is no denervation hypersensitivity, which indicates a lack
of increased expression of adrenergic receptors on peripheral neurons (44). Uptake of the noradrena-
line analog meta-iodobenzylguanidine is normal in postganglionic cardiac neurons (4548) and the
response to tilt is impaired with little increase in noradrenaline. In contrast, mainly postganglionic
sympathetic dysfunction is thought to account for autonomic failure associated with PD. In keeping
with this assumption, both basal and tilted noradrenaline levels are low.
Bladder Function
Assessment of bladder function is mandatory in MSA and usually provides evidence of involve-
ment of the autonomic nervous system already at an early stage of the disease. Following a careful
history regarding frequency of voiding, difficulties in initiating or suppressing voiding, and the pres-
ence and degree of urinary incontinence, a standard urine analysis should exclude an infection.
Postvoid residual volume needs to be determined sonographically or via catheterization to initiate
intermittent self-catheterization in due course. In some patients only cystometry can discriminate
between hypocontractile detrusor function and a hyperreflexic sphincter-detrusor dyssynergy.
The nature of bladder dysfunction is different in MSA and PD. Although pollakiuria and urgency
are common in both disorders, marked urge or stress incontinence with continuous leakage is not a
feature of PD, apart from very advanced cases. Urodynamic studies show a characteristic pattern of
abnormality in MSA patients (49). In the early stages there is often detrusor hyperreflexia, often with
bladder neck incompetence resulting from abnormal urethral sphincter function, which result in early
pollakiuria and urgency followed by urge incontinence. Later on, the ability to initiate a voluntary
micturition reflex and the strength of the hyperreflexic detrusor contractions diminish, and the blad-
der may become atonic, accounting for increasing postmicturition residual urine volumes.
The detrusor hyperreflexia may result from a disturbance of the pontine micturition center (50,51).
Alternatively, degeneration of substantia nigra and other regions of the basal ganglia that are impor-
tant in the control of micturition, may contribute to urological symptoms. The atonic bladder in
advanced MSA has been related to the progressive degeneration of the intermediolateral columns of
the thoracolumbar spinal cord (50), however, this remains speculative.
IMAGING
Magnetic Resonance Imaging (MRI)
MRI scanning of patients with MSA often, but not always, reveals atrophy of cerebellar vermis
and, less marked, of cerebellar hemispheres (52). There is also evidence of shrinkage of pons as well
as middle cerebellar peduncles (27), differentiating MSA-C from cortical cerebellar atrophy (CCA).
The pattern of infratentorial atrophy visible on MRI correlates with the pathological process of OPCA
affecting the cerebellar vermis and hemispheres, middle cerebellar peduncles, pons, and lower
brainstem (53). The MRI changes may be indistinguishable from those of patients with autosomal
dominant cerebellar ataxias (54). MRI measures of basal ganglia pathology in MSA such as width of
substantia nigra pars compacta, lentiform nucleus, and head of the caudate are less well established
and naked-eye assessments are often unreliable. In advanced cases putaminal atrophy may be detect-
able and may correlate with severity of extrapyramidal symptoms (55). However, in one study MRI-
based two-dimensional basal ganglia morphometry has proved unhelpful in the early differential
diagnosis of patients with levodopa-unresponsive parkinsonism (56). A significant progression of
atrophy to under the normal limit was observed in the cerebrum, frontal and temporal lobes, showing
the involvement of the cerebral hemisphere, especially the frontal lobe (57). Abnormalities on MRI
may include not only atrophy, but also signal abnormalities on T2-weighted images within the pon-
tocerebellar system and putamen. Signal hyperintensities sometimes seen within the pons and middle
cerebellar peduncles are thought to reflect degeneration of pontocerebellar fibers and therefore,
together with marked atrophy in these areas, indicate a major site of pathology in OPCA type MSA
(MSA-C) (27,58). The characteristic infratentorial signal change on T2-weighted 1.5 Tesla MRI (hot
cross bun sign) may also corroborate the clinical diagnosis of MSA (52). Putaminal hypointensities
in supposedly atypical parkinsonian disorders (APDs) were first reported in 1986 by two groups
using a 1.5 Tesla magnet and T2-weighted images (59,60). This change has subsequently been
observed by others in cases clinically thought to have MSA (27,55,61), and in some cases with
pathological confirmation (6264). A lateral to medial as well as posterior to anterior gradient is also
well established with the most prominent changes in the posterolateral putamen (55,60,62). This
putaminal hypointensity has been proposed as a sensitive and specific abnormality in patients with
MSA, and to reflect increased iron deposition. However, similar abnormalities may occur in patients
with classical PD (65,66) or may represent incidental findings in patients without basal ganglia disor-
ders (Wenning G, unpublished observations). The notion of increased iron deposition has been chal-
lenged by Brooks and colleagues (67) and later by Schwarz and colleagues (64). Recently it was
shown that hypointense putaminal signal changes were more often observed in MSA than in PD
patients using T2*-weighted gradient echo (GE) but not T2-weighted fast-spin echo images, indicat-
ing that T2*-weighted GE sequences are of diagnostic value for patients with parkinsonism (68).
Increased putaminal relative to pallidal hypointensities may be seen as well as a slit-like hyperintense
band lateral to the putamen (64,6971). These changes are consistent with a clinical diagnosis of
MSA. However, they appear to be nonspecific and have also been noted in clinically diagnosed PD
and PSP (52,66). The pattern consisting of hypointense and hyperintense T2 changes within the puta-
men is a highly specific MRI sign of MSA, whereas hypointensity alone remains a sensitive, but
nonspecific sign of MSA (72). The hyperintense signal correlated with the most pronounced reactive
microgliosis and astrogliosis or highest iron content in MRI-postmortem studies (62,64). Konagaya
et al. (73) reported that in a case of MSA, the slit hyperintensity at the putaminal margin represented
widened intertissue space owing to a severe shrinkage and rarefaction of the putamen. However, in
spite of these speculations the nature of this abnormal signal intensity remains uncertain.
Diffusion-weighted imaging (DWI) may represent a useful diagnostic tool that can provide addi-
tional support for a diagnosis of MSA-P. DWI, even if measured in the slice direction only, is able to
discriminate MSA-P and both patients with PD and healthy volunteers on the basis of putaminal
rADC (regional apparent diffusion coefficient) values (74). The increased putaminal rADC values in
MSA-P are likely to reflect ongoing striatal degeneration, whereas most neuropathologic studies
reveal intact striatum in PD. But, since in PSP compared to PD patients rADCs were also signifi-
cantly increased in both putamen and globus pallidus (75), increased putaminal rADC values do not
discriminate MSA-P from PSP.
Whether magnetic resonance volumetry will contribute to the differential diagnosis of MSA from
other parkinsonian disorders remains to be confirmed. Schulz et al. (76) found significant reductions
in mean striatal and brainstem volumes in patients with MSA-P, MSA-C, and PSP, whereas patients
with MSA-C and MSA-P also showed a reduction in cerebellar volume. Total intracranial volume-
normalized MRI-based volumetric measurements provide a sensitive marker to discriminate typical
and atypical parkinsonism. Voxel-based morphometry (VBM) confirmed previous region of interest
(ROI)-based volumetric studies (76) showing basal ganglia and infratentorial volume loss in MSA-P
patients (77). These data revealed prominent cortical volume loss in MSA-P mainly comprising the
cortical targets of striatal projections such as the primary sensorimotor, lateral premotor cortices, and
the prefrontal cortex, but also the insula. These changes are consistent with the established frontal
lobe impairment of MSA patients (78).
Proton magnetic resonance spectroscopy (MRS) is a noninvasive method that provides informa-
tion about the chemical pathology of disorders affecting the CNS. MRS has been used to identify
striatal metabolic changes in MSA (7982). However, the available data are conflicting and further
studies are clearly required to establish the role of MRS in the diagnosis of MSA.
Functional Imaging
Single-photon emission tomography (SPECT) or positron emission tomography (PET) studies of
patients with MSA-P have demonstrated the combined nigral and striatal pathology using [(123)I]G-CIT
[2G-carboxymethoxy-3G-(4-iodophenyl)tropane] (SPECT) or [10F]fluorodopa (PET) and a variety of
postsynaptic dopamine or opiate receptor ligands such as [123I]iodobenzamide (IBZM) (SPECT),
[11C]raclopride or [11C]diprenorphin (PET).
The Hammersmith Cyclotron Unit, using PET, found that putaminal uptake of the presynaptic
dopaminergic markers [18F]fluorodopa and S-[11C]nomifensine (8385) was similarly reduced in
MSA and PD; in approximately half the MSA subjects, caudate uptake was also markedly reduced,
as opposed to only moderate reduction in PD. However, discriminant function analysis of striatal
[18F]fluorodopa uptake separated MSA and PD patients poorly (85). Patients with PD, PSP, and
MSA share a marked loss of fluorodopa uptake in the putamen; however, uptake in the caudate
nucleus differs among the three groups, with patients who have MSA showing uptake rates interme-
diate between those of patients with PD (normal uptake) and with PSP (markedly reduced uptake)
(83). Measurements of striatal dopamine D2 receptor densities using raclopride and PET failed to
differentiate between idiopathic and atypical parkinsonism, demonstrating a similar loss of densities
in levodopa-treated patients with fluctuating PD, MSA, and PSP (86). PET studies using other ligands
such as [ 11 C]diprenorphine (nonselective opioid receptor antagonist) (87) and [ 18F]fluoro-
deoxyglucose (8890) have proved more consistent in detecting striatal degeneration and in distin-
guishing patients with MSA-P from those with PD, particularly when combined with a dopamine D2
receptor scan (91,92). Widespread functional abnormalities in MSA-C have been demonstrated using
[18F]fluorodeoxyglucose and PET (93). Reduced metabolism was most marked in the brainstem and
cerebellum, but other areas such as the putamen, caudate nucleus, thalamus, and cerebral cortex were
also involved, differentiating MSA-C from spinocerebellar ataxias (SCAs). Subclinical evidence of
striatal pathology in MSA-C, in the absence of extrapyramidal features, has been demonstrated using
the nonselective opioid receptor ligand diprenorphine and PET (94). In a PET study using
[18F]fluorodeoxyglucose, in comparison with normal controls putaminal hypometabolism was absent
in sporadic OPCA patients without autonomic failure and extrapyramidal features, but present in
those who were classified as OPCA-type MSA and therefore had autonomic dysfunction with or
without parkinsonian features at the time of examination (93). Striatal opiate receptors are reduced
not only in MSA-P (87) but also in MSA-C with associated autonomic failure (94) supporting its
nosological status as the cerebellar subtype of MSA. Differences in cerebellar benzodiazepine recep-
tor binding densities have also been shown in MSA-C, CCA, and SCA using [11C]flumazenil and
PET (95). Additionally, the poor levodopa response may be related to a deficiency in striatal D1
receptor binding, as shown by PET studies in clinically diagnosed patients with MSA using the ligand
[11C]SCH 23390 (96). This is a potentially helpful observation that may aid early differentiation of
MSA and PD if corroborated by other groups.
SPECT imaging studies of patients with dopa naive parkinsonism have used [123I]iodobenzamide
(IBZM) as D2 receptor ligand (21,22). A good response to apomorphine and subsequent benefit from
chronic dopaminergic therapy was observed in subjects with normal IBZM binding whereas subjects
with reduced binding failed to respond. Some of these patients developed other atypical clinical
features suggestive of MSA during follow-up (97). Other SPECT studies have also revealed signifi-
cant reductions of striatal IBZM binding in clinically probable MSA subjects compared to PD patients
(27,98). Since [123I]G-CIT SPECT reliably enables the visualization of the presynaptic dopaminergic
lesion, this method was used as a label of dopamine transporter (DAT) to study the progression of
presynaptic dopaminergic degeneration in PD and APD including MSA by Pirker and coworkers
(99). The results of the sequential [123I]G-CIT SPECT imaging demonstrate a rapid decline of striatal
G-CIT binding in patients with APD, exceeding the reduction in PD. Scintigraphic visualization of
postganglionic sympathetic cardiac neurons was found to differentiate patients with MSA from patients
with PD (4548), because patients in the latter group show a severely reduced cardiac uptake of the
radioactive ligand [123I]metaiodobenzylguanidine (MIBG). This method appears to be a highly sensi-
tive and specific tool to discriminate between MSA and PD already within 2 year of onset of symp-
toms; however, the test cannot distinguish MSA from other APD such as PSP (100).
NEUROPHYSIOLOGICAL TECHNIQUES
The external anal or urethral sphincter electromyogram (EMG) is a useful investigation in patients
with suspected MSA. Because of degeneration of Onufs nucleus, both anal and urethral external
sphincter muscles undergo denervation and re-innervation. Abnormality of the striated urethral
sphincter EMG in MSA was first shown by Martinelli and Coccagna in 1978 (101). Subsequently,
Kirby and colleagues (49) confirmed the presence of polyphasia and abnormal prolongation of indi-
vidual motor units in MSA, and also examined the potential diagnostic role of sphincter EMG in
patients with MSA and PD (102). Sixteen (62%) of 26 patients with probable MSA, and only 1 (8%)
of 13 with probable PD had a pathological EMG result (sensitivity 0.62, specificity 0.92). This test
also helps to identify patients in whom incontinence may develop or worsen following surgery. Anal
sphincter EMG is generally better tolerated, and yields identical results (50). In at least 80% of patients
with MSA, EMG of the external anal sphincter reveals signs of neuronal degeneration in Onufs
nucleus with spontaneous activity and increased polyphasia (103105). However, these findings do
not reliably differentiate between MSA and other forms of APD. An abnormal anal sphincter exami-
nation was present in 5 of 12 (41.6%) PSP patients (106). Furthermore, neurogenic changes of exter-
nal anal sphincter muscle have also been demonstrated in advanced stages of PD by several
investigators (107,108). Also chronic constipation, previous pelvic surgery, or vaginal deliveries can
be confounding factors to induce nonspecific abnormalities (109). In summary, in patients with prob-
able MSA, abnormal sphincter EMG, as compared to control subjects, has been found in the vast
majority of patients, including those who, as yet, have no urological or anorectal problems. The
prevalence of abnormalities in the early stages of MSA is as yet unclear. Patients with PD as a rule do
not show severe sphincter EMG abnormalities in the early stage of the disease, unless other causes
for sphincter denervation are present. However, sphincter EMG does not distinguish MSA from PSP
(110). For these reasons, this examination has not been included in the guidelines suggested by the
Consensus Conference (8).
In general, the value of evoked potential studies in the diagnosis of MSA is limited. Magnetic
evoked potentials are often, but not always, normal in MSA (111,112). Somatosensory, visual, and
acoustic evoked potentials may show prolonged latencies in up to 40% of patients, but most patients
show no abnormalities of central efferent and afferent neuronal pathways (112114).
Some investigators (115,116) have suggested that both somatic anterior horn cells and peripheral
nerves are commonly affected in MSA, and their involvement has therefore been regarded as part of
the clinical spectrum of MSA. Abnormalities of nerve conduction studies seem to be more frequent
in MSA-P (43%) compared to MSA-C (14%), suggesting that the peripheral nervous system is differ-
entially affected in the motor presentations of this disorder (117).
Excessive auditory startle responses (ASRs) may also help differentiate MSA both from PD and
other forms of APD (118). Exaggerated ASRs may reflect disinhibition of lower brainstem nuclei
owing to the degenerative disorder. ASRs appear to be more disinhibited in MSA-P than MSA-C,
and there is a lack of ASR habituation in MSA-C unlike MSA-P, suggesting involvement of different
neural structures in the two MSA-subtypes (119).
PATHOLOGY
In MSA-P, the striatonigral system is the main site of pathology but less severe degeneration can
be widespread and usually includes the olivopontocerebellar system (51). The putamen is shrunken
with gray-green discoloration. When putaminal pathology is severe there may be a cribriform appear-
ance. In early stages the putaminal lesion shows a distinct topographical distribution with a predilection
for the caudal and dorsolateral regions (120). Later on during the course of disease, the entire puta-
men is usually affected with the result that bundles of striatopallidal fibres are narrowed and poorly
stained for myelin. Degeneration of pigmented nerve cells occurs in the substantia nigra pars com-
pacta (SNC), whereas nonpigmented cells of the pars reticulata are reported as normal. The topo-
graphical patterns of neurodegeneration involving the motor neostriatum, efferent pathways, and
nigral neurons, reflect their anatomical relationship and suggest a common denominator or linked
degeneration (120).
In MSA-C, the brunt of pathology is in the olivopontocerebellar system whereas the involvement
of striatum and substantia nigra is less severe. The basis pontis is atrophic, with loss of pontine
neurons and transverse pontocerebellar fibers. In sections stained for myelin, the intact descending
corticospinal tracts stand out against the degenerated transverse fibers and the atrophic middle cer-
ebellar peduncles. There is a disproportionate depletion of fibers from the middle cerebellar peduncles
compared with the loss of pontine neurons, an observation consistent with a dying back process.
A supraspinal contribution to the autonomic failure of MSA is now well established. Cell loss is
reported in dorsal motor nucleus of the vagus (121) and involves catecholaminergic neurons of ven-
trolateral medulla (122). It has also been described for the EdingerWestphal nucleus and posterior
hypothalamus (123) including the tuberomamillary nucleus (124). Papp and Lantos (125) have shown
marked involvement of brainstem pontomedullary reticular formation with glial cytoplasmic inclu-
sions (GCIs), providing a supraspinal histological counterpart for impaired visceral function. Auto-
nomic neuronal degeneration affects the locus ceruleus, too (20). Disordered bladder, rectal, and
sexual function in MSA-P and MSA-C have also been associated with cell loss in parasympathetic
preganglionic nuclei of the spinal cord. These neurons are localized rostrally in the Onufs nucleus
between the sacral segments S2 and S3 and more caudally in the inferior intermediolateral nucleus
chiefly in the S3 to S4 segments (126). Degeneration of sympathetic preganglionic neurones in the
intermediolateral column of the thoracolumbar spinal cord is considered contributory to orthostatic
hypotension. If one considers only those reports in which formal cell counts have been made, with
very few exceptions all cases of MSA with predominant pathology in either the striatonigral or
olivopontocerebellar system show loss of intermediolateral cells (127). However, it is noteworthy
that there is not always a strong correlation between nerve cell depletion or gliosis and the clinical
degree of autonomic failure. It is estimated that more than 50% of cells within the intermediolateral
column need to decay before symptoms become evident (128). In the peripheral component of the
autonomic nervous system, Bannister and Oppenheimer have described atrophy of the glossopharyn-
geal and vagus nerves (129).
A variety of other neuronal populations are noted to show cell depletion and gliosis with consider-
able differences in vulnerability from case to case. Only a few of the reported lesions are discussed
here. Various degree of abnormalities in the cerebral hemisphere, including Betz cell loss, were
detected in pathologically proven MSA cases (57,130132). Furthermore, anterior horn cells may
show some depletion but rarely to the same extent as that occurring in motor neuron disease (126,133).
Depletion of large myelinated nerve fibres in the recurrent laryngeal nerve that innervates intrinsic
laryngeal muscles has been demonstrated in MSA patients with vocal cord palsy (134).
From a neuropathological viewpoint, there is little cause for confusion of MSA with other
neurodegenerative conditions. The GCI is the hallmark that accompanies the signs of degeneration
involving striatonigral and olivopontocerebellar systems. GCIs are distinctly different from filamen-
tous oligodendroglial inclusions, called coiled bodies, found in other neurodegenerative diseases,
including PSP, CBD, and argyrophilic grain disease (135138). Rarely MSA may be combined with
additional pathologies. Lewy bodies (LBs) have been reported in 810% of MSA cases and show a
distribution comparable with that of PD (139). This frequency is similar to that of controls and sug-
gests an incidental finding related to ageing and/or presymptomatic PD.
The discovery of GCIs in MSA brains in 1989 highlighted the unique glial pathology as biological
hallmark of this disorder (140). GCIs are argyrophilic and half-moon, oval, or conical in shape (141)
and are composed of 20- to 30-nm tubular filaments (142). Although inclusions have been described
in five cellular sites, i.e., in oligodendroglial and neuronal cytoplasm and nuclei as well as in axons
(143), GCIs (140) are most ubiquitous and appear to represent the subcellular hallmark lesion of
MSA (141). Their distribution selectively involves basal ganglia, supplementary and primary motor
cortex, the reticular formation, basis pontis, the middle cerebellar peduncles, and the cerebellar white
matter (125,141). GCIs contain classical cytoskeletal antigens, including ubiquitin and tau (141,144).
More recently, F-synuclein immunoreactivity has been recognized as the most sensitive marker of
GCIs (145) (Fig. 2). In fact, F-synuclein, a presynaptic protein that is affected by point mutations in
some families with autosomal dominant PD (146) and that is present in LBs (147), has also been
observed in both neuronal inclusions and GCIs (148152) in brains of patients with MSA. GCI fila-
ments are multilayered in structure, with F-synuclein oligomers forming the central core fibrils of the
Fig. 2. F-Synuclein immunostaining reveals GCIs in subcortical white matter. Courtesy of Prof. K. Jellinger.
Reproduced with kind permission of Whitehouse Publishing. Diagnosis and treatment of multiple system
atrophy: an update. ACNR 2004;3(6):510.
filaments (142). The accumulation of F-synuclein into filamentous inclusions appears to play a key
role not only in MSA, but also in a growing number of F-synucleinopathies such as PD, dementia
with Lbs (DLB), Down syndrome, familial Alzheimers disease (AD), and sporadic AD (153). The
F-synuclein accumulation in GCIs as well as in neuronal inclusions associated with MSA precedes
their ubiquitination (154). Importantly, F-synuclein, but not ubiquitin, antibodies also reveal numer-
ous degenerating neurites in the white matter of MSA cases (154). This suggests that an as yet
unrecognised degree of pathology may be present in the axons of MSA cases, although whether
neuronal/axonal F-synuclein pathology precedes glial F-synuclein pathology has not been examined.
Recent findings support an important role for glial cells and inflammatory reactions in many
neurodegenerative diseases including PD, DLB, and MSA (155157). Neuronal survival is critically
dependent on glial function, which can exert both neuroprotective and neurotoxic influences. Glial
cells are a primary target of cytokines and are activated in response to many cytokines, including
tumor necrosis factor (TNF)-F (158). This activation can trigger further release of cytokines that
might enhance or suppress local inflammatory responses and neuronal survival. These cytokines may
also participate in neurodegeneration either indirectly by activating other glial cells or directly by
inducing apoptosis (159161). Several studies indicated that TNF-F is toxic for dopaminergic neu-
rons in vitro (162) and in vivo (163), thus supporting the potential involvement of this pro-inflamma-
tory cytokine in the neurodegenerative processes in PD and other F-synucleinopathies. However, the
relationship between intracellular F-synuclein-positive inclusions and the proinflammatory response
in F-synucleinopathies remains obscure. The activation of microglial cells may be the final common
pathway, contributing both to demyelination and neuronal removal, irrespective of the mode of cell
death. PK 11195 selectively binds to benzodiazepine sites on activated microglia. 11C PK 11195 PET
has demonstrated activated microglia in vivo in the putamen, pallidum, substantia nigra, and pontine
region in five patients with MSA (164).
Fig. 3. Partial restored responsiveness to apomorphine following embryonic transplantation in the double
lesion rat model. The left figure shows apomorphine induced rotation rates following the double lesion as well
as transplantation of embryonic striatal, mesencephalic, combined striatal-mesencephalic, and sham grafts. The
figure on the right shows surviving embryonic graft tissue, expressing Dopamin-D2 receptors (red spots) within a
severely lesion host striatum, compared to a sham graft without evidence of regeneration. Modified from ref. 177.
Fig. 3. Regeneration of apomorphine responsiveness following embryonic transplantation in the double

lesion SND rat model as shown by behavioral studies and D-2 receptor autoradiography. (A) shows increased
apomorphine-induced rotation rates following transplantation of embryonic striatal tissue (line marked with an
asterisk) compared to nonsignificant changes in other transplant groups as well as sham controls (6-OHDA, 6-
hydroxydopamine; QA, quinolinic acid; TP, transplantation; W, weeks). (B) shows surviving embroynic stri-
atal graft tissue expressing foci of dompamine D-2 receptors (small arrows) within a severely lesioned host
striatum, compared to a sham graft without evidence of regeneration (C). Modified from ref. 177.
ANIMAL MODELS
A number of in vivo MSA models have become available as preclinical test bed for novel thera-
peutic interventions. Based on experiments in the early 1990s (165), several attempts have been
made to reproduce the core pathology of striatonigral degeneration (SND) that underlies L-Dopa-
unresponsive parkinsonism in MSA-P (166). The goal of these experimental studies was to replicate
the unique lesion pattern present in human MSA-P/SND, i.e., the combined degeneration of dopam-
inergic nigrostriatal pathways as well as corresponding striatal projections. This work utilized well-
established nigral and striatal lesion models that had been developed to mimic the core pathology of
PD and Huntingtons disease. These experiments produced several models mimicking various degrees
of disease severity, each having its own advantages and pitfalls (165,167176). Embryonic striatal
grafts have been shown to partially regenerate responsiveness to dopaminergic stimulation (177)
(see Fig. 3) in the unilateral double lesion rat model. One principal problem encountered with the
unilateral stereotaxic rat model was the interaction between the nigral and striatal lesion placement.
Also the behavioral and motor impairments obtained were remote from those observed in the human
disease. This was one of the reasons to move to a systemic primate model using the PD-like
toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the HD-like toxin, 3-nitropropionic
acid (3-NP). This strategy generated a reproducible symptomatology closer to human MSA-P/SND,
i.e., levodopa-unresponsive parkinsonism/dystonia correlated with striatal outflow pathway lesions
and severe nigral degeneration (173,174). However, because of ethical considerations, time-consum-
ing experiments, and the need for a great number of animals owing to a marked interindividual sus-
ceptibility to these mitochondrial toxins, the model strategy was switched to systemic MPTP + 3-NP
mouse models (171,172). These models allow screening of drugs in sufficient number of animals.
The systemic double toxin paradigm may also be applied to transgenic mice with targeted expression
of F-synuclein in oligodendrocytes (175). However, more work is needed to confirm the stability of
F-synuclein expression in these animals and particularly its deleterious effects upon oligodendroglial
and neuronal function.
TREATMENT
Autonomic Failure
Unfortunately there is no causal therapy of autonomic dysfunction available. Therefore the thera-
peutic strategy is defined by clinical symptoms and impairment of quality of life in these patients.
Because of the progressive course of MSA, a regular review of the treatment is mandatory to adjust
measures according to clinical needs.
The concept to treat symptoms of orthostatic hypotension is based on the increase of intravascular
volume and the reduction of volume shift to lower body parts when changing to upright position. The
selection and combination of the following options depend on the severity of symptoms and their
practicability in the single patient, but not on the extent of blood pressure drop during tilt test.
Nonpharmacological options include sufficient fluid intake, high salt diet, more frequent, but smaller
meals per day to reduce postprandial hypotension by spreading the total carbohydrate intake, and
custom-made elastic body garments. During the night, head-up tilt increases intravascular volume up
to 1 L within a week, which is particularly helpful to improve hypotension early in the morning. This
approach is successful in particular in combination with fludrocortisone, which further supports sodium
retention.
The next group of drugs to consider are the sympathomimetics. These include ephedrine (with
both direct and indirect effects), which is often valuable in central autonomic disorders such as MSA.
With higher doses, side effects include tremulousness, loss of appetite, and urinary retention in men.
Among the large number of vasoactive agents that have been evaluated in MSA, only one, the
directly acting F-adrenergic agonist midodrine, meets the criteria of evidence-based medicine (178
180). Side effects are usually mild and only rarely lead to discontinuation of treatment because of
urinary retention or pruritus, predominantly on the scalp.
Another promising drug appears to be the norepinephrine precursor L -threo-dihydroxy-
phenylserine (L-threo-DOPS), which has been used in this indication in Japan for years and efficacy
of which has now been shown by a recent open, dose-finding trial (181).
In case the above-mentioned drugs do not produce the desired effects, selective targeting is needed.
The somatostatin analog, octreotide, is often beneficial in postprandial hypotension (182), presum-
Table 3
Practical Management of MSA
A. Pharmacotherapy
I. For akinesia-rigidity
Levodopa up to 8001000 mg/d, if tolerated (n)
Dopamine agonists as second-line anti-parkinsonian drugs (dosing as for PD patients) (n)
Amantadine as third-line drug, 100 mg up to three times daily (n)
II. For focal dystonia
Botulinum toxin A (n)
III. For orthostatic hypotension
Head-up tilt of bed at night (n)
Elastic stockings or tights (n)
Increased salt intake (n)
Fludrocortisone 0,1-0, 3 mg/d (n)
Ephedrine 1545 mg t.i.d (n)
L-threo-DOPS (300 mg b.i.d.) (n)
Midodrine 2.5 g10 mg t.i.d. (n)
IV. For postprandial hypotension
Octreotide 2550 g s.c. 30 min before a meal (n)
V. For nocturnal polyuria
Desmopressin (spray: 1040 mg/night or tablet: 100400 mg/night) (n)
VI. For bladder symptoms
Oxybutynin for detrusor hyperreflexia (2.55 mg b.i.d-t.i.d.) (n)
Intermittent self-catheterization for retention or residual volume >100 ml (n)
B. Other therapies
Physiotherapy (n)
Speech therapy (n)
Occupational therapy (n)
Percutaneous endoscopic gastrostomy (PEG) (rarely needed in late stage) (n)
Provision of wheelchair (n)
CPAP (n) (rarely tracheostomy [n]) for inspiratory stridor
Reproduced with kind permission from John Wiley & Sons, Inc.: Wenning et al., Multiple System atrophy: an
update. Mov Disord 2003;18(suppl 6):3442.
ably because it inhibits release of vasodilatory gastrointestinal peptides (183); importantly it does not
enhance nocturnal hypertension (182).
The vasopressin analogue, desmopressin, which acts on renal tubular vasopressin-2 receptors,
reduces nocturnal polyuria and improves morning postural hypotension (184).
The peptide erythropoietin may be beneficial in some patients by raising red cell mass, second-
arily improving cerebral oxygenation (185,186).
A broad range of drugs (Table 3) have been used in the treatment of postural hypotension (187).
Unfortunately, the value and side effects of many of these drugs have not been adequately deter-
mined in MSA patients using appropriate endpoints.
In the management of neurogenic bladder including residual urine clean intermittent catheteriza-
tion three to four times per day is a widely accepted approach to prevent secondary consequences of
failure to micturate. It may be necessary to provide the patient with a permanent transcutaneous
suprapubic catheter if mechanical obstruction in the urethra or motor symptoms of MSA prevent
uncomplicated catheterization.
Pharmacological options with anti- or pro-cholinergic drugs or F-adrenergic substances are usu-
ally not successful to adequately reduce postvoid residual volume in MSA, but anticholinergic agents
like oxybutynin can improve symptoms of detrusor hyperreflexia or sphincter-detrusor dyssynergy in
the early course of the disease (50). Recently, F-adrenergic receptor antagonists (prazosin and
moxisylyte) have been shown to improve voiding with reduction of residual volumes in MSA patients
(188). Urological surgery must be avoided in these patients because postoperative worsening of bladder
control is most likely (50).
The necessity of a specific treatment for sexual dysfunction needs to be evaluated individually in
each MSA patient. Male impotence can be partially circumvented by the use of intracavernosal papav-
erine, prostaglandin E1, or penile implants (189). Preliminary evidence in PD patients (190) suggests
that sildenafil may also be successful in treating erectile failure in MSA: a recent trial confirmed the
efficacy of this compound in MSA, but also suggested caution because of the frequent cardiovascular
side effects (191). Erectile failure in MSA may also be improved by oral yohimbine (50).
Constipation can be relieved by increasing the intraluminal volume, which may be achieved by
using macrogol-water-solution (192).
Inspiratory stridor develops in about 30% of patients. Continuous positive airway pressure (CPAP)
may be helpful in some of these patients (193). In only about 4% a tracheostomy is needed and
performed.
Motor Disorder
General Approach
Because the results of drug treatment for the motor disorder of MSA are generally poor, other
therapies are all the more important. Physiotherapy helps maintain mobility and prevent contractures,
and speech therapy can improve speech and swallowing and provide communication aids. Dysphagia
may require feeding via a nasogastric tube or even percutaneous endoscopic gastrostomy (PEG).
Occupational therapy helps to limit the handicap resulting from the patients disabilities and should
include a home visit. Provision of a wheelchair is usually dictated by the liability to falls because of
postural instability and gait ataxia but not by akinesia and rigidity per se. Psychological support for
patients and partners needs to be stressed.
Parkinsonism
Parkinsonism is the predominant motor disorder in MSA and therefore represents a major target
for therapeutic intervention. Although less effective than in PD and despite the lack of randomized-
controlled trials, levodopa replacement represents the mainstay of anti-parkinsonian therapy in MSA.
Open-label studies suggest that up to 3040% of MSA patients may derive benefit from levodopa at
least transiently (13,26). Occasionally, a beneficial effect is evident only when seemingly unrespon-
sive patients deteriorate after levodopa withdrawal (25). Preexisting orthostatic hypotension is often
unmasked or exacerbated in levodopa-treated MSA patients associated with autonomic failure. In
contrast, psychiatric or toxic confusional states appear to be less common than in PD (13). Results
with dopamine agonists have been even more disappointing (194). Severe psychiatric side effects
occurred in a double-blind crossover trial of six patients on lisuride, with nightmares, visual halluci-
nations, and toxic confusional states (195). Wenning et al. (13) reported a response to oral dopamine
agonists only in 4 of 41 patients. None of 30 patients receiving bromocriptine improved, but 3 of 10
who received pergolide had some benefit. Twenty-two percent of the levodopa responders had good
or excellent response to at least one orally active dopamine agonist in addition. Anti-parkinsonian
effects were noted in 4 of 26 MSA patients treated with amantadine (13), however, there was no
significant improvement in an open study of 9 patients with atypical parkinsonism, including 5 sub-
jects with MSA (196).
Blepharospasm as well as limb dystonia, but not antecollis, may respond well to local injections of
botulinum toxin A.
Ablative neurosurgical procedures such as medial pallidotomy fail to improve parkinsonian motor
disturbance in MSA (197). However, most recently a beneficial short-term and long-term effect of
bilateral subthalamic nucleus high-frequency stimulation has been reported in four patients with
MSA-P (198). Further studies are needed to establish the scope of deep brain stimulation in MSA.
Cerebellar Ataxia
There is no effective therapy for the progressive ataxia of MSA-C. Occasional successes have
been reported with cholinergic drugs, amantadine, 5-hydroxytryptophan, isoniazid, baclofen, and
propanolol; for the large majority of patients these drugs proved to be ineffective.
One intriguing observation is the apparent temporary exacerbation of ataxia by cigarette smoking
(199,200). Nicotine is known to increase the release of acetylcholine in many areas of the brain and
probably also releases noradrenaline, dopamine, 5-hydroxytryptophan, and other neurotransmitters.
Nicotinic systems may therefore play a role in cerebellar function and trials of nicotinic antagonists
such as dihydro-G-erythroidine might be worthwhile in MSA-C.
Practical Therapy
Because of the small number of randomized controlled trials, the practical management of MSA is
largely based on empirical evidence (n) or single randomized studies (p), except for three random-
ized controlled trials of midodrine (pp) (178180). The present recommendations are summarized in
Table 3.
Future Therapies
Two European research initiativesEuropean MSA-Study Group (EMSA-SG) and
Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS)are presently con-
ducting multicentre intervention trials in MSA using candidate neuroprotective agents. For the first
time, prospective progression data using novel rating tools such as the Unified MSA Rating Scale
(UMSARS) (201) will become available. Furthermore, surrogate markers of disease progression will
be evaluated using structural and functional neuroimaging. Even if the ongoing trials are negative,
they will certainly stimulate further trial activity in MSA, which is desperately needed to tame this
beast.
LEGEND FOR THE VIDEO

60-yr-old patient with advanced MSA-P showing marked akinesia and rigidity as well as cerebel-
lar incoordination, particularly of lower limbs.
MAJOR RESEARCH ISSUES IN MSA

1. Pathogenesis of neuronal degeneration
- Interaction of glial and neuronal pathology
- Genetic susceptibility toward inclusion pathology
2. Optimized diagnostic criteria
3. Biomarkers of disease progression
4. Screening of candidate neuroprotective agents
5. Transgenic animal models
REFERENCES
1. Bower J, Maraganore D, McDonnell S, Rocca W. Incidence of progressive supranuclear palsy and multiple system
atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49:12841288.
2. Tison F, Yekhlef F, Chrysostome V, Sourgen C. Prevalence of multiple system atrophy. Lancet 2000;355(9202):495496.
3. Schrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive supranuclear palsy and multiple system atrophy: a
cross-sectional study. Lancet 1999;354:17711775.
4. Wermuth L, Joensen P, Bunger N, Jeune B. High prevalence of Parkinsons disease in the Faroe Islands. Neurology
1997;49(2):426432.
5. Chio A, Magnani C, Schiffer D. Prevalence of Parkinsons disease in Northwestern Italy: comparison of tracer method-
ology and clinical ascertainment of cases. Mov Disord 1998;13(3):400405.
6. Trenkwalder C, Schwarz J, Gebhard J, Ruland D, Trenkwalder P, Hense HW, et al. Starnberg trial on epidemiology of
Parkinsonism and hypertension in the elderly. Prevalence of Parkinsons disease and related disorders assessed by a
door-to-door survey of inhabitants older than 65 years. Arch Neurol 1995;52(10):10171022.
7. Nee LE, Gomez MR, Dambrosia J, Bale S, Eldridge R, Polinsky RJ. Environmental-occupational risk factors and
familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991;1:913.
8. Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, et al. Consensus statement on the diagnosis of
multiple system atrophy. Clin Auton Res 1998;8:359362.
9. Hanna P, Jankovic J, Kirkpatrick JB. Multiple system atrophy: the putative causative role of environmental toxins.
10. Vanacore N, Bonifati V, Fabbrini G, Colosimo C, Marconi R, Nicholl D, et al. Smoking habits in multiple system
atrophy and progressive supranuclear palsy. Neurology 2000;54:114119.
11. Quinn N. Multiple system atrophythe nature of the beast. J Neurol Neurosurg Psychiatry 1989;52(Suppl):7889.
12. Quinn N. Multiple system atrophy. In: Marsden CD, Fahn S, eds. Movement Disorders 3. London: Butterworth-
Heinemann, 1994:262281.
system atrophy. An analysis of 100 cases. Brain 1994;117(Pt 4):835845.
14. Magalhaes M, Wenning GK, Daniel SE, Quinn NP. Autonomic dysfunction in pathologically confirmed multiple sys-
tem atrophy and idiopathic Parkinsons diseasea retrospective comparison. Acta Neurol Scand 1995;91(2):98-102.
15. Quinn NP, Wenning G, Marsden CD. The Shy Drager syndrome. What did Shy and Drager really describe? Arch
Neurol 1995;52(7):656657.
16. Litvan I, Booth V, Wenning GK, Bartko JJ, Goetz CG, McKee A, et al. Retrospective application of a set of clinical
diagnostic criteria for the diagnosis of multiple system atrophy. J Neural Transm 1998;105(23):217227.
17. Colosimo C, Vanacore N, Bonifati V, Fabbrini G, Rum A, De Michele G, et al. Clinical diagnosis of multiple system
atrophy: level of agreement between Quinns criteria and the consensus conference guidelines. Acta Neurol Scand
2001;103:261264.
18. Osaki Y, Wenning GK, Daniel SE, Hughes A, Lees AJ, Mathias CJ, et al. Do published criteria improve clinical
diagnostic accuracy in multiple system atrophy? Neurology 2002;59(10):14861491.
19. Ben Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system
atrophy: a meta-analysis. Neurology 1997;48(2):384393.
20. Wenning G, Tison F, Ben-Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically
proven cases. Mov Disord 1997;12(2):133147.
21. Schwarz J, Tatsch K, Arnold G, Gasser T, Trenkwalder C, Kirsch C. 123I-iodobenzamide-SPECT predicts dopaminer-
gic responsiveness in patients with de novo parkinsonism. Neurology 1992;42:556561.
22. Schelosky L, Hierholzer J, Wissel J, Cordes M, Poewe W. Correlation of clinical response in apomorphine test with
D2-receptor status as demonstrated by 123I IBZM-SPECT. Mov Disord 1993;8(4):453458.
23. Wenning GK, Ben Shlomo Y, Hughes A, Daniel SE, Lees A, Quinn NP. What clinical features are most useful to distin-
guish definite multiple system atrophy from Parkinsons disease? J Neurol Neurosurg Psychiatry 2000;68(4):434440.
try 2002;72(3):300303.
25. Hughes A, Colosimo C, Kleedorfer B, Daniel SE, Lees AJ. The dopaminergic response in multiple system atrophy.
26. Parati E, Fetoni V, Geminiani C, Soliveri P, Giovannini P, Testa D, et al. Response to L-Dopa in multiple system
atrophy. Clin Neuropharmacol 1993;16(2):139144.
27. Schulz J, Klockgether T, Petersen D, Jauch M, Mller-Schauenburg W, Spieker S, et al. Multiple system atrophy:
natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psy-
chiatry 1994;57:10471056.
28. Wenning GK, Kraft E, Beck R, Fowler CJ, Mathias CJ, Quinn NP, et al. Cerebellar presentation of multiple system
atrophy. Mov Disord 1997;12(1):115117.
29. Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E. Progression and prognosis in multiple system atrophy: an
analysis of 230 Japanese patients. Brain 2002;125:10701083.
30. Gouider-Khouja N, Vidailhet M, Bonnet AM, Pichon J, Agid Y. Pure striatonigral degeneration and Parkinsons
disease: a comparative clinical study. Mov Disord 1995;10(3):288294.
31. Holmberg B, Rosengren L, Karlsson JE, Johnels B. Increased cerebrospinal fluid levels of neurofilament protein in
progressive supranuclear palsy and multiple-system atrophy compared with Parkinsons disease. Mov Disord
1998;13(1):7077.
32. Holmberg B, Johnels B, Ingvarsson P, Eriksson B, Rosengren L. CSF-neurofilament and levodopa tests combined with
discriminant analysis may contribute to the differential diagnosis of Parkinsonian syndromes. Parkinsonism Relat Disord
2001;8(1):2331.
33. Polinsky RJ, Brown RT, Lee GK, Timmers K, Culman J, Foldes O, et al. Beta-endorphin, ACTH, and catecholamine
responses in chronic autonomic failure. Ann Neurol 1987;21(6):573577.
34. Kimber JR, Watson L, Mathias CJ. Distinction of idiopathic Parkinsons disease from multiple-system atrophy by
stimulation of growth-hormone release with clonidine. Lancet 1997;349(9069):18771881.
35. Kaufmann H, Oribe E, Miller M, Knott P, Wiltshire-Clement M, Yahr MD. Hypotension-induced vasopressin
release distinguishes between pure autonomic failure and multiple system atrophy with autonomic failure. Neu-
rology 1992;42(3 Pt 1):590593.
36. Zoukos Y, Thomaides T, Pavitt DV, Cuzner ML, Mathias CJ. Beta-adrenoceptor expression on circulating mono-
nuclear cells of idiopathic Parkinsons disease and autonomic failure patients before and after reduction of central
sympathetic outflow by clonidine. Neurology 1993;43(6):11811187.
37. Clarke CE, Ray PS, Speller JM. Failure of the clonidine growth hormone stimulation test to differentiate multiple
system atrophy from early or advanced idiopathic Parkinsons disease. Lancet 1999;353(9161):13291330.
38. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy.
J Neurol Sci 1996;144(12):218219.
39. Bannister R, Mathias C. Investigation of autonomic disorders. In: Mathias C, Bannister R, eds. Autonomic Failure: A
Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford: Oxford University Press, 1999:169195.
40. Braune S, Auer A, Schulte-Mnting J, Schwerbrock S, Lcking C. Cardiovascular parameters: sensitivity to detect
autonomic dysfunction and influence of age and sex in normal subjects. Clin Auton Res 1996;6:315.
41. Braune S, Schulte-Mnting J, Schwerbrock S, Lcking CH. Retest variation of cardiovascular parameters in autonomic
testing. J Auton Nerv Syst 1996;60(3):103107.
42. Riley D, Chemlinsky T. Autonomic nervous system testing may not distinguish multiple system atrophy from
43. Ziegler M, Lake C, Kopin I. The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med
1977;296:293297.
44. Polinsky R, Kopin I, Ebert M, Weise V. Pharmacologic distinction of different orthostatic hypotension syndromes.
Neurology 1981;31:17.
45. Braune S, Reinhardt M, Schnitzer R, Riedel A, Lcking CH. Cardiac uptake of (123I)MIBG separates Parkinsons
disease from multiple system atrophy. Neurology 1999;53(5):10201025.
46. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. (123)I-metaiodobenzylguanidine myocardial scintigraphy in
47. Takatsu H, Nagashima K, Murase M, Fujiwara H, Nishida H, Matsuo H, et al. Differentiating Parkinson disease from
multiple-system atrophy by measuring cardiac iodine-123 metaiodobenzylguanidine accumulation. JAMA
2000;284(1):4445.
48. Taki J, Nakajima K, Hwang EH, Matsunari I, Komai K, Yoshita M, et al. Peripheral sympathetic dysfunction in patients
with Parkinsons disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med
2000;27(5):566-573.
49. Kirby R, Fowler CJ, Gosling J, Bannister R. Urethro-vesical dysfunction in progressive autonomic failure with mul-
tiple system atrophy. J Neurol Neurosurg Psychiatry 1986;49:554562.
50. Beck R, Betts C, Fowler C. Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62
cases. J Urol 1994;151(5):13361341.
51. Wenning GK, Tison F, Elliott L, Quinn NP, Daniel SE. Olivopontocerebellar pathology in multiple system atrophy.
Mov Disord 1996;11(2):157162.
53. Klockgether T, Schroth G, Diener HC, Dichgans J. Idiopathic cerebellar ataxia of late onset: natural history and MRI
morphology. J Neurol Neurosurg Psychiatry 1990;53:297305.
54. Wllner U, Klockgether T, Petersen D, Naegele T, Dichgans J. Magnetic resonance imaging in hereditary and idio-
pathic ataxia. Neurology 1993;43:318325.
55. Wakai M, Kume A, Takahashi A, Ando T, Hashizume Y. A study of parkinsonism in multiple system atrophy: clinical
and MRI correlation. Acta Neurol Scand 1994;90(4):225231.
56. Albanese A, Colosimo C, Bentivoglio A, Fenici R, Melillo G, Colosimo C, et al. Multiple system atrophy presenting as
parkinsonism: clinical features and diagnostic criteria. J Neurol Neurosurg Psychiatry 1995;59:144151.
57. Konagaya M, Konagaya Y, Sakai M, Matsuoka Y, Hashizume Y. Progressive cerebral atrophy in multiple system
atrophy. J Neurol Sci 2002;195(2):123127.
58. Savoiardo M, Strada L Girotti F. Olivopontocerebellar atrophy: MR diagnosis and relationship to multisystem atrophy.
Radiology 1990;174:693696.
59. Drayer B, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer S. Parkinson Plus syndrome: diagnosis using high
field MR imaging of brain iron. Radiology 1986;159:493-498.
60. Pastakia B, Polinsky R, Di Chiro G, Simmon JT, Brown R, Wener L. Multiple system atrophy (ShyDrager syndrome):
MR imaging. Radiology 1986;159:499502.
61. Olanow C. Magnetic resonance imaging in parkinsonism. Neurol Clin 1992;10:405420.

62. Lang A, Curran T, Provias J, Bergeron C. Striatonigral degeneration: iron deposition in putamen correlated with the
slit-like void signal of magnetic resonance imaging. Can J Neurol Sci 1994;21:311318.
63. OBrien C, Sung JH, McGeachie RE, Lee MC. Striatonigral degeneration: Clinical, MRI, and pathologic correlation.
Neurology 1990;40:710711.
64. Schwarz J, Weis S, Kraft E. Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the
putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996;60:98101.
65. Stern M, Braffman BH, Skolnick BE, Hurtig HI, Grossman RI. Magnetic resonance imaging in Parkinsons disease and
parkinsonian syndromes. Neurology 1989;39:15241526.
66. Schrag A, Kingsley D, Phatouros C, Mathias CJ, Lees AJ, Daniel SE, et al. Clinical usefulness of magnetic resonance
imaging in multiple system atrophy. J Neurol Neurosurg Psychiatry 1998;65(1):6571.
67. Brooks D, Luthert P, Gadian D, Marsden C. Does signal-attentuation on high-field T2-weighted MRI of the brain
reflect regional cerebral iron deposition? Observations on the relationship between regional cerebral water proton T2-
values and iron levels. J Neurol Neurosurg Psychiatry 1989;52:108111.
68. Kraft E, Trenkwalder C, Auer DP. T2*-weighted MRI differentiates multiple system atrophy from Parkinsons disease.
Neurology 2002;59(8):12651267.
69. Konagaya M, Konagaya Y, Iida M. Clinical and magnetic resonance imaging study of extrapyramidal symptoms in
70. Konagaya M, Konagaya Y, Honda H, Iida M. A clinico-MRI study of extrapyramidal symptoms in multiple system
atrophylinear hyperintensity in the outer margin of the putamen. No To Shinkei 1993;45(6):509513.
disease, MSA, PSP, and CBD. J Neural Transm 2003;110(2):151169.
signal changes on T2-weighted magnetic resonance imaging sequences: a specific marker of multiple system atrophy?
Arch Neurol 1999;56(2):225228.
73. Konagaya M, Sakai M, Matsuoka Y, Goto Y, Yoshida M, Hashizume Y. Patho-MR imaging study in the putaminal
margin in multiple system atrophy. No To Shinkei 1998;50(4):383385.
74. Schocke M, Seppi K, Esterhammer R, Kremser C, Jaschke W, Poewe W. Diffusion-weighted MRI differentiates the
Parinson variant of multiple system atrophy from PD. Neurology 2002;58:575580.
75. Seppi K, Schocke MF, Esterhammer R, Kremser C, Brenneis C, Mueller J, et al. Diffusion-weighted imaging discrimi-
nates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple system atrophy. Neurol-
ogy 2003;60(6):922927.
76. Schulz J, Skalej M, Wedekind D, Luft AR, Abele M, Voigt K, et al. Magnetic resonance imaging-based volumetry
differentiates idiopathic Parkinsons syndrome from multiple system atrophy and progressive supranuclear palsy. Ann
Neurol 1999;45:6574.
77. Brenneis C, Seppi K, Schocke M, Mller J, Luginger E, Bsch S, et al. Voxel-based morphometry detects cortical
atrophy in the parkinson variant of multiple system atrophy. Mov Disord 2003;18(10):11321138.
78. Robbins TW, James M, Lange KW, Owen AM, Quinn NP, Marsden CD. Cognitive performance in multiple system
atrophy. Brain 1992;115(Pt 1):271291.
79. Davie CA, Wenning GK, Barker GJ, Tofts PS, Kendall BE, Quinn N, et al. Differentiation of multiple system atrophy
from idiopathic Parkinsons disease using proton magnetic resonance spectroscopy. Ann Neurol 1995;37(2):204210.
80. Federico F, Simone IL, Lucivero V, Mezzapesa DM, de Mari M, Lamberti P, et al. Usefulness of proton magnetic
resonance spectroscopy in differentiating parkinsonian syndromes. Ital J Neurol Sci 1999;20(4):223229.
81. Ellis C, Lemmens G, Williams S, Simmons A, Leigh PN, Chaudhuri K. Striatal changes in striatonigral degeneration
and Parkinsons disease: a proton magnetic resonance spectroscopy study. Mov Disord 1996;11:104.
82. Hu M, Simmons A, Glover A. Proton magnetic resonance spectroscopy of the putamen in Parkinsons disease and
multiple system atrophy. Mov Disord 1998;13:182.
83. Brooks D, Ibanez V, Sawle GV, Quinn N, Lees AJ, Mathias CJ, et al. Differing patterns of striatal 18F-dopa uptake in
Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990;28:547555.
84. Brooks D, Salmon E, Mathias C, Quinn N, Leenders K, Bannister R, et al. The relationship between locomotor disabil-
ity, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atro-
phy, pure autonomic failure, and Parkinsons disease, studied with PET. Brain 1990;113:15391552.
85. Burn D, Sawle G, Brooks D. Differential diagnosis of Parkinsons disease, multiple system atrophy, and Steele
RichardsonOlszewski syndrome: discriminant analysis of striatal 18F-dopa PET data. J Neurol Neurosurg Psychiatry
1994;57(3):278284.
86. Brooks D, Ibanez V, Sawle G, Playford E, Quinn N, Mathias C, et al. Striatal D2 receptor status in patients with
Parkinsons disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and
positron emission tomography. Ann Neurol 1992;31(2):184192.
87. Burn D, Rinne J, Quinn N, Lees A, Marsden C, Brooks D. Striatal opioid receptor binding in Parkinsons disease,
striatonigral degeneration and SteeleRichardsonOlsewski syndrome A (11C)diprenorphine PET study. Brain
1995;118:951958.
88. De Volder A, Francart J, Laterre C, Dooms G, Bol A, Michel C, et al. Decreased glucose utilization in the striatum and
frontal lobe in probable striatonigral degeneration. Ann Neurol 1989;26:239247.
89. Eidelberg D, Takikawa S, Moeller JR, Dhawan V, Redington K, Chaly T, et al. Striatal hypometabolism distinguishes
striatonigral degeneration from Parkinsons disease. Ann Neurol 1993;33:518527.
90. Perani D, Bressi S, Testa D, Grassi F, Cortelli P, Gentrini S, et al. Clinical/metabolic correlations in multiple system
atrophy. A fludeoxyglucose F18 positron emission tomography study. Arch Neurol 1995;52:179-185.
91. Antonini A, Kazamuta k, Feigin A, Mandel F, Dhawan V, Margouleff C, et al. Differential diagnosis of parkinsonism
with 18F-fluorodeoxyglucose and PET. Mov Disord 1998;13(2):268274.
92. Ghaemi M, Hilker R, Rudolf J, Sobesky J, Heiss WD. Differentiating multiple system atrophy from Parkinsons dis-
ease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging. J Neurol Neurosurg Psychia-
try 2002;73(5):517523.
93. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M, St. Laurent RT. Patterns of cerebral glucose metabolism detected
with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol
1994;36:166175.
94. Rinne J, Burn DJ, Mathias CJ, Quinn NP, Marsden CD, Brooks DJ. Positron emission tomography studies on the
dopaminergic system and striatal opioid binding in the olivopontocerebellar atrophy variant of multiple system atro-
phy. Ann Neurol 1995;37:568573.
95. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M, St. Laurent RT. Benzodiazepine receptor binding in cerebellar
degenerations studied with positron emission tomography. Ann Neurol 1995;38:176185.
96. Shinotoh H, Inoue O, Hirayama K. Dopamine D1 receptors in Parkinsons disease and striatonigral degeneration: a
positron emission tomography study. J Neurol Neurosurg Psychiatry 1993;56:467472.
97. Schwarz J, Tatsch K, Arnold G, Ott M, Trenkwalder C, Kirsch CM, et al. 123I-iodobenzamide-SPECT in 83 patients
with de novo parkinsonism. Neurology 1993;43(6):1720.
98. Brcke T, Wenger S, Asenbaum S. Dopamine D2 receptor imaging and measurement with SPECT. Adv Neurol
1993;60:494500.
99. Pirker W, Djamshidian S, Asenbaum S, Gerschlager W, Tribl G, Hoffmann M, et al. Progression of dopaminergic
degeneration in Parkinsons disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study. Mov Disord
2002;17:4553.
100. Yoshita M. Differentiation of idiopathic Parkinsons disease from striatonigral degeneration and progressive supra-
nuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 1998;155:6067.
101. Martinelli P, Coccagna G. Etude electromyographique du sphincter strie de lanus dans trois cas de syndrome de Shy
Drager. In: Arbus L, Cadilhac J, eds. Electromyographie. Toulouse: Premieres Journees Languedociennes dElectro-
myographie, 1978:321-326.
102. Eardley I, Quinn NP, Fowler CJ, Kirby RS, Parkhouse HF, Marsden CD, et al. The value of urethral sphincter elec-
tromyography in the differential diagnosis of parkinsonism. Br J Urol 1989;64:360362.
103. Pramstaller PP, Wenning GK, Smith SJ, Beck RO, Quinn NP, Fowler CJ. Nerve conduction studies, skeletal muscle
EMG, and sphincter EMG in multiple system atrophy. J Neurol Neurosurg Psychiatry 1995;58(5):618621.
104. Palace J, Chandiramani VA, Fowler CJ. Value of sphincter electromyography in the diagnosis of multiple system
atrophy. Muscle Nerve 1997;20(11):13961403.
105. Tison F, Arne P, Sourgen C, Chrysostome V, Yeklef F. The value of external anal sphincter electromyography for the
diagnosis of multiple system atrophy. Mov Disord 2000;15(6):11481157.
106. Valldeoriola F, Valls-Sole J, Tolosa ES, Marti MJ. Striated anal sphincter denervation in patients with progressive
supranuclear palsy. Mov Disord 1995;10(5):550555.
107. Giladi N, Simon ES, Korczyn AD, Groozman GB, Orlov Y, Shabtai H, et al. Anal sphincter EMG does not distinguish
between multiple system atrophy and Parkinsons disease. Muscle Nerve 2000;23:731734.
108. Libelius R, Johannson F. Quantitative electromyography of the external anal sphincter in Parkinsons disease and
multiple system atrophy. Muscle Nerve 2000;23:12501256.
109. Colosimo C, Inghilleri M, Chaudhuri KR. Parkinsons disease misdiagnosed as multiple system atrophy by sphincter
electromyography. J Neurol 2000;247:559561.
110. Vodusek B. Sphincter EMG and differential diagnosis of multiple system atrophy. Mov Disord 2001;16(4):600607.
111. Wenning G, Smith SJM. Magnetic brain stimulation in multiple system atrophy. Mov Disord 1997;12(3):452453.
112. Abbruzzese G, Marchese R, Trompetto C. Sensory and motor evoked potentials in multiple system atrophy: compara-
tive study with Parkinsons disease. Mov Disord 1997;12(3):315321.
113. Abele M, Schulz JB, Burk K, Topka H, Dichgans J, Klockgether T. Evoked potentials in multiple system atrophy
(MSA). Acta Neurol Scand 2000;101(2):111115.
114. Delalande I, Hache JC, Forzy G, Bughin M, Benhadjali J, Destee A. Do visual-evoked potentials and spatiotemporal
contrast sensitivity help to distinguish idiopathic Parkinsons disease and multiple system atrophy? Mov Disord
1998;13(3):446452.
115. Montagna P, Martinelli P, Rizzuto N, Salviati A, Rasi F, Lugaresi E. Amyotrophy in ShyDrager syndrome. Acta
Neurol Belg 1983;83:142157.
116. Cohen J, Low P, Fealey R, Sheps S, Jiang NS. Somatic and autonomic function in progressive autonomic failure and
multiple system atrophy. Ann Neurol 1987;22:692699.
117. Abele M, Schulz J, Burk K, Topka H, Dichgans J, Klockgether T. Nerve conduction studies in multiple system atrophy.
Eur Neurol 2000;43(4):221223.
118. Kofler M, Muller J, Wenning GK, Reggiani L, Hollosi P, Bosch S, et al. The auditory startle reaction in parkinsonian
disorders. Mov Disord 2001;16(1):6271.
119. Kofler M, Muller J, Seppi K, Wenning GK. Exaggerated auditory startle responses in multiple system atrophy: a com-
parative study of parkinson and cerebellar subtypes. Clin Neurophysiol 2003;114(3):541547.
120. Kume A, Takahashi A, Hashizume Y. Neuronal cell loss of the striatonigral system in multiple system atrophy. J Neurol
Sci 1993;117:3340.
121. Sung J, Mastri A, Segal E. Pathology of ShyDrager syndrome. J Neuropathol Exp Neurol 1979;38:353368.
122. Benarroch EE, Smithson IL, Low PA, Parisi JE. Depletion of catecholaminergic neurons of the rostral ventrolateral
medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998;43(2):156163.
123. Shy G, Drager GA. A neurological syndrome associated with orthostatic hypotension. A clinicopathological study.
Arch Neurol 1960;2:511527.
124. Nakamura S, Ohnishi K, Nishimura M, Suenaga T, Akiguchi I, Kimura J, et al. Large neurons in the tuberomammillary
nucleus in patients with Parkinsons disease and multiple system atrophy. Neurology 1996;46(6):16931696.
125. Papp M, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to
clinical symptomatology. Brain 1994;117:235243.
126. Konno H, Yamamoto T, Iwasaki Y, Iizuka H. ShyDrager syndrome and amyotrophic lateral sclerosis. Cytoarchitec-
tonic and morphometric studies of sacral autonomic neurons. J Neurol Sci 1986;73(2):193204.
127. Daniel S. The neuropathology and neurochemistry of multiple system atrophy. In: Mathias C, Bannister R, eds. Auto-
nomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford: Oxford University Press,
1999:321328.
128. Oppenheimer DR. Lateral horn cells in progressive autonomic failure. J Neurol Sci 1980;46(3):393404.
129. Bannister R, Oppenheimer D. Degenerative diseases of the nervous system associated with autonomic failure. Brain
1972;95:457474.
130. Tsuchiya K, Ozawa E, Haga C, Watabiki S, Ikeda M, Sano M, et al. Constant involvement of the Betz cells and
pyramidal tract in multiple system atrophy: a clinicopathological study of seven autopsy cases. Acta Neuropathol (Berl)
2000;99:628636.
131. Wakabayashi K, Ikeuchi T, Ishikawa A, Takahashi H. Multiple system atrophy with severe involvement of the motor
cortical areas and cerebral white matter. J Neurol Sci 1998;156(1):114117.
132. Konagaya M, Sakai M, Matsuoka Y, Konagaya Y, Hashizume Y. Multiple system atrophy with remarkable frontal lobe
atrophy. Acta Neuropathol (Berl) 1999;97(4):423428.
133. Sima A, Caplan M, DAmato CJ, Pevzner M, Furlong JW. Fulminant multiple system atrophy in a young adult present-
ing as motor neuron disease. Neurology 1993;43:20312035.
134. Hayashi M, Isozaki E, Oda M, Tanabe H, Kimura J. Loss of large myelinated nerve fibres of the recurrent laryngeal
nerve in patients with multiple system atrophy and vocal cord palsy. J Neurol Neurosurg Psychiatry 1997;62:234238.
135. Braak H, Braak E. Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia.
Neuropathol Appl Neurobiol 1989;15(1):13-26.
136. Yamada T, McGeer PL. Oligodendroglial microtubular masses: an abnormality observed in some human
neurodegenerative diseases. Neurosci Lett 1990;120:163166.
137. Arima K, Nakamura M, Sunohara N, Ogawa M, Anno M, Izumiyama Y, et al. Ultrastructural characterization of the
tau-immunoreactive tubules in the oligodendroglial perikarya and their inner loop processes in progressive supranuclear
palsy. Acta Neuropathol (Berl) 1997;93(6):558566.
138. Chin SS, Goldman JE. Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol 1996;55(5):499508.
139. Wenning G, Quinn N. Are Lewy bodies non-specific epiphenomena of nigral damage? Mov Disord 1994;9(3):378379.
140. Papp M, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy
141. Lantos PL. The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol
1998;57(12):1099-1111.
142. Gai WP, Pountney DL, Power JH, Li QX, Culvenor JG, McLean CA, et al. alpha-Synuclein fibrils constitute the central
core of oligodendroglial inclusion filaments in multiple system atrophy. Exp Neurol 2003;181(1):6878.
143. Papp M, Lantos PI. Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in
multiple system atrophy. J Neurol Sci 1992;107:172182.
144. Cairns NJ, Atkinson PF, Hanger DP, Anderton BH, Daniel SE, Lantos PL. Tau protein in the glial cytoplasmic inclu-
sions of multiple system atrophy can be distinguished from abnormal tau in Alzheimers disease. Neurosci Lett
1997;230(1):4952.
145. Dickson DW, Lin W, Liu WK, Yen SH. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol
1999;9(4):721732.
146. Goedert M, Spillantini MG. Lewy body diseases and multiple system atrophy as alpha-synucleinopathies. Mol Psychia-
try 1998;3(6):462465.
147. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature
1997;388(6645):839840.
148. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. Alpha-synuclein immunoreactivity in glial cytoplasmic inclu-
sions in multiple system atrophy. Neurosci Lett 1998;249(23):180182.
149. Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, et al. Accumulation of alpha-synuclein/
NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol
(Berl) 1998;96:445452.
150. Arima K, Ueda K, Sunohara N, Arakawa K, Hirai S, Nakamura M, et al. NACP/alpha-synuclein immunoreactivity in
fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system
atrophy. Acta Neuropathol (Berl) 1998;96:439444.
151. Tu P, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, et al. Glial cytoplasmic inclusions in white matter oligoden-
drocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998;44(3):415422.
152. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous alpha-synuclein inclusions link
multiple system atrophy with Parkinsons disease and dementia with Lewy bodies. Neurosci Lett 1998;251(3):205208.
153. Trojanowski JQ. Tauists, Baptists, Syners, Apostates, and new data. Ann Neurol 2002;52(3):263265.
154. Gai WP, Power JH, Blumbergs PC, Blessing WW. Multiple-system atrophy: a new alpha-synuclein disease? Lancet
1998;352(9127):547548.
155. Hirsch EC, Hunot S, Damier P, Faucheux B. Glial cells and inflammation in Parkinsons disease: a role in
neurodegeneration? Ann Neurol 1998;44(3 Suppl 1):S115S120.
156. Togo T, Iseki E, Marui W, Akiyama H, Ueda K, Kosaka K. Glial involvement in the degeneration process of Lewy
body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies. J Neurol
Sci 2001;184(1):7175.
157. Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, et al. The role of glial cells in Parkinsons
disease. Curr Opin Neurol 2001;14(4):483-489.
158. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001;2(10):734744.
159. Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC. Immunocytochemical analysis of tumor necrosis
factor and its receptors in Parkinsons disease. Neurosci Lett 1994;172(12):151154.
160. Hunot S, Dugas N, Faucheux B, Hartmann A, Tardieu M, Debre P, et al. FcepsilonRII/CD23 is expressed in Parkinsons
disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J Neurosci
1999;19(9):34403447.
161. Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T. Tumor necrosis factor-alpha (TNF-alpha) increases
both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 1994;165(12):208210.
162. McGuire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey PM. Tumor necrosis factor alpha is toxic to embry-
onic mesencephalic dopamine neurons. Exp Neurol 2001;169(2):219230.
163. Aloe L, Fiore M. TNF-alpha expressed in the brain of transgenic mice lowers central tyroxine hydroxylase immunore-
activity and alters grooming behavior. Neurosci Lett 1997;238(12):6568.
164. Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, et al. [(11)C](R)-PK11195 PET imaging of micro-
glial activation in multiple system atrophy. Neurology 2003;61(5):686689.
165. Wenning G, Granata R, Laboyrie PM, Quinn NP, Jenner P, Marsden CD. Reversal of behavioural abnormalities by fetal
allografts in a novel rat model of striatonigral degeneration. Mov Disord 1996;11(5):522532.
166. Wenning G, Granata R, Puschban Z, Scherfler C, Poewe W. Neural transplantation in animal models of multiple system
atrophy: a review. J Neural Transm 1999;55:103113.
167. Scherfler C, Puschban Z, Ghorayeb I, Goebel GP, Tison F, Jellinger K, et al. Complex motor disturbances in a sequen-
tial double lesion rat model of striatonigral degeneration (multiple system atrophy). Neuroscience 2000;99(1):4354.
168. Ghorayeb I, Puschban Z, Fernagut PO, Scherfler C, Rouland R, Wenning GK, et al. Simultaneous intrastriatal 6-
hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration. Exp Neurol
2001;167(1):133147.
169. Waldner R, Puschban Z, Scherfler C, Seppi K, Jellinger K, Poewe W, et al. No functional effects of embryonic neuronal
grafts on motor deficits in a 3-nitropropionic acid rat model of advanced striatonigral degeneration (multiple system
atrophy). Neuroscience 2001;102(3):581592.
170. Ghorayeb I, Fernagut PO, Hervier L, Labattu B, Bioulac B, Tison F. A single toxin-double lesion rat model of
striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis.
Neuroscience 2002;115(2):533546.
171. Stefanova N, Puschban Z, Fernagut PO, Brouillet E, Tison F, Reindl M, et al. Neuropathological and behavioral changes
induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral
degeneration (multiple system atrophy). Acta Neuropathol (Berl) 2003;106(2):157166.
172. Fernagut PO, Diguet E, Bioulac B, Tison F. MPTP potentiates 3-nitropronionic acid-induced striatal damage in mice:
reference to striatonigral degeneration. Exp Neurol. 2004;185(1):4762.
173. Ghorayeb I, Fernagut PO, Aubert I, Bezard E, Poewe W, Wenning GK, et al. Toward a primate model of L-dopa-
unresponsive parkinsonism mimicking striatonigral degeneration. Mov Disord 2000;15(3):531536.
174. Ghorayeb I, Fernagut PO, Stefanova N, Wenning GK, Bioulac B, Tison F. Dystonia is predictive of subsequent altered
dopaminergic responsiveness in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine+3-nitropropionic acid model
of striatonigral degeneration in monkeys. Neurosci Lett 2002;335(1):3438.
175. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, et al. Hyperphosphorylation and insolubility of
alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 2002;3(6):583588.
176. Zuscik M, Sands S, Ross SA, Waugh DJJ, Gaivin RJ, Morilak D, et al. Overexpression of the alpha1B-adrenergic
receptor causes apoptotic neurodegeneration: multiple system atrophy. Nat Med 2000;6(12):13881394.
177. Puschban Z, Scherfler C, Granata R, Laboyrie P, Quinn NP, Jenner P, et al. Autoradiographic study of striatal dopamine
re-uptake sites and dopamine D1 and D2 receptors in a 6-hydroxydopamine and quinolinic acid double-lesion rat model
of striatonigral degeneration (multiple system atrophy) and effects of embryonic ventral mesencephalic, striatal or co-
grafts. Neuroscience 2000;95(2):377388.
178. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, et al. Neurogenic orthostatic hypotension: a
double-blind, placebo-controlled study with midodrine. Am J Med 1993;95(1):3848.
179. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic
hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA 1997;277(13):10461051.
180. Wright RA, Kaufmann HC, Perera R, Opfer-Gehrking TL, McElligott MA, Sheng KN et al. A double-blind, dose-
response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998;51(1):120124.
181. Mathias CJ, Senard JM, Braune S, Watson L, Aragishi A, Keeling JE, et al. L-threo-dihydroxyphenylserine (L-threo-
DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-
ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001;11(4):235242.
182. Alam M, Smith G, Bleasdale-Barr K, Pavitt DV, Mathias CJ. Effects of the peptide release inhibitor, octreotide, on day-
time hypotension and on nocturnal hypertension in primary autonomic failure. J Hypertens 1995;13(12 Pt 2):16641669.
183. Raimbach SJ, Cortelli P, Kooner JS, Bannister R, Bloom SR, Mathias CJ. Prevention of glucose-induced hypotension
by the somatostatin analogue octreotide (SMS 201-995) in chronic autonomic failure: haemodynamic and hormonal
changes. Clin Sci (Lond) 1989;77(6):623628.
184. Mathias CJ, Fosbraey P, da Costa DF, Thornley A, Bannister R. The effect of desmopressin on nocturnal polyuria,
overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br Med J (Clin Res Ed)
1986;293(6543):353354.
185. Perera R, Isola L, Kaufmann H. Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary
autonomic failure. Clin Auton Res 1995;5(4):211213.
186. Winkler A, Marsden J, Parton M, Watkins P, Chaudhuri K. Erythropoietin deficiency and anaemia in multiple system
atrophy. Mov Disord 2001;16:233239.
187. Mathias C, Kimber JR. Postural hypotension: causes, clinical features, investigation, and management. Annu Rev Med
1999;50:317326.
188. Sakakibara R, Hattori T, Uchiyama T, Suenaga T, Takahashi H, Yamanishi T, et al. Are alpha-blockers involved in
lower urinary tract dysfunction in multiple system atrophy? A comparison of prazosin and moxisylyte. J Auton Nerv
Syst 2000;79:191195.
189. Colosimo C, Pezzella FR. The symptomatic treatment of multiple system atrophy. Eur J Neurol 2002;9(3):195199.
190. Zesiewicz T, Helal M, Hauser RA. Sildenafil Citrate (Viagra) for the treatment of erectile dysfunction in men with
Parkinsons disease. Mov Disord 2000;15(2):305308.
191. Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafil citrate
(Viagra) in parkinsonism due to Parkinsons disease or multiple system atrophy with observations on orthostatic
hypotension. J Neurol Neurosurg Psychiatry 2001;71(3):371374.
192. Eichhorn TE, Oertel WH. Macrogol 3350/electrolyte improves constipation in Parkinsons disease and multiple system
193. Iranzo A, Santamaria J, Tolosa E, Barcelona Multiple System Atrophy Study Group. Continuous positive air pressure
eliminates nocturnal stridor in multiple system atrophy. Lancet 2000;356:13291330.
194. Lees A. The treatment of the motor disorder of multiple system atrophy. In: Mathias C, Bannister R, eds. Autonomic
Failure. Oxford: Oxford University Press, 1999:357363.
195. Lees A, Bannister R. The use of lisuride in the treatment of multiple system atrophy with autonomic failure (Shy
Drager syndrome). J Neurol Neurosurg Psychiatry 1981;44:347351.
196. Colosimo C, Merello M, Pontieri FE. Amantadine in parkinsonian patients unresponsive to levodopa: a pilot study.
J Neurol 1996;243(5):422425.
197. Lang AE, Lozano A, Duff J, Tasker R, Miyasaki J, Galvez-Jimenez N, et al. Medial pallidotomy in late-stage
Parkinsons disease and striatonigral degeneration. Adv Neurol 1997;74:199211.
198. Visser-Vandewalle V, Temel Y, Colle H, van der LC. Bilateral high-frequency stimulation of the subthalamic nucleus
in patients with multiple system atrophyparkinsonism. Report of four cases. J Neurosurg 2003;98(4):882887.
199. Graham J, Oppenheimer DR. Orthostatic-hypotension and nicotine sensitivity in a case of multiple system atrophy.
200. Johnsen J, Miller VT. Tobacco intolerance in multiple system atrophy. Neurology 1986;36:986988.
201. Wenning GK, Seppi K, Sampaio C, Quinn NP, Poewe W, Tison F. European Multiple System Atrophy Study Group
(EMSA-SG): Validation of the Unified MSA Rating Scale (UMSARS). Mov Disord 2002;17(Suppl 5):252.
Dementia With Lewy Bodies 361
21
Clinical Diagnosis of Dementia With Lewy Bodies
David J. Burn, Urs P. Mosimann, and Ian G. McKeith
INTRODUCTION
Dementia with Lewy bodies (DLB) is a dementia syndrome associated with visual hallucinations,
parkinsonism, and fluctuating levels of attention. Necroepidemiological studies place DLB second
to Alzheimers disease (AD) in prevalence, accounting for 1520% of all autopsy-confirmed
dementias. The prevalence of clinically diagnosed DLB in a Finnish population aged 75 yr or older
was found to be 5%, comprising 22% of all demented subjects (1).
The association of Lewy bodies with Parkinsons disease (PD) was made in 1912, but it was not
until nearly 50 yr later, in 1961, that Okazaki and colleagues reported the association of the same
inclusion body with severe dementia in two elderly male patients (2). In contrast to their brainstem
counterparts, cortical Lewy bodies are less eosinophilic and lack a clear halo, making them more
difficult to recognize using older haematoxylin and eosin staining methods. With the advent of more
sensitive immunohistochemical techniques, notably ubiquitin and F-synuclein antibodies, a signifi-
cantly greater burden of cortical Lewy body and neuritic pathology may be identified.
Cortical Lewy bodies may also be found in the majority of PD cases, with or without dementia, as
well as in DLB. Alzheimers-type pathological features, notably senile plaques, frequently coexist in
both DLB and PD with dementia (PDD). This dual pathology and clinicopathological overlap
between PDD and DLB on the one hand and AD and DLB on the other, encapsulates the nosologi-
cal debate currently surrounding DLB. Indeed, some authorities refer to DLB as the Lewy body
variant of Alzheimers disease, although dementia with Lewy bodies is the preferred term, fol-
lowing a Consensus meeting in 1996 (3).
This chapter will discuss the various components of the DLB clinical syndrome and explore the
diagnostic issues that arise in differentiating DLB from PDD and AD. For details on the pathology
the reader should see Chapters 4 and 8, and for the genetic aspects, Chapter 6.
CLINICAL FEATURES OF DEMENTIA WITH LEWY BODIES

The central feature of DLB is a progressive cognitive decline of sufficient magnitude to interfere
with normal social or occupational function, whereas core clinical components comprise fluctuating
cognition, recurrent and persistent visual hallucinations, and extrapyramidal signs (EPS). Supportive
features may increase diagnostic sensitivity, though exclusion criteria also need to be considered
(Table 1). Depression and REM sleep behavior disorder (RBD) have been suggested as additions to
the list of supportive features (4).

361
362 Burn, Mosimann, and McKeith
Table 1
Consensus Criteria for Clinical Diagnosis of Probable and Possible DLB
1. The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magni-
tude to interfere with normal social and occupational function. Prominent or persistent memory impair-
ment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests
of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent.
2. Two of the following core features are essential for a diagnosis of probable DLB and one is essential for
possible DLB:
a. fluctuation of cognition with pronounced variations in attention and alertness
b. recurrent visual hallucinations that are typically well formed and detailed
c. spontaneous motor features of parkinsonism
3. Features supportive of the diagnosis are:
a. repeated falls
b. syncope
c. transient loss of consciousness
d. neuroleptic sensitivity
e. systematized delusions
f. hallucinations in other modalities
g. REM sleep behavior disorder (4)
h. depression (4)
4. A diagnosis of DLB is less likely in the presence of:
a. stroke disease, evident as focal neurological signs or on brain imaging
b. evidence on physical examination and investigation of any physical illness or other brain disorder
sufficient to account for the clinical picture
Adapted from ref. 3.
Cognitive and Neuropsychological Profile

A meta-analysis of 21 controlled comparisons has shown a clear and profound pattern of visual-
perceptual and attentional-executive impairments in DLB (5). In terms of group differences, patients
with DLB always do worse than age-matched controls on neuropsychological tasks, with particularly
poor performance on visual perceptual and learning tasks, visual semantic tasks, and praxis tasks.
Simple global measures of performance (e.g., the Mini Mental State Examination [MMSE]) are usu-
ally equivalent to those of patients with AD of comparable severity, highlighting the insensitivity of
these tests to executive dysfunction. There are trends for better performance in DLB than AD patients
on verbal memory and orientation tasks, for example, logical memory from the Wechsler Memory
Scale. Patients with DLB lack the poor retention over delay intervals and increased propensity to
produce intrusion errors in the cued recall condition, typical of AD. Performance on visual tasks,
particularly praxis tasks, for example, Block Design from the Wechsler Adult Intelligence Scale, is
consistently more impaired in DLB than in AD. A DLB patient will perform more poorly on simple
bedside constructional tasks, for example copying a clock face, than an AD patient of comparable
MMSE (6).
The neuropsychological changes with progression of DLB are not well characterized, though the
clinical impression is that differences with AD are particularly pronounced in the early stages and, as
the disease evolves, these lessen. Rate of progression, as evidenced by change in mental test scores,
is equivalent to that seen in AD and vascular dementia (7).
Fluctuating Cognition
Variation in cognitive performance is commonly observed in all the major late-onset dementias. It
is frustrating to carers and has a major impact upon the patients ability to reliably perform everyday
activities. Fluctuating cognition (FC) may present in several ways, previously described as
sundowning or intermittent delirium, depending upon the severity and diurnal pattern. FC occurs
in 80% or more of DLB patients. The profile of attentional impairment and fluctuating attention in
DLB is indistinguishable from that recorded in PDD (8).
The severity of FC can be judged by experienced clinicians and is highly correlated with variabil-
ity in performance on computer-based attentional tasks. The variation can be detected over very short
periods of time (on a second-to-second basis), suggesting that FC derives from dysfunction of con-
tinuously active arousal systems (9). Questions posed to the carer such as are there times when his or
her thinking seems quite clear and then becomes muddled may be useful probes for this symptom.
Substantial variability in attentiveness may also be observed throughout the consultation, or between
one appointment and the next. The Clinician Assessment of Fluctuation and the One Day Fluctuation
Assessment Scale are validated instruments to record FC, correlating with both neuropsychological
and electrophysiological measures of fluctuation (10).
Neuropsychiatric Features
A majority of DLB patients (80%) experience neuropsychiatric symptoms, particularly hallucina-
tions, delusions, apathy, anxiety, and depression, at some stage of their illness (11). These symptoms
may be quantified using the Neuropsychiatric Inventory (NPI), a 12-item interview with the caregiver
rating frequency, severity, and associated carer distress of delusions, hallucinations, agitation, depres-
sion, anxiety, elation, apathy, disinhibition, irritability, aberrant motor behavior, sleep, and appetite
disturbances (12). The NPI-4, comprising delusions, hallucinations, depression, and apathy, may
represent a sufficiently sensitive abbreviated form of the NPI for practical use in the busy clinic
setting for patient assessment (13).
Visual hallucinations (VHs) are a core feature in the Consensus Criteria for the clinical diagnosis
of DLB. They are present in 33% of patients at the time of presentation (range 1164%) and occur at
some point in the course of the illness in 46% (1380%) (14).
VHs are the most common form of hallucination in DLB, although tactile, olfactory, and auditory
hallucinations may also occur. The VHs are complex in type, often containing detailed scenes featur-
ing mute people and animals (15). Affective responses to the hallucinations vary from indifference,
to amusement, or fear and combativeness. VHs and delusions often coexist, common delusions being
phantom border delusions (i.e., the belief that strangers live in the home), or paranoid delusions of
persecution, theft, and spousal infidelity. Delusions and hallucinations often trigger other behavioral
problems, such as aggression and agitation, leading to profound caregiver distress and precipitating
early nursing home admission.
VHs in DLB correlate strongly with Lewy body density in parahippocampal and inferior temporal
lobe cortices (16). See also Chapter 11.
Extrapyramidal Signs
The frequency of parkinsonian features at presentation in DLB ranges between 10% and 78%,
with 40100% of DLB cases displaying EPS at some stage of the illness (1719), with differences
likely to represent ascertainment bias, use of neuroleptic agents, and variable definition of clinical
phenomenology.
The Phenomenology of the Extrapyramidal Syndrome in DLB
Louis and coworkers compared EPS in 31 DLB and 34 PD pathologically confirmed cases (17).
Clinical information was obtained prospectively in some patients. DLB patients presenting with par-
kinsonism were, on average, 10 yr younger than the DLB patients presenting with neuropsychiatric
features (60.0 vs 70.9 yr). Of the DLB patients, 92% had at least one sign of parkinsonism, with 92%
having either rigidity or bradykinesia. A tremor of any type or a specific rest tremor was recorded in
76% and 55%, respectively, of the DLB patients. This compared with 88% and 85%, respectively, of
the PD group. Myoclonus was documented in 18.5% of the DLB patients but none of the PD group.
A trial of levodopa was used in 42% of the DLB group, with a clinical response recorded in 7 of the
10 patients (70%). The dose of levodopa required and the precise nature of the response were not
stated. In attempting to differentiate DLB from PD on the basis of the Parkinsonian syndrome, the
authors concluded that patients with DLB were 10 times more likely to have one of four clinical
features (myoclonus, absence of rest tremor, no perceived need to treat with levodopa, and no response
to levodopa). The positive predictive value for having DLB, given any one of these features was 85.7%
(sensitivity 66.7%, specificity 85.7%).
Gnanalingham and colleagues reported a comparison of clinical features, including EPS, in 16 DLB,
15 PD, and 25 AD patients, diagnosed according to published clinical criteria (20). Nine of 16 DLB
patients (56%) presented with EPS and 15 (94%) qualified for a second diagnosis of PD. A greater
rigidity score, assessed using the Unified Parkinsons Disease Rating Scale (UPDRS), and lower
scores on a finger-tapping test were more frequently noted in the DLB patients compared with the PD
group, whereas resting tremor and left/right asymmetry were less common. Twelve of 16 (75%) DLB
patients had received levodopa at some stage of their disease, and 10 were taking anti-parkinsonian
drugs at the time of the study. All cases were noted to have treatment responsiveness, although the
degree of motor improvement and the doses required were not stated.
An international, multicenter study reported parkinsonism in 92.4% of 120 DLB patients (19).
There was a small but statistically significant difference between male and female patients on a five-
item UPDRS subscale (the UPDRS-5), with male DLB patients more severely affected. This modi-
fied subscale comprising rest tremor, action tremor, bradykinesia, facial expression, and rigidity, is
independent of the severity of cognitive impairment (21). Older DLB patients tended to have higher
UPDRS scores, but the difference was not statistically significant. Cases with severe cognitive impair-
ment (MMSE < 18) had significantly more severe EPS than those with less cognitive decline using the
full UPDRS part III, but when this relationship was reexamined using the UPDRS-5 there was no
difference between the groups. Patients with more severe dementia may thus have difficulty under-
standing and executing some of the instructions. It is thus likely that severity of parkinsonism is
independent of cognitive decline.
Aarsland and colleagues compared EPS in 98 DLB and 130 PD patients (18). The DLB group was
older at time of assessment and had a shorter duration of disease compared with the PD patients.
Sixty-seven of the DLB patients (68%) had EPS. More severe action tremor, rigidity, bradykinesia,
difficulty arising from a chair, greater facial impassivity, and gait disturbance were described in the
DLB group.
The Spectrum of Parkinsonism in PD With and Without Dementia and DLB
Does the parkinsonian syndrome associated with DLB differ fundamentally from that seen in PD?
This seems highly improbable, and though clinical series may describe higher or lower frequencies of
certain EPS in DLB compared with PD, there are no absolute discriminating features. The pattern of
EPS in DLB does, however, seem to show an axial bias (e.g., greater postural instability and facial
impassivity), with a tendency toward less tremor, consistent with greater non-dopaminergic motor
involvement. According to the classification proposed by Jankovic based upon the UPDRS II and III
(22), the postural instability-gait difficulty (PIGD) phenotype of parkinsonism is overrepresented in
DLB, as indeed it may be in PDD (23). EPS in PD, PDD, and DLB may thus be a spectrum, with a
shift toward greater non-dopaminergic motor system involvement through PD to DLB. This is con-
sistent with previous studies reporting motor features mediated by non-dopaminergic pathways
(speech, posture, and balance) correlating with incident dementia in PD (24).
Progression of Parkinsonism in DLB
DLB patients with established parkinsonism have an annual increase in severity, assessed using
the UPDRS, of 9%, a figure comparable with PD (25). In contrast, and again in common with PD,
progression is more rapid in DLB patients with early parkinsonism (49% increase in motor UPDRS
score in 1 yr).
Falls, Syncope, Sleep Disorders, and Other Neurological Features

A retrospective clinical analysis of pathologically confirmed cases of PD and DLB revealed that
falls occurred at some point in the disease duration in 91% of 11 and 79% of 14 cases, respectively
(26). The mean latency to onset of recurrent falls was, however, much shorter in the DLB group at 48
months, compared with 118 mo in the PD group. In a prospective study, multiple falls (defined as
more than five falls) occurred in 37% of 30 DLB patients and only 6% of 35 AD patients (27). The
falls often resulted in injury. Other than having DLB, multiple falls were associated with parkin-
sonism, previous falls, greater impairment of activities of daily living, and older age.
Several pathophysiological mechanisms could underlie the falls in DLB, including degeneration
of brainstem nuclei, for example, the pedunculopontine nucleus, and impaired visuospatial process-
ing. Orthostatic hypotension, vasovagal syncope, and carotid sinus hypersensitivity, collectively
referred to as neurovascular instability, are common in patients with neurodegenerative dementia,
and also contribute to falls. Cardioinhibitory carotid sinus hypersensitivity occurs in over 40% of
DLB patients, compared with 28% AD cases and may reflect monoaminergic neuronal loss within
cardioregulatory brainstem centers (28).
A supranuclear gaze paresis has been described in DLB (2931). In combination with cognitive
impairment and falls, this may cause diagnostic confusion with SteeleRichardsonOlszewski syn-
drome (progressive supranuclear palsy [PSP]). Other neurological features rarely described in DLB
include an alien limb (32), chorea and dystonia (33).
Sleep disturbance is more common in DLB than in AD, as are daytime drowsiness and confusion
on waking (34). RBD is characteristic of synucleinopathic disorders and frequently commences before
the onset of dementia in DLB, sometimes by up to 20 yr (35). Over 90% of patients with RBD and
degenerative dementia meet criteria for possible or probable DLB (36).
DIAGNOSTIC ACCURACY AND DIFFERENTIAL DIAGNOSIS

Five sets of diagnostic criteria have been proposed to date to assist in the accurate diagnosis of
DLB (37). The most rigorous approach led to the formulation of the Consensus criteria (Table 1) (3).
Considering all the published studies together that have reported the diagnostic accuracy of the Con-
sensus criteria yields a mean sensitivity of 49% (range 083%) and specificity of 92% (79100%)
(37). All these studies compared DLB to other dementia syndromes, including AD or vascular demen-
tia, and the majority was retrospective. Discriminating value for the Consensus criteria is greatest at an
early stage, suggesting that DLB should be considered in any new dementia presentation (38).
Interrater reliability for the core clinical features of parkinsonism and hallucinations in DLB is
generally good, but only poor or moderate for fluctuating cognition. The application of validated
methods to recognize the latter may thus increase diagnostic accuracy.
Perhaps unsurprisingly, AD is the most frequent misdiagnosis in autopsy-confirmed DLB cases
(39,40). Pathologically, of course, the situation is frequently not clear-cut, with a variable admixture
of plaques and tangles, in addition to synuclein-positive inclusions. The degree of concomitant AD
tangle pathology has an important influence upon both the clinical diagnostic accuracy of DLB and
the clinical phenotype. In one study, the clinical diagnostic accuracy for DLB cases with low Braak
staging was 75% compared to only 39% in those cases with high Braak stages (41). HighBraak
stage DLB cases are also less likely to experience VHs during the disease course.
Despite a significant overlap in neuropathological and clinical features with DLB, Consensus
guidelines suggest that PD patients developing dementia more than 12 mo after the initial motor
symptoms should be diagnosed as PDD rather than DLB. At least 2530% of PD patients are
demented in cross-sectional studies (18) although the cumulative incidence of dementia is nearer
80% (42). Future research needs to clarify whether PDD and DLB are different representations of the
same neuropathological process, with different early clinical manifestations, or whether they are
independent disease processes ending in a similar common pathway.
When DLB presents as a primary dementia syndrome the key differential diagnoses are AD, vas-
cular dementia, delirium secondary to systemic or pharmacological toxicity, CreutzfeldtJakob dis-
ease, or other neurodegenerative syndromes characterized by EPS and dementia. The latter include
PSP and corticobasal degeneration (CBD). These conditions need to be excluded as far as possible by
taking a careful history (including the carer whenever possible) and performing a thorough neuro-
logical examination, supplemented where necessary by ancillary investigations (see next section,
Investigation). Table 2 summarizes the key clinical features in several neurodegenerative syndromes
featuring parkinsonism and cognitive impairment.
The value of simple bedside tests of cognitive function should not be overlooked. For example,
the inability of moderately impaired DLB patients to accurately copy pentagons has been reported
with a sensitivity of 88% and specificity of 59% compared with AD (6).
INVESTIGATION
No specific serum or cerebrospinal fluid biomarkers are yet available to increase diagnostic accu-
racy for DLB. Genetic testing cannot be recommended at present as part of the routine diagnostic
process. Most DLB cases are sporadic, although there are a few reports of autosomal dominant Lewy
body disease families (43,44). The APOE4 allele is overrepresented in DLB as in AD but not in PD
without dementia (45). No robust associations have been found between polymorphisms linked with
familial AD and DLB. The APP717 mutation, however, may be associated with familial AD and
extensive cortical Lewy bodies (46).
The additional value of ancillary investigations in the diagnostic process for DLB is also uncer-
tain, although the development and validation of functional neuroimaging techniques, in particular,
will almost certainly improve upon current clinical diagnostic sensitivity.
Neuroimaging
Structural Imaging Changes in DLB
Relative preservation of the hippocampal and medial temporal lobe compared to AD is character-
istic of DLB (47), possibly helping to explain the preservation of mnemonic function. Although
hippocampal volume is reduced, by around 15% compared to controls, the reduction is considerably
less than that seen in AD, with some 40% of DLB cases having no evidence of any atrophy. Rate of
volume loss over time using serial magnetic resonance imaging (MRI) is comparable with AD (2%
per year in AD and DLB compared with 0.5% in controls) (48). There are increased white matter
lesions in AD and these may contribute to the cognitive impairment. A similar increase has been
described in DLB cases (49), though effects on cognitive function have not yet been determined.
Functional Imaging Changes in DLB
Fluorodeoxyglucose positron emission tomography (PET) and single photon computed tomogra-
phy (SPECT) studies using blood flow markers such as 99mTc-HMPAO demonstrate many similari-
ties between DLB and AD subjects (50,51), with pronounced biparietal hypoperfusion and variable,
usually symmetric, deficits in frontal and temporal lobes. The biparietal hypoperfusion in DLB is,
however, more extensive than in AD cases matched for age and dementia severity, particularly in
Brodmann area 7, an area subserving visuospatial function (52).
Occipital hypometabolism on PET and SPECT is characteristic of DLB and affects both primary
visual cortex as well as visual association areas (Brodmann areas 1719). Occipital hypoperfusion
has reasonable specificity (86%) for distinguishing DLB from AD and controls, although the sensi-
tivity for this finding is relatively low (64%) (51). Consistent with findings from structural imaging
studies, temporal lobe perfusion is relatively preserved in DLB.
Significant reductions in striatal binding of G-carbomethoxy-iodophenyl-tropane (a ligand for the
dopamine transporter) using PET have been demonstrated in DLB but not AD, a difference that
Table 2
Comparison of Neurodegenerative Diseases Featuring Parkinsonism and Cognitive Impairment
DLB PD AD PSP CBD MSA
Parkinsonism symmetric, PIGD asymmetric, TD, variable, symmetric marked asymmetry, symmetric bradykinesia,
phenotype and late PIGD usually mild, late bradykinesia ++, PIGD rigidity dominant PIGD
* L-dopa response ++ +++ /++ (waning)
Other motor features myoclonus Gegenhalten alien limb, cerebellar ataxia,

(paratonia) stimulus-sensitive myoclonus
myoclonus, dystonia,
ideomotor apraxia
Eye movements impaired saccade normal normal SNGP/slow increased saccadic mild saccadic slowing
triggering vertical saccades latency (speed N)
Autonomic failure ++ (may be early) ++ (often late) +++ (often early)

Dementia early, executive, often late, early, severe fronto-subcortical frontal dementia mild (dementia an
and visuospatial executive, memory deficit and apathy may be early feature exclusion feature)
and visuospatial
Neuropsychiatric features
* VH +++ ++ (usually late) +
* depression ++ +++ + + (<apathy) ++ ++
, absent; + to +++ frequency of feature; N, normal; SNGP, supranuclear gaze palsy; PIGD, postural instability-gait difficulty; TD, tremor dominant; VH, visual hallucination.
367
would be predicted from the nigrostriatal dopaminergic pathology associated with DLB (53). FP-CIT
SPECT can also differentiate DLB from AD (54).
Scintigraphy with [123I]metaiodobenzyl guanidine (MIBG) enables quantification of postgangli-
onic sympathetic cardiac innervation. Cardiac MIBG scanning can differentiate DLB (where the
signal is reduced) from AD (where the signal is similar to control values) (55,56).
Neurophysiological Studies
The electroencephalogram (EEG) is diffusely abnormal in over 90% of DLB patients. Early slow-
ing of the dominant rhythm, with 4- to 7-Hz transient activity over the temporal lobe area, is charac-
teristic and correlates with a clinical history of loss of consciousness (57). It is not possible to reliably
differentiate DLB and AD subjects on the basis of the EEG, however (58). The diagnostic signifi-
cance of bursts of bilateral frontal rhythmic delta activity, reported to be more common in DLB than
AD, has yet to be established (59).
Multifocal action myoclonus, which occurs in approx 15% of DLB patients, is clinically more
severe than that associated with PD, although it has the same electrophysiologcal characteristics. The
balance of evidence favors a cortical source for the myoclonus (60). Since myoclonus also occurs in
AD, it will be interesting to determine whether concomitant cortical Alzheimers-type pathology influ-
ences the presence and severity of the myoclonus in Lewy body disorders.
DLB patients have fewer and abnormally delayed auditory startle responses (ASRs) of low ampli-
tude and short duration in extremity muscles compared with healthy controls (61). Virtually no
responses may be elicited in the lower limbs. Interestingly, the reduced ASR probability in advanced
DLB is similar to that found in PD patients with postural instability and recurrent falls, suggesting a
common brainstem pathophysiological mechanism for both disorders.
MANAGEMENT
General Considerations
Nonpharmacologic strategies for cognitive symptoms in DLB include orientation and memory
prompts and attentional cues, although such approaches are of limited benefit. For psychiatric symp-
toms, explanation, education, reassurance, and targeted behavioral interventions may alleviate patient
and carer distress.
In the acutely confused and psychotic patient, intercurrent infection and subdural haematoma
should be excluded. Other nonessential medication capable of causing confusion should be discon-
tinued. Potential therapeutic conflict may arise in the management of DLB over the so-called motion-
emotion conundrum, whereby measures to alleviate psychosis and cognitive deficits may lead to
deterioration in motor function and vica versa. Anti-parkinsonian drug treatment, if necessary, should
be restricted to levodopa. Anticholinergics, amantadine, selegiline, and dopamine agonists should
generally be avoided (14) (Fig. 1).
Nearly 50% of DLB patients receiving conventional high-affinity dopamine D2 receptor antipsy-
chotic agents experience life-threatening adverse effects, termed neuroleptic sensitivity reactions,
characterized by sedation, rigidity, postural instability, falls, and increased confusion, and associated
with a two- to threefold increased mortality (62). Even the use of so-called atypical antipsychotic
drugs may be associated with neuroleptic sensitivity reactions and low dosing may be more impor-
tant than the use of any specific drug (6365).
Cholinesterase Inhibitors in DLB

There is converging and consistent evidence that cholinesterase inhibitors (ChEIs) are effective
and relatively safe in the treatment of neuropsychiatric and cognitive symptoms in DLB. Open stud-
ies of donepezil and rivastigmine have reported improvement in cognitive and noncognitive symp-
toms, without significant deterioration in motor function (66,67). A placebo-controlled, double-blind
Fig. 1. Management approach to DLB.
study assessed the effect of rivastigmine (mean dose 7mg/d) in 120 DLB patients over 20 wk, fol-
lowed by a 3-wk withdrawal period (68). Patients taking rivastigmine were less apathetic, less anx-
ious, and had fewer delusions and hallucinations compared to placebo controls. Treatment effects
disappeared on drug withdrawal.
The long-term efficacy of rivastigmine was further assessed in an open-label study over 96 wk
(69). Improvements in cognitive and neuropsychiatric symptoms were noted after 24 wk, returning to
pretreatment levels after 36 wk. The presence, rather than absence, of VHs in DLB may predict a
good response to ChEIs, as evidenced by improved attention measures (70). In autopsy studies, DLB
cases with VHs have lower levels of cortical choline acetyltransferase, particularly in temporopari-
etal regions, compared with DLB patients without VHs (71). This may allow greater clinical improve-
ments to occur, with cholinergic replacement therapy having a more marked effect upon a lower
neurochemical baseline.
ChEIs are well tolerated in DLB subjects, with dropout rates (1031%) and gastrointestinal side
effects similar to those found in AD. Hypersalivation, rhinorrhea, and lacrimation may also occur in
approx 15% of DLB and PDD patients treated with donepezil (72). An early report of worsening of
parkinsonism in two of nine patients treated with donepezil has not been replicated in other studies,
which have consistently demonstrated either no change or improvement in EPS during ChEI
therapy (73).
Table 3
Future Research Directions for DLB
1. to improve the understanding of molecular mechanisms underpinning
F-synuclein processing and aggregation upstream to Lewy neurite and body
formation
2. to better define the clinicopathological boundaries between DLB and PD with
dementia
3. to define the role of ancillary investigations in increasing diagnostic accuracy
diagnostic algorithm
serum and cerebrospinal fluid biomarkers
4. to establish the extent of a genetic predisposition toward DLB
5. to define L-dopa responsiveness and tolerability
6. to determine the pharmacogenetic basis for variable treatment responsiveness
with ChEI
7. the development of disease modifying therapies, for example:
F-synuclein anti-aggregation agents
anti-G-amyloid agents
tau de-phosphorylating agents
Other Pharmacological Management of DLB

No placebo-controlled study has assessed the effects of antidepressant drugs in DLB. Tricyclic
antidepressants (e.g., amitriptyline, clomipramine, nortriptyline) should be avoided because of their
anticholinergic side effects and potential to exacerbate orthostatic hypotension. Selective serotonin
reuptake inhibitors (e.g., citalopram, sertraline, paroxetine) and the multireceptor antidepressants
(e.g., nefazodone, mirtazapine, and venlafaxine) may therefore be better options for the treatment of
depressed DLB patients (74).
Sleep disturbances, particularly RBD, may be cautiously treated with low-dose clonazepam (0.25
1.0 mg) at bedtime (36). Anticonvulsant drugs (e.g., carbamazepine, sodium valproate) may be occa-
sionally necessary to treat significant behavioral disturbances, although randomized controlled trial
data are lacking (75).
CONCLUSION AND FUTURE DIRECTIONS

DLB is a relatively young disease, in which the clinicopathological overlap between PD and AD
needs to be better defined. An accurate diagnosis of DLB has significant management and prognostic
implications for the patient; an improved diagnostic awareness is therefore important. Information
derived through the study of DLB may ultimately benefit patients with other synucleinopathies. For
example, the successful use of ChEI drugs in DLB has encouraged the design of trials and use of
these agents in PDD, strengthened by our knowledge of similar underlying pathophysiological mecha-
nisms.
Table 3 lists a number of future research directions for DLB. These include a better understanding
of underlying molecular biological mechanisms underpinning the disease, defining the role of addi-
tional investigations in refining diagnostic accuracy, and improved therapeutic approaches. Although
clearly something of a wish list, studies are already under way to address several of these issues.
LEGEND TO VIDEOTAPE
This video shows a 67-yr-old patient with a two-year history of probable DLB (MMSE 21), with
no previous neurological, psychiatric or medical history. Parkinsonian features appeared within the
first year of cognitive impairment. Medication comprised a cholinesterase inhibitor and low dose
co-careldopa.
Sequence 1: The caregivers view of early symptoms (including visuospatial problems and REM-
sleep behaviour disorder)
Sequence 2: The patients description of his visual hallucinations, occurring usually at night, but
not when falling asleep or waking up.
Sequence 3: Assessment of parkinsonian features, including reduced blink rate, significant
hypomimia, monotonous speech, bradyphrenia, limb bradykinesia and reduced arm swing when
walking.
Sequence 4: Illustrative components of the bed-side cognitive assessment. Memory function is
relatively preserved (learning of three words and recall), but there are difficulties in visuo-construc-
tional function (slowing and errors on the clock face including clock hands having the same length,
and use of a 0 instead of 9).
REFERENCES
1. Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. Dementia with Lewy bodies according
to the consensus criteria in a general population aged 75 years or older. J Neurol Neurosurg Psychiatry 2003;74:720724.
2. Okazaki H, Lipton LS, Aronson SM. Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with pro-
gressive dementia and quadraparesis in flexion. J Neuropathol Exp Neurol 1961;20:237244.
3. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathological diagnosis of dementia
4. McKeith IG, Perry EK, Perry RH. Report of the second dementia with Lewy body international workshop. Neurology
1999;53:902905.
5. Collerton D, Burn D, McKeith I, O Brien J. Systematic review and meta-analysis show dementia with Lewy bodies is
a visual perceptual and attentional-executive dementia. Dement Geriat Cog Disord, 2003;16:229237.
6. Ala TA, Hughes LF, Kyrouac GA, Ghobrial MW, Elble RJ. Pentagon copying is more impaired in dementia with Lewy
bodies than in Alzheimers disease. J Neurol Neurosurg Psychiatry 2001;70:483488.
7. Ballard CG, OBrien J, Morris CM, et al. The progression of cognitive impairment in dementia with Lewy bodies,
vascular dementia and Alzheimers disease. Int J Geriatr Psychiatry 2001;16:499503.
8. Ballard CG, Aarsland D, McKeith I, et al. Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurol-
ogy 2002;59:17141720.
9. Walker MP, Ayre GA, Cummings JL, et al. Quantifying fluctuation in dementia with Lewy bodies, Alzheimers dis-
ease, and vascular dementia. Neurology 2000;54:16161625.
10. Walker MP, Ayre GA, Cummings JL, et al. The Clinician Assessment of Fluctuation and the One Day Fluctuation
Assessment Scale. Two methods to assess fluctuating confusion in dementia. Brit J Psychiatry 2000;177:252256.
11. Ballard CG, Holmes C, McKeith IG, et al. Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical
and neuropathological comparative study with Alzheimers disease. Am J Psychiatry 1999;156:10391045.
12. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory:
13. McKeith IG, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-
14. McKeith IG, Burn DJ. Spectrum of Parkinsons disease, Parkinsons dementia, and Lewy body dementia. In: DeKosky
ST, ed. Neurologic Clinics: Dementia, vol. 18. Philadelphia: Saunders, 2000:865883.
15. Ballard C, McKeith I, Harrison R, et al. A detailed phenomenological comparison of complex visual hallucinations in
dementia with Lewy bodies and Alzheimers disease. Int Psychogeriatr 1997;9:381388.
16. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal
lobe. Brain 2002;125:391-403.
17. Louis ED, Klatka LA, Liu Y, Fahn S. Comparison of extrapyramidal features in 31 pathologically confirmed cases of
diffuse Lewy body disease and 34 pathologically confirmed cases of Parkinsons disease. Neurology 1997;48:376380.
18. Aarsland D, Ballard C, McKeith I, Perry RH, Larsen JP. Comparison of extrapyramidal signs in dementia with Lewy
bodies and Parkinsons disease. J Neuropsychiatry Clin Neurosci 2001;13:374379.
19. Del Ser T, McKeith I, Anand R, Cicin-Sain A, Ferrara R, Spiegel R. Dementia with Lewy bodies: findings from an
international multicentre study. Int J Geriatr Psychiatry 2000;15:10341045.
20. Gnanalingham KK, Byrne EJ, Thornton A, Sambrook MA, Bannister P. Motor and cognitive function in Lewy body
dementia: comparison with Alzheimers and Parkinsons disease. J Neurol Neurosurg Psychiatry 1997;62:243252.
21. Ballard C, McKeith I, Burn D, et al. The UPDRS scale as a means of identifying extrapyramidal signs in patients
suffering from dementia with Lewy bodies. Acta Neurol Scand 1997;96:366371.
22. Jankovic J, McDermott M, Carter J, et al. Variable expression of Parkinsons disease: a baseline analysis of the
DATATOP cohort. Neurology 1990;40:15291534.
23. Burn DJ, Rowan EN, Minnett T, et al. Extrapyramidal features in Parkinsons disease with and without dementia and
dementia with Lewy bodies: a cross-sectional comparative study. Mov Disord 2003;18:884889.
24. Foltynie T, Brayne C, Barker RA. The heterogeneity of idiopathic Parkinsons disease. J Neurol 2002;249:138145.
25. Ballard CG, OBrien J, Swann A, et al. One year follow-up of parkinsonism in dementia with Lewy bodies. Dement
Geriatr Cogn Disord 2000;11:219222.
26. Wenning GK, Ebersbach G, Verny M, et al. Progression of falls in postmortem-confirmed parkinsonian disorders. Mov
Disord 1999;14:947950.
27. Ballard CG, Shaw F, Lowery K, McKeith I, Kenny R. The prevalence, assessment and associations of falls in dementia
with Lewy bodies and Alzheimers disease. Dement Geriatr Cogn Disord 1999;10:97103.
28. Ballard C, Shaw F, McKeith I, Kenny R. High prevalence of neurovascular instability in neurodegenerative dementias.
Neurology 1998;51:17601762.
29. Fearnley JM, Revesz T, Brooks DJ, Frackowiak RS, Lees AJ. Diffuse Lewy body disease presenting with a supra-
nuclear gaze palsy. J Neurol Neurosurg Psychiatry 1991;54:159161.
30. de Bruin VM, Lees AJ, Daniel SE. Diffuse Lewy body disease presenting with supranuclear gaze palsy, parkinsonism,
and dementia: a case report. Mov Disord 1992;7:355358.
31. Brett FM, Henson C, Staunton H. Familial diffuse Lewy body disease, eye movement abnormalities, and distribution of
pathology. Arch Neurol 2002;59:464467.
32. Santacruz P, Torner L, Cruz-Snchez F, Lomena F, Catafau A, Blesa R. Corticobasal degeneration syndrome: a case of
Lewy body variant of Alzheimers disease. Int J Geriatr Psychiatry 1996;11:559564.
33. Lennox GG, Lowe JS. Dementia with Lewy bodies. Baillieres Clinical Neurology 1997;6:147166.
34. Grace JB, Walker MP, McKeith IG. A comparison of sleep profiles in patients with dementia with lewy bodies and
35. Boeve BF, Silber MH, Parisi JE, et al. Synucleiopathy pathology and REM sleep behavior disorder plus dementia or
36. Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorder and degenerative dementia: an association likely
reflecting Lewy body disease. Neurology 1998;51:363370.
37. Litvan I, Bhatia KP, Burn DJ, et al. SIC task force appraisal of clinical diagnostic criteria for parkinsonian disorders.
Mov Disord 2003;18:467486.
39. McKeith IG, Galasko D, Wilcock GK, Byrne EJ. Lewy body dementia: diagnosis and treatment. Brit J Psychiatry
1995;167:709717.
40. Lopez OL, Becker JT, Kaufer DI, et al. Research evaluation and prospective diagnosis of dementia with Lewy bodies.
41. Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia
42. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Srensen P. Prevalence and characteristics of dementia in Parkinson
43. Wakabayashi K, Hayashi S, Ishikawa A, et al. Autosomal dominant diffuse Lewy body disease. Acta Neuropathol
(Berl) 1998;96:207210.
44. Gwinn-Hardy K. Genetics of parkinsonism. Mov Disord 2002;17:645656.
45. Galasko D, Saitoh T, Xia Y, et al. The apolipoprotein E allele epsilon 4 is overrepresented in patients with the Lewy
body variant of Alzheimers disease. Neurology 1994;44:19501951.
46. Revesz T, McLaughlin JL, Rossor MN, Lantos PL. Pathology of familial Alzheimers disease with Lewy bodies. J
Neural Transm 1997;51:121135.
47. Barber R, Ballard C, McKeith IG, Gholkar A, OBrien JT. MRI volumetric study of dementia with Lewy bodies: a
comparison with AD and vascular dementia. Neurology 2000;54:13041309.
48. OBrien JT, Paling S, Barber R, et al. Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD and
vascular dementia. Neurology 2001;56:13861388.
49. Barber R, Scheltens P, Gholkar A, et al. White matter lesions on magnetic resonance imaging in dementia with Lewy
bodies, Alzheimers disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry 1999;67:6672.
50. Minoshima S, Foster NL, Sima AA, Frey KA, Albin RL, Kuhl DE. Alzheimers disease versus dementia with Lewy
bodies: cerebral metabolism distinction with autopsy confirmation. Ann Neurol 2001;50:358365.
51. Lobotesis K, Fenwick J, Phipps A, et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD.
Neurology 2001;56:643649.
52. Colloby SJ, Fenwick JD, Williams ED, et al. A comparison of (99m)Tc-HMPAO SPET changes in dementia with Lewy
bodies and Alzheimers disease using statistical parametric mapping. Eur J Nucl Med Mol Imaging 2002;29:615622.
53. Donnemiller E, Heilmann J, Wenning GK, et al. Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD and
123I-beta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease.
Eur J Nucl Med 1997;24:320325.

54. Walker Z, Costa DC, Walker RWH, et al. Differentiation of dementia with Lewy bodies from Alzheimers disease
using a dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 2002;73:134140.
55. Yoshita M, Taki J, Yamada M. A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between
dementia of the Alzheimers-type and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2001;71:583588.
56. Watanabe H, Ieda T, Katayama T, et al. Cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake in dementia with Lewy
bodies: comparison with Alzheimers disease. J Neurol Neurosurg Psychiatry 2001;70:781783.
57. Briel RC, McKeith IG, Barker WA, et al. EEG findings in dementia with Lewy bodies and Alzheimers disease. J Neurol
58. Barber PA, Varma AR, Lloyd JJ, Haworth B, Snowden JS, Neary D. The electroencephalogram in dementia with Lewy
bodies. Acta Neurol Scand 2000;101:5356.
59. Calzetti S, Bortone E, Negrotti A, Zinno L, Mancia D. Frontal intermittent rhythmic delta activity (FIRDA) in patients
with dementia with Lewy bodies: a diagnostic tool? Neurol Sci 2002;23:S65S66.
60. Caviness JN, Adler CH, Caselli RJ, Hernandez JL. Electrophysiology of the myoclonus in dementia with Lewy bodies.
Neurology 2003;60:523524.
61. Kofler M, Muller J, Wenning GK, et al. The auditory startle reaction in parkinsonian disorders. Mov Disord 2001;16:
6271.
62. McKeith IG, Fairbairn A, Perry RH, Thompson P, Perry EK. Neuroleptic sensitivity in patients with senile dementia of
Lewy body type. Brit Med J 1992;305:673678.
63. McKeith IG, Ballard CG, Harrison RW. Neuroleptic sensitivity to risperidone in Lewy body dementia. Lancet
1995;346:699.
64. Burke WJ, Pfeiffer RF, McComb RD. Neuroleptic sensitivity to clozapine in dementia with Lewy bodies. J Neuropsy-
chiatry Clin Neurosci 1998;10:227229.
65. Walker Z, Grace J, Overshot R, et al. Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychia-
try 1999;14:459466.
66. Samuel W, Caligiuri M, Galakso D, et al. Better cognitive and psychopathologic response to donepezil in patients
prospectively diagnosed as dementia with Lewy bodies: a preliminary study. Int J Geriatr Psychiatry 2000;15:794802.
67. McKeith IG, Grace JB, Walker Z, et al. Rivastigmine in the treatment of dementia with Lewy bodies: preliminary
findings from an open trial. Int J Geriatr Psychiatry 2000;15:387392.
68. McKeith IG, Spano PF, Del Ser T, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-
69. Grace J, Daniel S, Stevens T, et al. Long-term use of rivastigmine in patients with dementia with Lewy bodies: an open
label trial. Int Psychogeriatr 2001;13:199205.
70. Wesnes KA, McKeith IG, Ferrara R, et al. Effects of rivastigmine on cognitive function in dementia with Lewy bodies:
a randomised placebo-controlled international study using the cognitive drug research computerised assessment sys-
tem. Dement Geriatr Cogn Disord 2002;13:183192.
71. Perry EK, Marshall E, Kerwin J, et al. Evidence of a monoaminergic-cholinergic imbalance related to visual hallucina-
tions in Lewy body dementia. J Neurochem 1990;55:14541456.
72. Thomas AJ, Burn DJ, Rowan EN, et al. Efficacy of donepezil in Parkinsons disease with dementia and dementia with
Lewy bodies. submitted 2003.
73. Shea C, MacKnight C, Rockwood K. Donepezil for treatment of dementia with Lewy bodies: a case series of nine
patients. Int Psychogeriatr 1998;10:229238.
74. Nyth Al, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disor-
ders. A Nordic multicentre study. Brit J Psychiatry 1990;157:894901.
75. Sival RC, Haffmans PM, Jansen PA, Duursma SA, Eikelenboom P. Sodium valproate in the treatment of aggressive
behaviour in patients with dementia: a randomised placebo controlled clinical trial. Int J Geriatr Psychiatry
2002;17:579585.
Clinical Diagnosis 375
22
Clinical Diagnosis of Familial Atypical Parkinsonian
Disorders
Yoshio Tsuboi, Virgilio H. Evidente, and Zbigniew K. Wszolek
INTRODUCTION
Parkinsons disease (PD) is defined clinically as a disorder characterized by the presence of at
least two of four cardinal signs, i.e., resting tremor, bradykinesia, rigidity, and postural instability,
along with a good response to levodopa (1). Patients with typical PD do not manifest ataxia, chorea,
orthostatic hypotension unrelated to medications, vertical downward-gaze deficits, amyotrophy, early
dementia, or early hallucinations. When present, these signs suggest a diagnosis of atypical parkin-
sonism or parkinsonism-plus syndrome (2).
Both typical and atypical parkinsonism can be either sporadic or familial. The etiology of sporadic
forms remains unknown. However, recent advances in molecular genetics have allowed us to classify
familial forms into several separate categories. Typical forms of familial parkinsonism are found in
patients carrying PARK1-10 chromosomal abnormalities (Table 1). Although even these patients
may exhibit some atypical clinical features, the detailed discussion of kindreds with PARK1-10 is
beyond the scope of this chapter.
Atypical forms of familial parkinsonism with known chromosomal loci or mutations discussed in
this chapter are found in kindreds with frontotemporal dementia, ataxia, dystonia, abnormal copper
and iron accumulation, and mitochondrial dysfunction (Table 2). We have also included a brief dis-
cussion of Perry syndrome, a rare atypical familial parkinsonian disorder with an unknown genetic
abnormality but with worldwide occurrence.
CLINICAL DIAGNOSIS OF FAMILIAL ATYPICAL PARKINSONIAN

DISORDERS
Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17
The term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was
defined in 1996 during the International Consensus Conference in Ann Arbor, Michigan (3). At the
time of this meeting, only 13 families with syndromes linked to the chromosome 17q21-22 locus
were known (412). Currently, over 80 families with FTDP-17 are known (13). Data indicate that
some of these kindreds may share a common founder (14,15). However, distribution is worldwide,
with families described in North America, Europe, Asia, and Australia (414,16).
Molecular genetic studies have identified 31 unique tau gene mutations associated with FTDP-17
(8,1012,14,16). The three most prevalent are P301L, exon 10 5' +16, and N279K. These mutations
account for about 60% of known cases of FTDP-17 (16). Thus, the concept of FTDP-17 has evolved

375
376
Table 1
Familial Parkinsonism Associated With Known Gene Mutations or Loci
Range of Age
at Onset, yr Response to
Nomenclature Chromosome/loci Gene (mean) Phenotype Levodopa Pathology
Autosomal dominant
PARK1 4q21 F-Synuclein (2 mutations) 2085 (46) PD, some cases
with dementia Good Lewy body
PARK3 2p13 Unknown 3689 (58) PD, some cases
PARK4 4p15 Unknown 2448 (30s) PD, some cases
PARK5 4p14-15 UCH-L1 4951 (50) PD Good Unknown
PARK8 12p11.2-q13.11 Unknown 3868 (51) PD Good Pure nigral degeneration
PARK10 1p32 Unknown (65.8) PD Good Unknown
Autosomal recessive
PARK2 6q25.2-27 Parkin (multiple mutations) 658 (26) PD Good Nigral degeneration sometimes
with tau inclusions or Lewy
bodies
PARK6 1p35-36 Unknown 3248 (41) PD Good Unknown
PARK7 1p36 DJ-1 (2 mutations) 2740 (33) PD Good Unknown
PARK9 1p36 Unknown 11-16 PD, spasticity, Good Unknown
(Kufor-Rakeb dementia, gaze
syndrome) palsy
PD, Parkinsons disease; UCH-L1, ubiquitin carboxyterminal hydrase L1.
Tsuboi, Evidente, and Wszolek
Table 2
Familial Atypical Parkinsonism Associated With Known Gene Mutations or Loci
Range of Age
at Onset, yr
Nomenclature Chromosome/loci Gene (mean) Parkinsonism Other Features Response to Levodopa
Autosomal dominant
Clinical Diagnosis
FTDP-17 17q21-22 Tau 2576 (49) PD FTD, CBD, PSP, ALS Poor
SCA2 12q23-24.1 SCA2 (Ataxin-2) 1961 (39) PD Ataxia Good
SCA3 14q32.1 SCA3 (Ataxin-3) 3157 (42) PD Ataxia Good
DYT5 14q22.1 GCH <16 PD Diurnal fluctuation, Good
dystonia
DYT12 19q13 Unknown 1245 (22) Bradykinesia, PI Rapid-onset dystonia Poor
DYT14 14q13 Unknown 3 Rigidity, akinesia Dystonia Good
Huntingtons disease 4p16.3 Huntingtin 3550 Rigidity, akinesia Chorea Poor, occasionally good
Perry syndrome Unknown Unknown 3561 (48) PD Depression, weight loss, Fair
hypoventilation
Autosomal recessive
Wilsons disease 13q14-q21 ATP7B 758 Tremor, rigidity Intention tremor, Poor
KF ring,
behavioral disturbances
NBIA 20p12.3-13 PANK2 <20 Rigidity Chorea, dystonia, pyramidal Occasionally fair
signs, dementia
X-linked recessive
DYT3 (Lubag) Xq13.1 Unknown 1260 (35) PD Dystonia, focal tremor, Poor, occasionally good
chorea, myoclonus,
myorhythmia
Mitochondrial
Complex 1 Unknown 4179 (42) PD None Good
Complex 1 ND4 (31) PD Dementia, Good
dystonia,
ophthalmoplegia
ALS, amyotrophic lateral sclerosis; ATP7B, P-type adenosine triphosphatase; CBD, corticobasal degeneration; FTD, frontotemporal dementia; FTDP-17, frontotemporal
dementia and parkinsonism linked on chromosome 17; GCH, guanosine triphosphate cyclohydrolase I; KF, Kayser-Fleischer; NBIA, neurodegeneration with brain iron
accumulation; PANK2, pantothenate kinase 2; PD, Parkinsons disease; PI, postural instability; PSP, progressive supranuclear palsy; SCA, spinocerebellar ataxia.
377
378 Tsuboi, Evidente, and Wszolek
over the past several years to include the association with tau mutations. Some investigators now
refer to FTDP-17 as familial tauopathies or frontotemporal dementia and parkinsonism linked to
chromosome 17 associated with tau gene mutations (FTDP-17T). Of note, there are five kindreds
linked to the wld locus on chromosome 17 but no mutations have so far been identified in this critical
region, suggesting the presence of another gene (1721). The molecular genetic aspects of FTDP-17
are discussed separately in Chapter 5. Neuropathologic studies demonstrate tau deposition in neurons
alone or in both neurons and glial cells in multiple areas of the central nervous system, particularly in
the cerebral cortex and some subcortical nuclei (e.g., substantia nigra).
Clinical Description
FTDP-17 is characterized clinically by a combination of personality and behavioral dysfunction,
cognitive impairment, and motor signs. The average age at symptomatic onset is 49 yr (range, 25
76 yr). The average duration of survival after onset is 9 yr (range, 226 yr). Personality and behav-
ioral changes are the most common symptoms and are described in almost all known kindreds.
Cognitive impairment is also common and can occur in the initial or later stages of the illness. The
motor manifestations usually include atypical parkinsonism and can in fact be the presenting and
dominating clinical feature, often leading to disability within 23 yr.
The personality and behavioral manifestations of FTDP-17 include disinhibition, apathy, impaired
judgment, compulsive behavior, hyperreligiosity, neglect of personal hygiene, alcoholism, illicit drug
addiction, verbal and physical aggressiveness, and family abuse. Early in the disease, cognition is
characterized by relative preservation of memory, orientation, and visuospatial functions. Progres-
sive speech impairment with nonfluent aphasia, as well as executive dysfunction, may be seen in the
initial stages. Later in the course of the disease, progressive deterioration of memory, orientation, and
visuospatial functions occurs. Echolalia, palilalia, and verbal and vocal perseverations are frequently
observed. Finally, progressive dementia and mutism develop.
The motor signs consist mainly of parkinsonism and can be the initial manifestation of the disease.
In fact, some FTDP-17 patients are misdiagnosed as having PD or progressive supranuclear palsy
(PSP). However, in some families, parkinsonism is absent or occurs late in the course of the disease.
The parkinsonism in FTDP-17 is characterized by symmetrical bradykinesia, rigidity equally affecting
the axial and appendicular musculature, absence of resting tremor (13), postural instability, and poor or
no response to levodopa (22). Other motor disturbances seen in FTDP-17 include dystonia unrelated to
medications, supranuclear gaze palsy, upper and lower motor neuron dysfunction, myoclonus, postural
and action tremors, apraxia of eyelid opening and closing, dysphagia, and dysarthria.
Notably, considerable phenotypic heterogeneity exists in individuals with different mutations
(13,14,16). In addition, phenotypic variability is often seen in individuals carrying the same muta-
tion. The correlation between clinical signs and different tau mutations is presented in Table 3.
Determining the precise relationship between phenotype and genotype in FTDP-17 remains chal-
lenging because clinical information is often unavailable or insufficient. Nevertheless, some patterns
have emerged. Two major phenotypes are associated with FTDP-17: one in which dementia is pre-
dominant and one in which parkinsonism-plus is predominant (13,14,16). The dementia-predomi-
nant phenotype is more common and is usually associated with exonic mutations sparing the splicing
of exon 10. The parkinsonism-pluspredominant phenotype is often associated with intronic and
exonic mutations that affect exon 10 splicing, leading to an overproduction of four-repeat tau
isoforms.
Case 1: (Video 1) Pallido-Ponto-Nigral Degeneration (PPND)
With the N279K Tau Mutation (23)
This right-handed man first noted a tremor in his right leg at age 40. When he drove an automo-
bile, his left leg sometimes felt stiff and occasionally shook. His wife also noted that he turned his
body en bloc (see accompanying DVD video 1, segments A and B). At age 41, he was noted to have
Table 3
Clinical Features of Specific Mutations in the Tau Gene
Not in Exon 10
Exon 1 Exon 9 Exon 11 Exon 12 Exon 13 Exon 10 Exon 10 5' splice site
Average age at onset, yr
30 P301S
3140 L266V S320F G389R delN296 2
4150 G272V E342V N279K, P301L +3, +11, +14, +16
Clinical Diagnosis
>50 R5H, R5L V337M, R406W del280K, L284L, N296H, S305S +12, +13
K369I
Average survival, yr
5 R5H, R5L L266V G389R del280, delN296, N296H 2
610 G272V E342V, N279K, L284L, P301L, 1, +11, +12
K369I P301S, S305S
1115 S320F V337M +3, +14, +16
>15 R406W
First sign
Parkinsonism R5L N279K, P301L, delN296 1, +3, +11
Dementia R5H L266V S320F R406W L284L, delN296 +3, +12
Personality change G272V V337M, P301L, N296H 2, 1, +12, +14, +16
E342V,
K369I
Parkinsonism
Early-prominent N279K, delN296 1, +11
Late-prominent P301S, N296H +3, +12, +14, +16
Rare-minimal R5L G272V P301L 2
Dementia
Early-prominent L266V S320F V337M, R406W delN296 1, +12
Late-prominent G272V K369I del280K, L284L, P301L, P301S 2, +3, +11, +13
Rare-minimal N279K
Personality change
Early-prominent L266V, R406W del280K, L284L, P301L, P301S 2, 1, +12, +14, +16
G272V
Language difficulties G272V S320F G389R N279K, L284L, N296H, P301L 1, +14, +16
Late mutism V337M R406W N279K, del280K, N296H, P301S 2
Eye movement N279K, N296H, P301S, delN296, S305S 1, +3
abnormalities
Epilepsy P301S
Myoclonus V337M N279K, P301S +11
Pyramidal signs N279K, P301S 1, +3, +12
Amyotrophy P301L +14
379
Modified from Wszolek et al. (13) and Ghetti et al. (16). By permission of Lippincott Williams & Wilkins and ISN Neuropath Press.
a shuffling gait and reduced arm swing. His facial expression also had changed considerably, and
drooling became a problem. Subsequently, a resting tremor developed in both legs (in the left more
than the right) and occasionally in both hands. His balance deteriorated steadily over the next 2 yr. He
experienced many falls throughout the day and had difficulty standing up (see accompanying DVD
video 1, segments C and D). His balance was better in the morning than in the evening. Treatment
with carbidopa-levodopa was of limited benefit.
At age 44, the patient reported generalized stiffness in the muscles of his neck, tongue, and extremi-
ties. The stiffness was more pronounced in the afternoon and after the carbidopa-levodopa effect had
worn off (i.e., after 3 h). The tremor in his legs (particularly the left) was also worse several hours
after carbidopa-levodopa administration. He complained of frequent and uncontrollable yawning. He
chewed gum almost constantly to avoid yawning and excessive drooling. He remained independent
in most activities of daily living but needed occasional assistance with cutting food.
When examined at age 44, his Mini-Mental State Examination score was 30/30. His neck was
anteroflexed, and he had obvious parkinsonism in the form of facial hypomimia, markedly reduced
blinking, prominent drooling, and generalized body bradykinesia. He had severe postural instability,
and while walking he needed assistance from at least one person to prevent falls (video 1, segments
EG). Muscle tone was increased and was a mixture of rigidity and spasticity; the tone was more
pronounced in axial than in appendicular muscles. Muscle strength was normal. Deep tendon reflexes
were exaggerated, with bilateral ankle clonus (right more than left). Bilateral extensor plantar responses
were also noted.
At the time of this writing, he was 46 yr old, lived in a skilled nursing facility, and required
assistance in all activities of daily living.
Familial Parkinsonism With Ataxia

The inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of disorders character-
ized by dysfunction and degeneration of systems involved in motor coordination (24). The clinical
phenotypes vary. Additional clinical features include pyramidal signs, eye movement abnormali-
ties, dementia, chorea, and peripheral neuropathy. Currently, 19 SCA loci and mutations have been
identified.
Parkinsonism has been recognized as a clinical phenotype in the SCA3 mutation (25,26). The
autopsies performed on individuals with the SCA3 mutation demonstrated Purkinje cell loss and
torpedo-like structures in the axons of Purkinje cells. Cell loss is also frequently seen in brainstem
nuclei, including the substantia nigra, inferior olive, and pontine nuclei.
Recently, several families with the SCA2 mutation were described whose members manifested
with either ataxia and parkinsonism or with parkinsonism alone (2730). However, no autopsies have
been reported from these kindreds.
Table 4 outlines clinical data on all known SCA2 families with parkinsonism. Although parkin-
sonism is rare with the SCA2 mutation, it can be the only manifestation of the disease in some SCA2
families. For example, before the SCA2 mutation was identified in the Canadian (Alberta) kindred
(29), affected individuals in this family were thought to have PD. The parkinsonism in SCA2 is
characterized by asymmetrical rigidity, bradykinesia, resting tremor, and responsiveness to levodopa.
In a Taiwanese family, two affected individuals had supranuclear gaze palsy (27). The average age at
onset of parkinsonian symptoms in SCA2 kindreds is 47 yr (range, 1986 yr). Because many of the
affected individuals in these kindreds are still living, the average disease duration remains unclear.
Table 5 summarizes the clinical signs observed in SCA3 kindreds. In these families, parkinsonism
is usually associated not only with ataxia but also with oculomotor dysfunction and upper and lower
motor signs. However, in the African-American population, some affected members of families with
the SCA3 mutation exhibit a phenotype indistinguishable from that of idiopathic PD (31,32). The
Table 4
Clinical Features of SCA2 Families With Parkinsonism
Published Report
Gwinn-Hardy et al., Shan et al., Furtado et al., Lu et al.,
Feature 2000 (27) 2001 (28) 2002 (29) 2002 (30)
Origin Taiwanese-American Taiwan (2 families) Canada Taiwan
Number of affected 9 5 10 2
individuals
Age at disease onset, yr 1961 50 3186 4043
Initial symptoms B T B, T, dystonia T
Parkinsonism
Bradykinesia + + + +
Rigidity + + + +
Resting tremor + + +
Postural instability + + + +
Response to levodopa + + + +
Ataxic gait +
Dementia
Peripheral neuropathy Mild
Dystonia + +
Gaze palsy +
Length of CAG repeats 3343 3637 39 36
B, bradykinesia; T, tremor; +, present; , not present.
Table 5
Cerebellar and Extrapyramidal Signs in SCA3 Families
Signs Frequency (%)
Cerebellar
Gait ataxia 100
Limb ataxia 93.5
Nystagmus 92
Dysarthria 85.5
Extrapyramidal
Dystonia 23
Rigidity/bradykinesia 23
Modified from Jardim et al. (26). By permission of the American
Medical Association.
average age at onset of parkinsonian symptoms in SCA3 kindreds is 42 yr (range, 31-57 yr) (31). In
general, the average disease duration spans decades. However, as in SCA2 families, the length of
survival is unknown because many affected individuals are still living (31).
Familial Parkinsonism With Dystonia

Clinically, dystonia is defined as a syndrome of sustained muscle contractions causing twisting
and repetitive movement or abnormal postures (33). Familial dystonia syndromes are termed DYT
and numbered from 1 to 14 according to the associated chromosomal loci. Familial dystonias can be
focal or generalized, with onset in childhood or adulthood. Dystonia can respond to levodopa (DYT5),
Table 6
Clinical Features Seen in Dystonia Kindreds Associated With Parkinsonism
Rapid-Onset
Lubag Disease Dopa-Responsive Dystonia and Dopa-Responsive
Feature (DYT3) Dystonia (DYT5) Parkinsonism (DYT12) Dystonia (DYT14)
Inheritance X-linked recessive AD AD AD
Average age
at disease onset, yr 35 <10 24 3
Initial symptoms Parkinsonism or Dy Dy Dy Dy
Parkinsonism
Bradykinesia + + + +
Rigidity + + +
Resting tremor + +
Postural instability + + + +
Response to levodopa +/ + +
Dystonia Focal-generalized Focal-generalized Focal-segmental Focal-generalized
AD, autosomal dominant; Dy, dystonia; +, present; , not present.
alcohol (DYT8 and DYT9), or anticonvulsant medications (DYT10). Parkinsonian features have been
recognized in DYT3, DYT5, and DYT12. Clinical features of dystonia kindreds associated with
parkinsonism are summarized in Table 6.
DYT3, also known as X-linked dystonia-parkinsonism (XDP) or Lubag disease, was first identi-
fied in families residing on the Philippine island of Panay. The disease is inherited as an X-linked
recessive trait with high penetrance and is thus transmitted to men by their mothers. Female carriers
can manifest symptoms, although these are rare and much less severe than those in men. Onset is at a
mean age of 35 yr but can range from age 1260 yr.
The earliest feature in most DYT3 patients is mild parkinsonism. In particular, breakdown of rapid
alternating movements and subtle body bradykinesia are often seen early. In some patients, an asym-
metrical resting limb tremor similar to that in PD may in fact be misdiagnosed as PD. Other patients
may have a coarse type of action and postural appendicular or axial tremor similar to essential tremor.
With time, dystonia develops in the majority of patients. Those who develop segmental or multifocal
dystonia within the first year of the disease, especially in combination with parkinsonism, usually
have a more rapid progression. Patients with pure or predominant parkinsonism and either negative
or late-onset dystonia have a more benign course. These parkinsonian patients may be levodopa-
responsive. However, the dystonia can sometimes be exacerbated by levodopa.
When the family history cannot be adequately determined or when the maternal roots cannot be
traced back to the Philippine island of Panay, some patients with XDP can be misdiagnosed as suffer-
ing from idiopathic torsion dystonia, essential tremor, PD, or other forms of parkinsonism-plus syn-
drome (34,35). Neuropathologic studies demonstrate a patchy or mosaic pattern of neuronal loss and
gliosis in the striatum, with dorsal-to-ventral, rostral-to-caudal, and medial-to-lateral gradients (36).
Furthermore, gliotic changes occur in the globus pallidus and substantia nigra pars reticularis.
DYT5 is a dopa-responsive dystonia also known as autosomal dominant progressive dystonia
with marked diurnal fluctuation. This form of dystonia is caused by mutations in the guanosine triph-
osphate cyclohydrolase I gene (GTPCHI) on chromosome 14q22.1-q22.2 (37). More than 70 muta-
tions have been found in patients with DYT5. The age at onset is usually in the first decade and only
occasionally in adulthood. Dystonia in DYT5 can be focal (frequently affecting a foot) or it can be
generalized. Parkinsonian features include resting tremor, bradykinesia, rigidity, and postural insta-
bility. Parkinsonism usually occurs in adult-onset cases and at times can develop early in the course
of the disease. The most characteristic features of DYT5 include marked diurnal fluctuation and
excellent response to levodopa therapy. Some families with DYT5 can be difficult to distinguish
from kindreds with autosomal recessive juvenile parkinsonism carrying the parkin mutation PARK2.
There is considerable overlapping of clinical features between these two genetic conditions regarding
age at onset, clinical signs and symptoms, and response to dopaminergic therapy. However, the pat-
tern of inheritance is different: autosomal dominant in DYT5 and autosomal recessive in PARK2
families (38). Neuropathologic studies of DYT5 brains revealed no degenerative changes.
DYT12 has been described in only three families: two from the United States and one from Ireland
(39,40). Linkage analyses of the three families revealed a disease locus on chromosome 19q13. The
syndrome was termed rapid-onset dystonia and parkinsonism because of the acute development of
symptoms within hours (or at most a few days). The dystonia usually affects bulbar and upper limb
muscles, and the parkinsonian features include bradykinesia and postural instability. Resting tremor
and rigidity are not seen. Response to levodopa and dopamine agonists is poor. Despite the initial
rapid progression, the clinical course eventually levels off with no further deterioration. No brain
pathologic changes were seen in one autopsied case of DYT12.
A family from Switzerland with levodopa-responsive dystonia (DYT14) has also been described
(41). Linkage analysis showed a locus on chromosome 14q13 in close proximity to the GCH-1 gene.
The patients from this family developed dystonia in both legs at a mean age of 3 yr. Later in the
course of the disease, postural instability, frequent falls, and dystonia affecting the upper limbs were
also observed. In one family member, a severe akinetic rigid syndrome developed at age 73 yr. Treat-
ment with low-dose levodopa dramatically improved his symptoms. Neuropathologic studies revealed
neuronal loss in the substantia nigra without Lewy bodies.
Case 2: (Video 2, see accompanying DVD) DYT3 (XDP/Lubag Disease)
The patient was a 39-yr-old right-handed Filipino man who was born and raised in the province of
Iloilo on the Philippine island of Panay. At age 34, he noted a resting tremor of the right foot, diffi-
culty in handwriting, and intermittent hyperextension of the neck. One year later, he experienced
spontaneous jaw opening, slurring of speech, drooling, difficulty swallowing, and involuntary turn-
ing of the head to the left. By this time, he was forced to quit his profession as a dentist. By the third
year of his disorder, the patient was already severely disabled and had lost 30 pounds because of
difficulty in swallowing.
His medical history revealed no notable illness in the past. A review of the family history showed
similar symptoms in an uncle (brother of his mother), whose symptoms started during his late 30s.
On examination 3 yr after onset (at age 37), the patients dystonia was generalized in distribution
and included inversion of the right foot at rest, dorsiflexion of the toes on raising the left foot (video
2, segment A), spontaneous jaw-opening, retrocollis and torticollis (with abundant phasic move-
ments), hyperextension or arching of the back (video 2, segment B), and hyperextension and adduc-
tion of both arms on walking. As a sensory trick, the patient puts both hands in the occipital region in
order to partially alleviate the retrocollis (video 2, segment C). He also had moderate parkinsonism in
the form of hypophonic speech, reduced blinking, resting tremor of the right foot, diffuse rigidity,
bradykinesia, breakdown of rapid alternating movements on finger/hand/foot tapping and hand open-
ing/closing bilaterally, reduced arm swing, slowness in arising from a seated position, and retropul-
sion (video 2, segment D).
He received bromocriptine, diphenhydramine, tetrabenazine, reserpine, baclofen, tizanidine,
trihexyphenidyl, clonazepam, and haloperidol as monotherapy and in different combinations at maxi-
mally tolerated doses, with no change in his dystonia. Some improvement of the dystonia was
achieved with trihexyphenidyl (10 mg/d) and clonazepam (2 mg/d). Levodopa (375 mg/d) slightly
improved the resting tremor of the right foot but did not affect the bradykinesia. Levodopa was
stopped after 3 mo because of subjective worsening of his cervical dystonia. Botulinum toxin type A
injections to the neck muscles gave the best, albeit temporary, relief of his cervical dystonia but
caused considerable worsening of his dysphagia.
Familial Parkinsonism With Chorea (Huntingtons Disease)

Huntingtons disease (HD) is an adult-onset, progressive autosomal dominant neurodegenerative
disorder caused by an abnormal expansion of CAG trinucleotide repeats in a gene on chromosome 4
coding for the huntingtin protein (42). In most cases of HD, the phenotype is characterized by hyper-
kinetic movements (chorea), dementia, and personality disorder. However, phenotypic presentation
and age at onset of symptoms in HD are variable and depend on the length of the CAG repeat expan-
sion, with an inverse correlation between age at onset and the CAG repeat length (43). In addition,
patients with early onset and larger CAG repeat sizes present more often with parkinsonism, dysto-
nia, or eye movement abnormalities rather than chorea (44,45). Neuropathology in HD is character-
ized by a striking neuronal loss in the caudate and putamen, as well as a moderate neuronal loss in the
thalamus and cerebral cortex (46).
The clinical features seen in HD patients with parkinsonism, which include rigidity and bradyki-
nesia, are summarized in Table 7 (47,48). In patients with classic HD, age at onset is between 35 and
44 yr, but in those with prominent parkinsonism, onset occurs at a substantially younger age (49,50).
The parkinsonism in HD responds poorly to dopaminergic therapy. The akinetic rigid state is not
associated with chorea, but rather with dementia and seizures. This form of HD is more rapidly
progressive and is fatal within 10 yr.
A few cases of the akinetic rigid form of HD with later onset (age over 40 yr) have been reported.
Levodopa therapy can be beneficial in these late-onset akinetic rigid forms of HD (51,52). In the
terminal stages of the classic form of HD, rigidity and dystonia tend to replace chorea (53,54).
Familial Parkinsonism With Depression, Weight Loss, and Central

Hypoventilation (Perry Syndrome)
In 1975, Perry et al. (55,56) described a family presenting with parkinsonism, depression, weight
loss, and central hypoventilation. Subsequently, six other families with a similar phenotype were
identified in North America, Europe, and Asia (5762). The phenotype differs from other familial
autosomal dominant or recessive parkinsonian syndromes linked to known mutations or loci. Molecular
genetic study in these families is in progress, but the gene locus has not yet been identified. Neuro-
pathologic findings include severe neuronal loss and gliosis in the substantia nigra with few or no
Lewy bodies (5761).
Clinical Presentation
The pattern of inheritance is autosomal dominant with high penetrance. Table 8 summarizes the
clinical and pathologic features of seven kindreds described with this syndrome. The mean age at
onset is 46 yr (range, 3557). The phenotype consists of parkinsonism, weight loss, respiratory dys-
function, and depression. The parkinsonian features include a resting tremor, bradykinesia, and rigid-
ity. Depression and severe weight loss are usually seen in the early stages of the disease. Affected
individuals may die suddenly or die of respiratory failure (57,58,61). Suicide attempts also occur. The
most consistent clinical signs include parkinsonism and hypoventilation. A good response to levodopa
is seen in some but not all kindreds. The disease progression is relentless, leading to death in 28 yr.
Case 3: (Video 3, see accompanying DVD) Perry Syndrome (Fukuoka Family, Unknown
Genetic Locus)
This 43-yr-old right-handed man (61) was referred by his employer to the company physician
because of inability to perform his regular job duties. The examination performed at that time demon-
Table 7
Clinical Features Seen in Juvenile HD vs Adult-Onset HD Associated
With Parkinsonism
Adult Form of HD
Feature Juvenile HD Associated with Parkinsonism
Average age
at disease onset, yr <20 4564
Initial symptoms Parkinsonism Parkinsonism
Parkinsonism
Bradykinesia + +
Rigidity + +
Resting tremor
Postural instability + +
Response to levodopa +
Dystonia + +
Chorea +/ +/
HD, Huntingtons disease; +, present; , not present.
strated bradykinesia and depressed mood, which the patient was not aware of. When the patient was
examined in a tertiary care facility 6 mo later, the parkinsonian features noted included a masklike
facial expression, hypophonic speech, rigidity, and bradykinesia. His cognition was intact. The rigid-
ity was moderately severe and symmetrical in all four extremities, with no axial involvement noted.
His muscle strength was preserved. A mild bilateral postural hand tremor was present. Deep tendon
reflexes were symmetrical and hyperactive, especially in the lower extremities. Bilateral ankle clo-
nus was observed. Posture was stooped, gait was slow, and arm swing was reduced bilaterally. Pos-
tural stability was preserved. No sensory, cerebellar, or lower motor deficits were present. Therapy
with carbidopa-levodopa was initiated, with mild improvement initially. However, his health deterio-
rated. He lost 10 kg over the next 2 mo and began to require assistance in all activities of daily living.
Six months later, he was admitted to a psychiatric hospital for treatment of anxiety, nighttime dysp-
nea, and progressive weight loss. Discontinuation of the carbidopa-levodopa resulted the next day in
confusion and exacerbation of his tremor, akinesia, and rigidity. Prompt reinstatement of carbidopa-
levodopa therapy led to resolution of the confusion and improvement of the parkinsonism.
Clinical examination of the patient revealed a weight of 37 kg and notable tachypnea (30 breaths/
min). Orientation was intact, but calculation skills and immediate recall were impaired. Extraocular
movements were preserved. The parkinsonism was considerably more pronounced than it had been
14 mo earlier (video 3, segment A). The rigidity was present in both axial and appendicular muscles.
The patient was also more bradykinetic, and striking postural instability was noted (video 3, segment
B). A severe postural and resting tremor affecting all four extremities was seen. Bilateral ankle clo-
nus and a right Babinski sign were present.
Chest radiography, chest computed tomography, and pulmonary function tests were normal.
Polysomnography showed an apnea index of 6.96. The arterial blood gases measured on room air
showed a PCO2 of 47 mmHg and PO2 of 85.2 mmHg. A repeat arterial blood gas measurement made
1 mo later showed further deterioration, with a PCO2 of 51 mmHg. Two days later, PCO2 increased to
61 mmHg, necessitating ventilator support. Repeat polysomnography demonstrated irregular breathing
and central hypoventilation with hypoxia. At the time of writing, the patient was 47 yr old, severely
disabled, and in need of assisted breathing support and total nursing care. He was also depressed and
receiving antidepressant therapy. His parkinsonism was severe and not responsive to carbidopa-
levodopa.
386
Table 8
Characteristic Clinical and Pathologic Features of Families With Parkinsonism, Depression, Weight Loss, and Central Hypoventilation
(Perry Syndrome)
Published Reports
Perry et al.,
1975 (55);
Perry et al., Purdy et al., Roy et al., Lechevalier et al., Bhatia et al., Tsuboi et al., Elibol et al.,
Feature 1990 (56) 1979 (57) 1988 (58) 1992 (59) 1993 (60) 2002 (61) 2002 (62)
Residence Canada Canada USA France UK Japan Turkey
No. of affected 8 5 6 5 8 6 3
individuals
Mean age at onset, y (range) 48 (4252) 46 51 (4557) 52 (4557) 35, 43 41 (3843) Proband 46/M
Sister 49/F
Disease duration, y (range) 5 (46) 2, 3 3 (34) 7 (68) 3, 4 6 3, 5
Initial signs D, WL D, WL P, D P, D P P, D Apathy, P
Clinical features
P + + + + + + +
D + + + + + +
WL + + + + + +
HV + + + + + +
Resp. to L-dopa + + + + +
Outcome 1 suicide 1 sudden death 3 sudden deaths 2 deaths owing 1 sudden death 1 suicide 1 sudden death
to respiratory
failure
Pathologic features
Cell loss SN SN, caudate, SN, locus SN, dorsal SN, locus SN, locus NA
globus pallidus, ceruleus medullary nuclei ceruleus ceruleus
pons, medulla
Lewy bodies Few Few No No 2 in SN, 1 in bnM No NA
bnM, basal nucleus of Meynert; D, depression; HV, hypoventilation; LB, Lewy body; NA, not available; P, parkinsonism; Resp., response; SN, substantia nigra; WL,
weight loss; +, present; , not present.
Tsuboi, Evidente, and Wszolek
Familial Parkinsonism Owing to a Defect in Copper Metabolism

(Wilsons Disease)
Wilsons disease (WD) is an autosomal recessive disorder in which copper metabolism is impaired.
The causative WD gene, known as ATP7B, is located on chromosome 13q14-q21 and is involved in
the copper-transporting P-type adenosine triphosphatase interaction between copper and ceruloplas-
min (6365). More than 200 mutations have been found in this gene, and WD occurs worldwide. It is
a progressive disorder with a variable age at onset, ranging from 7 to 58 yr. The initial symptoms can
be hepatic, behavioral, or neurological (66). Most patients exhibit intracorneal pigmentation (Kayser
Fleischer ring) at the initial presentation (67). Neurological symptoms include various combinations
of resting tremor, intention tremor, dysarthria, unsteady gait, dystonia, bradykinesia, and rigidity
(68). On neuropathologic examination, the most striking changes, consisting of pigmentation and
spongy degeneration, are seen in the basal ganglia. Microscopically, the basal ganglia exhibit neuronal
loss as well as abundant protoplasmic astrocytes, including giant cells called Alzheimer cells (69).
Tremor and rigidity are the most common parkinsonian manifestations of WD (70). Throughout
the course of the illness, the tremor may be unilateral and present only at rest, and it may be indistin-
guishable from PD tremor. In the advanced stages of WD, some patients develop a wing-beating
type of tremor. Rigidity is frequently present, together with dystonia. A fixed open mouth and drool-
ing are common. If no treatment is administered, the disease is relentlessly progressive (68).
Familial Parkinsonism With Iron Metabolism Deficiency (Neurodegeneration

With Brain Iron Accumulation, HallervordenSpatz Syndrome)
Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of disorders
with sporadic and familial forms. This syndrome was previously known as HallervordenSpatz dis-
ease. It typically begins in childhood with extrapyramidal features, including chorea, rigidity, and
dystonia. In addition, pyramidal signs, progressive dementia, and, less commonly, retinitis
pigmentosa and seizures are also seen (71,72). Some familial cases present with late-onset parkin-
sonism that can occasionally be responsive to levodopa (73,74).
The molecular genetic study of an Amish family with NBIA demonstrated linkage to a locus on
chromosome 20p12.3-p13 (75). More recently, a mutation in the coding sequence of a pantothenate
kinase gene called PANK2 was found in this family (76). Additional missense and null mutations
have been identified in other familial forms of NBIA (77). The term PKAN (pantothenate kinase
associated neurodegeneration) means a defect of the gene PANK2 leading to a deficiency of the
enzyme pantothenate kinase. Interestingly, missense mutations in PANK2 were identified in indi-
viduals with atypical PKAN. There are also families with NBIA with no linkage to the PANK2 locus
(7779), suggesting the existence of another chromosomal locus for this disorder. Clinical features
similar to NBIA were seen in families with neuroferritinopathy who had mutations in the ferritin
light chain (78) and in families with aceruloplasminemia who had mutations in the gene encoding for
ceruloplasmin (79). A striking rust-brown pigmentation is seen in the globus pallidus and substantia
nigra pars reticulata (80). In these structures, many axonal spheroids are seen. The presence of Lewy
bodies and neurofibrillary tangles was also reported in NBIA (81,82).
NBIA is characterized by extrapyramidal features, including rigidity and dystonia. Age at onset in
familial forms is usually in the first or second decade. However, a later onset has also been reported
(73,74). Rigidity usually starts first in the lower extremities but later affects the upper extremities as well.
Involuntary choreoathetoid movements sometimes precede or accompany rigidity. Orobuccolingual
rigidity may be a presenting feature and can lead to difficulties in articulation and swallowing. Pyrami-
dal tract involvement is common. Cognitive dysfunction and epilepsy occur rarely (71).
Familial Parkinsonism With Mitochondrial Abnormality

Increasingly, mitochondrial dysfunction (particularly of complex I) has been recognized to play
an important role in the pathogenesis of PD. Complex I activity is decreased in the substantia nigra of
PD patients compared to normal controls (83). Similarly, cytoplasmic hybrid (cybrid) cell lines
expressing mitochondrial DNA (mtDNA) from the platelets of PD patients have impaired complex
I activity compared to platelets of normal controls (84,85). 1-Methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) or rotenone may produce PD in animal models by inhibiting complex I
mitochondrial activity. These data suggest that mitochondrial dysfunction plays an important role in
the pathogenesis of PD. In addition, mtDNA dysfunction has been identified in two large PD families
with a maternal mode of inheritance (86,87).
In the first family with maternally inherited PD, in which three generations were studied, cybrid
cell line cultures demonstrated decreased complex I activity (86). The average age at onset was 42 yr
(range, 4179 yr). The phenotype resembled classic PD, with a resting tremor, bradykinesia, and
rigidity. A good response to levodopa was observed. So far, no specific mutation has been identi-
fied in this family. The second family had a mixed phenotype resembling adult-onset multisystem
degeneration. The clinical features included levodopa-responsive parkinsonism, dementia, dysto-
nia, extraocular movement abnormalities, and pyramidal signs. A missense mtDNA mutation in
the gene for the nicotinamide dehydrogenase 4 (ND4) subunit of complex I was identified in this
family (87). One case was autopsied, showing loss of pigmented neurons in the substantia nigra and
absence of Lewy bodies.
GENETIC TESTING FOR ATYPICAL PARKINSONIAN DISORDERS

Recent discoveries on chromosomal loci and mutations in familial neurodegenerative conditions
have expanded our knowledge about the basic cellular mechanisms involved in neurodegeneration.
These have provided us with the option of genetic testing to establish a more precise diagnosis in
symptomatic individuals with or without an obvious family history. Presymptomatic (predictive) and
prenatal diagnosis are possible for several movement disorders, including some of those discussed
here, although a detailed discussion of molecular genetic testing is beyond the scope of this chapter.
A recent review on this subject was published by the Movement Disorders Society Task Force on
Molecular Diagnosis (88). Molecular genetic testing can be readily performed in affected individuals
presenting with parkinsonism with ataxia (SCA2 and SCA3), dystonia (DYT1), and chorea (HD).
The genetic tests for these conditions are commercially available. Appropriate genetic counseling
can be provided by a neurologist requesting such tests. However, presymptomatic and prenatal molecu-
lar testing, if requested by family members, should be performed by experienced personnel in special-
ized genetic centers. Clinical geneticists can also help locate laboratories where molecular genetic
testing can be performed for parkinsonian patients in whom known mutations are suspected. Testing
for such mutations is currently performed only on an experimental basis.
SUMMARY
Our knowledge of familial atypical parkinsonian disorders has increased greatly over the past
decade. Families with unique phenotypes have been newly discovered, and the molecular basis for
some of these phenotypes has been established. These molecular genetic discoveries allow us to
make more precise clinical diagnoses of several neurodegenerative conditions, including HD, SCA,
and dystonia. Future discoveries using transgenic animal models can be expected to lead to a better
classification of these disorders and to the development of improved treatments (and cures).
The refinement of molecular genetic techniques and a growing interest in the genetics of parkin-
sonism will undoubtedly lead to improved characterization and classification of familial atypical
parkinsonian syndromes. It is hoped that a classification based on genotype (rather than phenotype
alone) will lead to earlier and more accurate diagnoses and more timely and appropriate genetic
counseling. Differentiating atypical parkinsonism from idiopathic PD is important because prognosis
for each of these conditions varies. There is also a need to develop clinical and pathological criteria
for atypical parkinsonian conditions. If specific disease biomarkers are identified, they can further
improve accuracy of diagnosis, even in the early or presymptomatic stages.
Probands and families may be interested in genetic counseling; thus, appropriate referral needs to
be arranged by the treating neurologist. Genetic testing is already commercially available for some of
the atypical parkinsonian disorders and undoubtedly more diagnostic tests will become available in
the near future. Treatment for these rare conditions is still supportive in nature. It is hoped that better
symptomatic and curative therapies will eventually be developed. This will require a multifaceted
approach involving molecular genetics, transgenic animal models, cell biology, and a deeper under-
standing of the underlying pathologic features in each of these disorders.
DIRECTIONS FOR FUTURE RESEARCH

Better clinical and pathological characterization
Establishment of clinical and pathological diagnostic criteria
Search for biomarkers that will facilitate earlier diagnosis
Development of commercially available genetic testing
Development of better symptomatic and curative therapies
REFERENCES
1. Calne DB, Snow BJ, Lee C. Criteria for diagnosing Parkinsons disease. Ann Neurol 1992;32(Suppl):S125127.
2. Jankovic J. Parkinsonism-plus syndromes. Mov Disord 1989;4(Suppl 1): S95S119.
linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 1997;41:706715.
4. Pickering-Brown S, Baker M, Yen SH, et al. Picks disease is associated with mutations in the tau gene. Ann Neurol
2000;48:859867.
5. Lanska DJ, Currier RD, Cohen M, et al. Familial progressive subcortical gliosis. Neurology 1994;44:16331643.
6. Sumi SM, Bird TD, Nochlin D, Raskind MA. Familial presenile dementia with psychosis associated with cortical
neurofibrillary tangles and degeneration of the amygdala. Neurology 1992;42:120127.
7. Wszolek ZK, Pfeiffer RF, Bhatt MH, et al. Rapidly progressive autosomal dominant parkinsonism and dementia with
pallido-ponto-nigral degeneration. Ann Neurol 1992;32:312320.
8. Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B. Familial multiple system tauopathy
with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA 1997;94:
41134118.
9. Lynch T, Sano M, Marder KS, et al. Clinical characteristics of a family with chromosome 17-linked disinhibition-
dementia-parkinsonism-amyotrophy complex. Neurology 1994;44:18781884.
10. Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited
11. Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann
Neurol 1998;43:815825.
system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:77377741.
13. Wszolek ZK, Tsuboi Y, Farrer M, Uitti RJ, Hutton ML. Hereditary tauopathies and parkinsonism. Adv Neurol
2003;91:153163.
14. Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22:89107.
15. Tsuboi Y, Baker M, Hutton ML, et al. Clinical and genetic studies of families with the tau N279K mutation (FTDP-17).
Neurology 2002;59:17911793.
16. Ghetti B, Hutton M, Wszolek ZK. Frontotemporal dementia and parkinsonism linked to chromosome 17 associated
with tau gene mutations (FTDP-17T). In: Dickson D, ed. Neurodegeneration: The Molecular Pathology of Dementia
and Movement Disorders. Basel: International Society of Neuropathology Press, 2003:86102.
17. Basun H, Almkvist O, Axelman K, et al. Clinical characteristics of a chromosome 17-linked rapidly progressive famil-
ial frontotemporal dementia. Arch Neurol 1997;54:539544.
18. Lendon CL, Lynch T, Norton J, et al. Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to
17q21-22. Neurology 1998;50:15461555.
19. Heutink P, Stevens M, Rizzu P, et al. Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a
genetic and clinicopathological study of three Dutch families. Ann Neurol 1997;41:150159.
20. Rademakers R, Cruts M, Dermaut B, et al. Tau negative frontal lobe dementia at 17q21: significant finemapping of the
candidate region to a 4.8 cM interval. Mol Psychiatry 2002;7:10641074.
21. Froelich S, Basun H, Forsell C, et al. Mapping of a disease locus for familial rapidly progressive frontotemporal de-
mentia to chromosome 17q12-21. Am J Med Genet 1997;74:380385.
22. Wszolek ZK, Tsuboi Y, Uitti RJ, Reed L. Two brothers with frontotemporal dementia and parkinsonism with an N279K
mutation of the tau gene. Neurology 2000;55:1939.
23. Tsuboi Y, Uitti RJ, Delisle MB, et al. Clinical features and disease haplotypes of individuals with the N279K tau
gene mutation: a comparison of the pallidopontonigral degeneration kindred and a French family. Arch Neurol
2002;59:943950.
24. Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of
11 families, including descendants of the Drew family of Walworth. Brain 1982;105:128.
25. Schols L, Peters S, Szymanski S, et al. Extrapyramidal motor signs in degenerative ataxias. Arch Neurol 2000;57:
14951500.
26. Jardim LB, Pereira ML, Silveira I, Ferro A, Sequeiros J, Giugliani R. Neurologic findings in MachadoJoseph disease:
relation with disease duration, subtypes, and (CAG)n. Arch Neurol 2001;58:899904.
27. Gwinn-Hardy K, Chen JY, Liu HC, et al. Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese. Neurology
2000;55:800805.
28. Shan DE, Soong BW, Sun CM, Lee SJ, Liao KK, Liu RS. Spinocerebellar ataxia type 2 presenting as familial levodopa-
responsive parkinsonism. Ann Neurol 2001;50:812815.
29. Furtado S, Farrer M, Tsuboi Y, et al. SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET
findings. Neurology 2002;59:16251627.
30. Lu CS, Wu Chou YH, Yen TC, Tsai CH, Chen RS, Chang HC. Dopa-responsive parkinsonism phenotype of spinocer-
ebellar ataxia type 2. Mov Disord 2002;17:10461051.
31. Gwinn-Hardy K, Singleton A, OSuilleabhain P, et al. Spinocerebellar ataxia type 3 phenotypically resembling
Parkinson disease in a black family. Arch Neurol 2001;58:296299.
32. Subramony SH, Hernandez D, Adam A, et al. Ethnic differences in the expression of neurodegenerative disease:
MachadoJoseph disease in Africans and Caucasians. Mov Disord 2002;17:10681071.
33. Fahn S, Marsden CD, Calne DB. Classification and investigation of dystonia. In: Marsden CD, Fahn S, eds. Movement
Disorders 2. London: Butterworths, 1987:332358.
34. Evidente VG, Advincula J, Esteban R, et al. Phenomenology of Lubag or X-linked dystonia-parkinsonism. Mov
Disord 2002;17:12711277.
35. Evidente VG, Gwinn-Hardy K, Hardy J, Hernandez D, Singleton A. X-linked dystonia (Lubag) presenting predomi-
nantly with parkinsonism: a more benign phenotype? Mov Disord 2002;17:200202.
36. Evidente VGH, Dickson D, Singleton A, Natividad F, Hardy D. Novel neuropathological findings in Lubag or X-linked
dystonia-parkinsonism (abstract). Mov Disord 2002;17(Suppl 5):S294.
37. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by
mutations in the GTP cyclohydrolase I gene. Nat Genet 1994;8:236242.
38. Tassin J, Durr A, Bonnet AM, et al. Levodopa-responsive dystonia: GTP cyclohydrolase I or parkin mutations? Brain
2000;123:11121121.
39. Kramer PL, Mineta M, Klein C, et al. Rapid-onset dystonia-parkinsonism: linkage to chromosome 19q13. Ann Neurol
1999;46:176182.
40. Pittock SJ, Joyce C, OKeane V, et al. Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new
kindred. Neurology 2000;55:991995.
41. Grotzsch H, Pizzolato GP, Ghika J, et al. Neuropathology of a case of dopa-responsive dystonia associated with a new
genetic locus, DYT14. Neurology 2002;58:18391842.
42. The Huntingtons Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is
expanded and unstable on Huntingtons disease chromosomes. Cell 1993;72:971983.
43. Rubinsztein DC, Leggo J, Chiano M, et al. Genotypes at the GluR6 kainate receptor locus are associated with variation
in the age of onset of Huntington disease. Proc Natl Acad Sci USA 1997;94:38723876.
44. Squitieri F, Berardelli A, Nargi E, et al. Atypical movement disorders in the early stages of Huntingtons disease:
clinical and genetic analysis. Clin Genet 2000;58:5056.
45. Louis ED, Anderson KE, Moskowitz C, Thorne DZ, Marder K. Dystonia-predominant adult-onset Huntington disease:
association between motor phenotype and age of onset in adults. Arch Neurol 2000;57:13261330.
46. de la Monte SM, Vonsattel JP, Richardson EP Jr. Morphometric demonstration of atrophic changes in the cerebral
cortex, white matter, and neostriatum in Huntingtons disease. J Neuropathol Exp Neurol 1988;47:516525.
47. Campbell AMG, Corner BD, Norman RM, Urich H. The rigid form of Huntingtons disease. J Neurol Neurosurg
Psychiatry 1961;24:7177.
48. van Dijk JG, van der Velde EA, Roos RA, Bruyn GW. Juvenile Huntington disease. Hum Genet 1986;73:235239.
49. Bittenbender JB, Quadfasel FA. Rigid and akinetic forms of Huntingtons chorea. Arch Neurol 1962;7:3750.
50. Roos RA, Vegter-van der Vlis M, Hermans J, et al. Age at onset in Huntingtons disease: effect of line of inheritance
and patients sex. J Med Genet 1991;28:515519.
51. Racette BA, Perlmutter JS. Levodopa responsive parkinsonism in an adult with Huntingtons disease. J Neurol
52. Reuter I, Hu MT, Andrews TC, Brooks DJ, Clough C, Chandhuri KR. Late onset levodopa responsive Huntingtons
disease with minimal chorea masquerading as Parkinson plus syndrome. J Neurol Neurosurg Psychiatry 2000;68:
238241.
53. Thompson PD, Berardelli A, Rothwell JC, et al. The coexistence of bradykinesia and chorea in Huntingtons disease
and its implications for theories of basal ganglia control of movement. Brain 1988;111:223244.
54. Garcia Ruiz PJ, Gomez Tortosa E, Sanchez Bernados V, Rojo A, Fontan A, Garcia de Yebenes J. Bradykinesia in
Huntingtons disease. Clin Neuropharmacol 2000;23:5052.
55. Perry TL, Bratty PJ, Hansen S, Kennedy J, Urquhart N, Dolman CL. Hereditary mental depression and Parkinsonism
with taurine deficiency. Arch Neurol 1975;32:108113.
56. Perry TL, Wright JM, Berry K, Hansen S, Perry TL Jr. Dominantly inherited apathy, central hypoventilation, and
Parkinsons syndrome: clinical, biochemical, and neuropathologic studies of 2 new cases. Neurology 1990;40:18821887.
57. Purdy A, Hahn A, Barnett HJ, et al. Familial fatal Parkinsonism with alveolar hypoventilation and mental depression.
Ann Neurol 1979;6:523531.
58. Roy EP III, Riggs JE, Martin JD, Ringel RA, Gutmann L. Familial parkinsonism, apathy, weight loss, and central
hypoventilation: successful long-term management. Neurology 1988;38:637639.
59. Lechevalier B, Schupp C, Fallet-Bianco C, et al. Familial parkinsonian syndrome with athymhormia and hypoventilation
[French]. Rev Neurol (Paris) 1992;148:3946.
60. Bhatia KP, Daniel SE, Marsden CD. Familial parkinsonism with depression: a clinicopathological study. Ann Neurol
1993;34:842847.
61. Tsuboi Y, Wszolek ZK, Kusuhara T, Doh-ura K, Yamada T. Japanese family with parkinsonism, depression, weight
loss, and central hypoventilation. Neurology 2002;58:10251030.
62. Elibol B, Kobayashi T, Atac FB, et al. Familial parkinsonism with apathy, depression and central hypoventilation
(Perrys syndrome). In: Mizuno Y, Fisher A, Hanin I, eds. Mapping the progress of Alzheimers and Parkinsons
disease. New York: Kluwer Academic/Plenum Publishers, 2002:285290.
63. Bowcock AM, Farrer LA, Hebert JM, et al. Eight closely linked loci place the Wilson disease locus within 13q14-q21.
Am J Hum Genet 1988;43:664674.
64. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting
P-type ATPase similar to the Menkes gene. Nat Genet 1993;5:327337.
65. Tanzi RE, Petrukhin K, Chernove I, et al. The Wilson disease gene is a copper transporting ATPase with homology to
the Menkes disease gene. Nat Genet 1993;5:344350.
66. Gow PJ, Smallwood RA, Angus PW, Smith AL, Wall AJ, Sewell RB. Diagnosis of Wilsons disease: an experience
over three decades. Gut 2000;46:415419.
67. Arima M, Takeshita K, Yoshino K, Kitahara T, Suzuki Y. Prognosis of Wilsons disease in childhood. Eur J Pediatr
1977;126:147154.
68. Menkes JH. Wilson disease. In: Pulst S-M, ed. Genetics of Movement Disorders. Amsterdam: Academic Press,
2003:341352.
69. Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver.
Brain 1912;34:295509.
70. Lingam S, Wilson J, Nazer H, Mowat AP. Neurological abnormalities in Wilsons disease are reversible.
Neuropediatrics 1987;18:1112.
71. Dooling EC, Schoene WC, Richardson EP Jr. HallervordenSpatz syndrome. Arch Neurol 1974;30:7083.
72. Swaiman KF. HallervordenSpatz syndrome. Pediatr Neurol 2001;25:102108.
73. Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED. Late-onset HallervordenSpatz disease presenting as
familial parkinsonism. Neurology 1985;35:227234.
74. Alberca R, Rafel E, Chinchon I, Vadillo J, Navarro A. Late onset parkinsonian syndrome in HallervordenSpatz dis-
ease. J Neurol Neurosurg Psychiatry 1987;50:16651668.
75. Taylor TD, Litt M, Kramer P, et al. Homozygosity mapping of HallervordenSpatz syndrome to chromosome 20p12.3-
p13. Nat Genet 1996;14:479481.
76. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2)
is defective in HallervordenSpatz syndrome. Nat Genet 2001;28:345349.
77. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of HallervordenSpatz
syndrome. N Engl J Med 2003;348:3340.
78. Curtis AR, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-
onset basal ganglia disease. Nat Genet 2001;28:350354.
79. Gitlin JD. Aceruloplasminemia. Pediatr Res 1998;44:271276.
80. Hallervorden J, Spatz H. Eigenartige erkrankung im extrapyramidalen system mit besonderer beteiligung des globus
pallidus und der substantia nigra. Z Gesamte Neurol Psychiatrie 1922:79:254302.
81. Wakabayashi K, Yoshimoto M, Fukushima T, et al. Widespread occurrence of alpha-synuclein/NACP-immunoreactive
neuronal inclusions in juvenile and adult-onset HallervordenSpatz disease with Lewy bodies. Neuropathol Appl
Neurobiol 1999;25:363368.
82. Wakabayashi K, Fukushima T, Koide R, et al. Juvenile-onset generalized neuroaxonal dystrophy (HallervordenSpatz
disease) with diffuse neurofibrillary and Lewy body pathology. Acta Neuropathol (Berl) 2000;99:331336.
83. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in
Parkinsons disease. Neurochemistry 1990;54:823827.
84. Swerdlow RH, Parks JK, Miller SW, et al. Origin and functional consequences of the complex I defect in Parkinsons
disease. Ann Neurol 1996;40:663671.
85. Gu M, Cooper JM, Taanman JW, Schapira AH. Mitochondrial DNA transmission of the mitochondrial defect in
86. Swerdlow RH, Parks JK, Davis JN II, et al. Matrilineal inheritance of complex I dysfunction in a multigenerational
Parkinsons disease family. Ann Neurol 1998;44:873881.
87. Simon DK, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkin-
sonism associated with the 11778 mitochondrial DNA mutation. Neurology 1999;53:17871793.
88. Gasser T, Bressman S, Drr A, Higgins J, Klockgether T, Myers RH. Molecular diagnosis of inherited movement
disorders: Movement Disorders Society Task Force on Molecular Diagnosis. Mov Disord 2003;18:318.
Clinical Diagnosis of Vascular Parkinsonism 393
23
Clinical Diagnosis of Vascular Parkinsonism
and Nondegenerative Atypical Parkinsonian Disorders
Madhavi Thomas and Joseph Jankovic
Idiopathic Parkinsons disease (PD) is the most common cause of parkinsonism, accounting for
about 75% of all cases. Other causes of parkinsonism include multiple system atrophy (MSA), pro-
gressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and a variety of other
neurodegenerative disorders in which rest tremor, bradykinesia, rigidity, and other parkinsonian fea-
tures are present. Since these disorders are often associated with other neurological deficits, such as
dysautonomia (in MSA), vertical ophthalmoparesis (in PSP), and apraxia (in CBD), they are referred
to as parkinsonism plus syndromes. Whereas the above disorders are degenerative in nature, there
are other forms of parkinsonism, which are secondary to a variety of etiologic factors including
vascular parkinsonism (VP), hemiatrophy hemiparkinsonism, and toxic and metabolic causes.
It is important to review the cardinal features of PD that form the basis for diagnosis of parkin-
sonism. Cardinal motor features of PD are tremor, rigidity, bradykinesia, and postural instability. While
these may occur in idiopathic PD, the atypical parkinsonian sydromes have a combination of these
features in addition to the clinical features typical for each specific disorder. Proposed diagnostic crite-
ria for PD include definite, probable, and possible PD and all of these require sustained response to
levodopa (1). Although it is difficult to apply uniform diagnostic criteria to all the atypical parkinsonian
syndromes, most of them share a common feature of poor or no response to levodopa. In this review we
will discuss VP, and a variety of nondegenerative atypical parkinsonian syndromes (Table 1).
VP, also known as arteriosclerotic parkinsonism, multi-infarct parkinsonism, and lower body
parkinsonism, can result from lacunar infarctions, leukoaraiosis, and Binswangers disease. In 1929,
Critchley (2) described arteriosclerotic parkinsonism characterized by rigidity, pseudobulbar affect,
dementia, incontinence, and short stepped gait in an elderly hypertensive individual with multiple
ischemic insults in the basal ganglia. Zijlman et al. (3) in their report of clinico-pathological findings
of VP showed the variability of clinical presentation of VP both clinically and pathologically. Based
on the clinical evolution of symptoms in 17 patients in this clinico-pathological study, the following
criteria for VP were proposed: parkinsonism in the presence of cerebrovascular disease, a relation-
ship between the above two features, and (a) acute or delayed progressive onset with infarcts in or
near areas that can increase basal ganglia output, or decrease the thalamocortical drive directly result-
ing in contralateral bradykinetic rigid syndrome termed Vpa, and (b) in the case of insiduous onset of
parkinsonism with extensive subcortical white matter lesions, bilateral symptoms at onset, and the
presence of early shuffling gait, or early cognitive dysfunction, termed Vpi (3). These patients with
parkinsonism had atrophic gyri, ventricular dilatation, and major-artery atheroma on autopsy. There

393
394 Thomas and Jankovic
was extensive small vessel disease in the globus pallidus, caudate, putamen, and thalamus in the
parkinsonian brains, and nigral cell loss was present in four patients. Microscopic pathology included
gliosis, perivascular myelin pallor, hyaline thickening of arteriolar walls, and enlargement of perivas-
cular spaces, along with macroscopically visible infarcts in the basal ganglia in those patients with
VP. In all the 17 patients the pathologically examined frontal, temporal, parietal, occipital, and stri-
atal areas were equally affected by the small-vessel disease pathology (3). This study clearly demon-
strates the pattern of pathology and variability of clinical findings in patients with VP. Clinical
features are variable as shown in this study based on the onset of disease, resulting in a contralateral
bradykinetic syndrome in the case of acute or delayed progressive onset, and a bilateral involvement
in the case of insidious onset of VP. Three out of the 100 patients clinically diagnosed as PD had VP
in the London Brain Bank study, showing that VP can very closely resemble PD (4). Thompson and
Marsden described parkinsonian features in a series of patients with Binswanger disease (5).
Binswangers disease is a form of leukoencephalopathy that is mainly a result of hypoxic-ischemic
lesions in the distal watershed periventricular areas, associated with aging, hyperviscocity, and increased
fibrinogen levels, and has been reported to be associated with VP (57). Based on a review of published
series, VP can be defined as a syndrome resulting in short stepped gait, rigidity, with or without
dementia, predominant lower body involvement in the absence of tremor, and poor levodopa respon-
siveness. Some patients also exhibit incontinence, pseudobulbar affect, and freezing of gait (811).
VP can be clinically classified into three subgroups: (a) possible VP in patients who exhibit atypi-
cal parkinsonism and have a history of stroke and show vascular changes on their brain magnetic
resonance imaging (MRI), (b) probable VP in patients with onset of parkinsonism within less than
1 mo after acute stroke supported by evidence of a multi-infarct state on brain MRI, and (c) defi-
nite VP, which is characterized clinically as possible or probable VP but at autopsy there is ischemic
or hemorrhagic damage in the basal ganglia without any evidence of idiopathic PD, such the presence
of Lewy bodies (11). There are several clinical presentations of stroke-related parkinsonism, includ-
ing a syndrome indistinguishable from idiopathic PD, vascular PSP with clinical features similar to
those in idiopathic PSP (12,13), lower body parkinsonism (14), and parkinsonian gait disorders
(11,1517).
As there were no previously established clinical criteria for VP, Winikates and Jankovic proposed
a vascular rating scale for VP designed to establish diagnostic level of certainty (11,13). Parkin-
sonism was defined as presence of at least two of the four cardinal signs of tremor at rest, bradykine-
sia, rigidity, and loss of postural reflexes. The vascular rating scale has scores ranging from 0 to 6
based on pathological, historical, and neuroimaging evidence of vascular disease. Two points were
given for pathologically or angiographically proven diffuse vascular disease, one point for pathologi-
cal evidence of both vascular and neurodegenerative changes, one point for onset of symptoms within
1 mo of a clinical stroke, a history of two or more strokes, a history of two or more risk factors for
stroke, and neuroimaging evidence of diffuse vascular disease or vascular disease in two or more
vascular territories. When a vascular score of 2 or higher was used as a designation of VP such
patients could be clearly differentiated from idiopathic PD (11,12). Zijlmans et al. (3) also proposed
clinical criteria that include a differentiation between the unilateral and bilateral forms of VP.
Clinical features of patients with VP include older age at onset, male preponderance, higher fre-
quency of dementia, and, as expected, vascular risk factors. About 25% of these patients may present
with VP within a month after a stroke. Patients with VP typically present with gait difficulty and
during the course have predominant lower body involvement, postural instability, history of falls,
dementia, corticospinal findings, incontinence, pseudobulbar affect, and they are less likely to respond
to levodopa (8,10,11). Patients with severe subcortical ischemia (as evidenced by MRI) tend to have
more gait difficulties (4). In patients with lower body parkinsonism associated with VP, the upper
body function is typically preserved. Some patients mainly have gait difficulties with and without
freezing, mostly seen with multiple lacunar infarcts (11,12). Quantitative gait analysis in 12 patients
with PD, 12 with VP, and 10 controls showed that patients with VP had relatively well-preserved
armswing, with anterior rotation of the shoulders (17). Patients with VP were found to have more
postural abnormalities on postural stability testing leading to balance problems on dynamic
posturography testing (18). Patients with VP have less flexion posture of the elbow, hip, knee, and
trunk than patients with idiopathic PD. Larger studies using specific gait instruments, such as the
Gait and Balance Scale (GABS) (19), and other gait and balance analyses may help find other pat-
terns of gait and balance abnormalities with high sensitivity and specificity for VP.
In addition to Binswangers disease that has been associated with elevated fibrinogen levels, some
VPs have been found to have high titers of anticardiolipin antibodies (ACLAs) (20). In a study of
44 individuals with VP, 9 of the 22 tested (40.9%) patients had positive ACLA. Further studies are
needed to document the exact incidence of ACLAs in patients with VP. Patients with cerebral autoso-
mal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can some-
times present with parkinsonism. In the original descriptions patients had recurrent strokes,
pseudobulbar palsy, and dementia. The abnormality on genetic linkage analysis was localized to
chromosome 19q12, and the mutation in Notch-3 gene was subsequently identified (21). In autopsied
brains, patients with CADASIL have changes in the vessel wall similar to those seen in polyarteritis
nodosa, manifested by eosinophilic granularity or fibrinoid necrosis of the tunica media coupled with
basophilic granular degeneration of the media (22).
Elevated homocysteine levels have been also associated with ischemic events resulting in VP, but
this abnormality has been attributed to levodopa therapy (23,24). In one study, patients treated with
levodopa had a significant increase in plasma homocysteine levels compared to the levodopa-naive
patients, and patients with homocysteine levels in the higher quartile had increased risk of coronary
artery disease (relative risk 1.75) (24). Although there is no evidence that stroke or coronary artery
disease are any more frequent in PD patients than in individuals without PD, high homocysteine
levels may increase the risk of dementia associated with PD.
Once VP is clinically suspected MRI scan of the brain must be performed to confirm the presences
of subcortical ischemic changes on T1 and T2 images in the basal ganglia and white matter. As
expected, in patients with VP the number and intensity of MRI lesions is greater (10,25). Although
some authors have not been able to correlate asymmetric lesions with the side of symptoms in
patients with VP and PD (16,26), Chang et al. (27) showed that most patients with VP had MRI
correlates of ischemic changes. In their series of 11 patients they found common clinical features of
akinesia, rigidity, shuffling gait, reduced armswing, hesitation while turning, very similar to PD, but
these patients had more upright posture, more wide-based stance, and did not exhibit festination.
They have identified three patterns of ischemia on computed tomography (CT) or MRI including
frontal lobe, deep subcortical, and basal ganglia infarction associated with steady progression. They
report that patients with specific basal ganglia lacunar infarcts had a better prognosis with resolution
of PD symptoms, whereas those with frontal lobe infarction had a static course, and those with deep
subcortical infarcts not specifically confined to the basal ganglia had a progressive course. Autopsy
on one of their patients confirmed a multi-infarct state without any evidence of Lewy bodies (27).
Using functional imaging, such as 123I- G-CIT SPECT (single photon emission computed tomogra-
phy) and TRODAT-1 scanning, may further enhance the diagnosis of VP (28,29). TRODAT-1 is a
cocaine analog that can bind to the presynaptic dopamine transporter and has been found to be useful
in differentiating VP from PD. A significant reduction of the uptake was more pronounced in the
contralateral putamen of patients idiopathic PD than that in patients with VP (28). Proton MR spec-
troscopy shows preservation of dopaminergic neurons in VP (30). Tohgi et al. (31) have shown nar-
rowing of the width of SNc in patients who have both PD and vascular changes, but those with VP
have normal width of SNc on the MRI brain. In a small study including 13 patients, EEG
(electroencephelogram) slowing was less in those with VP compared to patients with PD (32), but
this observation needs to be confirmed in a larger group of patients.
A small proportion (up to 50%) of patients with VP respond to levodopa, the first line of therapy
in this population (5,14,16,33). Demikiran et al. (16) have also shown that 38% of patients with VP
have a response to levodopa therapy. Depending on the identification of stroke risk factors patients
should be started on antiplatelet therapy, or anticoagulation in those with atrial fibrillation and valvu-
lar heart disease with high risk of embolization. Occasionally, symptoms of VP may transiently
improve with CSF (cerebrospinal fluid) drainage similar to that seen in Normal Pressure Hydro-
cephalus (NPH) (34). This improvement, however, is rarely sustained and is not predictive of re-
sponse to CSF shunting.
PARKINSONISM OWING TO TOXIN EXPOSURE

Several studies have explored the role of various environmental causes of parkinsonism, espe-
cially exposure to industrial toxins, organic solvents, pesticides, and other putative toxins (35,36).
Population studies have shown a link between risk of PD, and chronic (more than 20 yr) exposure to
manganese, lead-copper combinations, and iron-copper (37). Mercury exposure has also been linked
to PD, but no firm evidence exists for mercury-induced parkinsonism. In the case-control study from
Singapore, scalp hair mercury level has been shown to be a poor predictor of risk of PD (38).
1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine
Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used as an experi-
mental model of PD since the discovery in 1982 that this meperidine analog can cause parkinsonism in
humans and certain animal species. MPTP after undergoing biotransformation to 1-methyl-4-
phenylpyridium ion (MPP+) via monoamine-oxidase B, is taken up to the dopaminergic terminal by
dopamine transporter where it inhibits complex I of the mitochondrial respiratory chain (3941). Indi-
viduals with MPTP-induced parkinsonism exhibited typical parkinsonian features including levodopa
responsiveness and levodopa-induced dyskinesias, and at autopsy had moderate to severe depletion of
pigmented neurons in the substantia nigra, gliosis, and microglial activation, but no convincing evi-
dence of Lewy bodies. Another mitochondrial complex I inhibitor, rotenone, a lipophilic pesticide,
has been described to cause parkinsonism in animals and has been used as a model for parkinsonism
(42). Unlike MPTP, rotenone is not selective for dopaminergic neurons, since it does not require the
dopamine transporter to gain access to the neuronal interior. These findings show that the exposure to
MPTP, and possibly other environmental toxins (such as paraquat and possibly other pesticides) can
cause clinical, biochemical, and pathological changes similar to those seen in idiopathic PD.
Manganese
Manganese exposure has been known to cause parkinsonism in the form of progressive dystonia,
parkinsonism, and psychiatric features for over 150 yr (43). Manganism is a term used to describe
neuropsychiatric symptoms in miners, smelters, and workers in the alloy industry. Clinical features
of manganese induced parkinsonism, usually present in the late or established phase of this disease,
include rigidiy, bradykinesia, and chiefly postural tremor. Patients also frequently exhibit dystonia,
characteristic gait called cock-walk, and postural instability with a tendency to fall backward, and
poor response to levodopa. Characteristic MRI feature of manganese toxicity is T1 hyperintensity in
the striatum and especially in the globus pallidus (43). Pathologically manganese toxicity is associ-
ated with atrophy of globus pallidus, caudate nucleus, the putamen, and substantia nigra pars
reticularis. Alzheimers type II astrocytes are also seen in the basal ganglia, thought to represent the
selective vulnerability of the basal ganglia (44).
Welding fumes contain a variety of elements including manganese, which is argued to be the
causative agent for parkinsonian symptoms in some welders. Racette et al. (45) performed a case-
controlled study comparing clinical features of PD in 15 welders to that of a control group of PD
patients. The welders had an earlier onset of PD, but otherwise the clinical features were identical to
those of PD including levodopa responsiveness, motor fluctuations, and dyskinesias. 6-[18F]fluoro-

dopa PET (positron emission tomography), performed in only two of the welders, showed findings of
decreased uptake in the posterior putamen similar to that seen in PD (45).
Carbon Monoxide
Parkinsonism can develop immediately or several weeks (delayed onset) after exposure to carbon
monoxide (CO) exposure. In a report of 242 patients who were exposed to CO, parkinsonism was
diagnosed in 23 (9.5%) patients (46) The predominant features included masked facies, short
stepped gait, hypokinesia, rigidity, retropulsion, positive glabellar sign, grasp reflex, cognitive prob-
lems, and urinary and/or fecal incontinence; 43% patients had mutism. Intentional tremor and pos-
tural instability was described in 21% of the patients. Majority of patients had clinical correlation
with abnormal CT scans with low-density lesions in the white matter, and in some low-density lesions
were present in globus pallidus. There was no correlation between the CT findings and the location of
the symptoms. Spontaneous recovery was noted in some patients, but most remained neurologically
impaired without meaningful improvement with levodopa (46,47). Lee and Marsden (47) described
two forms of CO-induced parkinsonism: (a) progressive type and (b) delayed relapsing type (parkin-
sonian and akinetic mute form). Patients with the progressive form, although they usually recover
from coma, have a poor prognosis. They remain in mute vegetative state with rigid, spastic state with
little or no spontaneous movement. The delayed relapsing type presents with parkinsonism with vari-
able symptoms including typical slow short stepped gait, with loss of armswing, retropulsion, rigid-
ity and bradykinesia, and stooped posture; sometimes patients may have tremor. Some have dystonia
of the hands and feet. In the akinetic mute patients the predominant features are apathy, mutism,
along with incontinence, emotional lability, and rigidity. CT scan findings include white matter low-
density lesions, and bilateral globus pallidus lesions that improve on subsequent scans in some cases
(47). In a study of 73 patients with CO poisoning, Parkinson et al. (48) found white matter changes in
the centrum semiovale and the periventricular white matter, seen as T2 hyperintensities on MRI
scans. Patients with lesions in the centrum semiovale were more likely to have cognitive deficits.
Cyanide Poisoning
Cyanide poisoning has been reported to cause parkinsonism in several case reports (4952). The
observed deficits include progressive parkinsonism in association with dystonia, and apraxia of eye-
lid opening, with CT and MRI correlation of lesions in the basal ganglia, cerebellum, and cerebral
cortex. T2 hyperintensities in the putamen are typical, but MRI changes may also include hemor-
rhagic necrosis in the cerebral cortex, especially in the sensorimotor cortex in addition to the changes
in the basal ganglia (52). These findings along with the temporal relationship to the onset of symptoms
and the exposure to cyanide should help diagnose parkinsonism owing to cyanide poisoning (53).
Solvent Exposure
Organic solvents have been long suspected to cause parkinsonism, including MSA (35). Methanol
has been reported to be associated with parkinsonism, especially after prolonged exposure. Patients
present with metabolic acidosis, coma, and parkinsonian features, particularly rigidity and bradyki-
nesia (54,55). Other solvents such as toluene, methyl ethyl ketone, carbon disulfide, and n-hexane
have all been linked to parkinsonism (56). MRI of the brain in these cases shows white matter changes.
[11C] raclopride PET provided evidence of decreased dopamine receptor type 2 binding in a patient
with methyl ethyl ketone exposure in addition to decreased F-dopa uptake on PET, identical to the
changes seen in idiopathic PD (56).
Ethanol
Alcohol-induced parkinsonism is a rare and poorly characterized disorder. Transient form of par-
kinsonism has been reported in alcoholics during withdrawal. This disorder is seen in chronic alco-
holics of both sexes, usually older than 50 yr with no evidence of hepatic dysfunction (57). The
condition develops a few days after the consumption of the last drink; rarely during acute intoxica-
tion. The patients often show other features of alcohol withdrawal and alcoholism including postural
tremor, ataxia, and confusion. Most of the patients have previous history of transient episodes of
parkinsonism. CT and MRI studies do not show any specific changes. Some patients have moderate
to severe brain atrophy resulting from alcoholism, and one patient had basal ganglia calcifications
(57). Levodopa has been tried in these patients with limited success. The condition is self-limited and
all patients improve with abstinence. In some cases the duration of parkinsonism lasts up to weeks or
months. None of the patients with these transient episodes have developed parkinsonism in a 10-yr
follow-up study. The hypothesis is that patients susceptible to transient parkinsonism may have under-
lying nigral degeneration and develop parkinsonism owing to superimposed alcohol use (57).
INFECTIOUS CAUSES OF PARKINSONISM

Human Immunodeficiency Virus
The association of human immunodeficiency virus (HIV) infection and movement disorders has
been recognized since the first descriptions of neurological complications of HIV-associated AIDS
(58). Secondary parkinsonism has been reported by various authors as case reports, but Mattos et al.
(59) have reported movement disorders in 28 HIV patients of whom 14 patients had parkinsonism.
The mean age at onset of parkinsonism was 37.2 yr (range 2563). They report mean Hoehn and Yahr
scale of 2.5 (range of 15). The clinical features included tremor, and rapid progression of parkinso-
nian symptoms with time of onset to death being five mo in eight patients. Five patients were levodopa
responsive. Imaging study with CT scans showed hydrocephalus ex-vacuo, and one patient had toxo-
plasmosis involving the basal ganglia. One patient with T1 enhancement on the MRI of the brain had
ipsilateral ophthalmoplegia and contralateral parkinsonism. Only two of the patients with parkin-
sonism had other parkinsonian risk factors such as metaclopramide exposure and neurotoxoplasmosis
(59). Maggi et al. (60) described parkinsonism in a patient with AIDS and toxoplasmosis with abulia,
VII cranial nerve impairment, hypomimia, speech impairment, difficulty arising from a chair, stooped
posture, short stepped gait and freezing of gait, cogwheel rigidity, and bradykinesia in association
with toxoplasma lesion in the bilateral lenticular nucleii and the right frontobasal region (60). Pres-
ence of parkinsonism and tremor has been reported by other authors, and the management involves
treatment of opportunistic infections, symptomatic treatment of parkinsonism, and antiretroviral
therapy (61). Bradykinesia, postural instability, gait disorder, and hypomimia are common features
of HIV-related parkinsonism with dementia. Parkinsonian features have been reported in association
with dopamine receptor antagonists, opportunistic infections such as toxoplasmosis, or HIV itself.
Some patients with HIV have clinical features identical to idiopathic PD (62). Dopaminergic medica-
tion has been thought to accelerate the course of HIV viral infection as shown in the study of levodopa
and selegiline in the SIV-infected (Simian immunodeficiency virus) macaque model (63).
Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE), a slow viral disease caused by measles virus with a
mutated M-protein, has been long recognized to cause parkinsonism, myoclonus, dystonia, chorea,
athetosis, stereotypies, and a variety of other movement disorders. Sawaishi et al. (64) reported a case
of SSPE with documented lesions in the substantia nigra as well as the putamen, globus pallidus, and
caudate nuclei, seen on the MRI scans of the brain. Parkinsonian symptoms described in SSPE
include bradykinesia and rigidity. Previous descriptions of MRI findings include lesions in the
putamen and caudate, but sparing the globus pallidus and thalamus (64). Treatment with levodopa
and amantadine has been reported to provide some symptomatic relief (65).
Other Infections
Mycoplasma pneumoniae has been reported to cause parkinsonism in a young boy with flulike
symptoms, followed by parkinsonism with bradykinesia, hypomimia, hypophonia, and dystonia with
MRI findings of increased signal (T1 or T2) in the basal ganglia (66). The patient had elevated myco-
plasma antibody levels and his symptoms and MRI abnormalities spontaneously resolved. Posten-
cephalitic encephalitis has been associated with parkinsonism since the epidemic in early 1900s.
Although the incidence of postencephalitic parkinsonism has markedly decreased, well-documented
cases have been reported recently, including those caused by the West Nile virus (67,68).
METABOLIC CAUSES OF PARKINSONISM

Important metabolic causes of parkinsonism include hypothyroidism and parathyroid dysfunc-
tion. Patients with hyperparathyroidism have clinical presentation identical to that of idiopathic PD,
but the syndrome is levodopa resistant. The symptoms, however, may be relieved after resolution of
the parathyroid dysfunction by surgical removal of the parathyroid adenoma. Hypoparathyroidism
may also cause levodopa unresponsive parkinsonism (69,70).
Bilateral striopallidodentate calcinosis, also known as Fahrs disease, is a rare disorder with cal-
cium deposition in the subcortical nucleii and white matter bilaterally. Parkinsonism is reported in
57% of patients with this disorder; other movement disorders seen in Fahrs disease include chorea,
tremor, dystonia, athetosis, and orofacial dyskinesias (71). Additional neurological manifestations
include cognitive impairment, cerebellar signs, speech disorder, gait disorder, pyramidal signs, sen-
sory symptoms, and psychiatric features (72). Patients have parkinsonism without evidence of par-
athyroid dysfunction in association with dementia and cerebellar signs. Lewy bodies may be found
on autopsy. Response to levodopa is variable (72). No gene has yet been identified although linkage
to chromosome 14 has been suggested (73).
POSTANOXIC PARKINSONISM
Parkinsonism can rarely result from hypoxic ischemic injury. Different movement disorders includ-
ing chorea, tics, athetosis, dystonia, and myoclonus have been reported. Patients can develop parkin-
sonism with or without dystonia weeks to months after the ischemic event (74). MRI findings include
T1 hyper intensities in the basal ganglia bilaterally, indicative of ischemia or gliosis. In the case
described by Li et al. (74), the clinical findings included mainly an akinetic rigid syndrome with
hypomimia, limitation of down gaze, dysarthria, rigidity, postural tremor, slow rapid alternating
movements, shuffling gait, start hesitation, and freezing of gait occurring 3 wk after an anoxic injury
owing to cardiac arrest. There was no improvement with dopaminergic drugs. The autopsy examina-
tion showed multiple old infarcts with the presence of macrophages indicative of old hemorrhagic
infarct in the basal ganglia.
DRUG-INDUCED PARKINSONISM
A discussion of secondary parkinsonism would not be complete without at least a brief review of
drug induced parkinsonism. Drug-induced parkinsonism, one of the most common causes of second-
ary parkinsonism, may coexist with tardive dyskinesia. In a study in patients in the hospital, 51% of
the 95 patients had drug-induced parkinsonism (75). The symptoms in drug induced parkinsonism
are often bilateral at onset, whereas idiopathic PD is asymmetric at onset, but this clinical observation
does not reliably differentiate between the two forms of parkinsonism. Tremor in drug-induced par-
kinsonism is generally high-frequency 7- to 8-Hz action tremor rather than a rest tremor as seen in
idiopathic PD. Women tend to have drug-induced parkinsonism more frequently than men, the oppo-
site of gender distribution in idiopathic PD. Most of the cases of drug-induced parkinsonism occur in
patients over 40 yr of age. Parkinsonian symptoms occur generally 1030 d after starting the drug. It
is important to wait 3 months after withdrawal of medication before diagnosing drug-induced parkin-
sonism. The withdrawal of the suspected drug is usually followed 48 weeks later by the disappear-
ance of clinical symptoms. In some cases, the parkinsonian symptoms, however, persist and these
cases are suspected to have preclinical PD, in which the initial symptoms were triggered by the
exposure to the dopamine receptor-blocking drug (76). There are a variety of drugs including dopam-
ine depletors, dopamine blockers, antihypertensives such as methyldopa and amiodarone, calcium
channel blockers such as flunarizine and cinnarazine, and serotonine selective reuptake inhibitors
such as fluoxetine, all of which can cause drug-induced parkinsonism. Drug-induced parkinsonism
can be treated by withdrawal of the causative agent, but in some cases amantadine and levodopa have
been useful (77). Drug-induced parkinsonism is associated with other involuntary movements in-
cluding bucco-lingulo-masticatory syndrome, focal dystonia, stereotypies, akathisia, and gait distur-
bance (78). Recovery is noted in 6070% patients in 7 weeks after drug withdrawal, but it may take
about 1518 months in some patients (79). Hardie et al. (78) reported persistence of parkinsonian
symptoms in 14 patients after drug withdrawal. Striatal dopamine transporter imaging is normal unlike
that seen in idiopathic PD (80).
PERIPHERALLY INDUCED TREMOR AND PARKINSONISM

There are several disorders that have been reported to result from trauma to the peripheral nervous
system. These include tremor, dystonia, segmental myoclonus, hemifacial spasm, and in some cases
parkinsonism. Among 146 patients with peripherally induced movement disorders, 28 had tremor
with or without parkinsonism (81). Eleven patients had tremor-dominant parkinsonism. Clinical fea-
tures included rest and action tremor, and bradykinesia and rigidity in those with parkinsonism. Onset
of movement disorder was temporally related to the injury, and was within 25 months after injury.
Injuries varied from whiplash to sprain, dental procedure, fracture, overuse, or surgery. Patients had the
injury in various areas including arm, neck, lumbar region, and teeth. A majority of patients had injuries
in the arms. The condition seemed to spread to the other parts of the body beyond the initial site of
injury, and it is unclear if any of them may have had predisposition to parkinsonism, and the trauma
in some way has led to the earlier onset of parkinsonism (81). F-Dopa PET scans showed a reduction in
F-Dopa uptake suggesting that some patients with peripherally induced parkinsonism may be predis-
posed to develop the disorder because of a subclinical dopaminergic degeneration.
REVERSIBLE PARKINSONISM IN CHILDHOOD

Parkinsonism is uncommon in childhood and is often owing to a variety of genetic disorders such
as parkin mutation, juvenile Huntingtons disease, Wilsons disease, and pantothenate kinase-associ-
ated neurodegeneration (82). Acquired causes of childhood onset parkinsonism include neuroleptic
exposure, cytosine arabinoside, cyclophosphamide, amphotericin B, methotrexate, hypoxic ischemic
encephalopathy, and hydrocephalus (83,84).
DEVELOPMENTAL FORMS OF PARKINSONISM

Developmental forms of parkinsonism include syndromes induced by in utero or perinatal viral
(or other) infection, such as maternal influenza during pregnancy or in utero or perinatal trauma or
maternal stress. In utero influenza has been reported to be a cause of parkinsonism in a young child
(85). Parkinsonism was reported in children born to mothers with encephalitis lethargica (85).
Asphyxia during delivery, prenatal disturbances, premature birth, or early-childhood meningoen-
cephalitis, often in combination with a complicated pregnancy, were all described to predispose to
parkinsonian syndromes. The clinical symptoms included rigidity, hypokinesia, and in a small per-
centage, tremor. These children also had other neurological abnormalities including cognitive prob-
lems, behavioral difficulties, headaches, and strabismus. Treatment with levodopa was reported to be
effective. Dyskinesia was noted to be a side effect 830 months after therapy, and by 3 years levodopa
Table 1
Secondary Causes of Parkinsonism
Vascular (includes parkinsonism and PSP): with vascular risk factors, hyperhomocystinemia, and CADASIL.
Toxin exposure: MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine), manganese, carbon monoxide,
cyanide, ethanol, methanol, and other solvents.
Infectious: HIV (human immunodeficiency virus), SSPE (subacute sclerosing pan encephalitis), mycoplasma
pneumoniae infection.
Metabolic: Hyperparathyroidism.
Post-anoxic
Drug-induced: Neuroleptic agents, dopamine depletors, amiodarone, calcium channel blockers.
Peripherally induced: parkinsonism owing to injury.
Reversible parkinsonism in childhood: Hypoxic ischemic injury, neuroleptics, cytosine arabinoside, cyclo-
phosphamide, amphotericin B, methotrexate, encephalitis, pineal germinoma, neuroleptic malignant
syndrome, stroke, head injury, hydrocephalus, kernicterus, and radiation necrosis.
Hemiatrophy-hemiparkinsonism
Structural lesions causing parkinsonism: Posterior fossa tumors, right temporal lobe hemorrhage, intrinsic
brainstem tumors.
Other causes: Multiple sclerosis.
was withdrawn. This was a reversible syndrome with very slight progression, and was though to be
a result of decreased metabolic activity. Overall, a minority of patients with pre- or perinatal infec-
tions or trauma present with parkinsonism with eventual resolution of symptoms and a favorable
prognosis.
An important to recognize but poorly understood syndrome is that of cerebral palsy or static
encephalopathy that later progresses and causes gradual neurological deterioration. In a study of
delayed-onset progressive movement disorders after static brain lesions, about 15% had parkinsonism
(86). The precipitating insults included perinatal hypoxic ischemia, stroke, head injury, encephalitis,
CO, kernicterus, and radiation necrosis.
HEMIPARKINSONISM-HEMIATROPHY
Hemiparkinsonism-hemiatrophy (HPHA) syndrome was first described by Klawans in 1981 (87),
who described four individuals with known hemiatrophy with narrow extremities on one side who
developed delayed-onset hemiparkinsonism between ages 31 and 40 with tremor on the same side as
the hemiatrophy along with rigidity, akinesia, and dystonia, but no evidence of hypomimia, or abnor-
mal posture or lack of postural reflexes. Their symptoms remained unilateral between 5 and 35 yr
after onset of illness. They did not respond well to levodopa. HPHA can be differentiated from idio-
pathic PD by the clinical features of hemiatrophy, asymmetric parkinsonism more prominent on the
side of hemiatrophy, dystonia, early age at onset, history of birth injury, and slow progression of the
disease. Mean age of onset of parkinsonism in HPHA is 43.7 yr (range 3161), and mean duration of
symptoms was 9.4 yr (range: 135 yr). The first symptom in majority of cases is tremor, followed by
bradykinesia and dystonia. In some cases the tremor may become bilateral (8890). Greene et al. (90)
have reported dopa-responsive dystonia in some patients with HPHA. In one case report of a 47-yr-
old woman with HPHA, the patient developed unusual symptoms of exertional- induced weakness of
the right ankle followed by prolonged inversion and dorsiflexion of her foot (91). The symptoms later
evolved into tremor, stiffness, and lack of dexterity of muscles on the right side. She had good
Table 2
Showing the Clinical Features of Nondegenerative Atypical Parkinsonian Disorders
that Help in Diagnosis
Parkinsonian Disorder Distinguishing Clinical Features Supportive MRI Findings
Vascular parkinsonism Acute, delayed, or insidious onset Subcortical ischemic changes on
with bradykinesia, rigidity, short brain MRI
stepped gait, with or without
dementia, postural instability lower
body involvement. Patients have
freezing of gait, absence of tremor,
poor levodopa responsiveness.
Some patients have pseudobulbar
affect. High index of suspicion in
presence of vascular risk factors,
and an older patient with atypical
clinical presentation.
MPTP-induced parkinsonism Features similar to idiopathic PD No specific changes
in presence of toxin exposure.
Manganese-induced parkinsonism Parkinsonism with postural tremor, T1 hyperintensity in the striatum
dystonia, cock-walk, postural and globus pallidus on brain MRI
instability in presence of exposure
to manganese
Carbon monoxide-induced parkin- Masked facies, short stepped gait, T2 hyperintensities in the white
sonism rigidity hypolinesia, cognitive matter on brain MRI
impairment, mutism postural
tremor, urinary or fecal inconti-
nence, dystonia, emotional lability,
postural instability
Cyanide-induced parkinsonism Parkinsonism, with dystonia, T2 hyperintensities in the putamen
apraxia of eyelid opening, with hemorrhagic necrosis in the cere-
temporal relation to the onset of bral cortex, especially in the sen-
symptoms and exposure to cyanide sorimotor cortex
Methanol-induced parkinsonism Metabolic acidosis, coma, parkin- Subcortical white matter changes
sonism, especially rigidity, and
bradykinesia
Ethanol-induced parkinsonism Transient parkinsonism seen dur- No specific changes
ing alcohol withdrawal, developing
a few days after consumption of
the last drink. Most patients have
previous transient episodes.
HIV-related parkinsonism Rapid progression of parkinsonian MRI abnormalities in case of CNS
symptoms tremor, in presence of opportunistic infections such as
HIV with or without related CNS toxoplasmosis, CMV (cytomega-
infections such as toxoplasmosis lovirus)
SSPE-related parkinsonism Parkinsonism in presence of other Lesions in caudate and putamen,
abnormalities suggestive of SSPE but sparing the blobus pallidus and
Mycoplasma-related parkinsonism Parkinsonism with flulike symp- thalamus
toms, and dystonia, with elevated Increased T1 and T2 signal in the
mycoplasma antibody levels basal ganglia
Bilateral striatopallidodentate Parkinsonism, cognitive impair- MRI findings of calcium in the
calcinosis (Fahrs disease) ment, celebellar signs, speech subcortical white matter and basal
abnormalities, pyramidal signs, ganglia
psychiatric features and sensory
abnormalities
Table 2 (Continued)
Parkinsonian Disorder Distinguishing Clinical Features Supportive MRI Findings
Post-anoxic parkinsonism Parkinsonism with or without T1 hyperintensities in the basal

dystonia weeks to months after the ganglia bilaterally
ischemic event
Drug-induced parkinsonism Parkinsonism in association with No specific changes
other involuntary movements
including bucco-lingulo-mastica-
tory syndrome, dystonia, stereo-
types, akathisia and gait
disturbance with history of expo-
sure todopamine receptorblocking
drug
Peripherally induced parkinsonism Tremor-dominant parkinsonism No specific changes described
following injury
Developmental parkinsonism Parkinsonism following some Abnormal in presence of clear
insult in utero, or immediate post- ischemic event
natal period in association with
tremor, cognitive dysfuncion,
behavioral abnormalities, head-
aches, and strabismus
Hemiatrophy-hemiparkinsonism Hemiatrophy in association with Hemiatrophy on MRI of the brain,
hemiparkinsonism dystonia, but may have associated skull
without postural instability asymmetry
Tends to remain unilateral for 5
35 yr after onset of parkinsonian
symptoms; Early age at onset,
history of birth injury, slow pro-
gression of the disease are very
typical features.
Structural lesions causing parkin- Parkinsonism in presence of MRI changes are usually consistent
sonism tumors, hemorrhage typically con- with the space occupying lesion.
tralateral to the lesion and some-
Parkinsonism owing to multiple times ipsilateral to the lesion
sclerosis Parkinsonian features in presence MRI lesions in substantia nigra,
of other symptoms of multiple and in the cervicomedullary
sclerosis junction
response of the dystonia parkinsonism to levodopa. Her MRI showed atrophy in the substantia
nigra. The unusual constellation of exertional dystonia with parkinsonism and hemiatrophy demon-
strates the wide range of clinical features seen in this syndrome. An unusual case of brain
hemihypoplasia with contralateral hemiatrophy and hemiparkinsonism was described (92). MRI of
the brain showed skull and encephalic asymmetry and hypoplasia of the right side and the 99mTc ECD
SPECT showed global hypoperfusion of the right hemisphere.
STRUCTURAL LESIONS CAUSING PARKINSONISM

A variety of structural lesions can cause parkinsonism. Siderowf et al. (93) argue that the first
described case of PSP in a patient with progressive opthalmoparesis and postural instability, and
structural lesion with a tumor in the right cerebral peduncle is not idiopathic PSP. Brainstem astrocy-
toma was reported to be the cause of unilateral parkinsonian symptoms; the symptoms resolved after
resection of the tumor (94). A frontal meningioma can sometimes present with rest tremor without
other signs of parkinsonism (95). Dopa-responsive parkinsonism has been reported resulting from a
right temporal lobe hemorrhage (96). Intrinsic brainstem tumors can cause parkinsonism. Posterior
fossa tumors present with pyramidal tract signs, cerebellar signs, and hydrocephalus in addition to
parkinsonism. The parkinsonian symptoms predominantly are seen contralateral to the lesion. In
some cases ipsilateral symptoms have also been reported. The parkinsonism associated with mass
lesions of the infratentorial compartment is usually on the contralateral side with other cranial nerve
lesions or sensory symptoms depending on the location of the lesion. MRI of the brain is usually
diagnostic. Pathophysiologic mechanisms include mechanical compression or distortion of the ros-
tral midbrain and substantia nigra, infiltration and destruction of substantia nigra, impairment of the
nigrostriatal pathways, and a combination of these mechanisms (97).
OTHER UNUSUAL CAUSES OF SECONDARY PARKINSONISM
Parkinsonism was reported after a wasp sting resulting in a progressive syndrome of frequent
freezing, rigidity, and bradykinesia, in addition to dystonia in the left arm (98). The patient was
reported to have had emotional lability and bilateral frontal release signs. The brain MRI showed
marked destruction of the striatum and pallidum bilaterally, and enlargement of the lateral and third
ventricles. There were circulating antibodies against the basal ganglia and cerebral cortex. The patient
responded to immunosuppressive therapy with plasma exchange and intravenous immunoglobulin.
Multiple sclerosis (MS) has also been reported to cause parkinsonism (99). One patient presented
mainly with gait difficulty, with slowness, short steps, and unsteadiness. She also developed rest
tremor, hypomimia, and hypophonia. There were other features suggestive of multiple sclerosis in
the form of diplopia, brisk reflexes, and sensory loss. The patient improved with steroids. So far in
the literature nine cases including this case report of MS have been reported with findings of parkin-
sonism (99). Three patients had hemiparkinsonism, and the rest of the patients had bilateral symp-
toms with rest tremor, hypomimia, rigidity, bradykinesia, and gait difficulties, very similar to
idiopathic PD. Very limited information is available regarding levodopa responsiveness. MRI find-
ings showed lesions in the periventricular area, pons, substantia nigra, and in corpus callosum in
those with bilateral parkinsonism. In those with hemiparkinsonsim, lesions were in the left substantia
nigra, periventricular area, and adjacent to the red nucleus (99).
MAJOR RESEARCH ISSUES
As discussed above, there are several forms of nondegenerative parkinsonism with variable clini-
cal features as shown in Table 2, VP being the most common. One of the mysteries of VP is what,
besides the usual stroke risk factors, predisposes the affected individual to develop VP since not
everyone with hypertension, diabetes, or other stroke risk factors develops VP. Further studies of the
relationship between anticardiolipin antibodies and VP (20) are needed before routine screening of
these patients for these antibodies can be recommended. It is not clear why some patients improve
with dopaminergic drugs whereas others do not. CSF withdrawal may benefit some patients with
VP, but this improvement is transient (34). More studies are needed to determine whether CSF shunt-
ing would benefit some patients.
FUTURE DIRECTIONS
As discussed above, several of these non-degenerative forms of parkinsonism support the evi-
dence for multiple etiologic factors leading to selective neuronal vulnerability.
Investigation of neuroprotective potential of specific agents such as CPI 1189 for HIV dementia
has shown some improvement with motor function, but the study is not designed for efficacy (100).
Future studies in this area may help treat HIV-induced parkinsonism. Parkinsonism induced by toxic
exposure or specific infectious etiology may provide a direct clue to the dysfunction in mitochondrial
and other specific cellular mechanisms such as inflammation, and lysosomal dysfunction, which may
help identify specific targets for therapy. Further research into the cellular mechanisms in various
types of parkinsonism are needed in order to clarify the mode of insult an specific signal transduction
pathways involved in disease mechanisms.
LEGEND TO VIDEOTAPE
Patient 1: Video segment shows a patient with a wide based gait, slightly decreased arm swing on
the right side, with MRI findings of ischemic changes in the subcortical white matter. This patient
with VP failed to respond to levodopa.
Patient 2: Patient shows freezing of gait with predominant gait difficulties in the absence of any
upper body involvement typically observed in VP.
Patient 3: A patient with mild hypomimia, bradykinesia in the upper limbs, but disproportionate
degree of gait difficulties showing broad-based gait, and freezing of gait while turning. The diagnosis
of VP is supported by ischemic changes on MRI scan.
REFERENCES
1. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:3339.
2. Critchley M. Atherosclerotic parkinsonism. Brain 1929;52:2383.
3. Zijlmans JCM, Daniel S, Hughes AJ, Revesz T, Lees AJ. A clinicopathological investigation of vascular parkinsonism
(VP). Mov Disord published online March 16, 2004.
4. Daniel SE, Lees AJ. Parkinsons disease society brain bank, London: overview and research. J Neural Transm Suppl
1993;39:165172.
5. Thompson PD, Marsden CD. Gait disorder of subcortical arteriosclerotic encephalopathy: Binswanger disease. Mov
Disord 1987;2:18.
6. Roman GC. New insight into Binswanger disease. Arch Neurol 1999;56:10611106.
7. Mark MH, Sage JI, Walters AS, et al. Binswanger disease presenting as levodopa responsive parkinsons disease.
Clinicopathological study of three cases. Mov Disord 1995;10:450454.
8. Chang CM, Yu YL, Ng HK Leung SY, Fong KY. Vascular pseudoparkinsonism. Acta Neurol Scand 1992;86:588592.
9. Yamanouchi H, Nagura H. Neurological signs and frontal white matter lesions in vascular parkinsonisma clinico-
pathological study. Stroke 1997;28:965969.
10. Van Zagaten M, Lodder J, Kessels F. Gait disorder and parkinsonian signs in patients with stroke related to small deep
infarcts and white matter lesions. Mov Disord 1998;13:8995.
11. Winikates J, Jankovic J. Clinical correlates of vascular parkinsonism. Arch Neurol 1999;56:98102 .
12. Dubinsky RM, Jankovic J. Progressive supranuclear palsy and a multi-infarct state. Neurology 1987;37:570576.
13. Winikates J, Jankovic J. Vascular PSP. J Neural Transm Suppl 1994;42:189201.
14. Fitzgerald P, Jankovic J. Lower body parkinsonism: evidence for vascular etiology. Mov Disord 1989;4:249260.
15. Jankovic J, Nutt JG, Sudarsky L. Classification, diagnosis and etiology of gait disorders. In: Ruzicka E, Hallett M,
Jankovic J, eds. Gait disorders. Advanced in Neurology, vol. 87, Philadelphia: Lippincott Williams & Wilkins,
2001:119134.
16. Demikiran M, Bozdemir H, Sarica Y. Vascular parkinsonism, a distinct heterogeneous clinical entity. Acta Neurol
Scand 2001;104:6367.
17. Trenkwalder C, Paulus W, Keafeczyc S, et al. Postural stability differentiates lower body from idiopathic parkin-
sonism. Acta Neurol Scand 1995;91:444452.
18. Zijlmans JCM, Poels PJE, Duysens J, et al. Quantitative gait analysis in patients with vascular parkinsonism. Mov
Disord 1996;5:501508.
19. Thomas M, Suteerawattanon M, Caroline KS, et al. Gait and Balance Scale: validation and utilization. J Neurol Sci
2004;217:8999.
20. Huang Z, Jacewicz M, Pfeiffer RF. Anticardiolipin antibody in vascular parkinsonism. Mov Disord 2002;17:992997.
21. Joutel A, Coprechot C, Ducros A, et al. Notch-3 mutation in CADASIL, a heriditary adult onset condition causing
stroke and dementia. Nature 1997;383:707-710.
22. Rafalowska J, Fidzianska A, Dziewulska D, et al. CADASIL: new cases and new questions. Acta Neuropathol 2003;Sep
30 Epub ahead of print
23. Kuhn W, Roebroek R, Blom H, et al. Elevated plasma levels of homocysteine in Parkinsons disease. Eur Neurol
1998;40:225227.
24. Rogers JD, Sanchez-Saffon A, Frol AB, Diaz-Arrstia R. Elevated plasma homocysteine levels in patients treated with
levodopa. Association with vascular disease. Arch Neurol 2003;60:5964.
25. Eadie MJ, Sutherland JM. Atherosclerosis in parkinsonism. J Neurol Neurosurg Psychiatry 1964;27:237240.
26. Izelberg R, Bronstein NM, Reider I, Korczyn AD. Basal ganglia lacunes and parkinsonism. Neuroepidemiology
1994;13:108112.
27. Chang CM, Yu Yl, Ng HK, Fong KY. Vascular pseudoparkinsonism. Acta Neurol Scand 1992;86:588592.
28. Tzen KY, Lu CS, Yen TC, et al. Differential diagnosis of Parkinsons disease and vascular parkinsonism by 99mTc-
TRODAT-I.J Nuclear Med 2001;42:408413.
29. Bencsits G, Pirker W, Asenbaum, et al. Comparison of the 123I beta-CIT snf SPECT in lower body parkinsonism and
Parkinsons disease [Abstract]. Mov Disord 1998;13(Suppl):106.
30. Zijlmans JC, de Koster A, Vant Jof MA, et al. Proton magnetic resonance spectroscopy in suspected vascular parkin-
sonism. Acta Neurol Scand 1994;90:405411.
31. Tohgi H, Takahashi S, Abe T, Utsugisawa K. Symptomatic characteristics of parkinsonism and the width of substantia
nigra pars compacta on MRI according to the ischemic changes in the putamen and the cerebral white matter: implica-
tions for the diagnosis of vascular parkinsonism. Eur Neurol 2001;46:110.
32. Zijlmans JC, Pasman JW, Horstink MW, et al. EEG findings in patients with vascular parkinsonism. Acta Neurol Scand
1998;94:243247.
33. Tolosa ES, Santamaria J. Parkinsonism and basal ganglia infarcts. Neurology 1984;34:15161518.
34. Ondo WG, Chan LL, Levy JK. Vascular parkinsonism: clinical correlates predicting motor improvement after lumbar
puncture. Mov Disord 2002;17:9197.
35. Hanna P, Jankovic J, Kilkpatrick J. Multiple system atrophy: the putative causative role of environmental toxins. Arch
Neurol 1999;56:9094;
36. Petrovitch H, Ross GW, Abbott RD, et al. Plantation work and risk of Parkinson disease in a population-based longitu-
dinal study. Arch Neurol 2002;59:17871792.
37. Gorell JM, Johnson CC, Rybicki BA, et al. Occupational exposure to manganese, copper, lead, iron, mercury, and zinc
and the risk of Parkinsons disease. Neurotoxicology 1999;20:239247.
38. Ngim CH, Devathasan G. Epidemiologic study on association between body burden mercury level and idiopathic
Parkinsons disease. Neuroepidemiology 1999;8:128141.
39. Langston et al, 1999;Jenner P. The contribution of the MPTP-treated primate model to the development of new treat-
ment strategies for Parkinsons disease. Parkinsonism Relat Disord 2003;9:131137.
40. Langston JW, Ballard P, Tetrud J, Irwin I. Chronic parkinsonism in humans due to a product of meperidine analog
41. Langston JW, Forno LS, Tetrud J, et al. Evidence of active nerve cell degeneration in the substantia nigra of humans
years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 1999;46:598605.
42. Gao HM, Liu B, Hong JS. Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopamin-
ergic neurons. J Neurosci 2003;23:61816187.
43. Nelson K, Golnick J, Korn T, Angle C. Manganese encephalopathy: Utility of early magnetic resonance imaging. Br J
Ind Med 1993;50:510513.
44. Normadin L, Hazel AS. Manganese neurotoxicity: an update of pathophysiologic mechanisms. Met Brain Dis
2002;17:374387.
45. Racette BA, McGee-Minnich L, Moerlein SM, et al. Welding-related parkinsonism clinical features and pathophysiol-
ogy. Neurology 2001;56:813.
46. Choi IS. Parkinsonism after carbon monoxide poisoning. Eur Neurol 2002;48:3033.
47. Lee MS, Marsden CD. Neurological sequelae following carbon monoxide poisoning: clinical course and outcome accord-
ing to the clinical types and brain computed tomography scan findings. Mov Disord 1994;9:550558.
48. Parkinson RB, Hopkins RO, Cleavinger HB et al.White matter hyperintensities and neuropsychological outcome fol-
lowing carbon monoxide poisoning. Neurology 2002;58:15251532.
49. Sohn YH, Jeong Y, Kim H, et al. The brain lesion responsible for parkinsonism after carbon monoxide poisoning. Arch
Neurol 2000;57:12141218.
50. Carella F, Grassi MP, Savoiardo M, et al. Dystonic-parkinsonian syndrome after cyanide poisoning: clinical and MRI
findings. J Neurol Neurosurg Psychiatry 1988;51:13451348.
51. Messing B. J Extrapyramidal disturbances after cyanide poisoning (first MRT-investigation of the brain). Neural Transm
Suppl 1991;33:141-147.
52. Rachinger J, Fellner FA, Stieglbauer J, Trenler J. MR changes after acute cyanide intoxication. Am J Neuroradiol
2002;23:13981401.
53. Rosenow F, Herholz K, Lanfermann H, et al. Neurological sequelae of cyanide intoxication. The pattern of clinical,
magnetic resonance imaging, and positron emission tomography findings. Ann Neurol 1995;38:825828.
54. Ley CO, Gali FG. Parkinsonian syndrome after methanol intoxication. Eur Neurol 1983;22:405409.
55. Finkelstein Y, Vardi J. Progressive parkinsonism in a young experimental physicist following long term exposure to
methanol. Neurotoxicology 2002;23:521525.
56. Hageman G, van Der Hock J, van Hout M, et al. Parkinsonism, pyramidal signs, polyneuropathy and cognitive decline
after long term occupational solvent exposure. J Neurol 1999;246:198206.
57. Neilman J, Lang AE, Fornazzari L, Carlen PL. Movement disorders in alcoholism: a review. Neurol 1990;40:741746.
58. Nath A, Jankovic J, Pettigrew LC. Movement disorders and AIDS. Neurology 1987;37:3641.
59. de Mattos JP, de Rosso ALZ, Correa RB, et al. Movement disorders in 28 HIV-infected patients. Arq. Neuro-psiquiatr.
2002;60:525530.
60. Maggi P, de Mari M, Moramarco G, et al. Parkinsonism in a patient with AIDS and cerebral opportunistic granuloma-
tous lesions. Neurol Sci 2000;21:173176.
61. Cardoso F. HIV-related movement disorders: epidemiology, pathogenesis and management. CNS Drugs 2002;16:
663668.
62. Kotsulieri E, Sopper S, Scheller C, et al. Parkinsonism in HIV dementia. J Neural Transm 2002;109:767775.
63. Czub S, Koutsilleri E, Sopper S, et al. Enhancement of CNS pathology in early simian immunodeficiency virus infec-
tion by dopaminergic drugs. Acta Neuropathol 101:8591.
64. Sawaishi Y, Yano T, Watanabe Y, Takada G. Migratory basal ganglia lesions in subacute sclerosing panencephalitis
(SSPE): clinical implications of axonal spread. J Neurol Sci 1999;168:137140.
65. Mossakowski MJ, Mathesian G. A parkinsonian syndrome in the course of subacute encephalitis. Neurology
1961;11:461461.
66. Kim JS, Choi IS, Lee MC. Reversible parkinsonism and dystonia following probable mycoplasma infection. Mov
Disord 1995;10:510512.
67. Savant CS, Singhal BS, Jankovic J, Khan M, Virani A. Substantia nigra lesions in viral encephalitis. Mov Disord
2003;18:213216.
68. Bosanko CM, Gilroy J, Wang A-M, et al. West Nile virus encephalitis involving the substantia nigra. Arch Neurol
2003;60:14481452.
69. Kovacs CS, Howse DC, Yendt HR. Reversible parkinsonism induced by hypercalcemia and primary hyperparathyroid-
ism. Arch Intern Med 1993;153:11341136.
70. Hirooka Y, Yuasa K, Hibi K et al. Hyperparathyroidism associated with parkinsonism. Intern Med 1992;31:904907.
71. Manyam BV, Walters AS, Nara KR. Bilateral striopallidodentate calcinosis: clinical characteristics of patients seen in
a registry. Mov Disord 2001;16:258264.
72. Manyam BV, Walters AS, Keller IA, Ghobrial M. Parkinsonism associated with autosomal dominant bilateral
striopallidodentate necrosis. Parkinsonism Relat Disord 2001;7:289295.
73. Brodaty H, Mitchell P, Luscombe G, Kwok JJ, et al. Familial idiopathic basal ganglia calcification (Fahrs disease)
without neurological, cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q. Hum
Genet 2002;110:814.
74. Li JY, Lai PH, Chen CY, Wang JS, Lo YK. Post anoxic parkinsonism: clinical radiologic, and pathologic correlation.
Neurology 2000;55:591593.
75. Stephen PJ, Williamson J. Drug induced parkinsonism in the elderly. Lancet 1984;2:10821083.
76. Rajput A, Rozdilsky B, Hornykiewicz O, et al. Reversible drug-induced parkinsonism. Clinicopathologic study of two
cases. Arch Neurol 1982;39:644646.
77. Montastruc JL, Llau ME, Rascol O, Senard JM. Drug induced parkinsonism: a review. Fundam Clin Pharmacol
1994;8:293306.
78. Hardie RJ, Lees AJ. Neuroleptic induced parkinsons syndrome: clinical features and results of treatment with levodopa.
J Neurol Neurosurg Psych 1988;51:8508554.
79. Consentino C, Torres L, Scortiati C et al. Movement disorders secondary to adulterated medication. Neurology
2000;55:598599.
80. Tolosa E, Coelho M, Gallardo M. DAT imaging in drug-induced and psychogenic parkinsonism. Mov Disord
2003;18(Suppl 7):S28S33.
81. Cardoso F, Jankovic J. Peripherally induced tremor and parkinsonism. Arch Neurol 1995;52:263270.
82. Thomas M, Hayflick SJ, Jankovic J. Clinical heterogeneity of neurodegeneration with iron accumulation-1
(HallervordenSpatz syndrome) and pantothenate kinase associated neurodegeneration (PKAN). Mov Disord
2004;19:3642.
83. Jankovic J, Newmark M, Peter P. Parkinsonism and acquired hydrocephalus. Mov Disord 1986;1:5964.
84. Reiderer P, Foley P. Mini-review: multiple developmental forms of parkinsonism. The basis for further research as to
the pathogenesis of parkinsonism. J Neural Transm 2002;109:14691475.
85. Pranzatelli M, Mott SH, Pavlakis SG, Conry JA, Tate ED. Clinical spectrum of secondary parkinsonism in childhood:
a reversible disorder. Pediatr Neurol 1994;10:131140.
86. Scott BL, Jankovic J. Delayed-onset progressive movement disorders after static brain lesions. Neurology 1996;46:6874.
87. Klawans HL. Hemiparkinsonism as a late complication of hemiatrophy. Neurology 1981;31:625628.
88. Buchman AS, Goetz C, Klawans HL. Hemiparkinsonism with hemiatrophy. Neurology 1988;38:527530.
89. Jankovic J. Hemiparkinsonism and hemiatrophy. Neurology 1988;38:1815.
90. Greene PE, Bressman SB, Ford B, Hyland K. Parkinsonism, dystonia, hemiatrophy. Mov Disord 2000;15:537541.
91. Lang AE. Hemiatrophy, Juvenile-onset exertional alternating leg paresis, hypotonia, and hemidystonia and adult-onset
hemiparkinsonism: the spectrum of Hemiparkinsonism-Hemiatrophy syndrome. Mov Disord 1995;10:489494.
92. Marchioni E, Soragna D, Versino M et al. Hemiparkinsonism-hemiatrophy with brain hemihypoplasia. Mov Disord
1999;14:359363.
93. Siderowf AD, Galetta SL, Hurtig HI, Liu GT. Mov Disord 1998 ;13:170174.
94. Cicarelli G, Pelecchia MT, Maiuri F, Barone P. Brain stem cystic astrocytoma presenting with pure parkinsonism. Mov
Disord 1999;14:364366.
95. Wenning GK, Luginger E, Sailer U, et al. Postoperative parkinsonian tremor in a patient with a frontal meningioma.
Mov Disord 1999;14:366368.
96. Ling M, Aggrawal A, Morris JGL. Dopa-responsive parkinsonism secondary to right temporal lobe hemorrhage Mov
Disord 2002;17:402403.
97. Pohle T, Krauss J. Parkinsonism in children resulting from mesencephalic tumors. Mov Disord 1999;14:842846.
98. Leopold NA, Bara-Jimenez W, Hallett M. Parkinsonism after a wasp sting. Mov Disord 1999;14:122127.
99. Folgar S, Gatto EM, Raina G, Micheli F. Parkinsonism as a manifestation of multiple sclerosis. Mov Disord
2003;18:108113.
100. Clifford DB, McArthur JC, Schifitto G. A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor
impairment. Neurology 2002;59:15681573.
Neurophysiology of Atypical Parkinsonism 409
24
Role of Electrophysiology in Diagnosis and Research
in Atypical Parkinsonian Disorders
Josep Valls-Sol
INTRODUCTION
Correct clinical diagnosis of patients with parkinsonism is not always possible in spite of the
continuous effort in defining diagnostic criteria (1). Parkinsonism, defined as the combination of
bradykinesia and rigidity (2), may be a predominant clinical feature of several diseases, including
idiopathic Parkinsons disease (IPD) and several other entities commonly known as Parkinson-plus
syndromes or atypical parkinsonian disorders (APDs). In these entities, parkinsonism is accompa-
nied by other clinical signs, or red flags (3), that should warn the physician of the existence of a
degenerative disorder. Even though rather specific clinical patterns have been described in patients
with APDs, such as predominantly autonomic failure, cerebellar, or pyramidal dysfunction, in mul-
tiple system atrophy (MSA), axial rigidity, ocular motility disorders, and falls early in the course of
the disease, in progressive supranuclear palsy (PSP), myoclonus and asymmetrical higher cortical
limb dysfunction, in corticobasal degeneration (CBD), and fluctuating cognitive deficits, visual hal-
lucinations, and REM sleep behavior disorder, in diffuse Lewy-body disease (LBD), these signs are
not always evident or they may pass unrecognized by nonspecialized neurologists. In some condi-
tions, such as for instance CBD, similar clinical expressions may be common to different pathologies
(4), and the same disease may encompass diverse clinical presentations (5). In others, such as MSA
with parkinsonian features (MSA-P), patients may behave like IPD until death (6), making it almost
impossible to establish a clinical separation between the two diseases. Nowadays, the definite clini-
cal diagnosis still resides in the pathological postmortem examination (1,7,8).
When in doubt, the clinician may seek help in laboratory exams. Unfortunately, however, there are
not yet laboratory methods that can supply a diagnosis of certainty for APDs. Although single photon
emission computer tomography (SPECT) and positron emission tomography (PET) have shown
postsynaptic dopaminergic deficits in APDs (9), these tests are not yet capable of differentiating
between the various degenerative syndromes featuring parkinsonism. Though electrophysiological
studies do not usually provide the diagnosis, they can be of great help in the recognition of patho-
physiological mechanisms underlying the presentation of some symptoms and signs. In parkinsonism,
pallidal hyperactivity might be responsible for reduced activation of thalamocortical projections, and
for an abnormal control of brainstem circuits (1012). The situation might be slightly different in
APDs, in which the basal ganglia pathology is accompanied by neuronal loss and atrophy in many
nuclei of the brainstem and cerebellum, and dysfunctions might be present in various circuits. It is

409
410 Valls-Sol
therefore logical that, although some clinical neurophysiological manifestations are common to both
types of disorders, there are a few specific and distinctive features of each syndrome that may be
clinically useful.
Neurophysiological studies are suited to demonstrate, document, and quantify clinical observa-
tions. They are not expensive, and mainly noninvasive. They may occasionally bring information on
neurological functions that is not obtainable with other means. One such example is, for instance, the
measure of excitability in neuronal structures or circuits. In this chapter, we describe the neurophysi-
ological observations made in patients with the principal disorders grouped under the term APDs,
and discuss how the results compare between different patient groups.
NEUROPHYSIOLOGICAL CORRELATE OF PARKINSONISM

Patients with APDs usually present with the main clinical signs characteristic of parkinsonism,
i.e., bradykinesia and rigidity. Although clinicians identify bradykinesia and rigidity with no need for
neurophysiological recordings, these are convenient for quantitation of the dysfunction. Bradykine-
sia and, specially, rigidity are present with varying degree and localization in patients with parkin-
sonism. They may not be observed at all in patients at early stages of the cerebellar variant of multiple
system atrophy (MSA-C), though they will eventually appear during the course of the disease.
Hypokinesia and Bradykinesia

Hypokinesia and bradykinesia are abnormalities of movement, and the best way to quantify them
is with the use of reaction time task paradigms. Akinesia is defined as a delay in movement initiation,
whereas bradykinesia is defined as the slowness of movement execution (13). There are many studies
on reaction time in patients with IPD, but considerably less in APDs. Reaction time can be studied
using different methods, ranging from the execution of a task (14,15), the release of a switch or a
lever (16,17), the onset of limb displacement (18,19), or the onset of electromyogram (EMG) activity
(20,21). In paradigms of simple reaction time (SRT), the subject knows all details about the requested
motor performance before the imperative signal is delivered. In paradigms of choice reaction time
(CRT), subjects have to process some of the information contained in the imperative signal itself.
When measuring SRT as the onset of EMG activity in wrist extensors in patients with IPD, PSP, and
MSA, Valldeoriola et al. (22) found a significantly larger delay of reaction time in patients with PSP
in comparison to the other groups of patients (Fig. 1). This is in fitting with previously reported
results of an investigation of reaction time to progressively complex tasks in PSP patients (23). These
authors found an increased central processing time in patients with PSP compared with both IPD and
control subjects. PSP patients might have degraded cognition, with a delay in stimulus identification
and categorization processes (24).
The mechanisms underlying hypokinesia can be studied using EMG analysis of reaction time
tasks. Hallett and Khoshbin (10) found that IPD patients were unable to appropriately scale the size
of the first agonist burst to the requirements of a ballistic movement. They proposed that such defect
represented a physiological mechanism of bradykinesia. It is likely that the increased pallidal inhibi-
tion of thalamocortical excitatory connections accounts for such an abnormal energization of the
motor cortex. A proper study of the triphasic pattern in patients with APDs has not been done so far.
However, in a small group of PSP patients, Molinuevo et al. (25) observed abnormalities of the
triphasic pattern that were similar to those observed in IPD patients.
Rigidity
Rigidity in patients with parkinsonism manifests as a difficulty of complete muscle relaxation,
with often permanent tonic background EMG activity (11). Several neurophysiological tests have
been used to assess rigidity, although direct clinico-neurophysiological correlations have proven more
difficult than with bradykinesia. Rigidity has been considered to be the cause of some neurophysi-
Fig. 1. Histograms of the mean and 1 standard deviation of simple reaction time values (expressed in ms)
for EMG activity, onset of movement and task execution in healthy volunteers, and in patients with IPD,
PSP, and MSA.
ological findings in IPD, such as an increased size of the F wave (26), increased size of long loop
reflex responses to stretch (27) or to electrical stimuli (2830), abnormalities in the silent period
induced by transcranial magnetic stimulation (31,32), reduced reciprocal inhibition (33,34), and
reduced autogenic (Ib) inhibition of the soleus H reflex (35). However, none of those tests is spe-
cific for rigidity, which continues to be assessed by clinical evaluation of the resistance to passive
movements.
Like with bradykinesia, most tests directed to the evaluation of rigidity have been proven in
patients with IPD, and more scarcely in patients with APDs. However, it is not unreasonable to
admit that when and where rigidity is present, patients with APDs would present similar abnormali-
ties as those described for IPD. Direct surface electrophysiological recording of a muscle in rigid
patients in resting conditions may be enough to notice that there is increased muscle activity with
respect to normal subjects. Electrophysiological evidence for that can be found when testing the
relaxation time after a sustained contraction (36). The stretch reflex, which is the most paradigmatic
electrophysiological test for limb rigidity, has not been properly tested in patients with APDs. In
these patients, rigidity often predominates in axial muscles and is very mild in limb muscles, making
it more difficult for neurophysiological evaluation. The shortening reaction (3740) is a relatively
poorly studied long latency reflex that occurs in the muscle shortened during a passive movement. Its
frequent presence in patients with IPD could reflect the difficulties of these patients in modulating
sensory signals generated by either joint afferents (38), tendon organ afferents (39), or both. Unfortu-
nately, however, there have not been recent studies on such an interesting phenomenon.
The pathophysiology of rigidity may be related to abnormalities in propriospinal reflexes. In their
study of IPD patients, Delwaide et al. (35) postulate that reduced autogenic inhibition mediated by Ib
interneurons would be a neurophysiological correlate of rigidity. Interestingly, however, in the sole
study published so far on spinal physiological mechanisms in APD patients, Fine et al. (41) reported
increased Ib inhibition in patients with PSP. The observation of such an opposite behavior between
IPD and PSP patients might be useful for differential diagnosis but points to the fact that neurophysi-
412 Valls-Sol
ological observations might only be one manifestation of dysfunctional mechanisms. Further studies
are required to find out the mechanisms by which the Ib interneurons are modulated in a different
direction in PSP and IPD, and what is the exact role of this dysfunction in the generation of rigidity.
NEUROPHYSIOLOGICAL TESTS IN THE ASSESSMENT OF ATYPICAL

PARKINSONIAN DISORDERS
Some neurophysiological features are specific or distinctive of patients with APDs. However, this
does not mean that the electrophysiological findings hold the key for the diagnosis, since sensitivity
and specificity of the tests has not been properly examined yet. The most relevant of these observa-
tions are described below, where they are grouped according to the neurophysiological method or
technique in which the observation is based.
Brainstem Reflexes
The brainstem is a crucial structure for integration of reflexes and functions related to motor con-
trol. These structures receive modulatory inputs from more rostral centers, including the basal gan-
glia. There are many nuclei and circuits of interest in the brainstem for neurophysiological studies.
However, it is still difficult to assign the results of some neurophysiological observations to specific
brainstem centers or circuits. Therefore, most data gathered from the study of the brainstem in patients
with APDs have the value of an empirical finding, and the exact anatomical/pathological correlation in
humans is mainly based on hypothesis and theoretical knowledge from animal experiments.
Table 1 summarizes the observations made in patients with parkinsonism regarding facial move-
ments and brainstem reflexes. Although many brainstem circuits are dysfunctional in patients with
APDs, the examination of brainstem reflexes and functions yields more interesting results in patients
with PSP than in any other form of parkinsonism.
Eye and Eyelid Movements
Some of the most striking features differentiating PSP from other disorders presenting with par-
kinsonism regard facial expression and gaze disturbances (42). A list of abnormalities reported so far
regarding eye or eyelid movements in these patients is shown in Table 2. The resting blink rate, of 24
per minute in normal controls, was found to be reduced in most patients with parkinsonism (43), but
significantly more so in patients with PSP, whose mean blinking frequency can be reduced to as little
as 4 blinks per minute. Blinking rate may be an expression of the level of dopamine activity.
Clinical evidence of eye movement abnormalities is not always present in the initial phases of the
disease (42). If the possibility of PSP is suspected on the basis of some other clinical features, record-
ing of eye movements by electro-oculography might be of some help. Surface electrodes are placed
in the upper, lower, nasal, and temporal edges of the orbit and the subject is requested to make
horizontal and vertical eye movements (44). Electro-oculogram recordings may show characteristic
abnormalities in patients with PSP (45), including slowness of vertical eye movements, absent Bells
phenomenon, and square wave jerks (Fig. 2). In the study reported by Vidailhet and coworkers, 9 out
of 10 patients with PSP had vertical-gaze paralysis with preserved reflex eye movements. Vidailhet
et al. (46) also showed slowness of horizontal eye movement and microsaccades that would help in
distinguishing patients with PSP from those with other parkinsonisms. Some eye movement abnor-
malities are already apparent at simple inspection. A PSP patient exhibiting slowness of saccades and
limitation of vertical eye movement with preserved oculo-cephalic reflexes is shown in video segment 1.
Reflex Responses of the Orbicularis Oculi
In contrast to the reduced frequency of spontaneous blinking, reflex responses of the orbicularis
oculi to trigeminal nerve inputs are of normal latency (47). The normality of reflex responses to
trigeminal nerve stimuli is in contrast to the absence or significant reduction of the responses to
auditory inputs (48). Whether the response of the orbicularis oculi to loud auditory stimulus is part of
Table 1
Characteristics of Some Brainstem Reflexes and Functions in Patients With Parkinsonism
Test IPD PSP MSA CBD
Spontaneous Reduced Extremely Reduced Enhanced Normal
blinking frequency Normal Reduced
Excitability recovery Enhanced Enhanced Enhanced Normal
curve (paired pulses)
Blinking to loud auditory Normal Reduced Normal or Increased Normal
stimuli
Blinking to median nerve Normal Reduced or Absent Normal Normal
stimuli
Auditory prepulse Reduced Reduced ? ?
inhibition
Somatosensory prepulse Normal Reduced ? ?
inhibition
IPD, idiopathic Parkinsons disease; PSP, progressive supranuclear palsy; MSA, multiple system atrophy
(strionigral degeneration); CBD, corticobasal degeneration; ?, data unknown.
Table 2
Eye and Eyelid Movement Abnormalities Observed in Patients With PSP
Reduced spontaneous blinking (43)
Blepharospasm (42)
Supranuclear palsy of eyelid opening (45)
Supranuclear palsy of eyelid closing (42)
Reduced voluntary suppression of vestibular ocular reflex (VOR) (42)
Eyelid retraction (Cowpers sign) (42)
Square-wave jerks (46)
Absent eyelid responses to acoustic stimuli (48)
Absent eyelid responses to median nerve stimuli (47)
the generalized startle reaction or is an auditory blink reflex with separate physiological characteris-
tics is still a matter of debate (49,50). In any case, the reduction of orbicularis oculi responses to
auditory stimuli is indeed an important observation of some clinical utility in the differential diagno-
sis of APDs.
The palmomental reflex is usually elicited by scratching the volar aspect of the thenar eminence or
the thumb. This leads to a reflex movement of the chin that is considered abnormal when it shows
reduced habituation (51). Electromyographic recording of facial muscle responses during elicitation
of the palmomental reflex permits the quantitation of the responses (52). The facial reflex response is
not limited to the mentalis muscle but is usually accompanied by an ipsilateral eyelid movement that
can be apparent with simple inspection and readily demonstrated with surface electromyographic
recording (Fig. 3A). Interestingly, in patients with PSP, contraction of eyelid muscles is not present
even when the mentalis response is evident (see the second part of video segment 1 on accompanying
DVD). In a protocolized study of facial reflexes in patients with parkinsonism, Valls-Sol et al. (47)
analyzed the responses elicited simultaneously in the mentalis and orbicularis oculi muscles by
median nerve electrical stimulation. The study included patients with IPD, PSP, MSA, CBD, and
healthy volunteers. Responses in the mentalis muscle were found in most patients and in 2 out of 10
normal subjects. In all of them, whenever there were responses in the mentalis muscle, there were
414 Valls-Sol
Fig. 2. Electro-oculogram in a healthy subject (A) and in a patient with PSP (B) during fixation to an object
(upper traces) and voluntary saccades (lower traces). Note the presence of small eye movements during fixa-
tion, and of a slow and staircase eyeball displacement during the saccadic movement.
Fig. 3. Facial reflex responses to median nerve stimulation in a patient with IPD (A), and in a patient with
PSP (B). Note the absence of orbicularis oculi response in the patient with PSP even though the mentalis muscle
response (lower traces) is similar in both patients.
also responses in the orbicularis oculi muscle. The exception were the patients with PSP, who had no
orbicularis oculi responses even if the responses of the mentalis muscle were not different from those
observed in the other groups of patients (Fig. 3B). This abnormality probably reflects the activation
of two different circuits by the median nerve afferent volley. The mentalis response could be con-
veyed through the cortico-nuclear tract, since this tract innervates predominantly lower facial moto-
neurons (53), and a transcortical loop has been suggested because of the contiguity between thumb
and chin areas in the brain sensorimotor region (52,54). The selective damage of the pontine reticular
formation in patients with PSP would be responsible for the absence of the orbicularis oculi response.
Enhancement of mentalis response may occur because of disinhibition of thalamo-cortical connec-
tions from their striatal control (54).
One of the earliest contributions of electromyography to the assessment of central nervous system
(CNS) abnormalities in patients with parkinsonism was made by Kimura in 1973 (55). Kimura dem-
onstrated in these patients the existence of an abnormal decrease of habituation of the blink reflex to
paired supraorbital nerve electrical stimuli. The fact that the abnormalities occurred in the R2 but not
in the R1 component of the blink reflex suggested that the disturbance lies in the interneurons rather
than in the motoneurons. Since then, many authors have studied the blink reflex excitability recovery
curve to paired stimuli, by dividing the size of the response to the test stimulus by that of the response
to the conditioning stimulus. This sign has been reported not only in parkinsonism, but in many other
disorders as well (56,57). It is therefore of little use for differential diagnosis between degenerative
disorders. In clinical practice, the assessment of enhanced trigemino-facial reflex excitability may be
of interest for documenting the existence of an abnormal function of brainstem interneurons in patients
in whom clinical assessment is dubious or at early stages of their disease. We found similar interneu-
ronal brainstem excitability enhancement in IPD, PSP, and MSA patients (47). Figure 4 shows the
proposed circuit of basal ganglia control of trigemino-facial reflex excitability, according to Basso
and Evinger (58) and Basso et al. (59), and the dysfunction likely occurring in parkinsonism.
Other Facial Reflexes
Neurophysiological abnormalities have been reported in other brainstem reflexes in parkinsonism,
although they have not been investigated specifically in APDs (6062). It has been shown that the
second inhibitory period of the masseteric exteroceptive inhibitory reflex has an enhanced excitabil-
ity recovery cycle, similar to that of the blink reflex in patients with IPD. The same excitability
recovery abnormalities have been reported in parkinsonism and dystonia (60).
The Startle Reaction and the Startle-Induced Modulation of Reaction Time
The startle reaction in experimentation animals is known to be generated in the nucleus reticularis
pontis caudalis (nRPC), which activates the reticulospinal tract inducing muscle responses in facial
and spinal motoneurons (63). In humans, the startle reaction is also thought to originate in corre-
sponding nuclei of the brainstem, and spread caudally and rostrally to limb and facial muscles.
Abnormalities in the startle reaction can be related to enhancement or reduction of the response
size. One example of abnormal startle response enhancement is hyperkeplexia (64), whereas an
abnormal startle response reduction takes place in patients with PSP (48). The decrease of the
startle reaction in PSP patients should not be surprising, since neuronal loss in these patients involves
specifically the cholinergic neurons of the lower pontine reticular formation, where the startle reac-
tion is generated. Neuronal loss has been reported in the pedunculo-pontine tegmental nucleus and
the nucleus reticularis pontis caudalis (6567). In the study carried out by Vidailhet et al. (48), the
response was absent in three out of eight patients, and it was small and delayed in the other five
patients. The same finding was later replicated by Valldeoriola et al. (22), who carried out a compara-
tive study of PSP and other APDs.
Whereas response enhancement is easy to identify because of reactions of larger size and decreased
habituation, assessment of an abnormal reduction of the response may be more difficult because of the
fact that the response habituates easily in healthy subjects (49). For this reason, the observations
made in experiments in which the startling stimulus was applied together with the imperative signal
in the context of a reaction time task paradigm should be helpful for clinical purposes. Using such
methods, Valls-Sol and coworkers (6870) made a few interesting observations in healthy subjects:
1. The startling stimulus applied together with the imperative signal of a reaction time task induces a signifi-
cant acceleration in the execution of the intended movement. The ballistic movement is executed without
any distortion but at a significantly faster speed (70).
416 Valls-Sol
Fig. 4. Basal ganglia control of trigemino-facial reflex excitability. The basal ganglia modulate the excit-
ability of the blink reflex through the output signals arising from the globus pallidus pars interna (GPi) and the
substantia nigra pars reticulata (SNr). According to Basso et al. (58) and Basso and Evinger (59), the GPi/SNr
complex sends inhibitory inputs to the superior colliculus (SC), which is excitatory for the nucleus raphe magnus
(nRM). This, in turn, inhibits the trigeminal neurons of the spinal nucleus. In PD, there is increased GPi/SNr
inhibition of the SC which, as a consequence, reduces its excitatory inputs to the nRM. The less active nRM
induces less inhibition of the spinal trigeminal nucleus, which becomes dis-inhibited (hyperexcitable). As with
bradykinesia, it is difficult to know whether the same mechanisms apply to APDs. I, inhibitory; E, excitatory of
stimulus.
2. The response to the startling stimulus is enhanced. The same startling stimulus that would give rise to a
relatively small and inconsistent response when given alone induce a significantly larger response when is
applied during motor preparation (68).
3. Habituation of the response to the startling stimulus is significantly reduced. In a study in which auditory
stimuli were applied at the same rate in different experimental conditions, Valls-Sol et al. (69) found that
habituation of the response to the startling stimulus was reduced in facial and cervical muscles when
subjects were engaged in preparation for a ballistic reaction.
Clinical application of the collision between a startle reaction and the voluntary activity in a reac-
tion time task paradigm (the StartReact effect) was reported by Valldeoriola et al. (22). These authors
found that patients with PSP not only had absent startle reaction but they were also not able to accel-
erate their voluntary reaction when the startling stimulus was applied together with the imperative
signal.
In contrast to patients with PSP, patients with MSA have normal auditory startle reaction in facial
and cervical muscles (71). Furthermore, when the responses of cranial and limb muscles are analyzed
together, MSA patients had enhanced probability of a response, shortened onset latency, and enlarged
response magnitude compared to normal controls (72,73). In the only analysis of the startle response in
patients with LBD, Kofler et al. (73) reported fewer and abnormally delayed ASR of low amplitude and
short duration in extremity muscles in comparison to healthy controls. Two more details of the studies
of Kofler and coworkers (72,73) are relevant for the discussion of the contribution of the startle
reaction to the differential diagnosis of APD patients. One is the fact that three patients with MSA
had no response to the startle reaction, indicating that absence of the startle reaction is not a feature
exclusive to PSP patients (48). A particularly high density of oligodendroglial cytoplasmatic inclu-
sions in the brainstem area responsible for the generation of the reticulospinal tract was assumed to
be the cause of absent startle response in those MSA patients. Another observation made by Kofler
et al. (72) was the existence of subtle differences in the characteristics of the response between
MSA-P and MSA-C patients. Whereas MSA-P patients had a higher startle probability and a larger
area and shorter latency of the motor response, patients with MSA-C had less habituation. Differ-
ences between the two groups in the inhibitory effect of the cerebellum over the motor cortex may be
responsible for such neurophysiological observation (72).
Prepulse Inhibition
A weak stimulus preceding by about 100 ms the startling stimulus has an effect of inhibition upon
the startle reaction (prepulse inhibition). The prepulse stimulus may be of the same or a different
sensory modality as the stimulus inducing the startle (50). In the blink reflex, an auditory prepulse
causes enhancement of the R1 and depression of the R2 to electrical supraorbital nerve stimuli (74).
In a study of prepulse inhibition in patients with IPD, Nakashima et al. (75) found that auditory
prepulse stimuli induced an abnormally reduced inhibition of the R2 response of the blink reflex, and
Lozza et al. (76) reported an abnormally reduced blink reflex inhibition after index finger stimula-
tion. However, some patients with IPD have an abnormal auditory prepulse inhibition and a normal
somatosensory prepulse inhibition (77). The different behavior of auditory and somatosensory
prepulse stimuli in IPD patients could be owing to differences in the prepulse effectiveness of the
same vs different sensory modality, differences in the arrival time of prepulse inputs to the brainstem
centers, or to selective impairment of reticular formation neurons activated by auditory inputs. Patients
with PSP have also absent or significantly reduced prepulse inhibition to both auditory and somatosen-
sory prepulses (Fig. 5), revealing an even more striking dysfunction of the prepulse circuit in PSP
compared to IPD. No data are available so far regarding prepulse inhibition in MSA patients.
Spinal Reflexes
A variety of tests determining the excitability of propriospinal interneurons (78,79) have been
applied to patients with IPD, demonstrating reduced reciprocal (33,34) and autogenetic (Ib) inhibi-
tion (35), possibly related to the clinical expression of rigidity. These exams have not been done in
patients with APDs, except for a single study of autogenetic inhibition (Ib inhibition) in patients with
PSP (41). In such a study, the authors showed enhancement of the inhibition, the exact opposite of
what was reported in patients with IPD. The explanation why opposite results have been found in
these two groups of patients is, up to now, not clear.
Audiospinal facilitation is known as the effect of an auditory stimulus on spinal reflexes, specifi-
cally the soleus H reflex. The methods for audiospinal facilitation were developed by Rossignol and
Jones (80) and Delwaide et al. (81). The stimulus to the posterior tibial nerve to induce the H reflex is
applied between 0 and 110 ms after a loud acoustic stimulus. Healthy subjects have H reflex facilita-
tion beginning at intervals between 60 and 80 ms, and lasting until the intervals of 100 or 110 ms.
However, audiospinal facilitation is abnormally reduced in patients with IPD (12,81). Our own pre-
liminary observations in patients with the clinical diagnosis of probable PSP is that they exhibit the
same abnormality (82).
Surface EMG Recording of Abnormal Movements

The recording of abnormal movements by means of surface EMG recording yields interesting
information for the analysis of tremor, such as in patients with IPD (82). Tremor has also been reported
in up to 74% of MSA patients (83). However, this figure included several types of tremor, with only a
few patients exhibiting the resting tremor typical of IPD, and a large proportion of unclassifiable
hands and finger jerky tremors, such as those shown in video segment 2. Electrophysiological
studies of these latter movements have shown that their characteristics are closer to myoclonus than
to tremor (84). A piezoelectric accelerometer was used to record finger movements and analyze the
418 Valls-Sol
Fig. 5. Prepulse inhibition of the blink reflex in a healthy volunteer and in a patient with PSP. The traces of
the upper row show the responses to a stimulus to the supraorbital nerve applied at the vertical line. Ipsilateral
recordings (ipsi) show R1 and R2 responses whereas contralateral recordings show only the R2. The traces of
the lower row show the responses to the same stimulus when a prepulse is applied 100 ms before (arrows).
(A) Normal auditory prepulse inhibition in a healthy volunteer; (B) Absent auditory prepulse inhibition in a
patient with PSP. (C) Absent somatosensory prepulse inhibition in the same patient.
frequency spectrum of the signal through fast Fourier transformation. This procedure showed that
movements of MSA patients were rather non-rhythmic in comparison to those of patients with other
forms of tremor (Fig. 6). Salazar et al. (84) suggested the term minipolymyoclonus to be used to
describe these small amplitude, irregular, jerklike abnormal movements. Other forms of myoclonus
have been also reported in a few MSA patients (30,85), which might have their origin in a reduced
inhibition of the strio-palido-thalamo-cortical circuit (86). Table 3 shows a list of disorders in which
activity defined as minipolymyoclonus has been encountered, together with some of the most rel-
evant neurophysiological findings.
Myoclonus is also an apparent feature in patients with CBD (87), in whom they are thought to be
of cortical origin in spite of lacking neurophysiological evidence. The expected findings of cortical
myoclonus, such as giant somatosensory evoked potentials and jerk-locked EEG potentials, are incon-
sistent in CBD. The cortical response is occasionally absent, which is attributed to the marked frontopa-
rietal cortical atrophy and neuronal degeneration characteristic of these patients (88,89). Cortical
atrophy of inhibitory neurons could lead to the enhanced (disinhibited) motor cortex excitability.
The C wave, or focal reflex myoclonus (90), is a response seen in forearm muscles after electri-
cal stimulation of ipsilateral cutaneous nerves of the hand. This response is thought to be mediated by
fast-conducting afferent and efferent pathways and might have a latency as short as 43.1+/3.2 ms
(87). In some patients, focal reflex myoclonus might be elicited by stimuli of an intensity below
perception threshold, which suggests a direct connection from the thalamic nuclei to the motor cortex
(91). The C response should not be mistaken for the long latency excitatory response of the cutaneo-
muscular reflexes (92,93). The cutaneo-muscular reflex can be elicited during a sustained tonic vol-
untary contraction of the forearm muscles. The long latency excitatory component of the
cutaneo-muscular reflex is abnormally enhanced in patients with IPD or MSA (30). However, the
latency of such a response is longer than that of the C reflex.
Fig. 6. Surface EMG recording from wrist extensors (A), accelerometric recording of finger movements
(B), and FastFourier analysis of the movement recording (C) in a patient with MSA and minipolymyoclonus.
See the absence of a dominant frequency peak.
Table 3
Disorders Featuring Minipolymyoclonus
Disorder Dominant Clinical Sign EMG Bursts EEG C wave
Motoneuron disease Fasciculation atrophy Asynchronous (120 Hz) Not described Not described
Polyneuropathy Absent tendon jerks Slow and asynchronous Not described Not described
Severe sensory deficit
Alzheimers disease Dementia Multifocal Slow waves Present
Epileptiform
activity
Negative
frontal wave
Myoclonic epilepsy Seizures Synchronized or irregular Slow negative Present
frontal wave
Syringomyelia Weakness. Spasticity Asynchronous and Not described Not described
Sensory deficit irregular
MSA-P Rigid-akinetic syndrome Synchronous (112 Hz) Normal Present
Autonomic Reflexes and Functions

Autonomic nervous system dysfunction is the key to the diagnosis in patients with MSA who
present with parkinsonism or cerebellar syndromes (3), and is presently a required criterion for the
diagnosis of probable MSA (94). Clinically relevant autonomic dysfunctions in these patients are
orthostatic hypotension, urinary and fecal incontinence, erectile dysfunction in males, sudomotor
disregulation, and abnormalities in respiratory control during sleep. Autonomic dysfunction, i.e.,
urinary incontinence (97%) and constipation (83%), has also been reported in patients with LBD (95).
420 Valls-Sol
Orthostatic hypotension may result from the inability to increase sympathetic activity when stand-
ing. This can be shown as an abnormal regulation of baroreflex responses to different stimuli (96).
Using readily available electrophysiological equipment, it is also possible to monitor heartbeat fre-
quency. Recording the R-R interval variation by means of the signal trigger and the delay line unit of
an electromyograph shows graphically the reduced adaptation of the heart beat rate to a postural
change or to the Valsalva maneuver (77). The main drawback of this test is that patients with severe
bradykinesia might be unable to perform adequately the maneuvers, and reduced R-R interval varia-
tion could actually be owing to insufficient stimulation. One of the possibilities to test R-R interval
variation using methods that do not require the patients cooperation is based on the fact that the
startle response is normal in MSA patients (71,72), and on the observation that a startle accelerates
heartbeat frequency in normal subjects (97). In a group of six MSA patients, a startling acoustic
stimulus induced the normal motor component of the startle reaction but a significantly smaller change
of the R-R interval in comparison to healthy volunteeers (98).
The sympathetic sudomotor skin response, or SSR (99), may reveal dysfunctions in the autonomic
control of sudomotor reflexes. Loss of sympathetic neurons of the intermediolateral column might
explain the finding of frequently abnormal SSRs in patients with MSA (100). Other tests of sudomo-
tor function, such as the evaluation of the amount of sweat production to direct gland stimulation
with intradermal methacholine, have also demonstrated a decreased sweat response in patients with
MSA (101).
Sleep disorders are frequent in patients with MSA and in those with LBD. Some of these disorders
might be related to autonomic dysfunction. In the study of Plazzi et al. (102), 35 out of 39 patients
with MSA had REM sleep behavior disorders. These preceded the diagnosis in 44% of the cases.
Polysomnographic studies revealed subclinical obstructive sleep apnea in 6 patients, laryngeal stri-
dor in 8 patients, and periodic leg movements during sleep in 10 patients. Laryngeal stridor, owing to
vocal cord abductor paralysis during sleep, is probably caused by selective denervation atrophy of
the cricoarytenoid muscle resulting from selective loss of neurons in the nucleus ambiguous (103),
and may lead to chocking and death in advanced stages of MSA. This can be prevented with tracheo-
stomy (104) or with continuous positive air pressure (105). REM sleep behavior disorder has also
been considered a sign heralding LBD (106) and, in a more recent study, it is considered as a possible
hallmark of a synucleinopathy in the setting of a cognitive dementia or parkinsonism (107).
Needle EMG Recording of the Sphincter Muscles

In MSA patients, manifestations of autonomic dysfunctions such as erectile impotence are usually
accompanied by increased urinary frequency and urgency, leading soon to incontinence, associated
with large residual urine volumes (108). The severity of urinary symptoms is one main red flag that
should warn the neurologist of the possibility that the parkinsonian patient thought to have IPD is
actually facing the diagnosis of probable MSA (3). Urinary incontinence in MSA patients might be
because of autonomic dysfunction, loss of pontine control of micturition, striatal sphincter denerva-
tion, or a combination of them all. Striatal sphincter denervation is attributed to the selective loss of
motoneurons in the nucleus of Onuff at the S2-S3 medullary segments. Needle electromyography
of the external anal sphincter, therefore, is considered an important neurophysiological test in the
assessment of patients with parkinsonism, as most patients with MSA show denervation-reinnerva-
tion signs (109,110). We and others have confirmed that anal sphincter denervation is prominent in
patients with MSA, although similar types of abnormalities have been found in a large proportion of
patients with PSP as well as in some patients with IPD (111,112). Therefore, the utility of anal or
vesical sphincter needle EMG in the diagnosis of MSA is still under debate (113,114). Chronic con-
stipation, local trauma related to delivery, and other pudendal nerve long-standing lesions may give
rise also to sphincter denervation (115,116), which may diminish the validity of the sign as a true
marker of motoneuronal loss. In the consensus statement for the diagnosis of MSA (94), sphincter
EMG abnormalities are considered as a supportive laboratory finding.
Transcranial Magnetic Stimulation

There are not many studies published on the use of transcranial magnetic stimulation (TMS) in
patients with APDs in comparison to the large body of literature published in patients with IPD.
However, finding an abnormality in central conduction time in a patient with parkinsonism should be
considered as a red flag to warn of the likely existence of a degenerative disorder different from IPD.
Central motor conduction time has been found slightly delayed in a number of patients with MSA, in
both the parkinsonian (117) and cerebellar variants (118).
Many other cortical and subcortical functional measures can be determined with single-pulse TMS,
including resting and active threshold, stimulus-response curves, silent period duration, or cortical
maps, but only a few studies of this kind have been carried out in patients with APDs. Most of them
have been performed in patients with CBD, a disorder featuring clinical signs of asymmetrical sen-
sorimotor cortex involvement. Recording from muscles of the more affected side, Lu et al. (119)
reported shortened TMS-induced silent period, and Strafella et al. (120) reported enhanced facilita-
tion and reduced inhibition of MEPs modulated by digital nerve stimulation. These findings are likely
reflecting motor cortical excitability enhancement.
Patients with CBD exhibit lack of voluntary control of limb movements (video segment 3), or
alien-hand syndrome, which suggests a cortical dysfunction (121,122). In normal subjects, unilat-
eral TMS, applied with the figure of 8 coil, induces hand muscle responses restricted to the con-
tralateral side. However, in 6 out of 10 patients with CBD, Valls-Sol et al. (123) found bilateral
responses to focal, unilateral, TMS applied to the side contralateral to the alien hand (Fig. 7). Ipsilat-
eral responses were delayed with respect to the contralateral ones by a mean of 7.7 2.2 ms, a time
allowing for conduction through the corpus callosum. Such abnormality was not found in any of 10
normal subjects, 8 patients with Alzheimers disease, or 6 patients with IPD presenting with pre-
dominantly unilateral rigidity. This finding points again to an enhanced motor cortex excitability in
the hemisphere contralateral to the alien hand, which may be unable to inhibit transcallosal excitatory
inputs from the other hemisphere.
Paired-pulse TMS has been also used in the study of corticospinal tract functions in patients with
APD. Intrahemispheric cortico-cortical inhibition was found abnormally reduced in patients with MSA-
P, but not in patients with MSA-C (124). It has also been abnormal in the study of patients with CBD
(125,126), suggesting the possibility of its clinical utility in the early phases of the disease (126).
TMS is an important tool not only for the assessment of cortical motor function but also for the
analysis of the modulatory effects that descending pathways might have on segmental reflexes.
Using methods similar to those proposed by Delwaide and collaborators with auditory stimuli (81),
we examined the effects of TMS on the soleus H reflex in normal subjects and in patients with
parkinsonism. In healthy volunteers, TMS induced early (530 ms) and late (60100 ms) phases of
significant facilitation of the soleus H reflex (127). The second phase is absent or significantly
reduced in about 50% of patients with IPD (82), and in all eight patients with PSP examined so far
(unpublished results).
Evoked Potentials
The early components of the somatosensory evoked potentials in patients with IPD are normal,
except for the N30 recorded at the frontal lobe, which shows reduced amplitude (128). According to
Rossini and collaborators, the reduced amplitude of the N30 might be owing to an abnormal sen-
sorimotor integration (129). A different kind of abnormality has been reported in patients with PSP.
In these patients, Kofler and collaborators (130) reported an enhancement of the amplitude of the
early components of the somatosensory evoked potentials, which was considered to be the conse-
quence of cortical disinhibition. More recently, Miwa and Mizuno (131) confirmed the finding and
proposed that the observation of enlarged somatosensory evoked potentials can be useful in the dif-
ferentiation of PSP patients from other patients with movement disorders.
422 Valls-Sol
Fig. 7. Recordings from bilateral thenar muscles to focal, unilateral, transcranial magnetic stimulation (TMS)
in a healthy control subject (A), and in a patient with CBD (B). Upper traces result from left-hemisphere TMS,
and lower traces from right-hemisphere TMS. Note the presence of a delayed ipsilateral MEP in the patient.
The premotor evoked potentials are abnormal in patients with IPD, likely reflecting a disturbance
in preparation of the motor act. Deecke et al. (132) showed that there was a delay and reduction of the
bereitschaftpotential, and abnormalities in event-related potentials have been also published. How-
ever, there are no studies of the premotor potentials in patients with APDs.
NEUROPHYSIOLOGICAL TESTS MOST USEFUL

FOR DIFFERENTIAL DIAGNOSIS IN PATIENTS WITH APD
There is no single clinical neurophysiology test that can be used to distinguish with certitude
between patients with APD at an individual level. This situation of clinical neurophysiology is com-
mon to many other conditions. In practicing clinical neurophysiology, the examiner is constantly
looking for data that can bring more cues to confirm or refute an hypothesis made on the basis of
clinical exam. The selection of tests useful for differential diagnosis in patients with APD can only be
orientative or suggestive, but conclusive. One of the roles of those whose work is devoted to clinical
neurophysiology should be to search for new methods and technical improvements to bring further
understanding on pathophysiological mechanisms of the disease process.
From the authors point of view, the neurophysiological tests that better characterize parkinsonism
and, specifically, the APDs, are listed in Table 4. Performance of ballistic movements within a reac-
tion time task paradigm is useful to test the mechanisms of motor preparation and execution, even
though very much should still be learned on the physiology of motor preparation for the test to pro-
vide its full potential of information. Brainstem and spinal reflexes have to be conveniently modu-
lated by the descending motor commands for them to be integrated in the subjects normal motor
behavior. Although many tests have given interesting information on the abnormal brainstem and
spinal reflex modulation in patients with parkinsonism, a good clinical correlate of these abnormali-
ties is still pending. The evaluation of autonomic reflexes and the sphincter EMG provides informa-
tion on specific abnormalities that can be predominant in certain groups of patients. They reflect the
involvement of specific groups of neurons, well correlated with pathologic findings. However, they
are not useful for the diagnosis on an individual patient basis since similar abnormalities can be
Table 4
Selection of Neurophysiological Findings Allowing for Characterization of Specific Disorders
Presenting With Parkinsonism
Disorder Results of Neurophysiological Tests
IPD Mild delay of reaction time in performance of ballistic movements
Reduced prepulse inhibition of the blink reflex to auditory stimuli, with normal prepulse
inhibition to somatosensory stimuli
Regular alternating tremor at rest
PSP Absent startle reaction to auditory stimuli
Absent orbicularis oculi response to a median nerve electrical stimulus eliciting a response
in the mentalis muscle
Reduced prepulse inhibition of the blink reflex to both auditory and somatosensory stimuli
MSA Signs of denervation-reinnervation in sphincter muscles
Signs of autonomic dysfunction
Minipolymyoclonus
CBD Spontaneous and reflex myoclonus
Asymmetry in cortical maps of representation of hand muscles
LBD REM sleep behavior disorder
present in other groups of patients. TMS, short latency evoked potentials, and event-related poten-
tials, are all offering many possibilities for the study of motor and sensory pathways as well as brain
sensorimotor integration and high level processing of information. Although many studies have been
carried out in patients with parkinsonism, very few reports on APDs have been published so far. A
large amount of research is under way regarding the physiological mechanisms of TMS and event-
related potentials. Many of them are already available for clinical application and more will be in the
near future, allowing for better characterization of the abnormalities involving sensory and motor
functions of patients with APDs.
FURTHER RESEARCH IN NEUROPHYSIOLOGY OF APD

There is a large amount of possibilities for research in neurophysiology of parkinsonism and of
movement disorders in general. Neurophysiology offers the advantage of a good temporal resolution
of events and should bring further understanding of what is wrong in the CNS that leads to motor
dsyfunction. The research in clinical neurophysiology will probably continue until the pathophysi-
ological mechanisms of the diseases are well understood. However, meaningful information can only
be obtained if a careful neurological examination is followed by an imaginative albeit meticulous
neurophysiological study. Undoubtedly, the most rewarding situation would be the one in which
neurologists and clinical neurophysiologists join their efforts. Relevant and interesting information
derived from neurophysiological studies should stir up the interest of clinicians, whereas challenging
questions arising from clinical exams should stimulate the imagination of the clinical neurophysiolo-
gist in devising new techniques for more careful documentation of the signs.
Although the cooperation between clinical and neurophysiological experts is the first condition
for the development of future lines of research, the second one is the development of better methods
for clinical diagnosis of the diseases. Neurophysiology would be able to provide accurate informa-
tion on the pathophysiology of movement disorders only if the diagnostic uncertainty is reduced to
negligible levels. A thorough neurophysiological characterization of patients with APDs, appropri-
ately classifed into well-differentiated groups, would certainly bring information that may be useful
in the future to improve the diagnostic accuracy but, most of all, the pathophysiology of the diseases.
Suggestions for future research lines are listed in Table 5. Some of them are based on clinical
features that should be the focuss of neurophysiological studies. However, some techniques may be
424 Valls-Sol
Table 5
Lines of Future Research in Neurophysiology of APD
Clinical Feature Research Lines
Motor systems Documentation of bradykinesia when performing natural tasks
Methods for enhancing energization of the motor tract
Readiness and premotor potentials
Relationship between mental processes and motor actions
Role of external cues and rhythms on movement performance
Dysfunction of subcortical motor pathways
Source of rest and action tremor oscillations
Sensory systems Multilevel sensorimotor integration
Long latency and event-related evoked potentials
Intersensory facilitation vs collision between sensory stimuli
Spinal cord reflexes Alpha motoneuronal excitability
The role of propriospinal inhibitory circuits in rigidity
Brainstem physiology Relationship between basal ganglia and brainstem nuclei
Recording pedunculopontine tegmental nucleus functions
Physiology of automatic movements
Spontaneous and reflex blinks
Cortical stimulation Modulation of cortical responses with sensory inputs
Ipsilateral effects of TMS
Repetitive transcranial magnetic stimulation
able to demonstrate features of the disease that point to the dysfunction of certain nervous system
centers or structures. Among those techniques, TMS and event-related potentials are probably the
most promising ones. Since their implantation, TMS and especially repetitive TMS (rTMS) have
opened a large avenue of research in parkinsonism and other movement disorders. They will cer-
tainly bring more possibilities for neurophysiological interventions in the near future, including thera-
peutic actions. It has been demonstrated that the introduction of a variable amount of electrical current
in brain tissues by applying rTMS of different intensities and frequencies induces excitability changes
that can in turn be measured by conventional TMS or other methods (133). Since 1994 (134), rTMS
has been used as a therapy in patients with IPD. Although there has been contradictory observations
up to the most recently published papers (135,136), researchers will certainly keep trying until the
technique finds its position among the armamentarium of neurophysiological interventions in patients
with APDs. Recording event-related brain potentials should provide information on structures that may
be dysfunctional in parkinsonism. Cognitive negative variation has been reported to be improved
after subthalamic nucleus stimulation (137), indicating the sensitivity of the test to basal ganglia
cortical loop function. A variety of other neurophysiological techniques could be in the list of sug-
gestions for future studies. The reader may find helpful information regarding many of those
procedures in the specialized literature. However, apart from knowing technical details, the researcher
interested in neurophysiology of parkinsonism should exercise imagination to find new ways to dem-
onstrate specific features of the disease.
LEGENDS FOR THE VIDEO SEGMENTS

Video segment 1. Two patients with PSP featuring slow and limited voluntary eye movements.
The second patient shows responses of the lower facial muscles, but not of the periocular muscles, to
a scratch stimulus to the thenar eminence.
Video segment 2. Two patients with MSA-P showing minipolymyoclonus. Note the irregular
movements, sometimes limited to one finger
Video segment 3. Two patients with corticobasal degeneration. The first patient shows some fea-
tures of alien limb. The second patient had asymmetrical upper limb appraxia.
REFERENCES
1. Litvan I, Bhatia KP, Burn DJ, et al. SIC Task force appraisal of clinical diagnostic criteria for Parkinsonian disorders.
Mov Disord 2003;18:467486.
2. Jankovic J, Rajput AH, McDermott MP, Perl DP. The evolution of diagnosis in early Parkinsons disease. Arch Neurol
2000;57:369372.
3. Quinn N. Multiple system atrophythe nature of the beast. J Neurol Neursurg Psychiatry 1989;Suppl:7889.
4. Boeve BF, Maraganore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal ganglionic
degeneration. Neurology 1999;53:795800.
5. Bergeron C, Pollanen MS, Weyer L, Black SE, Lang AE. Unusual clinical presentations of cortical basal ganglionic
degeneration. Ann Neurol 1996;40:893900.
6. Hughes AJ, Colosimo C, Kleedorfer B, Daniel SE, Lees AJ. The dopaminergic response in multiple system atrophy.
7. Poewe W, Wenning G. The differential diagnosis of Parkinsons disease. Eur J Neurol 2002;9(Suppl 3):2330.
8. Dickson DW, Bergeron C, Chin SS, et al. Office of rare diseases neuropathologic criteria for corticobasal degeneration.
Exp Neurol 2002;61:935946.
9. Brooks DJ, Ibez V, Sawle GV, et al. Striatal D2 receptor status in patients with parkinsons disease, striatonigral
degeneration, and progressive supranuclear palsy, measured with IIC-raclopride and positron emission tomography.
Ann Neurol 1992;31:184192.
10. Hallett M, Khoshbin SA. A physiological mechanism of bradykinesia. Brain 1980;103:301314.
11. Berardelli A, Sabra AF, Hallett M. Physiological mechanisms of rigidity in Parkinsons disease. J Neurol Neurosurg
Psychiatry 1983;46:4583.
12. Delwaide P, Pepin JL, DePasqua V, Maertens de Noordhout A. Projections from the basal ganglia to tegmentum: a
subcortical route for explaining the pathophysiology of Parkinsons disease signs? J Neurol 2000;247(Suppl 2):7581.
13. Hallett M. Clinical neurophysiology of akinesia. Rev Neurol 1990;146:585-590.
14. Rafal RD, Posner MI, Walker JA, Friedrich FJ. Cognition and the basal ganglia. Separating mental and motor compo-
nents of performance in Parkinsons disease. Brain 1984;107:10831094.
15. Bloxham CA, Dick DJ, Moore M. Reaction times and attention in Parkinsons disease. J Neurol Neurosurg Psychiatry
1987;50:11781183.
16. Daum I, Quinn N. Reaction times and visuospatial processing in Parkinsons disease. J Clin Exp Neuropsychol
1991;13:972982.
17. Godaux E, Koulischer D, Jacquy J. Parkinsonian bradykinesia is due to depression in the rate of rise of muscle activity.
Ann Neurol 1992;31:93100.
18. Evarts EV, Teravainen H, Calne DB. Reaction time in Parkinsons disease. Brain 1981;104:167186.
19. Pullman SL, Watts RL, Juncos JL, Chase TN, Sanes JN. Dopaminergic effects on simple and choice reaction time
performance in Parkinsons disease. Neurology 1988;38:249254.
20. Berardelli A, Dick JPR, Rothwell JC, Day BL, Marsden CD. Scaling of the size of the first agonist EMG burst during
rapid wrist movements in patients with Parkinsons disease. J Neurol Neurosurg Psychiatry 1986;49:12731279.
21. Pascual-Leone A, Valls-Sol J, Brasil-Neto JP, Cohen LG, Hallett M. Akinesia in Parkinsons disease. I. Shortening of
simple reaction time with focal, single pulse transcranial magnetic stimulation. Neurology 1994;44:884891.
22. Valldeoriola F, Valls-Sol J, Tolosa E, Ventura PJ, Nobbe FA, Mart MJ. The effects of a startling acoustic stimulus on
reaction time in patients with different parkinsonian syndromes. Neurology 1998;51:13151320.
23. Dubois B, Pillon B, Legault F, Agid Y, Lhermitte F. Slowing of cognitive processing in progressive supranuclear palsy.
A comparison with Parkinsons disease. Arch Neurol 1988;45:11941199.
24. Johnson R Jr, Litvan I, Grafman J. Progressive supranuclear palsy: altered sensory processing leads to degraded cogni-
tion. Neurology 1991;41:12571262.
25. Molinuevo JL, Valls-Sol J, Valldeoriola F. The effect of transcranial magnetic stimulation on reaction time in progres-
sive supranuclear palsy. Clinical Neurophysiology 2000;111:20082013.
26. Abbruzzese G, Vische M, Ratto S, Abbruzzese M, Favale E. Assessment of motor neuron excitability in parkinsonian
rigidity by the F wave. J Neurol 1985;232:246249.
27. Rothwell JC, Obeso JA, Traub MM, Marsden CD. The behavior of the long latency stretch reflex in patients with
Parkinsons disease. J Neurol Neurosurg Psychiatry 1983;46:3544.
28. Deuschl G, Lucking CH. Physiology and clinical applications of hand muscle reflexes. Electroenceph Clin Neurophysiol
1990;Suppl 41:84101.
29. Fuhr P, Zeffiro T, Hallett M. Cutaneous reflexes in Parkinsons disease. Muscle Nerve 1992;15:733739.
30. Chen R, Ashby P, Lang AE. Stimulus-sensitive myoclonus in akinetic rigid syndromes. Brain 1992;115:18751888.
426 Valls-Sol
31. Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis MS, Mutani R. Parkinsons disease rigidity: magnetic MEPs
in a small hand muscle. Neurology 1991;41:14491456.
32. Valls-Sol J, Pascual-Leone A, Brasil-Neto JP, McShane L, Hallett M. Abnormal facilitation of the response to
transcranial magnetic stimulation in patients with Parkinsons disease. Neurology 1994;44:735741.
33. Bathien N, Rondot P. Reciprocal continuous inhibition in rigidity of parkinsonism J Neurol Neurosurg Psychiatry
1977;40:2024.
34. Lelli S, Panizza M, Hallett M. Spinal cord inhibitory mechanisms in Parkinsons disease. Neurology 1991;41:553556
35. Delwaide P, Pepin JL, Maertens de Noordhout A. Short latency autogenic inhibition in patients with parkinsonian
rigidity. Ann Neurol 1991;30:8389.
36. Grasso M, Mazzini L, Schieppati M. Muscle relaxation in Parkinsons disease: a reaction time study. Mov Disord
1996;11:411420.
37. Angel RW, Lewitt PA. Unloading and shortening reactions in Parkinsons disease. J Neurol Neurosurg Psych
1978;41:919923.
38. Bathien N, Toma S, Rondot P. tude de la raction de raccourcissement prsente chez lhomme dans diverses affec-
tions neurologiques. Electroenceph Clin Neurophys 1981;51:156164.
39. Berardelli A, Hallett M. Shortening reaction of human tibialis anterior. Neurology 1984;34:242246.
40. Diener C, Scholz E, Guschlbauer B, Dichgans J. Increased shortening reaction in Parkinsons disease reflects a diffi-
culty in modulating long loop reflexes. Mov Disord 1987;2:3136.
41. Fine EJ, Hallett M, Litvan I, Tresser N, Katz D. Dysfunction of Ib (autogenic) spinal inhibition in patients with progres-
sive supranuclear palsy. Mov Disord 1998;13:668672.
42. Golbe LI, Davis PH, Lepore FE. Eyelid movement abnormalities in progressive supranuclear palsy. Mov Disord
1989;4:297302.
43. Karson CN, Burns S, LeWitt P, Foster NL, Newman RP. Blink rates and disorders of movement. Neurology
1984;34:677678.
44. Heide W, Koenig E, Trillenberg P, Kmpf D, Zee DS. Electrooculography: technical standards and applications.
Electroenceph Clin Neurophysiol 1999;(Suppl 52):223240.
45. Chu FC, Reingold DB, Cogan DG, Williams AC. The eye movement disorders of progressive supranuclear palsy.
Ophthalmology 1979;86:422428.
46. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Eye movements in parkinsonian syndromes. Ann Neurol 1994;35:
420426.
47. Valls-Sol J, Valldeoriola F, Tolosa E, Mart MJ. Distinctive abnormalities of facial reflexes in patients with progres-
sive supranuclear palsy. Brain 1997;120:18771883.
48. Vidailhet M, Rothwell JC, Thompson PD, Lees AJ, Marsden CD. The auditory startle response in the Steele
RichardsonOlszewsky syndrome and Parkinsons disease. Brain 1991;115:11811192.
49. Brown P, Rothwell JC, Thompson PD, Day BL, Marsden CD. New observations on the normal auditory startle reflex in
man. Brain 1991;114:18911902.
50. Valls-Sol J, Valldeoriola F, Molinuervo JL, Cossu G, Nobbe F. Prepulse modulation of the startle reaction and the
blink reflex in normal human subjects. Exp Brain Res 1999;129:4956.
51. Heilman KM. Exploring the enigmas of frontal lobe dysfunction. Geriatrics 1976;31:8187.
52. Dehen H, Bathien N, Cambier J. The palmo-mental reflex. An electrophysiological study. Eur Neurol 1975;13:395404.
53. Jenny AB, Saper CB. Organization of the facial nucleus and corticofacial projection in the monkey: a reconsideration
of the upper motor neuron facial palsy. Neurology 1987;37:930939.
54. Maertens de Noordhout A, Delwaide PJ. The palmomental reflex in Parkinsons disease. Comparisons with normal
subjects and clinical relevance. Arch Neurol 1988;45:425427.
55. Kimura J. Disorders of interneurons in parkinsonism. The orbicularis oculi reflex to paired stimuli. Brain 1973;96:8796.
56. Smith SJ, Lees AJ. Abnormalities of the blink reflex in Gilles de la Tourette syndrome. J Neurol Neurosurg Psychiatry
1989;52:895898.
57. Eekhof JL, Aramideh M, Bour LJ, Hilgevoord AA, Speelman HD, Ongerboer de Visser BW. Blink reflex recovery
curves in blepharospasm, torticollis spasmodica, and hemifacial spasm. Muscle Nerve 1996;19:1015
58. Basso MA, Powers AS, Evinger C. An explanation for reflex blink hyperexcitability in Parkinsons disease. I. Superior
colliculus. J Neurosci 1996;16:73087317.
59. Basso MA, Evinger C. An explanation for reflex blink hyperexcitability in Parkinsons disease. II Nucleus raphe
magnus. J Neurosci 1996;16:73187330.
60. Cruccu G, Pauletti G, Agostino R, Berardelli A, Manfredi M. Masseter inhibitory reflex in movement disorders.
Huntingtons chorea, Parkinsons disease, dystonia, and unilateral masticatory spasm. Electroenceph Clin Neurophysiol
1991;81:2430.
61. Alfonsi E, Nappi G, Pacchetti C, et al. Changes in motoneuron excitability of masseter muscle following exteroceptive
stimuli in Parkinsons disease. Electroencephalogr Clin Neurophysiol 1993;89:2934
62. Deuschl G, Goddemeier C. Spontaneous and reflex activity of facial muscles in dystonia, Parkinsons disease, and in
normal subjects. J Neurol Neurosurg Psychiatry 1998;64:320324.
63. Davis M, Gendelman DS, Tischler MD, Gendelman PM. A primary acoustic startle circuit: lesion and stimulation
studies. J Neurosci 1982;2:791805.
64. Brown P, Rothwell JC, Thompson PD, Britton TC, Day BL, Marsden CD. The hyperekplexias and their relationship to
the normal startle reflex. Brain 1991;114:19031928.
65. Zweig RM, Whitehouse PJ, Casanova MF, Walker LC, Jankel WR, Price DL. Loss of pedunculopontine neurons in
progressive supranuclear palsy. Ann Neurol 1987;22:1825.
66. Malessa S, Hirsch EC, Cervera P, et al. Progressive supranuclear palsy: loss of cholinergic acetyltransferase-like
immunoreactive neurons in the pontine reticular formation. Neurology 1991;41:15931597.
67. Juncos JL, Hirsch EC, Malessa S, Duyckaerts C, Hersh LB, Agid Y. Mesencephalic cholinergic nuclei in progressive
supranuclear palsy. Neurology 1991;41:2530.
68. Valls-Sol J, Sol A, Valldeoriola F, Muoz E, Gonzlez LE, Tolosa ES. Reaction time and acoustic startle. Neurosci
Lett 1995;195:97100
69. Valls-Sol J, Valldeoriola F, Tolosa E, Nobbe F. Habituation of the startle reaction is reduced during preparation for
execution of a motor taskin normal human subjects. Brain Res 1997;751:155159.
70. Valls-Sol J, Rothwell JC, Goulart F, Cossu G, Muoz JE. Patterned ballistic movements triggered by a startle in
healthy humans. J Physiol 1999;516:931938.
71. Valldeoriola F, Valls-Sol J, Toloa E, Nobbe FA, Muoz JE, Mart MJ. The acoustic startle response is normal in
patients with multiple system atrophy. Mov Disord 1997;12:697700.
72. Kofler M, Mller J, Seppi K, Wenning GK. Exaggerated auditory startle responses in multiple system atrophy: a com-
parative study of parkinson and cerebellar subtypes. Clin Neurophysiol 2003;114:541547.
73. Kofler M, Mller J, Wenning G, et al. The auditory startle reaction in parkinsonian syndromes. Mov Disord 2001;16:
6271.
74. Ison JR, Sanes JN, Foss JA, Pinckney LA. Facilitation and inhibition of the human startle blink reflexes by stimulus
anticipation. Behav Neurosci 1990;104:418429.
75. Nakashima K, Shimoyama R, Yokoyama Y, Takahashi K. Auditory effects on the electrically elicited blink reflex in
patients with Parkinsons disease. Electroenceph Clin Neurophysiol 1993;89:108112.
76. Lozza A, Pepin JL, Rapisarda G, Moglia A, Delwaide PJ. Functional changes of brainstem reflexes in Parkinsons
disease. Conditioning of the blink reflex R2 component by paired and index finger stimulation. J Neural Transm
1997;104:679687.
77. Valls-Sol J. Neurophysiological characterization of parkinsonian syndromes. Neurophysiol Clin 2000;30:352367.
78. Pierrot-Deseilligny E, Mazires L. Circuits rflexes de la moelle epinire chez lhomme. Rev Neurol 1984;140(Part
I):605614
79. Pierrot-Deseilligny E, Mazires L. Circuits rflexes de la moelle epinire chez lhomme. Rev Neurol 1984;140(Part
II):681694.
80. Rossignol S, Jones GM. Audio-spinal influence in man studied by the H-reflex and its possible role on rhythmic move-
ments synchronized to sound. Electroenceph Clin Neurophysiol 1976;41:8392.
81. Delwaide P, Pepin JL, Maertens de Noordhout A. The audiospinal reaction in Parkinsonian patients reflects functional
changes in reticular nuclei. Ann Neurol 1993;33:6369
82. Valls-Sol J, Valldeoriola F. Neurophysiological correlate of clinical signs in Parkinsons disease. Clinical Neuro-
physiology 2002;113:792805.
system atrophy. An analysis of 100 cases. Brain 1994;117:835845.
84. Salazar G, Valls-Sol J, Mart MJ, Chang H, Tolosa ES. Postural and action myoclonus in patients with parkinsonian
type multiple system atrophy. Mov Disord 2000;15:7783.
85. Gouider-Khouja N, Vidailhet M, Bonnet AM, Pichon J, Agid Y. Pure striatonigral degeneration and Parkinsons
disease: a comparative clinical study. Mov Disord 1995;10:288294.
86. Patel S, Slater P. Analysis of the brain regions involved in myoclonus produced by intracerebral picrotoxin. Neuro-
science 1987;20:687693.
87. Thompson PD, Day BL, Rothwell JC, Brown P, Britton TC, Marsden CD. The myoclonus in corticobasal degeneration.
Evidence for two forms of cortical reflex myoclonus. Brain 1994;117:11971208.
88. Gibb WRG, Luthert PJ, Marsden CD. Corticobasal degeneration Brain 1989;112:11711192.
89. Brunt ERP, vanWeerden TW, Pruim J, Lakke JWPF. Unique myoclonic pattern in corticobasal degeneration. Mov
Disord 1995;10:132142.
90. Sutton GG, Mayer RF. Focal reflex myoclonus. J Neurol Neurosurg Psychiatry 1974;37:207217.
91. Mauguire F, Desmedt JE, Courjon J. Astereognosis and dissociated loss of frontal or parietal components of soma-
tosensory evoked potentials in hemispheric lesions: detailed correlations with clinical signs and computerized tomo-
graphic scanning. Brain 1983;106:271311.
92. Caccia MR, McComas AJ, Upton ARM, Blogg T. Cutaneous reflexes in small muscles of the hand. J Neurol Neursurg
Psychiatry 1973;36:960977.
428 Valls-Sol
93. Jenner JR, Stephens JA. Cutaneous reflex responses and their central nervous pathways studied in man. J Physiol
1982;333:405-419.
1999;163:9498.
95. Horimoto Y, Matsumoto M, Akatsu H, et al. Autonomic dysfunctions in dementia with Lewy bodies. J Neurol
2003;250:530533.
96. Benarroch EE, Chang FLF. Central autonomic disorders. J Clin Neurophysiol 1993;10:3950.
97. Holand S, Girard A, Laude D, Meyer-Bisch C, Elghozi JL. Effects of an auditory startle stimulus on blood pressure and
heart rate in humans. J Hypertens 1999;17:18931897.
98. Valls-Sol J, Veciana M, Len L, Valldeoriola F. Effects of a startle on heart rate in patients with multiple system
atrophy. Mov Disord 2002;17:546549.
99. Shahani BW, Halperin JJ, Boulu P, Cohen J. Sympathetic skin response: a method of assessing unmyelinated axon
dysfunction in peripheral neuropathies. J Neurol Neurosurg Psychiatry 1984;47:536542.
100. Bordet R, Benhadjali J, Destee A, Hurtevent JF, Bourriez JL, Guieu JD. Sympathetic skin response and R-R interval
variability in multiple system atrophy and idiopathic Parkinsons disease. Mov Dis 1996;11:268272.
101. Baser SM, Meer J, Polinsky RJ, Hallett M. Sudomotor function in autonomic failure. Neurology 1991;41:15641566.
102. Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders in multiple system atrophy. Neurology
1997;48:10941097.
103. Bannister R, Gibson W, Michaels L, Oppenheimer DR. Laryngeal abductor paralsysis in multiple system atrophy. A
report on three necropsied cases, with observation on the laryngeal muscles and the nuclei ambigui. Brain
1981;104:351368.
104. Isozaki E, Naito A, Horiguchi S, Kawamura R, Hayashida T, Tanabe H. Early diagnosis and stage classification of vocal
cord abductor paralysis in patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996;60:399402.
105. Iranzo A, Santamara J, Tolosa E, et al. Continuous positive air pressure eliminates nocturnal stridor in multiple system
atrophy. The Lancet 2000;356:13291330.
106. Turner RS. Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia with Lewy bodies. J Geriatr
Psychiatry Neurol 2002;15:195199.
107. Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or
108. Kirby R, Fowler CJ, Gosling J, Bannister R. Urethro-vesical dysfunction in progressive autonomic failure with mul-
tiple system atrophy. J Neurol Neurosurg Psychiatry 1986;49:554562.
109. Sakuta M, Nakanishi T, Toyokura Y. Anal muscle electromyograms differ in amyotrophic lateral sclerosis and Shy
Drager syndrome. Neurology 1978;28:12891293.
110. Eardley I, Quinn NP, Fowler CJ, et al. The value of urethral sphincter electromyography in the differential diagnosis of
parkinsonism. Br J Urol 1989;64:360362.
111. Valldeoriola F, Valls-Sol J, Tolosa ES, Mart MJ. Striated anal sphincter denervation in patients with progressive
supranuclear palsy. Mov Disord 1995;10:550555.
112. Giladi N, Simon ES, Korczyn AD, et al. Anal sphincter EMG does not distinguish between multiple system atrophy and
Parkinsons disease. Muscle Nerve 2000;23:731734.
113. Rodi Z, Denislic M, Vodusek DB. External anal sphincter electromyography in the differential diagnosis of parkin-
sonism. J Neurol Neurosurg Psychiatry 1996;60:460461.
114. Libelius R, Johansson F. Quantitative electromyography of the external anal sphincter in Parkinsons disease and mul-
tiple system atrophy. Muscle Nerve 2000;23:12501256.
115. Kiff ES, Swash M. Slowed conduction in the pudendal nerves in idiopathic (neurogenic) faecal incontinence. Br J Surg
1984;71:614616.
116. Podnar S, Vodusek DB. Standardization of anal sphincter electromyography: effect of chronic constipation. Muscle
Nerve 2000;23:17481751.
117. Abbruzzese G, Marchese R, Trompetto C. Sensory and motor evoked potentials in multiple system atrophy: a compara-
tive study with Parkinsons disease. Mov Disord 1997;12:315321.
118. Cruz Martinez A, Arpa J, Alonso M, Palomo F, Villoslada C. Transcranial magnetic stimulation in multiple system and
late onset cerebellar atrophies. Acta Neurol Scand 1995;92:218224.
119. Lu CS, Ikeda A, Terada K, et al. Electrophysiological studies of early stage corticobasal degeneration. Mov Disord
1998;13:140146.
120. Strafella A, Ashby P, Lang AE. Reflex myoclonus in cortical-basal ganglionic degeneration involves a transcortical
pathway. Mov Disord 1997;12:360369.
121. Goldberg G, Mayer NH, Toglia JU. Medial frontal cortex infarction and the alien hand sign. Arch Neurol 1981;38:
683686.
122. Feinberg TE, Schindler RJ, Flanagan NG, Haber LD. Two alien hand syndromes. Neurology 1992;42:1924.
123. Valls-Sol J, Tolosa E, Mart MJ, et al. Examination of motor output pathways in patients with corticobasal ganglionic
degeneration using transcranial magnetic stimulation. Brain 2001;124:11311137.
124. Marchese R, Trompetto C, Buccolieri A, Abbruzzese G. Abnormalities of motor cortical excitability are not correlated
with clinical features in atypical parkinsonism. Mov Disord 2000;15:12101214.
125. Hanajima R, Ugawa Y, Terao Y, Ogata K, Kanazawa I. Ipsilateral cortico-cortical inhibition of the motor cortex in
various neurological disorders. J Neurol Sci 1996;140:109116.
126. Frasson E, Bertolasi L, Bertasi V, et al. Paired transcranial magnetic stimulation for the early diagnosis of corticobasal
ganglionic degeneration. Clin Neurophysiol 2003;114:272278.
127. Goulart F, Valls-Sol J, Alvarez R. Posture-related modification of soleus H reflex excitability. Muscle Nerve
2000;23:925932.
128. Rossini PM, Babiloni F, Bernardi G, et al. Abnormalities of short-latency somatosensory evoked potentials in parkinso-
nian patients. Electroenceph Clin Neurophysiol 1989;74:277289.
129. Rossini PM, Filippi MM, Vernieri F. Neurophysiology of sensorimotor integration in Parkinsons disease. Clin Neurosci
1998;5:121130.
130. Kofler M, Mller J, Reggiani L, Wenning GK. Somatosensory evoked potentials in progressive supranuclear palsy.
J Neurol Sci 2000;179:8591.
131. Miwa H, Mizuno Y. Enlargements of somatosensory-evoked potentials in progressive supranuclear palsy. Acta Neurol
Scand 2002;106:209212.
132. Deecke L, Englitz HG, Kornhuber HH, Schmitt G. Cerebral potential preceding voluntary movement in patients with
bilateral or unilateral Parkinson akinesia. In: Desmedt JE, ed. Progress in Clinical Neurophysiology, vol. 1. Basel:
Karger, 1977:151163.
133. Rizzo V, Siebner HR, Modugno N, et al. Shaping the excitability of human motor cortex with premotor rTMS. J Physiol
2004;554:483495.
134. Pascual-Leone A, Valls-Sole J, Brasil-Neto JP, Cammarota A, Grafman J, Hallett M. Akinesia in Parkinsons disease.
II. Effects of subthreshold repetitive transcranial motor cortex stimulation. Neurology 1994;44:892898.
135. Ikeguchi M, Touge T, Nishiyama Y, Takeuchi H, Kuriyama S, Ohkawa M. Effects of successive repetitive transcranial
magnetic stimulation on motor performances and brain perfusion in idiopathic Parkinsons disease. J Neurol Sci
2003;209:4146.
136. Okabe S, Ugawa Y, Kanazawa I. Effectiveness of rTMS on Parkinsons Disease Study Group. 0.2-Hz repetitive
transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinsons
disease. Mov Disord 2003;18:382388.
137. Gerschlager W, Alesch F, Cunnington R, et al. Bilateral subthalamic nucleus stimulation improves frontal cortex function
in Parkinsons disease. An electrophysiological study of the contingent negative variation. Brain 1999;122:23652373.
Role of CT and MRI 431
25
Role of CT and MRI in Diagnosis and Research
Mario Savoiardo and Marina Grisoli
INTRODUCTION
In degenerative disorders, computed tomography (CT) is usually requested only to avoid a misdi-
agnosis or to exclude an unlikely tumor or another unexpected pathology. It is true, however, that CT
can demonstrate atrophic changes that, in cases in which they are typically distributed, may contrib-
ute to the diagnosis.
In a few atypical parkinsonian disorders, such as progressive supranuclear palsy and
olivopontocerebellar degeneration, CT was used up to the mid-1980s to support the clinical diagno-
sis. At present, however, its role is very limited. In this group of disorders, demonstration of atrophy
or other structural changes of deep nuclei is not obtainable by CT and not even always by magnetic
resonance imaging (MRI). There is no question, however, that, in atypical parkinsonian disorders,
MRI is a very useful and easily available diagnostic tool. We shall, therefore, focus on the MRI
findings that can be demonstrated in these diseases, and review what is now widely accepted and
consolidated, what is strongly diagnostic if not pathognomonic of a specific disorder, what is less
predictive or uncertain, and what should be studied in future investigations.
After a few comments on Parkinsons disease (PD), we shall discuss multiple system atrophy
(MSA) of the parkinsonian type (MSA-P) and cerebellar type (MSA-C), progressive supranuclear
palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), and, briefly, vas-
cular parkinsonism and toxic and metabolic conditions causing parkinsonism.
PARKINSONS DISEASE
A few papers have described that, on MRI, atrophy of the pars compacta of the substantia nigra
can be demonstrated in T2-weighted thin sections (13). Its isointense narrow band, delimited ante-
riorly by hypointensity of the medial part of the cerebral peduncle and the loss of signal intensity
owing to iron deposits in the pars reticulata and, posteriorly, in the red nucleus, becomes progres-
sively thinner. However, the smudging of the hypointensity, which should indicate atrophy of the
pars compacta, can also be observed in an unknown proportion of cases in patients with atypical
parkinsonian disorders (4,5). Other sequences and quantification of brain iron have been proposed
(6,7). MRI observation of the substantia nigra is, therefore, not easy. It requires a dedicated examina-
tion that has not become a routine study in any center because of two other reasons. First, the neurolo-
gists do not need MRI to diagnose PD and, second, neuroradiologists and neurologists rely on other
observations to support a differential diagnosis between PD and atypical parkinsonian disorders.
Actually, in most of the papers dealing with MRI in PD and parkinsonisms, the substantia nigra is

431
432 Savoiardo and Grisoli
disregarded or ignored. The normal MRI features of patients with PD are used as a control for a
series of other abnormalities affecting specific nuclei, structures, or areas that point to a specific
parkinsonian disorder.
An important advancement in the MRI diagnosis of PD has been proposed by Hutchinson and
Raff (8,9). A ratio between the signals obtained with two different sequences suppressing the signal
from white matter and gray matter, respectively, exquisitely demonstrated the substantia nigra to the
point that serial studies could be expected to even predict the disease. So far, this technique has not
been commonly used (10), probably because of technical difficulties in obtaining the ratio.
The neuroradiological differential diagnosis of MSA, PSP, and CBD from PD, therefore relies
upon the demonstration of lesions in the nuclei or areas that pathology shows to be characteristically
affected in each specific disorder. In a few instances, the neuroradiologist has helped the pathologist
to pinpoint subtle abnormalities that turned out to be useful for the diagnosis.

MSA has been separated into MSA-P and MSA-C according to the predominant parkinsonian or
cerebellar features. The former corresponds to the old term striatonigral degeneration (SND), the
latter to sporadic olivopontocerebellar atrophy (OPCA). The term ShyDrager syndrome is no longer
been considered useful by the Consensus Conference on MSA (11), but a proposal to introduce the
term MSA-A (autonomic featurespredominant MSA) was recently made by Horimoto et al. (12) to
indicate those MSA patients in whom autonomic dysfunction predominated over cerebellar or par-
kinsonian features.
For the purpose of identifying the MRI characteristic features or markers or pointers of the differ-
ent atypical parkinsonian disorders, one should consider the pathology of the specific disorder (13).
There is no doubt that in MSA-P or SND the pathology is mostly in the putamen, whereas in MSA-C
the changes are in the brainstem and cerebellum. In MSA-A, most of the abnormalities are in the
spinal cord and may be, therefore, disregarded when considering MRI.
Multiple System Atrophy of the Parkinsonian Type

The MRI abnormalities observed in MSA-P have been described in several papers; they should be
considered separately according to whether they are obtained at low- or high-field intensity MRI
(1419).
Low-field intensity MRI (up to 0.5T) demonstrates increased signal intensity in proton density
and T2-weighted images in the dorsolateral and posterior part of the putamen, where loss of neurons
and gliosis in a loose tissue have been described (20,21). These findings correspond to an increased
amount of water in the tissue (Fig. 1). Atrophy of the putamen has been commonly observed (22) but
only recently emphasized by Yekhlef et al. (23).
High-field intensity MRI (usually 1.5T) shows a different feature, i.e., putaminal hypointensity in
T2-weighted images that may completely or almost completely mask the hyperintensity described
above (1619,2426). The hypointensity is caused by a magnetic susceptibility effect mainly owing
to deposits of iron in the same putaminal areas (27); this effect is proportional to the square of the
magnetic field intensity and is, therefore, usually evident only at high-field MRI. A lateral rim of
hyperintensity, indicating a band devoid of iron right on the lateral margin of the posterior part of the
putamen, may be recognizable (25), particularly if we observe proton density and T2-weighted
images together. In fact, the magnetic susceptibility effect is much less evident in proton density
images. This slit-like lateral rim of hyperintensity has been briefly called the putaminal slit (12).
In conclusion, at 1.5 T MRI putaminal hypointensity in T2-weighted images more marked in the
posterior part of this nucleus and the associated thin lateral rim of hyperintensity are the features of
MSA-P (17,25,26,28,29) (Fig. 2).
Fig.1. MSA-P. 0.5 T, coronal T2-weighted image shows increased signal intensity in the right putamen in a
patient with parkinsonism prevalent on the left side.
A very thin line of milder hyperintensity along the entire lateral profile of the putamen, at the
interface with the external capsule, may be confused with the lateral hyperintense rim or
putaminal slit. This very subtle line has been occasionally observed in atypical parkinsonian dis-
orders (30). In our experience, a very thin line that also borders the anterior part of the putamen,
often without associated hypointensity, may be a nonsignificant finding since we have observed it,
although rarely, mainly in normal subjects (Fig. 2B). As in the figure shown by Macia et al. (30), it
should be noted that the evidence of this line is mostly along the anterior part of the putamen,
whereas the abnormalities documented by pathology in MSA-P and shown by MRI typically affect
the posterior putamen (21,27).
All these details are important when one is investigating sensitivity and specificity of MRI abnor-
malities in MSA-P. Specificity, sensitivity, and positive predictive value of the putaminal abnormali-
ties have been investigated in a limited number of studies (18,19,23). The specificity is high, but
sensitivity has been considered low, generally not higher than 5060% (18,19). As most
neuroradiologists know, conventional spin-echo (CSE) images are more sensitive than fast spin-echo
(FSE) images to magnetic susceptibility effects owing to iron deposits in the tissue. In MSA-P,
Righini et al. (31) have elegantly demonstrated that, by using CSE thin sections (3 mm) and compari-
son of proton density and T2-weighted images vs FSE 5 mm T2-weighted images, the sensitivity is
increased from 45% to more than 83%.
Another trivial explanation of the difference in sensitivity between different series is the length of
the disease at time of MRI examination. Only very few investigations have dealt with the MRI dem-
onstration of the progression of MSA (12,26). In the series reported by Watanabe et al. (26), fre-
quency of putaminal abnormalities went up from 38.5% in patients with 2 yr or less from motor
impairment to 80% in patients with more than 4 yr from motor impairment.
Of course, MRI abnormalities supporting the diagnosis of MSA-P have a greater importance if
they are recognizable in the early stages of the disease, when the clinical diagnosis is still uncertain,
rather than in its late stages. Detection of subtle abnormalities that may indicate the diagnosis of
MSA-P rather than PD on the first MRI examination, performed at the time of the first visit by a
neurologist, may occur, but such episodes are still anecdotical. How early the abnormalities appear is
an aspect that needs to be clarified.
A few proton MR spectroscopy (MRS) studies have demonstrated that N-acetylaspartate (NAA)
and choline (Cho) were reduced in the lentiform nucleus of MSA patients (32,33). The NAA/creatine
(Cr) ratio was particularly decreased in MSA-P patients, probably reflecting putaminal neuronal loss
(32). MRS, however, has not been widely used to help differentiate patients with MSA from patients
with PD.
The use of diffusion-weighted imaging (DWI) has been recently proposed to help differentiating
MSA-P from PD (34). The Innsbruck group demonstrated that the patients with MSA-P presented an
increased regional apparent diffusion coefficient (rADC) in the putamen compared with both patients
with PD and normal subjects (34). In another study, however, DWI failed to discriminate MSA-P and
PSP (35). The advantage of DWI is that one can obtain measurements and quantification. It is not
clear, however, whether DWI studies of the basal ganglia in MSA-P patients will prove to have a
greater sensitivity than the CSE sequences of MRI, as described by Righini et al. (31).
Multiple System Atrophy of the Cerebellar Type

In MSA-C there are two types of abnormalities, atrophy and signal changes, which do not depend
on magnetic field intensity (36). Atrophy has a very characteristic distribution; it mainly involves the
pons, middle cerebellar peduncles, and cerebellum. Therefore, the diagnosis can be suspected when
one simply observes, in the MRI sagittal midline section, the decreased bulking of the pons compared
to the midbrain and particularly the medulla oblongata. The flattening of the profile of the pons
begins, in fact, in its caudal part (Fig. 3A). In addition to atrophy, signal changes may be recognized
in proton density and T2-weighted images consisting of slight hyperintensity in the structures that
degenerate or become gliotic (36). They include: (a) the pontine nuclei and their fibers (the transverse
pontine fibers) that run mostly on the anterior and posterior aspect of the basis pontis, cross the
midline on the raphe, and reach the cerebellum through the middle cerebellar peduncles (Figs. 3B and
C); and (b) the whole cerebellum, because of loss of Purkinje cells and degeneration of their fibers
and consequent diffuse gliosis. To make the resulting MRI picture more characteristic, these signal
abnormalities are combined with the signal preservation of the structures that do not degenerate (17).
They are mainly the superior cerebellar peduncles and the corticospinal tracts. The axial sections of
the pons, therefore, present a typical aspect with a sort of cross recognized in the early papers (36),
later defined as the hot cross bun sign (18,26) or simply the cross sign (12) (Figs. 3B and C).
Coronal sections are particularly useful to demonstrate the cerebellar hyperintensity when it is very
slight, by allowing a comparison in the same image of the infratentorial and the supratentorial struc-
tures (17,36). They also beautifully demonstrate the atrophy of the middle cerebellar peduncles (36).
Fig. 2. (opposite page) MSA-P. 1.5 T, axial sections (AE). First examination (A,B) performed when the
patient, with a 2-yr history of dysautonomia, developed mild right-sided parkinsonism. The proton density
image (A) is normal whereas the T2-weighted image (B) shows mildly decreased signal intensity in the poste-
rior part of the left putamen (curved arrow), consistent with iron deposits. The very subtle bands of
hyperintensity along the anterior part of the putamina (arrowheads) probably are a nonsignificant finding. On
the follow-up examination performed 19 mo later, when the parkinsonian signs always prevalent on the right
side had progressed, hyperintensity in proton density image (C) in the left posterior putamen has developed
(arrowheads). In the T2-weighted sections (D and, adjacent cranial section, E), more marked hypointensity and
a lateral rim of hyperintensity are visible.
Fig. 3. MSA-C. T1-weighted midline sagittal section in an early case (A) shows flattening of the inferior
part of the profile of the pons and cerebellar atrophy. In an advanced case, T2-weighted axial sections on the
lower (B) and upper pons (C) show atrophy of the pons, middle cerebellar peduncles, and cerebellum with
characteristic signal changes. The left corticospinal tract is indicated by an arrow; the margins of the
hyperintense middle cerebellar peduncles (open arrows) are poorly defined with respect to the CSF (B). (C)
Arrowheads point to the hyperintense anterior and posterior right transverse pontine fibers; an arrow indicates
the left superior cerebellar peduncle. On the midline, the raphe is hyperintense.
Both specificity and sensitivity of MRI pontine and cerebellar signs in MSA-C are very high
(13,18,19). In the series reviewed by Schrag et al. (19), 83% of MSA-C patients could be unequivo-
cally classified based on the MRI findings. If the disease is advanced, sensitivity may be greater than
90% (26). Specificity may decrease if we do not exclude patients with hereditary ataxias (25). Patients
with spinocerebellar ataxias (SCAs), particularly SCA1, SCA2, and SCA3, may share the same fea-
tures both at MRI and histology (3739). A few of our cases of SCA2, which together with SCA1 is
the most common inherited spinocerebellar ataxia in Italy, had an MRI scan that was indistinguish-
able from that of a patient with MSA-C except for the presence of some degree of cerebral atrophy.
As with MSA-P, one problem in MSA-C is to know how early the MRI signs of atrophy and signal
changes develop in the course of the disease, i.e., how helpful can MRI be in the early stages of MSA-
C. According to Horimoto et al. (12), the initial changes of the cross sign were seen in all their
cases of MSA-C within the first 2 or 3 yr after onset of symptoms. As expected, patients with MSA-
C normally present pontine and cerebellar changes earlier, with greater severity and more rapid pro-
gression than other signs of MSA such as putaminal changes, which usually appear later and have a
slower progression. Reciprocally, patients with MSA-P have earlier and more severe putaminal
involvement, though posterior fossa changes in these patients may appear later and remain milder.
It is, therefore, somewhat misleading to consider indifferently the putaminal and the posterior fossa
abnormalities as indicators of MSA and to verify their specificity and sensitivity. In our opinion, one
must always consider the clinical presentation (MSA-P or MSA-C or perhaps MSA-A) and should
then investigate whether the appropriate MRI signs, i.e., those fitting with the diagnosis, are present
(13,17,19,23,26). Occasionally, however, the inappropriate MRI sign had an earlier progression
than the clinically appropriate one (12). Of course, both putaminal and brainstem-cerebellar signs
should be present in a full-blown MSA.
Large multicentric studies including hundreds of patients from different countries will probably
answer all the questions regarding specificity, sensitivity, positive predictive values, time of appear-
ance, and progression of the MRI signs in MSA-P, MSA-C, and PSP (40).
In the attempt to find measurable data, Kanazawa et al. (41) investigated brainstem and cerebellar
involvement in patients with MSA-C using DWI. They found significant differences in the apparent
diffusion coefficient (ADC) values of the pons, middle cerebellar peduncles, cerebellar white matter,
and putamen between MSA-C patients and controls. The ADC values also correlated with the dura-
tion of the disease. ADC values of MSA-C patients in the pons, middle cerebellar peduncles, and
cerebellar white matter were also higher than those obtained in a few patients with SCA3 and SCA6.
Measurable data can also be obtained by MRS. Mascalchi et al. demonstrated decreased NAA/Cr
and Cho/Cr ratios in the pons and cerebellum of MSA-C patients vs controls (42). MRS, however, is
a complex and time-consuming examination that is performed in only a few specialized centers. To
obtain measurable data, it is easier to obtain DWI sequences that require a very short acquisition time
and calculate the ADC maps (35).
Measurable data are required when dealing with large number of patients in research studies. They
are also necessary in longitudinal studies to quantify the progression of the disease. They are hardly
needed in the everyday examinations of patients with atypical parkinsonian disorders in whom a
diagnosis or a support to a specific diagnosis is required by the clinician. Specificity and sensitivity
of MRI findings in these disorders are not yet fully established; much more time will be needed to
evaluate sensitivity and specificity in diffusion or spectroscopy studies.

With regard to MRI diagnosis of PSP, all the attention has been given to atrophy of the midbrain
where pathologic changes are known to occur (43). Signal changes in this region have also been
noted. Less attention has been paid to basal ganglia abnormalities and cerebral atrophy, which are
more variable and less useful for the diagnosis.
MRI simply confirmed what pneumoencephalography first, and later CT (44,45) have shown:
demonstration of midbrain atrophy is the cardinal neuroradiologic feature of PSP diagnosis. This
demonstration can be achieved by observing the midbrain size either in axial sections or in the mid-
line sagittal section (17,23,25). The latter has the advantage of showing a direct comparison between
the size of the midbrain and that of the pons, not only in the sagittal diameter, but also in height, or
vertical or caudo-cranial diameter. The midbrain size is, in fact, reduced in all the directions. The
upper profile of the normal midbrain in sagittal section is characterized by a slight superior convexity
with the highest point approximately midway between the aqueduct and the mamillary bodies. In
PSP, this profile flattens and may even become concave in its posterior part, because of atrophy and
reduced height of the midbrain tegmentum associated with enlargement of the third ventricle. Thin-
ning of the tectum particularly in its superior part may also be observed in sagittal sections (25)
(Fig. 4A). Atrophy of the midbrain is found in 7589% of the clinically diagnosed PSP patients
(19,23,46).
Simple linear measurements of the midbrain have been suggested in axial and sagittal sections
(47). No overlap was found between the measures obtained in PSP patients (range of midbrain diam-
eter: 1115 mm) vs PD patients and normal subjects (range 1719 and 1720 mm, respectively),
whereas some overlapping occurred between PSP and MSA-P patients (range 1419 mm, mean 16.7).
As mentioned above, disproportionate dilatation of the third ventricle, compared to the lateral
ones, may be caused by diencephalic extension of atrophy. This finding was evident in about one-
fourth of our cases.
One absolutely marginal feature that is sometimes seen in PSP patients in sagittal MR images is
hyperextension of the head. This feature, however, may be a clue for the diagnosis. The hyperex-
tended position may be assumed during the examination by patients who were correctly positioned
by the MRI technician at the beginning of the examination. The neuroradiologist who recognizes the
unusual hyperextension of the head should immediately observe the midbrain, looking for atrophy
and signal changes that may confirm the suspicion of PSP (17,25).
Signal changes in the midbrain are the second aspect that one should look for in suspected PSP
patients. When present, they consist of mild hyperintensity in proton density and T2-weighted images,
mainly in the tegmentum and periaqueductal region where gliosis and tau-positive lesions are found in
pathological sections (48,49) (Fig. 4B). These abnormalities may extend caudally to the pontine teg-
mentum (49). Signal changes in the midbrain are recognizable in about 60% of the PSP patients (46).
Mild to moderate cerebral atrophy may be observed in most of the patients, sometimes more
marked in the frontal and temporal lobes (19), but without the focal and asymmetric distribution
found in CBD (46) (see the following section).
Occasional abnormalities in the basal ganglia (atrophy of the lenticular nucleus with pallidal
hyperintensity) have sometimes been reported (19), but the typical combination of T2 putaminal
hypointensity with lateral hyperintense rim seen in 1.5 T studies of MSA-P patients are absent (25,28).
DWI has only rarely been used to study PSP. In one study, regional ADCs (rADCs) were increased
in the basal ganglia of PSP patients; the values allowed discrimination from patients with PD but did
not discriminate PSP and MSA-P (35). No results of the MRI observations were given so that it
remains undefined whether DWI performs better, equally, or worse than MRI in discriminating PSP,
MSA-P, and PD. In another study on only five PSP patients, ADCs in the prefrontal and precentral
white matter were higher than in controls (50).
MRS reports on PSP are also rare. NAA deficit in the lentiform nucleus, consistent with neuronal
loss, was found in PSP and in MSA patients, whereas patients with PD did not differ from controls
(33). Tedeschi et al. (51) examined patients with PD, PSP, and CBD. Compared with the control
subjects, PSP patients presented reduced NAA/Cr or NAA/Cho in the brainstem, centrum semiovale,
frontal and precentral cortex, and lentiform nucleus. These data demonstrate that, in addition to
brainstem and basal ganglia involvement, the frontal association and motor cortex are also affected;
abnormalities in the centrum semiovale suggest involvement of the axons connecting the basal gan-
Fig. 4. PSP. T1-weighted midline sagittal section (A) in a patient with 5-yr history of disease. The midbrain
is atrophic. The superior profile is concave (arrowhead); the tectum is thin in its cranial part; the antero-poste-
rior diameter is 14 mm. Compare with the normal midbrain of Fig. 3A. The tectal and periaqueductal areas
show a mild or questionable hyperintensity (arrowhead) in the proton density image (B).
glia to the cortex (51). In another PSP series, in which a decrease of NAA in the lentiform nucleus
was found, the authors reported that three of their nine PSP patients presented the eye of the tiger
sign in the pallida (52). A similar observation was made by other authors in a case of CBD (53),
suggesting that the eye of the tiger sign described by Sethi et al. (54) is not specific of Hallervorden
Spatz disease (HSD). In 1.5 T T2-weighted images, the pallidum is normally hypointense in adults or
old patients because of normal accumulation of iron. Any hyperintense area within the pallidum,
because of lacunar infarct or dilatation of VirchowRobin spaces or rarefaction of fibers and gliosis
that probably accompany calcium deposits, may justify the appearance of the eye of the tiger. In fact,
contrary to what we expected, we have observed some hyperintensity in T2-weighted images in a few
cases in which CT demonstrated calcifications in the pallidum, a nearly physiologic finding in old
age. What is striking in children or adolescents with HSD, is that the hypointensity owing to iron
deposits is extraordinarily marked for their age. Even if HSD may present in adulthood, the age of the
patient should be considered when one sees an anteromedial hyperintensity in a hypointense pallidum.
In other words, the hypointensity should be evaluated considering the patients age.
HSD was recently found to be related to mutations in the gene encoding pantothenate kinase 2
(PANK2), and the specific MRI pattern described (54,55) has been found to distinguish patients with
PANK2 mutations (56). The same MRI findings may be seen in HARP syndrome (hypoprebeta-
lipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) which is, however,
part of the pantothenate kinaseassociated neurodegeneration (57). It will, therefore, be very interest-
ing to carefully rule out any possible misinterpretation (i.e., lacunar infarcts or dilated perivascular
spaces) and eventually obtain the appropriate genetic tests in the patients with PSP or other disorders
presenting the eye of the tiger sign or similar signal abnormalities.
MRI diagnosis of CBD has been examined in only a few papers (19,23,46,5861). The essential
aspect that should be sought to support the clinical diagnosis of CBD is asymmetrical posterior fron-
tal and parietal atrophy; atrophy occurs in the hemisphere contralateral to the side of the clinical
manifestations. The unilateral atrophy is manifested by dilatation of the ipsilateral cortical sulci and
lateral ventricle, with concomitant loss of bulk of the white matter (Fig. 5). The cortical atrophy may
be marked, with sometimes a knife edge thinning of the postcentral gyrus (Fig. 5F). Occasionally,
slightly increased signal intensity in proton density and T2-weighted images may be seen in the
atrophic cortex and subjacent white matter. Proton density or FLAIR images are more reliable than
T2-weighted images in showing the cortical hyperintensity (Figs. 5C,D,F); in T2-weighted images,
the hyperintensity of the cortex may be masked by the higher signal intensity of the adjacent cere-
brospinal fluid.
One interesting aspect is that the asymmetric atrophy is usually not mentioned in MRI reports,
unless the neuroradiologist is aware of the possibility of a specific diagnosis based on the asymmetry.
We did not mention asymmetry in our first reports of CBD cases. When the neurologist called our
attention to this aspect, we easily recognized the site of predominant atrophy (always contralateral to
the side of prevalent clinical involvement, unknown to us) in all the six cases that had been studied.
Fig. 5. (opposite page) CBD. In a 66-yr-old male with clinical manifestations prevalent on the left side (A
E), the T1-weighted sagittal sections on the left (A) and right (B) hemispheres show more marked right atrophy,
prevalent in the parietal area. FLAIR coronal sections on the anterior and posterior parietal areas (C and D)
confirm the asymmetry of atrophy. The right ventricle is slightly larger and minimal hyperintensity is present in
the white matter of the right parietal lobe. Marked hyperintensity around the occipital horns is present bilater-
ally (D). In the same patient, right parietal atrophy is also evident on CT scan (E). In a different patient, a 72-yr-
old woman with clinical manifestations on the left side, axial proton density image (F) shows hyperintense
cortex in the atrophic postcentral gyrus (arrowheads).
Atrophy, of course, can be recognized in the axial sections of the brain on MRI, but coronal sec-
tions are particularly helpful to demonstrate the asymmetry, which is the cardinal feature for diagno-
sis of CBD. Coronal sections, however, are not routinely obtained in many institutions: this is perhaps
the reason for the relatively scarce sensitivity of a few reported MRI studies in diagnosing CBD (19).
Three-dimensional volume-rendered images may beautifully demonstrate the extent and distribution
of the cortical involvement (61) but a surface display of MR-generated images is not part of a stan-
dard examination of the brain and is very rarely performed.
In spite of the known pathologic involvement of the basal ganglia and substantia nigra, in these
areas signal abnormalities such as pallidal hyperintensity or putaminal hypointensity are rarely
observed on MRI (19,60). Putaminal hypointensity associated with the hyperintense posterolateral
rim was never observed in our 25 patients. However, Yekhlef et al. reported a constant presence of
putaminal atrophy in their series of 26 cases. They also reported midbrain atrophy in 75% of their
patients, whereas this feature was very rare (1 of 16 cases, or 6.3%) in our series (46), so that it could
be used for differentiation of CBD from PSP. Our last review (60) confirms the rarity of midbrain
atrophy in patients with CBD (2 of 25 cases, or 8%).
As we have seen, there are very marked discrepancies between the various series; further observa-
tions are needed to assess the value of MRI in the diagnosis of CBD. The basic bias is owing to the
fact that asymmetry is considered the hallmark of CBD, whereas from pathology we know that cases
with symmetric involvement are indeed present and also a few MRI series report cases with clinical
diagnosis of CBD without cortical asymmetries (46,58). Undoubtedly, if asymmetry is considered
crucial for the neuroradiological diagnosis, occurrence of CBD will be underestimated.
Regarding DWI, it has been suggested that patients with CBD may present white matter abnor-
malities more severe on the side with predominant cortical atrophy, even when no abnormalities are
detected by T2-weighted and FLAIR images (62). To our knowledge, however, no series with a
significant number of cases of CBD has been studied with DWI.
Nine CBD patients were studied with MRS by Tedeschi et al. (51). Reduced NAA/Cho or NAA/
Cr were found in the lentiform nucleus, parietal cortex, and centrum semiovale. Significant asymme-
tries were present in the parietal areas with more marked abnormalities in the parietal cortex con-
tralateral to the clinically most affected side.

MRI studies on DLB are rather rare, probably because they do not show peculiar signal changes or
localized atrophy that may support the diagnosis. Except for a report by Hashimoto et al. (63), most
MRI studies have been published by the group of Barber et al. in Newcastle upon Tyne (6467). The
few studies we performed in our patients with DLB concur with the published data.
The essential findings of a series of volumetric studies indicate that patients with dementia, either
vascular or owing to Alzheimers disease (AD) or DLB, present brain atrophy compared with control
subjects. Atrophy in DLB is less marked than in patients with AD, with particular preservation of
mesial temporal structures including amigdala, hippocampus, subiculum, and parahippocampal and
dentate gyri. Preservation of these structures may, therefore, help to differentiate DLB from AD
(63,65). Total brain volume is not significantly different in patients with DLB and vascular dementia
(66), but white matter and basal ganglia hyperintensities in T2-weighted images are more frequent
and extensive in patients with vascular dementia than in patients with AD and DLB (64).
Occipital hypoperfusion has been demonstrated in DLB (68,69). Because the visual hallucinations
of DLB might also be related to structural changes in the occipital lobes, volumetric MRI measure-
ments have been performed (70,71). The results are conflicting: in one series, occipital lobe volumes
in DLB were not significantly different from those of AD and control groups (70); in the other series
(71), occipital lobe atrophy was found in DLB but also in AD patients. Therefore, on the basis of
these volumetric studies, discrimination of these two types of dementia was not possible.
Although the concept of vascular parkinsonism, proposed by Critchley in 1929, was almost aban-
doned for many years, it has once more come to the fore. The prevalence and incidence of vascular
parkinsonism is variable in different series. Diagnosis of vascular parkinsonism is usually suggested
by acute onset or other signs of cerebrovascular disease, but needs to be confirmed by imaging stud-
ies (72). This is the form of parkinsonism that frequently can be diagnosed by CT, without requiring
MRI to demonstrate the lesions.
The lesions usually are lacunar or small infarcts in the basal ganglia, mostly in the putamina (Fig. 6).
A single lesion in one putamen may sometimes justify the contralateral parkinsonism. Parkinsonism
may also be associated with multiple infarcts or white matter lesions in the subcortical arterioscle-
rotic encephalopathy (72), which is more accurately shown by MRI. In this disease, precise clinico-
radiological correlations are difficult to obtain. Parkinsonian symptoms and signs may be associated
with lesions in the basal ganglia or in the white matter of the cerebral hemispheres probably because
of involvement of the striato-thalamic connections with the frontal cortex.
TOXIC AND METABOLIC PARKINSONISM

A long series of toxic and metabolic disorders, acquired or inherited, may cause parkinsonian
symptoms and signs (72). Many times the diagnosis is straightforward, known from the medical
history, but the support of imaging studies may be useful in defining at least the extent of damage.
This is the case of post-anoxic encephalopathy or carbon monoxide intoxication, in which the lesions
involve the white matter and the basal ganglia where they are prevalent in the pallida (73,74). The
same prevalent pallidal location is seen in cyanide intoxication (75). In other conditions, such as the
unusual parkinsonian presentation of Wilsons disease, the correct diagnosis may be unsuspected and
MRI, by demonstrating putaminal and lateral thalamic abnormalities or more extensive basal ganglia
and brainstem involvement (25), may orient the diagnostic work-up to a rapid conclusion.
One condition in which MRI may suggest the correct diagnosis is manganese intoxication. This is
manifested by hyperintensity in T1-weighted images in the pallida, sometimes extending caudally to
the substantia nigra. Manganese accumulates in the pallida in many conditions, including liver cir-
rhosis with portacaval shunt and hepatic encephalopathy (76,77), long-term parenteral nutrition (78),
environmental exposure in miners or industrial workers (79), or in other less clear conditions (80).
Therefore, demonstration of pallidal hyperintensities in T1-weighted images should prompt investi-
gations of blood manganese concentrations (Fig. 7).
PROSPECTS FOR FUTURE RESEARCH

In research on atypical parkinsonian disorders, MR investigations can be expanded in at least two
main directions.
One implies the collection of large series in multicentric studies, particularly regarding the less
common disorders such as CBD or DLB, so that the sensitivity and specificity of the MRI findings
can be reliably established. However, in order to make them widely and reliably applicable, the study
protocols should be carefully planned, taking into account the existing knowledge of the sensitivity
of different sequences and the total time required for an examination. Longitudinal studies are also
needed. Comparison of sensitivity and specificity of MRI findings in a certain disease observed in
different series may be meaningless if the series are not comparable because of different disease
duration. Up to now, longitudinal studies have only been performed very rarely and in very few
diseases. By observing the evolution of the various imaging findings, the neuroradiologist will be
able to recognize the earliest findings of a given disorder and thus anticipate the diagnosis.
The other direction of MR investigations regards the advanced MR techniques, such as MRS,
diffusion studies, and volumetric and functional studies. The latter are discussed in another chapter.
Fig. 6. Vascular parkinsonism. In this 66-yr-old patient with pseudobulbar signs and progressive parkin-
sonism with shuffling gait, coronal T1- (A) and axial T2-weighted sections (B) show multiple lacunes or small
infarcts in the basal ganglia and thalami. Hyper- and hypointensity consistent with an old, small hemorrhagic
lesion is present in the right putamen (B).
Fig. 7. Parkinsonism in chronic manganese intoxication. Pallidal hyperintensity in T1-weighted axial sec-
tion prompted investigations on possible manganese intoxication. Improvement following chelating treatment
was obtained (courtesy of Dr. M. C. Valentini, Turin).
As for MRS and diffusion imaging, we tried to give an overview of what is now available. The
number of studies dealing with these techniques, however, is rather limited. First of all, these tech-
niques should be applied in a greater number of cases and the results should be compared with the
MRI results in the same patients in order to understand their relative diagnostic value and to establish
if they offer some advantage in terms of diagnosis. They can, of course, bring additional knowledge
and offer quantitative data; quantification is necessary when dealing with large series of patients and
in longitudinal studies.
In MRS, most studies have focused on changes in NAA, a neuronal marker that is expected to
decrease in degenerative disorders, and on choline and creatine, which are considered indicators of
cell membranes turnover and energy supply in the tissue, respectively. Since gliosis is often promi-
nent in various degenerative disorders, short TE techniques (such as STEAM with TE = 34 ms)
should be used more widely in order to evaluate myoinositol, a putative marker of gliosis.
Diffusion-tensor MR imaging characterizes the diffusion of water molecules in the tissue and
makes measurements of the damage to the brain tissue at microscopic level possible. In a few atypical
parkinsonisms, regional ADC values in the appropriate areas have been examined. From the tensor, it
is possible to calculate the degree of anisotropy of the tissue. Fractional anisotropy, which is an index
that measures the anisotropy of the tissue, could also be applied in investigations on fiber tract dam-
age in degenerative disorders such as MSA-C in which fiber tract abnormalities are a characteristic
MRI feature.
Correlating all these in vivo measurements with the corresponding pathologic findings will be
necessary to assess the value of these new techniques and gain further insights in the pathogenesis of
the disorders in which they are applied.
446
Table 1
Distribution of Characteristic MR Abnormalities in Atypical Parkinsonian Disorders
MSA-P MSA-C PSP CBD
MRI Putamen Pons, middle cerebellar Midbrain and diencephalon Parieto-frontal regions, asymmetrical
Atrophy peduncles, cerebellum
MRI 1.5T: hypointensity Hyperintensity in PD Slight hyperintensity in PD Rare, slight hyperintensity in PD and
signal abnormalities in T2-w.i. in posterior lateral and T2-w.i. in transverse and T2-w.i. in periaqueductal T2-w.i. in atrophic cortex
putamen with lateral rim pontine fibers (cross sign), area and subcortical white matter
of hyperintensity middle cerebellar peduncles,
0.5T: usually only hyper- cerebellum
intensity in PD and T2-w.i.
in posterior lateral putamen
DWI ADC in putamen ADC in pons, middle ADC in basal ganglia and Asymmetrical white matter
cerebellar peduncles, frontal white matter abnormalities reported in atrophic
cerebellum regions
MRS NAA and Cho in lentiform NAA and Cho in pons NAA in brainstem, NAA in lentiform nucleus,
nucleus and cerebellum lentiform nucleus, parietal cortex and
frontal and motor cortex, centrum semiovale
centrum semiovale
Savoiardo and Grisoli
PROSPECTS FOR FUTURE MR RESEARCH

MRI large series in multicentric studies to evaluate its sensitivity and specificity in
different atypical parkinsonian disorders
longitudinal studies to assess the course of the disease
MRS for early detection and quantification of metabolic abnormalities
DWI and diffusion tensor imaging (DTI)
for early detection and quantification of changes of diffusivity in different brain areas
MRS, DWI, and DTI: are they better than MRI in early diagnosis?
ACKNOWLEDGMENTS
We are indebted to Dr. Floriano Girotti for his helpful discussions and comments.
REFERENCES
1. Duguid JR, De La Paz R, De Groot J. Magnetic resonance imaging of the midbrain in Parkinsons disease. Ann Neurol
1986;20:744747.
2. Rutledge JN, Hilal SK, Silver AJ, Defendini R, Fahn S. Study of movement disorders and brain iron by MR. AJNR Am
J Neuroradiol 1987;8:397411.
3. Braffman BH, Grossman RI, Goldberg HI, et al. MR imaging of Parkinson disease with spin-echo and gradient-echo
sequences. AJNR Am J Neuroradiol 1988;9:10931099.
4. Stern MB, Braffman BH, Skolnick BE, Hurtig HI, Grossman RI. Magnetic resonance imaging in Parkinsons disease
and parkinsonian syndromes. Neurology 1989;39:15241526.
5. Gorell JM, Ordidge RJ, Brown GG, Deniau J-C, Buderer NM, Helpern JA. Increased iron-related MRI contrast in the
substantia nigra in Parkinsons disease. Neurology 1995;45:11381143.
6. Oikawa H, Sasaki M, Tamakawa Y, Ehara S, Tohyama K. The substantia nigra in Parkinson disease: proton density-
weighted spin-echo and fast short inversion time inversion-recovery MR findings. AJNR Am J Neuroradiol
2002;23:17471756.
7. Vymazal J, Righini A, Brooks RA, et al. T1 and T2 in the brain of healthy subjects, patients with Parkinson disease, and
patients with multiple system atrophy: relation to iron content. Radiology 1999;211:489495.
8. Hutchinson M, Raff U. Parkinsons disease: a novel MRI method for determining structural changes in the substantia
nigra. J Neurol Neurosurg Psychiatry 1999;67:815818.
9. Hutchinson M, Raff U. Structural changes of the substantia nigra in Parkinsons disease as revealed by MR imaging.
AJNR Am J Neuroradiol 2000;21:697701.
10. Hu MTM, White SJ, Herlihy AH, Chaudhuri KR, Hajnal JV, Brooks DJ. A comparison of 18F-dopa PET and inversion
recovery MRI in the diagnosis of Parkinsons disease. Neurology 2001;56:11951200
Syst 1998;74:189192.
12. Horimoto Y, Aiba I, Yasuda T, et al. Longitudinal MRI study of multiple system atrophy - when do the findings appear,
or what is the course? J Neurol 2002;249:847854.
13. Testa D, Savoiardo M, Fetoni V, et al. Multiple system atrophy: clinical and MR observations on 42 cases. Ital J Neurol
Sci 1993;14:221216.
14. Drayer BP, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer S. Parkinson plus syndrome: diagnosis using high
field MR imaging of brain iron. Radiology 1986;159:493498.
15. Pastakia B, Polinsky R, Di Chiro G, Simmons JT, Brown R, Wener L. Multiple system atrophy (ShyDrager syn-
drome): MR imaging. Radiology 1986;159:499502.
16. Savoiardo M, Strada L, Girotti F, et al. MR imaging in progressive supranuclear palsy and ShyDrager syndrome.
J Comput Assist Tomogr 1989;13:555560.
17. Savoiardo M, Girotti F, Strada L, Ciceri E. Magnetic resonance imaging in progressive supranuclear palsy and other
parkinsonian disorders. J Neural Transm 1994;42(Suppl):93110.
18. Schrag A, Kingsley D, Phatouros C, et al. Clinical usefulness of magnetic resonance imaging in multiple system atro-
phy. J Neurol Neurosurg Psychiatry 1998;65:6571.
19. Schrag A, Good CD, Miszkiel K, et al. Differentiation of atypical parkinsonian syndromes with routine MRI. Neurol-
ogy 2000;54:697702.
20. Fearnley JM, Lees AJ. Striatonigral degeneration. A clinicopathological study. Brain 1990;113:18231842.
21. Goto S, Matsumoto S, Ushio Y, Hirano A. Subregional loss of putaminal efferents to the basal ganglia output nuclei
may cause parkinsonism in striatonigral degeneration. Neurology 1996;47:10321036.
22. Konagaya M, Konagaya Y, Iida M. Clinical and magnetic resonance imaging study of extrapyramidal symptoms in
disease, MSA, PSP, and CBD. J Neural Transm 2003;110:151169.
24. Lang AE, Curran T, Provias J, Bergeron C. Striatonigral degeneration: iron deposition in putamen correlates with the
slit-like void signal of magnetic resonance imaging. Can J Neurol Sci 1994;21:311318.
25. Savoiardo M, Grisoli M. Magnetic resonance imaging of movement disorders. In: Jankovic JJ, Tolosa E, eds.
Parkinsons Disease and Movement Disorders, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:596609.
26. Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system atrophy. An analysis of 230 Japanese
patients. Brain 2002;125:10701083.
27. Borit A, Rubinstein LJ, Urich H. The striatonigral degenerations: putaminal pigments and nosology. Brain 1975;98:
101112.
signal changes on T2-weighted magnetic resonance imaging sequences. A specific marker of multiple system atrophy?
Arch Neurol 1999;56:225228.
29. Bhattacharya K, Saadia D, Eisenkraft B, et al. Brain magnetic resonance imaging in multiple-system atrophy and
Parkinson disease. A diagnostic algorithm. Arch Neurol 2002;59:835842.
30. Macia F, Yekhlef F, Ballan G, Delmer O, Tison F. T2-hyperintense lateral rim and hypointense putamen are typical but
not exclusive of multiple system atrophy. Arch Neurol 2001;58:10241026.
31. Righini A, Antonini A, Ferrarini M, et al. Thin section MR study of the basal ganglia in the differential diagnosis
between striatonigral degeneration and Parkinson disease. J Comput Assist Tomogr 2002;26:266271.
32. Davie CA, Wenning GK, Barker GJ, et al. Differentiation of multiple system atrophy from idiopathic Parkinsons
disease using proton magnetic resonance spectroscopy. Ann Neurol 1995;37:204210.
33. Federico F, Simone IL, Lucivero V, et al. Proton magnetic resonance spectroscopy in Parkinsons disease and atypical
parkinsonian disorders. Mov Disord 1997;12:903909.
34. Schocke MFH, Seppi K, Esterhammer R, et al. Diffusion-weighted MRI differentiates the Parkinson variant of multiple
system atrophy from PD. Neurology 2002;58:575580.
35. Seppi K, Schocke MFH, Esterhammer R, et al. Diffusion-weighted imaging discriminates progressive supranuclear
palsy from PD, but not from the parkinson variant of multiple system atrophy. Neurology 2003;60:922927.
36. Savoiardo M, Strada L, Girotti F, et al. Olivopontocerebellar atrophy: MR diagnosis and relationship to multisystem
atrophy. Radiology 1990;174:693696.
37. Brk K, Abele M, Fetter M, et al. Autosomal dominant cerebellar ataxia type I. Clinical features and MRI in families
with SCA 1, SCA 2, and SCA 3. Brain 1996;119:14971505.
38. Murata Y, Yamaguchi S, Kawakami H, et al. Characteristic magnetic resonance imaging findings in MachadoJoseph
39. Di Donato S. The complex clinical and genetic classification of inherited ataxias. I. Dominant ataxias. Ital J Neurol Sci
1998;19:335343.
40. Verin M, Rolland Y, Defebvre L, Delmaire C, Payan C, the NNIPPS Study Group. Neuroprotection and natural hystory
in Parkinson plus syndrome (NNIPPS): preliminary results of the magnetic resonance imaging (MRI) study in progres-
sive supranuclear palsy (PSP) and multiple system atrophy (MSA). Neurology 2003;60(Suppl 1):A293A294.
41. Kanazawa M, Shimohata T, Tanaka K, Onodera O, Tsuji S, Okamoto K. Evaluation of brainstem involvement of
multiple system atrophy by diffusion-weighted MRI. Neurology 2003;60(Suppl 1):A210.
42. Mascalchi M, Cosottini M, Lolli F, et al. Proton MR spectroscopy of the cerebellum and pons in patients with degen-
erative ataxia. Radiology 2002;223:371378.
44. Masucci EF, Borts FT, Smirniotopoulos JG, Kurtzke JF, Schellinger D. Thin-section CT of midbrain abnormalities in
progressive supranuclear palsy. AJNR Am J Neuroradiol 1985;6:767772.
45. Schonfeld SM, Golbe LI, Sage JI, Safer JN, Duvoisin RC. Computed tomographic findings in progressive supranuclear
palsy: correlation with clinical grade. Mov Disord 1987;2:263278.
46. Soliveri P, Monza D, Paridi D, et al. Cognitive and magnetic resonance imaging aspects of corticobasal degeneration
and progressive supranuclear palsy. Neurology 1999;53:502507.
47. Warmuth-Metz M, Naumann M, Csoti I, Solymosi L. Measurement of the midbrain diameter on routine magnetic
resonance imaging. A simple and accurate method of differentiating between Parkinson disease and progressive supra-
nuclear palsy. Arch Neurol 2001;58:10761079.
48. Aiba I, Hashizume Y, Yoshida M, Okuda S, Marakani N, Ujihira N. Relationship between brainstem MRI and patho-
logical findings in progressive supranuclear palsystudy in autopsy cases. J Neurol Sci 1997;152:210217.
49. Yagishita A, Oda M. Progressive supranuclear palsy: MRI and pathological findings. Neuroradiology
1996;38(Suppl):S60S66.
50. Ohshita T, Oka M, Imon Y, Yamaguchi S, Mimori Y, Nakamura S. Apparent diffusion coefficient measurements in
progressive supranuclear palsy. Neuroradiology 2000;42:643647.
51. Tedeschi G, Litvan I, Bonavita S, et al. Proton magnetic resonance spectroscopic imaging in progressive supranuclear
palsy, Parkinsons disease and corticobasal degeneration. Brain 1997;120:15411552.
52. Davie CA, Barker GJ, Machado C, Miller DH, Lees AJ. Proton magnetic resonance spectroscopy in SteeleRichardson
Olszewski syndrome. Mov Disord 1997;12:767771.
53. Molinuevo JL, Muoz E, Valldeoriola F, Tolosa E. The eye of the tiger sign in cortical-basal ganglionic degeneration.
Mov Disord 1999;14:169171.
54. Sethi KD, Adams RJ, Loring DW, el Gammal T. HallervordenSpatz syndrome: clinical and magnetic resonance imag-
ing correlations. Ann Neurol 1988;24:692694.
55. Savoiardo M, Halliday WC, Nardocci N, et al. HallervordenSpatz disease: MR and pathologic findings. AJNR Am J
Neuroradiol 1993;14:155162.
56. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of HallervordenSpatz
syndrome. N Engl J Med 2003;348:3340.
57. Ching KHL, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ. HARP syndrome is allelic with pantothenate kinase-
associated neurodegeneration. Neurology 2002;58:16731674.
58. Gimnez-Roldn S, Mateo D, Benito C, Grandas F, Prez-Gilabert Y. Progressive supranuclear palsy and corticobasal
ganglionic degeneration: differentiation by clinical features and neuroimaging techniques. J Neural Transm
1994;42(Suppl):7990.
59. Grisoli M, Fetoni V, Savoiardo M, Girotti F, Bruzzone MG. MRI in corticobasal degeneration. Eur J Neurol 1995;2:
547552.
dementias. In: Litvan I, Goetz CG, Lang AE, eds. Corticobasal Degeneration and Related Disorders. Advances in
Neurology, vol. 82. Philadelphia: Lippincott Williams & Wilkins, 2000:197208.
61. Kitagaki H, Hirono N, Ishii K, Mori E. Corticobasal degeneration: evaluation of cortical atrophy by means of hemi-
spheric surface display generated with MR images. Radiology 2000;216:3138.
62. Ikeda K, Iwasaki Y, Ichikawa Y. Cortical and MRI aspects of corticobasal degeneration and progressive supranuclear
palsy [Letter]. Neurology 2000;54:1878.
63. Hashimoto M, Kitagaki H, Imamura T, et al. Medial temporal and whole-brain atrophy in dementia with Lewy bodies:
a volumetric MRI study. Neurology 1998;51:357362.
64. Barber R, Scheltens P, Gholkar A, et al. White matter lesions on magnetic resonance imaging in dementia with Lewy
bodies, Alzheimers disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry 1999;67:6672.
65. Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, OBrien JT. Medial temporal lobe atrophy on MRI in
dementia with Lewy bodies. Neurology 1999;52:11531158.
66. Barber R, Ballard C, McKeith IG, Gholkar A, OBrien JT. MRI volumetric study of dementia with Lewy bodies. A
comparison with AD and vascular dementia. Neurology 2000;54:13041309.
67. Barber R, McKeith IG, Ballard C, Gholkar A, OBrien JT. A comparison of medial and lateral temporal lobe atrophy in
dementia with Lewy bodies and Alzheimers disease: magnetic resonance imaging volumetric study. Dement Geriatr
Cogn Disord 2001;12:198205.
68. Ishii K, Yamaji S, Kitagaki H, Imamura T, Hirono N, Mori E. Regional cerebral blood flow difference between demen-
tia with Lewy bodies and AD. Neurology 1999;53:413416.
69. Lobotesis K, Fenwick JD, Phipps A, et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not
AD. Neurology 2001;56:643649.
70. Middelkoop HAM, van der Flier WM, Burton EJ, et al. Dementia with Lewy bodies and AD are not associated with
occipital lobe atrophy on MRI. Neurology 2001;57:21172120.
71. Gerlach M, Stadler K, Aichner F, Ransmayr G. Dementia with Lewy bodies and AD are not associated with occipital
lobe atrophy on MRI [Letter]. Neurology 2002;59:1476.
72. Riley DE. Secondary parkinsonism. In: Jankovic JJ, Tolosa E, eds. Parkinsons Disease and Movement Disorders, 4th
ed. Philadelphia: Lippincott Williams & Wilkins, 2002:199211.
73. Chang KH, Han MH, Kim HS, Wie BA, Han MC. Delayed encephalopathy after acute carbon monoxide intoxication:
MR imaging features and distribution of cerebral white matter lesions. Radiology 1992;184:117122.
74. Sohn YH, Jeong Y, Kim HS, Im JH, Kim JS. The brain lesions responsible for parkinsonism after carbon monoxide
poisoning. Arch Neurol 2000;57:12141218.
75. Rosenow F, Herholz K, Lanfermann H, et al. Neurological sequelae of cyanide intoxicationthe patterns of clinical,
magnetic resonance imaging, and positron emission tomography findings. Ann Neurol 1995;38:825828.
76. Spahr L, Butterworth RF, Fontaine S, et al. Increased blood manganese in cirrhotic patients: relationship to pallidal
magnetic resonance signal hyperintensity and neurological symptoms. Hepatology 1996;24:11161120.
77. Hauser RA, Zesiewicz TA, Martinez C, Rosemurgy AS, Olanow CW. Blood manganese correlates with brain magnetic
resonance imaging changes in patients with liver disease. Can J Neurol Sci 1996;23:9598.
78. Fell JM, Reynolds AP, Meadows N, et al. Manganese toxicity in children receiving long-term parenteral nutrition.
Lancet 1996;347(9010):12181221.
79. Kim Y, Kim KS, Yang JS, et al. Increase in signal intensities on T1-weighted magnetic resonance images in asymptom-
atic manganese-exposed workers. Neurotoxicology 1999;20:901907.
80. Hernandez EH, Valentini MC, Discalzi G. T1-weighted hyperintensity in basal ganglia at brain magnetic resonance
imaging: are different pathologies sharing a common mechanism? Neurotoxicology 2002;23:669674.
Functional MRI Techniques in Atypical Parkinsonism 451
26
Role of Functional Magnetic Neuroimaging
in Diagnosis and Research
Hartwig Roman Siebner and Gnther Deuschl
INTRODUCTION
Recent advances in magnetic resonance imaging (MRI) have opened up new possibilities to map
distinct aspects of human brain function in vivo. Functional magnetic resonance imaging (fMRI) is
widely used to assess changes in regional neuronal activity at high spatial and temporal resolution
(1,2). Magnetic resonance spectroscopy (MRS) provides a means to probe distinct aspects of brain
metabolism at a regional level (3,4). Water diffusion magnetic resonance imaging (dMRI) can be
used to study the integrity of white matter tracks in the brain (5). MRI has already been successfully
applied to study the pathophysiology of movement disorders such as Parkinsons disease (PD) (6,7).
The aim of this chapter is to summarize how these innovative MRI methods may be useful for diag-
nosis and research of atypical parkinsonian disorders.
FUNCTIONAL MAGNETIC RESONANCE IMAGING

Neuroimaging techniques, such as single photon emission tomography (SPECT), positron emis-
sion tomography (PET), and fMRI, provide a means of mapping regional neuronal activity in vivo in
the intact human brain. Blood oxygen level-dependent (BOLD) fMRI uses echo-planar imaging (EPI)
to detect changes in the oxygenation state of the blood (8). Recent studies of the monkey brain com-
bined BOLD-sensitive fMRI with electrophysiological measurements to demonstrate that the BOLD
signal primarily measures the input and processing of neuronal information within a brain region (2).
Since the BOLD signal is an intrinsic signal, BOLD-sensitive fMRI does not require the injection
of a contrast agent. Compared to PET and SPECT, BOLD-sensitive fMRI does not involve exposure
to radiation, is widely available, and offers a higher spatial and temporal resolution. Moreover, event-
related fMRI protocols allow studies to investigate changes in the BOLD signal related to a single
movement, whereas SPECT and PET can only map the averaged regional cerebral blood flow (rCBF)
changes caused by multiple trials. Because of these methodological advantages, BOLD-sensitive
fMRI has largely replaced PET and SPECT of rCBF as a tool to study the functional architecture of
the human brain.
In recent years, BOLD-sensitive fMRI has been extensively used as a research tool to study the
functional consequences of nigrostriatal dopamine loss in idiopathic PD. So far, most studies have
investigated changes in BOLD signal related to volitional hand movements (912). These studies
have disclosed a movement-related dysfunction in basal ganglia-thalamocortical loops that are

451
452 Siebner and Deuschl
involved in manual motor control. However, the pattern of abnormal movement-related activity in
frontal motor areas has been variable across studies (912). Since these studies used motor tasks that
differed in terms of movement parameters and cognitive load, the implication is that, in PD, func-
tional impairment of the various basal ganglia-thalamocortical motor loops is highly dependent on
the motor context. In addition to motor activation studies, BOLD-sensitive fMRI has also success-
fully been employed to assess nonmotor functions such as attention to action and working memory in
PD (12,13). Repeated fMRI measurements have also been used to image the acute effects of a thera-
peutic intervention. For instance, pharmacological fMRI studies have consistently demonstrated a
partial normalization of movement-related activation in frontal motor areas after oral administration
of levodopa (911).
At present, there are no fMRI studies investigating atypical parkinsonian disorders. However, the
experience with fMRI gathered in PD indicates that fMRI can successfully be applied in atypical
parkinsonian disorders. The main potential of fMRI lies in its ability to assess the functional conse-
quences of the underlying neurodegenerative process. Activation studies with fMRI can not only
reveal regional abnormalities in task-related activity but also disclose abnomal functional integration
among brain regions that form a functional network (12). The pathology of atypical parkinsonian
disorders affects brain regions that are not subject to neurodegeneration in PD (14). Therefore, fMRI
studies may be particularly revealing if the behavioral paradigm activates a functional system that is
specifically affected by the suspected atypical parkinsonian syndrome. For instance, in patients with
progressive supranuclear palsy (PSP), fMRI studies that explore distinct aspects of voluntary control
of eye movements such as smooth pursuit and saccade generation may reveal specific functional
abnormalities in regions involved in ocular motor control. Therefore, fMRI may provide a better
understanding of the pathophysiology and help to establish a specific profile of abnormal brain acti-
vation for the various atypical parkinsonian disorders.
In contrast to PET activation studies, fMRI activation studies allow to acquire many hundreds of
brain volumes during a single session. Therefore, single-subject fMRI provides sufficient statistical
power to analyze individual activation patterns. This is of relevance in atypical parkinsonian disor-
ders since it may be difficult to recruit a sufficient number of well-characterized patients to ensure
sufficient statistical power for between-group comparisons.
Pharmacological fMRI provides a means to objectively measure the functional effects of thera-
peutic agents on neuronal activity. Serial fMRI measurements of the functional response to levodopa
can be used to address the question why a subgroup of patients with multiple system atrophy (MSA)
shows a sustained levodopa response during the course of the disease. In conjunction with structural
MRI, long-term fMRI studies might be of value to monitor disease progression in patients with atypi-
cal parkinsonian disorders.
MAGNETIC RESONANCE SPECTROSCOPY

MRS provides chemical information on tissue metabolites (3,4). The molecules that can be stud-
ied by MRS in human brain tissue are hydrogen 1 (1H) and phosphorus 31 (31P). Magnetic resonance
sensitivity is far greater for protons than it is for phosphorus (3). Therefore, most commercial MR
scanners are capable of only proton MRS. Spectra are usually obtained from localized brain regions.
The brain region is defined on a single slice by placing a small voxel, on the order of 1 or 2 cm2, in the
area of interest. The compounds that can be observed in proton spectra are primarily identified by
their frequency (i.e., their position in the spectrum), expressed as the shift in frequency in pars per
million (ppm) relative to a standard. A normal spectrum shows peaks from N-acetyl groups, espe-
cially N-acetylaspartate (NAA) at 2.0 ppm, creatine (Cr), and phosphocreatine at 3.0 ppm, and cho-
line-containing phospholipids (Ch) at 3.2 ppm (3). An additional peak at 1.3 ppm arises from the
methyl resonance of lactate and is normally barely visible above the baseline noise (3). Pathologic
conditions that involve regional neuronal loss lead to region-specific decreases in the relative NAA
concentrations (3,4). Since NAA is a marker of neuronal integrity, proton MRS provides a
noninvasive means of quantifying neuronal loss or damage in vivo. Ch and other lipids are markers of
altered neuronal membrane synthesis. Cr is a possible marker of defective energy metabolism. Typi-
cally, individual metabolic ratios obtained from peak areas of the spectrum are used as input to the
statistical analysis. Because total Cr concentration is relatively resistant to change, Cr is often used as
an internal standard to which the concentrations of other metabolites are normalized.
Proton MRS has been used by several groups to study brain metabolism in nondemented PD yield-
ing conflicting results (1527). In general, the majority of these studies have failed to detect consis-
tent abnormalities for NAA, Ch, or Cr in the basal ganglia (1519,21,24,25; but see refs. 20,26,27) or
the cerebral cortex (19,21,25; but see refs. 22,23). A multicenter study that included 151 patients with
PD and 97 age-matched controls found no overall differences in the striatal proton spectra between
groups (16). However, there was a decrease in the NAA/Cho ratio in a subgroup of elderly patients
(aged 5170 yr) and patients that were not treated with levodopa (16). These findings suggest that
proton MRS may reveal subtle metabolic abnormalities in patients with PD depending on age and
medication. Therefore, heterogeneities of clinical features across patient groups may at least in part
account for discrepancies across studies (1527).
Three out of four proton MRS studies have reported abnormal proton spectra in patients with
atypical parkinsonian disorders (15,18,19; but see ref. 26). Davie et al. (15) performed proton MRS
of the lentiform nucleus in seven patients with MSA-P (predominantly striatonigral variant) and five
patients with MSA-C (olivocerebellar variant). Compared with healthy controls, the NAA/Cr ratio was
significantly decreased in patients with MSA (15). Tedeschi et al. (19) found a reduced NAA/Cre ratio
in the brainstem, centrum semiovale, and frontal and precentral cortex, and a reduced NAA/Ch ratio
in the lentiform nucleus in 12 patients with PSP compared with healthy controls (Fig. 1). The same
study also included nine patients with corticobasal degeneration (CBD). CBD patients also showed
an abnormal metabolic pattern with a reduced NAA/Cre ratio in the centrum semiovale and a reduced
NAA/Ch ratio in the lentiform nucleus and the parietal cortex contralateral to the most affected side
(Fig. 1). A reduction in NAA/Ch and NAA/Cr ratios in the lentiform nucleus was also observed by
Federico et al. (18) in seven patients with MSA and seven patients with PSP. All three studies addi-
tionally examined the proton spectra in a group of PD patients and found no abnormalities in the
selected region of interest (15,18,19). It should be noted, however, that Clarke et al. failed to find any
abnormality for NAA, Ch, and Cr in six patients with probable MSA (26).
In summary, the published data suggest that proton MRS may be of potential diagnostic value in
atypical parkinsonian disorders. However, the demonstration of significant group differences in
patients with well-defined clinical features does not imply that proton MRS can reliably discrimi-
nate between PD and atypical parkinsonian disorders in individual patients. A recent study by Alexon
et al. used pattern recognition techniques (i.e., neural network and related data analyses) to analyze
proton spectra in 15 patients with probable PD, 11 patients with possible PD, 5 patients with atypical
PD, and 14 healthy age-matched controls (27). In contrast to conventional analyses, all information
within the proton spectrum can be entered in the statistical analysis simultaneously. The neuronal
networks approach allowed them to distinguish between the four groups with considerable accuracy;
approximately 88% of the predictions were correct. By contrast, conventional analysis revealed no
significant differences in metabolite ratios among groups.
Proton MRS of the basal ganglia in conjunction with statistical analyses that take into account the
pattern of the entire proton spectrum may help to distinguish PD from atypical parkinsonian disor-
ders at initial presentation. Discriminative power may be further increased by using a multimodal
imaging approach that combines MRS with other imaging techniques such as structural MRI or
18F-6-fluorodopa PET.
Fig 1. H-MRS findings in control subjects and patients with parkinsonian disorders.PSP, progressive supra-
nuclear palsy; PD, Parkinsons disease; CBD, corticobasal degeneration. Columns and error bars present means
SD. Asterisks indicate significant differences between controls and PSP patients and between controls and
CBD (*p = 0.05, **p < 0.01, ***p < 0.001). The data were taken from Table 2 published in ref. 19.
Phosphorus MRS provides information on levels of cerebral phospholipids and high-energy phos-
phates. The cerebral phosphorus spectra contains at least seven resonances that can be attributed to
phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr),
and adenosine triphosphate (ATP). So far, only one group has used MRS to investigate the phospho-
rus spectra in 13 patients with PD and 15 patients with MSA (28). Assuming a constant cytosolic
concentration of ATP, Barbiroli et al. measured PCr and Pi and calculated cytosolic pH and free
Mg2+ (28). Compared with an age-matched control group, patients with PD showed a significant
increase in Pi and a decrease in cytosolic free Mg2+, whereas PCr was reduced and Pi was increased
in patients with MSA. In the MSA group, there was no difference in the phosphorus spectra between
the MSA-P and the MSA-C variants of MSA. A discriminant analysis that considered only the con-
centrations of PCr and Mg2+ provided a correct classification of MSA and PD patients in 93% of the
cases. These preliminary data suggest that, in addition to proton MRS, phosphorus MRS may be
useful to probe cerebral phosphate metabolism and ion contents in patients with atypical parkinso-
nian disorders.
DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING
Water diffusion-weighted MRI produces quantitative maps of microscopic displacement of water

molecules that occur as part of the physical diffusion process. This is achieved by sensitizing the
magnetic resonance signal to the random motion of water molecules by using strong magnetic field
gradients. By varying the magnetic field gradient, one can obtain different degrees of diffusion-
weighted images and calculate an apparent diffusion coefficient (ADC) for each voxel (5).
Since diffusion of water molecules is highly sensitive to microstructural changes in the cerebral
tissue, diffusion-weighted MRI has become a firmly established method to probe the functional integ-
rity of brain tissue, especially in acute cerebral ischemia (29). Diffusion-weighted MRI has a high
sensitivity to detect structural abnormalities. However, it is important to bear in mind that diffusion-
weighted MRI has a low specificity in terms of underlying pathophysiology since various mecha-
nisms (e.g., edema, neurotoxicity, Wallerian degeneration) can affect the diffusion process in the
cerebral tissue.
Three studies have characterized water diffusion in patients with atypical parkinsonian disorders.
Patients with PSP showed an increase in ADCs in the prefrontal and precentral white matter (30) and
the basal ganglia (31,32). An increase in ADCs was also found in patients with the MSA-P variant of
MSA (32), but not in patients with PD (31,32). These data indicate that diffusion-weighted imaging
may help to distinguish between PD and atypical parkinsonian disorders, but fails to discriminate
between PSP and MSA.
The microstructure of the brain tissue imposes directional constraints to the diffusion of water
molecules in the brain (referred to as anisotropy). Diffusion is particularly anisotropic in white matter
tracts because water preferentially diffuses along the direction of white matter fibres. Anisotropic
diffusion is more adequately characterized by a diffusion tensor. A diffusion tensor is an array of nine
coefficients that fully characterizes the directional properties of water diffusion in space.
Diffusion tensor-encoded MRI (DT-MRI) uses different gradient orientations to characterize the
diffusion tensor in each voxel of the brain (5). The diffusion tensor is often displayed as an elipsoid
(5). The average size of the ellipsoid represents the overall displacement of the water molecules in a
given voxel (mean diffusivity). The eccentricity of the ellipsoid characterizes the degree of anisot-
ropy. A sphere indicates isotropic diffusion whereas an elongated (cigar-shaped) or flat (pancake-
shaped) ellipsoid indicates anisotropic diffusion. The main axis of the ellipsoid corresponds to the
preferential direction of diffusion.
In the white matter, the main axis of the diffusion tensor is thought to represent the prevailing
orientation of white matter bundles in each voxel. DT-MRI allows one to track white matter fibers by
connecting neighboring voxels on the basis of their main direction of the diffusion tensor (i.e., main
fiber orientation) (33). Anisotropy measurements can be used to identify subtle abnormalities in the
organization of white matter tracks that are not evident with plain, anatomical MRI (34). However, it
is worth bearing in mind that currently available DT-MRI techniques can only visualize white matter
bundles that consist of a large number of axons, limiting fiber tracking to the white matter. Further-
more, DT-MRI can not probe the directional and functional status of the information flow along the
white matter tracts. DT-MRI also has a considerable potential for functional mapping of subcortical
gray matter. A recent study employed DT-MRI to differentiate the nuclei in the thalamus and to map
their connectivity (35).
Because DT-MRI provides a unique approach to tracking anatomical connectivity in vivo, DT-MRI
can provide important new insights into the neuroanatomical basis of atypical parkinsonian disorders
linking clinical symptoms with impaired anatomical connectivity. Though no DT-MRI study has
been published on atypical parkinsonian disorders at this stage, it is safe to state that DT-MRI pro-
vides a promising tool to pinpoint characteristic patterns of abnormal connectivity, especially in
CBD and MSA. This may be used to separate atypical parkinsonian disorders from PD.
MRI-BASED MORPHOMETRY
MRI-based volumetry of structural MR images can reveal the pattern of atrophic changes in patients
with atypical parkinsonian syndromes. Using a region-of-interest (ROI) analysis, it has been shown
that the patterns of atrophy in predefined regions of interest allow the separation PD from MSA and
PSP (36) as well as PSP from CBD (37). For instance, a recent study by Grschel and colleagues
demonstrated that the volumes of midbrain, parietal white matter, temporal gray matter, brainstem,
frontal white matter, and pons separate best between patients with PSP or CBD (37). A stepwise
linear discriminant analysis resulted in two canonical discriminant functions, which allowed for the
correct prediction of the diagnosis in 95% of healthy control subjects as well as in 76% of all PSP and
83% of all CBD patients (37). The discriminant functions revealed similar results in patients with
definite PSP/CBD and in patients with possible and probable PSP/CBD (37). Prospective studies are
now needed to show whether MRI-based volumetry will have clinical applicability.
In recent years, voxel-based morphometry (VBM) of structural MRI data has been introduced as a
simple and objective approach for characterizing small-scale differences in white and gray matter
(36). VBM refers to a voxel-wise statistical comparison of the local concentration of gray (or white)
matter between two groups of subjects. The procedure involves spatial normalization of high-resolu-
tion MR images into the same stereotactic space followed by segmentation of the gray (or white)
matter. The smoothed gray matter segments are then compared using parametric statistical tests and
the theory of Gaussian random fields (38). Other voxel-based morphometric approaches, such as
deformation-based or tensor-based morphometry, allow the study of regional differences in brain
shapes between groups of subjects (38). In contrast to conventional ROI analyses, VBM and related
approaches provide whole-brain coverage and are highly sensitive to subtle structural changes within
a single brain region. Since VBM is an automated procedure, the analysis is highly observer indepen-
dent. Finally, VBM is not affected by partial volume effects. VBM cannot only be applied to high-
resolution structural MRI, but VBM can also be used to investigate between-group differences of ADC
maps or fractional anisotropy maps. This allows to screen for regional changes in neuronal integrity
(i.e., VBM of ADC maps) or regional changes in fiber orientation (i.e., VBM of DT-weighted MRI).
FUTURE DIRECTIONS
Apart from proton MRS, none of the MRI approaches described in this chapter have yet been used
to study the pathophysiology of atypical parkinsonian disorders. Therefore, the potential of these
techniques for the diagnosis and research of atypical parkinsonian disorders remains to be defined.
Based on the MRI experience gathered with other neuropsychiatric disorders, we anticipate that fMRI,
MRS, and water diffusion MRI will significantly contribute to early diagnosis and advance our
understanding of pathophysiological evolution of the different atypical parkinsonian disorders.
Future advances in MR technology and new MR techniques (e.g., magnetization transfer technique)
will further increase the diagnostic and research potential of MRI in parkinsonian disorders (39).
It is important to bear in mind that these MRI techniques can readily be combined with each other
and with high-resolution structural MRI. Indeed, multimodal MRI studies that combine structural
and functional MR techniques represent the most promising approach to exploit MRI as a research
tool. Since VBM of structural MRI images maps the pattern of structural abnormalities, VBM pro-
vides complementary anatomic information for the interpretation of altered neuronal activity as
revealed by fMRI. The same applies for DT-MRI which, in combination with fMRI, might provide
important clues to altered functional connectivity in patients with atypical parkinsonism. On an indi-
vidual basis, interfacing fMRI with structural MRI and DT-MRI may considerably enhance diagnos-
tic accuracy of MRI in the differential diagnosis of the atypical parkinsonian disorders.
ROLE OF FUNCTIONAL MAGNETIC RESONANCE IMAGING

IN DIAGNOSIS AND RESEARCH OF ATYPICAL PARKINSONIAN
SYNDROMES
A. Functional magnetic resonance imaging (fMRI)
Mapping the functional consequences of neurodegeneration
Assessing the effect of therapeutic interventions
Monitoring disease progression
B. Magnetic resonance spectroscopy (MRS)
Noninvasive characterization of regional abnormalities in tissue metabolism
Discrimination between PD and atypical parkinsonian syndromes
C. Diffusion-weighted magnetic resonance imaging (dMRI)
Probing for microstructural changes in the cerebral tissue (ADC-maps)
Mapping abnormalities in the organization of white matter tracts (DT-imaging)
PD, Parkinsons disease; ADC, apparent diffusion coefficient; DT, diffusion tensor.
REFERENCES
1. Turner R, Howseman A, Rees GE, Josephs O, Friston K. Functional magnetic resonance imaging of the human brain:
data acquisition and analysis. Exp Brain Res 1998;123:512.
2. Logothetis NK. The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal.
Phil Trans R Soc Lond B 2002;357:10031037.
3. Rudkin TM, Arnold DL. Proton magnetic resonance spectroscopy for the diagnosos and management of cerebral disor-
ders. Arch Neurol 1999;56:919926.
4. Ross B, Bluml S. Magnetic resonance spectroscopy of the human brain. Anat Rec 2001;265:5484.
5. Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI. Nature Rev Neurosci 2003;4:
469480.
6. Brooks DJ. Morphological and functional imaging studies on the diagnosis and progression of Parkinsons disease.
J Neurol 2000;247(Suppl 2):1118.
7. Ceballos-Baumann AO. Functional imaging in Parkinsons disease: activation studies with PET, fMRI and SPECT.
J Neurol 2003;250(Suppl 1):1523.
8. Ogawa S, Lee TM, Nayak As, Glynn P. Oxygenation-sensitive contrast in magnetic reonance image of rodent brain at
high magnetic fields. Magn Resonance Med 1990;14:6878.
9. Sabatini U, Boulanouar K, Fabre N, Martin F, Carel C, Colonnese C, et al. Cortical motor reorganization in akinetic
patients with Parkinsons disease: a functional MRI study. Brain 2000;123:394403.
10. Haslinger B, Erhard P, Kampfe N, Boecker H, Rummeny E, Schwaiger M, et al. Event-related functional magnetic
resonance imaging in Parkinsons disease before and after levodopa. Brain 2001;124:558570.
11. Buhmann C, Glauche V, Sturenburg HJ, Oechsner M, Weiller C, Buchel C. Pharmacologically modulated fMRI: corti-
cal responsiveness to levodopa in drug-naive hemiparkinsonian patients. Brain 2003;126:451461.
12. Rowe J, Stephan KE, Friston K, Frackowiak R, Lees A, Passingham R. Attention to action in Parkinsons disease:
impaired effective connectivity among frontal cortical regions. Brain 2002;125:276289.
13. Mattay VS, Tessitore A, Callicott JH, Bertolino A, Goldberg TE, Chase TN, et al. Dopaminergic modulation of cortical
function in patients with Parkinsons disease. Ann Neurol 2002;51:156164.
14. Brooks D. Diagnosis and management of atypical parkinsonian syndromes. J Neurol Neurosurg Psychiatry
2002;72(Suppl.1):i10i16.
15. Davie CA, Wenning GK, Barker GJ, Tofts PS, Kendall BE, Quinn N, et al. Differentiation of multiple system atrophy
from idiopathic Parkinsons disease using proton magnetic resonance spectroscopy. Ann Neurol 1995;37:204210.
16. Holshouser BA, Komu M, Moller HE, Zijlmans J, Kolem H, Hinshaw DB Jr, et al. Localized proton NMR spectroscopy
in the striatum of patients with idiopathic Parkinsons disease: a multicenter pilot study. Magn Reson Med.
1995;33:589594.
17. Clarke CE, Lowry M, Horsamn A. Unchanged basal ganglia N-acetylaspartate and glutamate in idiopathic Parkinsons
disease as measured by proton magnetic resonance spectroscopy. Mov Dis 1997;12:297301.
18. Federico F, Simone IL, Lucivero V, De Mari M, Giannini P, Iliceto G, et al. Proton magnetic resonance spectroscopy in
Parkinsons disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1997;62:239242.
19. Tedeschi G, Litvan I, Bonavita S, Bertolino A, Lundbom N, Patronas N J, et al. Proton magnetic resonance spectro-
scopic imaging in progressive supranuclear palsy, Parkinsons disease and corticobasal degeneration. Brain
1997;120:15411552.
20. Choe BY, Park JW, Lee KS, Son BC, Kim MC, Kim BS, et al. Neuronal laterality in Parkinsons disease with unilateral
symptom by in vivo 1H magnetic resonance spectroscopy. Invest Radiol. 1998;33:450455.
21. Hoang TQ, Bluml S, Dubowitz DJ, Moats R, Kopyov O, Jacques D, et al. Quantitative proton-decoupled 31P MRS and
1H MRS in the evaluation of Huntingtons and Parkinsons diseases. Neurology 1998;50:10331040.
22. Hu MT, Taylor-Robinson SD, Chaudhuri KR, Bell JD, Morris RG, Clough C, et al. Evidence for cortical dysfunction in
clinically non-demented patients with Parkinsons disease: a proton MR spectroscopy study. J Neurol Neurosurg Psy-
chiatry 1999;67:2026.
23. Lucetti C, Del Dotto P, Gambaccini G, Bernardini S, Bianchi MC, Tosetti M, et al. Proton magnetic resonance spectros-
copy (1H-MRS) of motor cortex and basal ganglia in de novo Parkinsons disease patients. Neurol Sci 2001;22:6970.
24. ONeill J, Schuff N, Marks WJ Jr, Feiwell R, Aminoff MJ, Weiner MW. Quantitative 1H magnetic resonance spectros-
copy and MRI of Parkinsons disease. Mov Disord 2002;17:917927.
25. Summerfield C, Gomez-Anson B, Tolosa E, Mercader JM, Marti MJ, Pastor P, et al. Dementia in Parkinson disease: a
proton magnetic resonance spectroscopy study. Arch Neurol. 2002;59:14151420.
26. Clarke CE, Lowry M. Basal ganglia metabolite concentrations in idiopathic Parkinsons disease and multiple system
atrophy measured by proton magnetic resonance spectroscopy. Eur J Neurol 2000;7:661665.
27. Axelson D, Bakken IJ, Susann Gribbestad I, Ehrnholm B, Nilsen G, Aasly J. Applications of neural network analyses to
in vivo 1H magnetic resonance spectroscopy of Parkinson disease patients. J Magn Reson Imaging. 2002;16:1320.
28. Barbiroli B, Martinelli P, Patuelli A, Lodi R, Iotti S, Cortelli P, et al. Phosphorus magnetic resonance spectroscopy in
multiple system atrophy and Parkinsons disease. Mov Disord 1999;14:430435.
29. Moseley ME, Kucharczyk J, Mintorovitch J, Cohen Y, Kurhanewicz J, Derugin N, et al. Diffusion-weighted MR-
imaging of acute stroke.: correlation with T2-weighted an magnetic susceptibility-enhanced imaging in cats. Am L
Neuroradiol 1990;11;423429.
30. Oshiata T, Oka M, Imon Y, Yamaguchi S, Mimori Y, Nakamura S. Apparent diffusion coefficient measurements in
progressive nuclear palsy. Neuroradiology 2000;42:643647.
31. Schocke MF, Seppi K, Esterhammer R, Kremser C, Jaschke W, Poewe W, et al. Diffusion-weighted MRI differentiates
the Parkinson variant of multiple system atrophy from PD. Neurology 2002;58:575580.
32. Seppi K, Schocke MF, Esterhammer R, Kremser C, Brenneis C, Mueller J, et al. Diffusion-weighted imaging discrimi-
nates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple system atrophy. Neurol-
ogy 2003;60:922927.
33. Conturo TE, Lori NF, Cull TS, Akbudak E, Snyder AZ, Shimony JS, et al. Tracking neuronal fibre pathways in the
living human brain. Proc Natl Acad Sci USA 1999;96:1042210427.
34. Sommer M, Koch MA, Paulus W, Weiller C, Buechel C. Disconnection of speech-relevant brain areas in persistent
developmental stuttering. Lancet 2002;360:380383.
35. Behrens TE, Johansen-berg H, Woolrich MW, Smith SM, Wheeler-Kingshott CA, Boulby PA, et al. Non-invasive
mapping of connections between human thalamus and cortex using diffusion imaging. Nat Neurosci 2003;6:750757.
36. Schulz JB, Skalej M, Wedekind D, Luft AR, Abele M, Voigt K, et al. Magnetic resonance imaging-based volumetry
differentiates idiopathic Parkinsons syndrome from multiple system atrophy and progressive supranuclear palsy. Ann
Neurol 1999;45:6574.
37. Grschel K, Hauser TK, Luft A, Patronas N, Dichgans J, Litvan I, et al. Magnetic resonance imaging-based volumetry
differentiates progressive supranuclear palsy from corticobasal degeneration. Neuroimage 2004;21:714724.
38. Ashburner J, Friston K. Voxel-based morphometrythe methods. Neuroimage 2000;11:805821.
39. Hanyu H, Asano T, Sakurai H, takasaki M, Shindo H, Abe K. Magnetisation transfer measurements of the subcortical
grey and white matter in Parkinsons disease with and without dementia in progressive nuclear palsy. Neuroradiology
2001;43:542546.
PET in Atypical 459
27
PET and SPECT Imaging in Atypical Parkinsonian
Disorders
Alexander Gerhard and David J. Brooks
In this chapter we discuss the roles of positron emission tomography (PET) and (single photon
emission computed tomography (SPECT) in the diagnosis and pathological understanding of atypi-
cal parkinsonian disorders. We will concentrate on multiple system atrophy (MSA), progressive
supranuclear palsy (PSP), and corticobasal degeneration (CBD), but also consider dementia with
Lewy bodies (DLB).
INTRODUCTION
PET and SPECT are both imaging modalities using radioactively labeled tracers to image receptor
binding, metabolic pathways or blood flow in the brain. PET relies on short-lived 11C- and 18F-based
tracers prepared on site with the aid of a cyclotron and its resolution is usually better (~45 mm) than
that of conventional SPECT cameras (~78 mm) but SPECT is cheaper and more widely available as
it uses 123I- and 99mTc-based tracers with longer half-lives that can be produced centrally.
Some PET and SPECT tracers in routine use and the parameters that they measure when used in
the investigation of atypical parkinsonian disorders are listed in Table 1.
These relatively noninvasive techniques are unique in their ability to monitor the function of bio-
logical pathways in vivo. This is especially true for PET as positron-emitting radiotracers can usually
be prepared without altering the chemical properties of the moleculecarbon and hydrogen atoms
are ubiquitous in organic molecules and can be substituted by the positron emitting isotopes 11C and
18Ffor a review, see ref. 1.
PET and SPECT biomarkers allow us to image variations in receptor binding, activity of meta-
bolic pathways, and perfusion in typical and atypical parkinsonian disorders and so characterize and
diagnose these disorders. These imaging techniques are also well suited for longitudinal measurements.
A general caveat when defining the functional imaging characteristics of parkinsonian disorders is
the fact that these disorders can be classified with a degree of certainty during life only based on
consensus clinical criteria. It is well known that this clinical diagnosis may subsequently prove erro-
neous when compared retrospectively with autopsy findings (see Chapter 4).
The pathology of each disorder will briefly be described to the extent that is necessary to understand
the principle of the PET and SPECT techniques with reference to the relevant chapters in this book.

459
460 Gerhard and Brooks
Table 1
Commonly Used PET and SPECT Tracers With the Receptors/Processes They Label In Vivo
PET
18FDGglucose metabolism
H215Oblood flow
[18F]dopamarker of the ability (of the putamen and caudate) to decarboxylate exogenous levodopa
and store the resultant dopamine
[11C]SCH23390D1-type receptor binding
[11C]raclopride and [11C]methylspiperoneD2-type receptor binding
[11C]diprenorphinenonselective opioid binding
[11C] PK11195marker of microglial activation
[11C]NM4PA and 11C-physostigmine acetylcholinesterase levels
SPECT
[123I]G-CIT and [123I]FP-CITdopamine transporter density
[123I]IBZM and [123I]epidiprideD2 receptors

MSA is a sporadic neurodegenerative disease characterized by a progressive akinetic-rigid syn-
drome, cerebellar dysfunction, and autonomic insufficiency (2). Typical histopathological changes
consist of neuronal loss in the nigrostriatal and olivopontocerebellar pathways with F-synuclein posi-
tive, argyrophilic staining, glial cytoplasmic inclusions (3) associated with reactive astrocytes, and
activated microglia (4).
PET and SPECT have been used to assess the following aspects of the underlying pathology:
metabolic changes, dopaminergic dysfunction, opioid dysfunction, and microglial activation.
In this chapter we use the terminology recommended by the most recent consensus statement (2)
designating patients as MSA-P if parkinsonian features predominate and MSA-C if cerebellar fea-
tures predominate. The consensus criteria have only been stringently applied in more recent papers;
previously the less well-defined terms striatonigral degeneration (SND) and sporadic
olivopontocerebellar atrophy (sOPCA) have been used to describe these forms of MSA.
Metabolic Changes
18FDG PET measures regional cerebral glucose metabolism (rCMRGlc), reflecting primarily the
function of nerve terminal synaptic vesicles. The metabolic rate in a given region, therefore, reflects
the activity of afferent projections to and interneurons in a region rather than that of its efferent
projections. It is currently not possible to decide whether increases in rCMRGlc detected with PET
represent excitatory or inhibitory activity (5).
A number of 18FDG PET studies have investigated the changes in rCMRGlc in MSA. In patients
with the parkinsonian type of MSA, decreases of rCMRGlc in the lentiform nuclei and brainstem
have been described (69). This contrasts with idiopathic Parkinsons disease (PD) where lentiform
glucose metabolism is normal or slightly elevated (10,11). On the basis of these reports 18FDG PET
seems to be able to discriminate 80100% of MSA-P and idiopathic PD cases by comparing striatal
rCMRGglc (Fig. 1).
MSA patients with cerebellar features show decreases in cerebellar rCMRGglc (8,12), in some
cases even without obvious cerebellar atrophy on MRI (13). Glucose hypometabolism in frontal
regions (6)possibly owing to the degeneration of fiber systems connecting the cortex and basal
gangliais apparent in more advanced patients but usually absent in early cases (12,14).
PET in Atypical 461
Fig. 1. Integrated images of 18FDG uptake of (A) a healthy control person (B) a patient with probable MSA-
P coregistered to the individual MRI (horizontal section); 18FDG uptake is markedly reduced in the caudate and
putamen of the MSA patient.
Dopaminergic Dysfunction
[18F]-dopa is the most commonly used PET radiotracer for the study of striatal dopaminergic
nerve terminal function in parkinsonism. [18F]-dopa PET measures the rate of decarboxylation of
[18F]fluorodopa to [18F]fluorodopamine by the enzyme dopa-decarboxylase and its subsequent stor-
age in the striatal dopaminergic nerve terminals (presynaptic marker) (15). [11C]nomifensine is a
marker of striatal monaminergic reuptake sites. Widely used presynaptic SPECT markers that bind to
the striatal dopamine transporter (DAT) are the tropane derivatives [123I]G-CIT and [123I]FP-CIT.
The postsynaptic dopaminergic system has been studied with [11C]SCH23390 (a PET D1 receptor
ligand) and [11C]raclopride and [123I]IBZM (PET and SPECT D2 receptor ligands, respectively).
In patients with MSA-P, the function of both the pre- and postsynaptic dopamine system is impaired.
Mean putaminal uptake of [18F]-dopa , [11C]nomifensine, and [123I]G-CIT are reduced to ~50% of nor-
mal values (1618) and individual levels of putaminal [18F]-dopa uptake correlate with locomotor
function (Fig. 2) (16,19).
Pathological studies suggest that the substantia nigra is more uniformly affected in MSA than in
PD where ventrolateral areas are targeted (20,21). A number of studies using markers of presynaptic
dopaminergic function have reported similar putamen reductions in MSA-P and PD but a greater
reduction of uptake in the caudate nucleus in the former, a relative sparing of caudate function
being observed in PD (9,16,18). Other groups have not replicated this greater involvement of caudate
dopaminergic function in MSA compared with PD and reported that caudate [18F]-dopa Ki values are
of limited value for discriminating between these disorders (11,19).
Using formal discriminant analysis, Burn and coworkers were able to distinguish MSA-P from PD
correctly in about 70% of cases with 18F-dopa PET (22), suggesting it is a less sensitive tool than
FDG PET for the differential diagnosis of these disorders.
Studies on postsynaptic D2 receptor binding with [11C]raclopride PET have found varying degrees
of overlap between normals, PD, and MSA patients. Brooks and colleagues found a lesser decline of
striatal [11C]raclopride binding in L-dopa-resistant striatonigral degeneration than in chronically L-
dopa-treated PD patients (23). In other studies, patients with probable MSA-P have been more readily
Fig. 2. Parametric Ki maps of [18F]-dopa PET scans of (A) a healthy control person (B) a patient with
probable MSA-P coregistered to the individual MRI (horizontal section) showing almost completely reduced
Ki values in the caudate and putamen of the MSA patient.
discriminated from PD patients and normal controls showing reduced striatal (19) or putaminal (11)
D2 binding. MSA putaminal D2 binding correlated with locomotor scores in one study (19).
Similar results have been obtained with the D2 receptor marker [123I]IBZM and SPECT, which
correctly distinguished five out of seven patients with probable MSA from normals and PD patients
on the basis of their decreased striatal D2-binding potential (24). IBZM SPECT correctly predicts the
response to dopaminergic medication in 70% of parkinsonian patients, those subjects having normal
striatal IBZM uptake usually showing a good response. On follow up after 2456 mo, the diagnosis
of MSA-P and PD remained unaltered in the majority of these subjects (25,26).
[123I]G-CIT SPECT is a marker of dopamine transporter function and sensitively visualizes the
presynaptic dopaminergic lesion in MSA-P patients, revealing a mean 50% reduction in striatal bind-
ing. However, a similar reduction is seen in PD and so [123I]G-CIT SPECT is of limited value for
distinguishing these disorders (27). As expected, the differentiation of the disorders improves mark-
edly when [123I]G-CIT SPECT is combined with the marker of D2 receptors [123I]iodobenzfuran
SPECT (24).
Opioid Dysfunction
Striatal projections to the external pallidum contain the opioid peptide enkephalin whereas those
to the internal pallidum express dynorphin. The basal ganglia are rich in , P, and I opioid receptor
subtypes.
[11C]diprenorphine is a nonspecific opioid antagonist that binds with similar affinity to all three
receptor subtypes. From autopsy studies it is known that metenkephalin levels in the striatum are
reduced in MSA-P whereas they are preserved in PD (28). Burn and colleagues were able to demon-
strate in a small series that putaminal uptake of [11C]diprenorphine was reduced in 50% of MSA-P
patients but normal in nondyskinetic PD patients (29).
PET in Atypical 463
Fig. 3. Binding potential map for a patient with probable MSA-P (B) coregistered to the individual MRI.
Increased [11C]47-PK11195 binding can be seen in the putamen and pallidum (indicated by the arrow). The
color scale is callibrated for binding potential values from 0 to 1. White indicates values >1. Extracerebral
binding has been masked. (A) Illustrates the typical distribution of binding in a 59-yr-old healthy volunteer in
transverse view (BP map coregistered to the MRI).
Microglial Activation
In MSA, microglial activation has been described as part of the neuropathological process (4).
Microglia constitute 20% of glial cells and are ontogenetically related to cells of mononuclear-
phagocyte lineage. They respond to brain injury by swelling and expressing cytokines and other
immunologically relevant molecules and have been used as an early marker of active brain disease
(30). The mitochondria of activated microglia express peripheral benzodiazepine binding sites
(PBBSs). PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide]
is a selective ligand for PBBSs (31) and, when labeled with [11C], can be used as a PET tracer. In
lesions without invading blood-borne cells, activated microglia are the primary source of PBBS
expression (32).
In five patients with probable MSA, we were recently able to detect increased [11C]-PK11195
signal in the dorsolateral prefrontal cortex, caudate, putamen, pallidum, thalamus, pons, and substan-
tia nigra (Fig. 3) (33).
This pattern accords well with the known neuropathological distribution of microglial activation
in MSA and provides information about the location of active disease. [11C]-PK11195 PET seems to
be a valuable tool to characterize the inflammatory component of the pathological process in MSA.

Metabolic Studies
Neuropathological criteria for PSP include the accumulation of intraneuronal globose neurofibril-
lary tangles in and often atrophy of the following structures: pallidum and subthalamic nucleus, sub-
stantia nigra, pontine tegmentum, oculomotor and pontine nuclei, striatum, and prefrontal and
precentral cortices (34). These pathological findings have been reflected by changes in function
observed in a number of PET and SPECT studies using 18FDG or blood flow markers (3541). The
studies reported ~25% decreases of regional cerebral metabolism in the frontal cortex, striatum, and
thalamus.
Two more recent studies localized the metabolic changes in PSP using SPM (statistical parametric
mapping) (42), which explores focal changes in brain metabolism without having to make a priori
hypotheses. This confirmed the earlier studies using region of interest analysis but highlighted the
involvement of the frontal eye fields in premotor cortex (43,44).
The decreases in frontal metabolism (hypofrontality) may reflect primary frontal cortical pathol-
ogy but are more likely to arise because of pallidal degeneration since internal pallidal neurons project
via the ventrolateral thalamus to premotor and prefrontal areas (45).
Dopaminergic System
In PSP the nigrostriatal dopaminergic projections are uniformly affected and caudate and putamen
dopamine content is equivalently reduced to 1025 % of normal levels (46,47).
The uniform degeneration of nigrostriatal dopaminergic projections is reflected by findings from
PET and SPECT studies of the presynaptic dopaminergic system in PSP. The first [18F]dopa PET
study in PSP found a decrease in striatal dopamine formation and storage that correlated with disease
severity but was unable to clearly separate caudate and putamen signals owing to the low 1.5-cm
resolution of the PET camera (36). Using higher-resolution cameras it became possible to show that,
in contrast to PD, the Ki values in the PSP group were uniformly reduced in putamen and caudate to
~40% of normal values (48). Applying discriminant analysis the differential involvement of the cau-
date [18F]dopa uptake has allowed 90% of clinically probable PSP patients to be seperated from PD
(22). A similar difference in the degree of caudate involvement between PSP and PD was found using
the PET dopamine transporter marker [11C]-WIN 35,428 (49). Another interesting application of
[18F]dopa PET has been the demonstration of reduced striatal [18F]dopa uptake in 5 out of 15 asymp-
tomatic members of a PSP kindred; one of these subjects developed clinical PSP 2 yr after the scan,
thus indicating that [18F]dopa PET has the ability to detect familial PSP preclinically (43).
[123I]G-CIT and FP-CIT SPECT have also been used in PSP to demonstrate presynaptic degenera-
tion of dopamine terminals. Although it has been possible to demonstrate the relative caudate spar-
ing in PD compared to PSP, especially in relatively early cases (50,51), other groups have found
these approaches of limited value in discriminating PSP from PD (27).
D2 receptor binding in PSP patients has been examined as early as 1986 using the D2 antagonist
[76Br]bromospiperone (52). A mean fall of 24% in equilibrium striatum/cerebellar uptake ratios was
observed, but 50% of their PSP cases had striatal D2 binding within the normal range.
Brooks and colleagues studied nine PSP patients with [11C]raclopride PET (53); the PSP group
showed 24% and 9% significant reductions of tracer caudate and putamen:cerebellar uptake ratios,
and again only 50% of patients had individually reduced uptake ratios. In a larger series of 32 patients
with probable PSP, 20 of these subjects showed reduced basal ganglia/frontal cortex [123I-IBZM
signal ratios, indicating a reduction of D2 receptors in approx two-thirds of PSP patients (54). A
smaller number of patients with probable PSP (n = 6) were scanned with the D2 marker
[123I]iodobenzfuran (IBF SPECT); 8% and 21% reductions of binding potential in the posterior puta-
men and caudate were found, which failed to reach statistical significance (24).
These PET and SPECT findings of moderate reductions of striatal D2 receptor binding in PSP are
in agreement with neuropatholgical findings reporting ~30% reductions in D2 density in the caudate
and putamen of these patients (55).
Cholinergic, Opioid, and Benzodiazepine Binding

Burn and colleagues examined striatal opioid binding in PSP (29). [11C]diprenorphine binding
was reduced in all six PSP patients. Interestingly, caudate and putamen were equally affected, whereas
in MSA-P patients caudate binding remained normal.
When using N-methyl-4-[11C]piperidyl and PET to measure acetylcholinesterase (AChE) activity
in 12 patients with PSP, Shinotoh and coworkers found a prominent reduction (38%) of thalamic
PET in Atypical 465
AChE activity whereas the cortical activity was only slightly reduced (56). Using 11C-physostigmine
PET, Pappata and colleagues have also reported reduced striatal AChE levels in PSP, which corre-
lated with disability (57).
A recent autoradiographic study in PSP (58) found degeneration of striatal cholinergic and dopam-
inergic terminals, whereas central benzodiazepine receptor binding remained unaffected. Since basal
ganglia cholinergic terminals seem to degenerate in a selective manner in PSP, striatal VAChT (ace-
tylcholine vesicular transporter) reduction may provide a unique neurochemical imaging marker for
distinction of PSP from other types of basal ganglia neurodegeneration.
PET and [11C]flumazenil (FMZ), a nonselective central benzodiazepine receptor antagonist, can
be used to examine the density of benzodiazepine/GABAA receptors. Since probably all cortical
neurons express GABAA receptors, the density of these receptors provides a measure of the integrity
of intrinsic cerebral cortical neurons. In a group of 12 PSP patients, a slight reduction of
[11C]flumazenil was detected in the anterior cingulate gyrus but no other abnormalities were found (59).
Although it is known from autoradiographic postmortem studies that benzodiazepine binding is
reduced in the pallidum and preserved in the striatum of PSP patients (58), the low expression of
these receptors in the pallidum and proximity of the putamen probably make current functional imag-
ing techniques too insensitive to detect these changes (60).
Metabolic Studies
In CBD there is a characteristic asymmetrical distribution of swollen ubiquitin- and tau-positive
achromatic neurons in the posterior frontal, inferior parietal, and superior temporal cortical areas as
well as in the thalamus, striatum, and substantia nigra (61).
Over the last 12 yr a number of groups have examined regional cerebral oxygen metabolism
(rCMRO2) (62) and rCMRGlc (6366) in patients with clinically probable CBD. All these studies,
which examined between five and eight patients each, found strikingly asymmetrical reductions in
resting levels of brain function, with the hypometabolism being most evident in the brain hemisphere
contralateral to the more affected limbs. Particularly targeted were the posterior frontal, inferior
parietal, and superior temporal regions along with thalamus and striatum. Whereas these studies
used a region of interest approach, Hosaka and colleagues recently performed a voxel-based com-
parison of rCMRGlc with statistical parametric mapping and essentially found a similar pattern of
hypometabolism in their group of CBD patients (44).
The pattern of decreased metabolic activity in frontal and parietal cortex and basal ganglia has also
been shown with SPECT and the perfusion marker 99Technetiumhexamethylpropylenamine (HMPAO)
(67). These changes were not only found in the hemisphere contralateral to the more affected body side
but also ipsilaterally suggesting that the disease process is bilateral even at a stage when the clinical
manifestations are unilateral.
Dopaminergic System
In CBD the substantia nigra is uniformly involved, which results in similar levels of dopamine
loss in both caudate and putamen (68).
Sawle and coworkers (62) found striatal 18F-6-fluorodopa uptake was reduced in an asymmetric
pattern, caudate and putamen being similarly involved in all six cases examined with the reduction
being most pronounced contralateral to the clinically more affected limbs. Uptake into mesial frontal
cortex was also halved, indicating that not only the nigrostratal but also the mesofrontal dopaminer-
gic projections are impaired in this condition.
A subsequent report using [18F]dopa PET confirmed Sawles findings (65), whereas Laureys and
colleagues noted relatively minor caudate involvement in their early CBD cases (69).
Fig. 4. Integrated images of 18FDG uptake of (A) a healthy control person (B) a patient with dementia with
Lewy bodies co-registered to the individual MRI (horizontal section); 18FDG uptake is markedly reduced in the
occipital lobe of the DLB patient.
Investigation of D2 receptor density with [123I]IBZM and SPECT suggests a reduction in the stria-
tum of CBD patients but has been restricted to a single case so far (70).

Metabolic Studies
DLB has not been examined as extensively with PET and SPECT as other atypical parkinsonian
disorders. Albin and colleagues have reported the 18FDG PET findings of six demented individuals
with pathologically verified diffuse Lewy body disease (71), three of whom had had pure DLB and
three combined DLB and Alzheimers disease (DLB-AD) pathology. These patients showed hypome-
tabolism in association cortices with relative sparing of subcortical structures and primary
somatomotor cortex, a pattern reported previously in AD. The main difference in comparison to
patients with AD was the more pronounced hypometabolism in the occipital association cortex and
primary visual cortex, indicating the presence of diffuse cortical abnormalities in DLB and suggest-
ing that FDG-PET may possibly be useful in discriminating DLB from AD antemortem (Fig. 4).
This finding has been confirmed in larger series of 13 patients with DLB and 53 patients with AD
(72). Similar differences in brain perfusion patterns between DLB and AD have been found using
99mTechnetium labeled perfusion markers and SPECT (73).
A direct metabolic comparison of patients with PD and DLB has not been performed to date to our
knowledge; since occipital decreases in occipital metabolic activity has been described in PD (74) as
well, it would be very interesting to determine whether occipital hypometabolism discriminates not
only between DLB and AD but also between DLB and PD.
Dopaminergic System
The presynaptic system has been characterized in DLB using both PET and SPECT. Using
[18F]dopa PET, Hu and colleagues (75) described a reduction of striatal dopamine uptake in 6 patients
with DLB whereas the values in the 10 AD patients were not significantly different from normal.
PET in Atypical 467
Table 2
Synopsis of the Characteristic PET and SPECT Findings in Different Parkinsonian Disorders
Imaging Modality
and Measured Parameter MSA-P PSP CBD DLB PD
FDG-PET (glucose decreased in decreased in decreased in decreased in normal or
metabolism in afferent lentiform nucleus striatum, thalamus, striatum, thalamus, occipital cortex slightly
projections and and frontal regions and frontal areas inferior parietal, elevated in
interneurons) and posterior frontal lentiform
cortex; often nucleus
asymmetric
F-dopa-PET (presynaptic reduced in reduced in putamen reduced in reduced in reduced in
dopa metabolism) putamen caudate and caudate caudate and putamen caudate and putamen
putamen caudate
Raclopride-PET and low or normal low or normal low in striatum ? normal or raised
IBZM SPECT
(postsynaptic putaminal
D2 receptor density)
Diprenorphine PET reduced in reduced in caudate ? ? reduced in
(opioid receptor density) putamen and putamen striatum of
dyskinetic
patients
Walker and coworkers have recently evaluated the integrity of the the nigrostriatal metabolism
using the presynaptic marker 123 I-labeled 2 -carbomethoxy-3 -(4-iodophenyl)-N-(3-
fluoropropyl)nortropane (FP-CIT), and SPECT in 27 patients with DLB, 17 with AD, 19 drug-naive
PD patients, and 16 controls. There was a good seperation of the DLB and PD patients from AD
patients and normals on the basis of the reduced striatal uptake ratios in these two groups whereas it
was not possible to distinguish DLB and PD patients (76). As the DLB cases were all rigid, however,
and the AD cases were not, the FP-CIT SPECT may simply have been discriminating the parkin-
sonism rather than the type of dementia.
CONCLUSIONS
A general problem when examining parkinsonian disorders remains the fact that clinical criteria
only allows one to diagnose these disorders with limited certainty. Only a few PET or SPECT series
have later been compared with neuropathology, but clearly this is necessary to determine how sensi-
tive and specific imaging modalities are when used for the purposes of differential diagnosis. Never-
theless, PET has been shown to be helpful in distinguishing around 80% of atypical parkinsonian
disorders from idiopathic PD and, to a lesser extent, from each other by demonstrating different
degrees and patterns of metabolic and dopaminergic impairment.
Table 2 gives a synopsis of the characteristic PET and SPECT findings in different parkinsonian
disorders.
Since PET and SPECT have the unique ability to measure physiological and pathological param-
eters of brain metabolism and receptors, they are invaluable research tools given that they are rela-
tively noninvasive and allow longitudinal examinations. The possibility of longitudinal measurements
has been explored in atypical PD in only one G-CIT SPECT study so far (77), demonstrating a more
rapid degeneration of the nigrostriatal dopaminergic system in atypical parkinsonian disorders than
in idiopathic PD.
For example, we are currently undertaking a longitudinal study comparing findings with serial
[11C]47-PK11195 and 18F-dopa PET in MSA and PD hoping to clarify the still largely hypothetical
role of neuroinflammatory glial responses in neurodegenerative diseases. PET studies like this
have the potential to elucidate the neuropathological processes in atypical parkinsonian disorders and
will hopefully ultimately lead to better treatment options.
SUMMARY/ OUTLOOK
PET and SPECT are unique imaging tools that allow to investigate physiological and pathological aspects
of Parkinsonian disorders in vivo and longitudinally.
Especially FDG PET is helpful in distinguishing atypical Parkinsonian disorders from idiopathic PD and
from each other.
Future research should be aimed at correlating different imaging modalities to each other and where pos-
sible to postmortem findings.
The use of new PET markers for microglial activation and amyloid deposits for in vivo pathology will
aid the development and evaluation of new therapies (e.g., of minocyline in MSA to suppress microglial
activation).
REFERENCES
1. Cherry SR, Phelps ME. Imaging brain function with positron emission tomography. In: Toga AW, Mazziotta JC, eds.
Brain Mapping: The Methods. San Diego: Academic, 1996:191222.
Syst 1998;74:189192.
3. Lantos PL, Papp MI. Cellular pathology of multiple system atrophy: a review [Editorial]. J Neurol Neurosurg Psychia-
try 1994;57:129133.
4. Schwarz SC, Seufferlein T, Liptay S, et al. Microglial activation in multiple system atrophy: a potential role for NF-
kappaB/rel proteins. Neuroreport 1998;9:30293032.
5. Jueptner M, Weiller C. Review: does measurement of regional cerebral blood flow reflect synaptic activity? Implica-
tions for PET and fMRI. Neuroimage 1995;2:148156.
6. De Volder AG, Francart J, Laterre C, et al. Decreased glucose utilization in the striatum and frontal lobe in probable
striatonigral degeneration. Ann Neurol 1989;26:239247.
7. Eidelberg D, Takikawa S, Moeller JR, et al. Striatal hypometabolism distinguishes striatonigral degeneration from
8. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M, St Laurent RT. Patterns of cerebral glucose metabolism detected
with positron emission tomography differ in multiple system atrophy and olivopontocerebellar atrophy. Ann Neurol
1994;36:166175.
9. Otsuka M, Ichiya Y, Hosokawa S, et al. Striatal blood flow, glucose metabolism and 18F-dopa uptake: difference in
Parkinsons disease and atypical parkinsonism. J Neurol Neurosurg Psychiatry 1991;54:898904.
10. Antonini A, Vontobel P, Psylla M, et al. Complementary positron emission tomographic studies of the striatal dopam-
inergic system in Parkinsons disease. Arch Neurol 1995;52:11831190.
11. Ghaemi M, Hilker R, Rudolf J, Sobesky J, Heiss WD. Differentiating multiple system atrophy from Parkinsons dis-
ease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging. J Neurol Neurosurg Psychia-
try 2002;73:517523.
12. Perani D, Bressi S, Testa D, et al. Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18
positron emission tomographic study. Arch Neurol 1995;52:179185.
13. Otsuka M, Ichiya Y, Kuwabara Y, et al. Glucose metabolism in the cortical and subcortical brain structures in multiple
system atrophy and Parkinsons disease: a positron emission tomographic study. J Neurol Sci 1996;144:7783.
14. Taniwaki T, Nakagawa M, Yamada T, et al. Cerebral metabolic changes in early multiple system atrophy: a PET study.
J Neurol Sci 2002;200:7984.
15. Firnau G, Sood S, Chirakal R, Nahmias C, Garnett ES. Cerebral metabolism of 6-[18F]fluoro-L-3,4-
dihydroxyphenylalanine in the primate. J Neurochem 1987;48:10771082.
16. Brooks DJ, Salmon EP, Mathias CJ, et al. The relationship between locomotor disability, autonomic dysfunction, and
the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and
Parkinsons disease, studied with PET. Brain 1990;113:15391552.
17. Salmon E, Brooks DJ, Leenders KL, et al. A two-compartment description and kinetic procedure for measuring regional
cerebral [11C]nomifensine uptake using positron emission tomography. J Cereb Blood Flow Metab 1990;10:307316.
PET in Atypical 469
18. Brucke T, Asenbaum S, Pirker W, et al. Measurement of the dopaminergic degeneration in Parkinsons disease with
[123I] beta-CIT and SPECT. Correlation with clinical findings and comparison with multiple system atrophy and
progressive supranuclear palsy. J Neural Transm Suppl 1997;50:924.
19. Antonini A, Leenders KL, Vontobel P, et al. Complementary PET studies of striatal neuronal function in the differen-
tial diagnosis between multiple system atrophy and Parkinsons disease. Brain 1997;120:21872195.
20. Goto S, Hirano A, Matsumoto S. Subdivisional involvement of nigrostriatal loop in idiopathic Parkinsons disease and
striatonigral degeneration. Ann Neurol 1989;26:766770.
21. Fearnley JM, Lees AJ. Striatonigral degeneration. A clinicopathological study. Brain 1990;113:18231842.
22. Burn DJ, Sawle GV, Brooks DJ. Differential diagnosis of Parkinsons disease, multiple system atrophy, and Steele
RichardsonOlszewski syndrome: discriminant analysis of striatal 18F-dopa PET data. J Neurol Neurosurg Psychiatry
1994;57:278284.
23. Brooks DJ, Ibanez V, Sawle GV, et al. Striatal D2 receptor status in patients with Parkinsons disease, striatonigral
degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography.
Ann Neurol 1992;31:184192.
24. Kim YJ, Ichise M, Ballinger JR, et al. Combination of dopamine transporter and D2 receptor SPECT in the diagnostic
evaluation of PD, MSA, and PSP. Mov Disord 2002;17:303312.
25. Schwarz J, Tatsch K, Arnold G, et al. 123I-iodobenzamide-SPECT predicts dopaminergic responsiveness in patients
with de novo parkinsonism. Neurology 1992;42:556561.
26. Schwarz J, Tatsch K, Gasser T, et al. 123I-IBZM binding compared with long-term clinical follow up in patients with
de novo parkinsonism. Mov Disord 1998;13:1619.
27. Pirker W, Asenbaum S, Bencsits G, et al. [123I]beta-CIT SPECT in multiple system atrophy, progressive supranuclear
palsy, and corticobasal degeneration. Mov Disord 2000;15:11581167.
28. Goto S, Hirano A, Matsumoto S. Met-enkephalin immunoreactivity in the basal ganglia in Parkinsons disease and
striatonigral degeneration. Neurology 1990;40:10511056.
29. Burn DJ, Rinne JO, Quinn NP, Lees AJ, Marsden CD, Brooks DJ. Striatal opioid receptor binding in Parkinsons
disease, striatonigral degeneration and SteeleRichardsonOlszewski syndrome, A [11C]diprenorphine PET study.
Brain 1995;118:951958.
30. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996;19:312318.
31. Banati RB, Newcombe J, Gunn RN, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis:
Quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000;123:23212337.
32. Banati RB, Myers R, Kreutzberg GW. PK (peripheral benzodiazepine)binding sites in the CNS indicate early and
discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol
1997;26:7782.
33. Gerhard A, Banati RB, Goerres GB, et al. [11C](R)-PK11195 PET imaging of microglial activation in multiple system
atrophy. Neurology 2003;61:686689.
34. Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic criteria for SteeleRichardsonOlszewski
35. DAntona R, Baron JC, Samson Y, et al. Subcortical dementia. Frontal cortex hypometabolism detected by positron
tomography in patients with progressive supranuclear palsy. Brain 1985;108:785799.
36. Leenders KL, Frackowiak RS, Lees AJ. SteeleRichardsonOlszewski syndrome. Brain energy metabolism, blood
flow and fluorodopa uptake measured by positron emission tomography. Brain 1988;111:615630.
37. Johnson KA, Sperling RA, Holman BL, Nagel JS, Growdon JH. Cerebral perfusion in progressive supranuclear palsy.
J Nucl Med 1992;33:704709.
38. Otsuka M, Ichiya Y, Kuwabara Y, et al. Cerebral blood flow, oxygen and glucose metabolism with PET in progressive
supranuclear palsy. Ann Nucl Med 1989;3:111118.
39. Karbe H, Grond M, Huber M, Herholz K, Kessler J, Heiss WD. Subcortical damage and cortical dysfunction in progres-
sive supranuclear palsy demonstrated by positron emission tomography. J Neurol 1992;239:98102.
40. Goffinet AM, De Volder AG, Gillain C, et al. Positron tomography demonstrates frontal lobe hypometabolism in
progressive supranuclear palsy. Ann Neurol 1989;25:1319.
41. Foster NL, Gilman S, Berent S, Morin EM, Brown MB, Koeppe RA. Cerebral hypometabolism in progressive supra-
nuclear palsy studied with positron emission tomography. Ann Neurol 1988;24:399406.
42. Friston K, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak R. Statistical parametric maps in functional
imaging: a general linear approach. Hum Brain Mapp 1995;2:189210.
43. Piccini P, de Yebenez J, Lees AJ, et al. Familial progressive supranuclear palsy: detection of subclinical cases using
18F-dopa and 18fluorodeoxyglucose positron emission tomography. Arch Neurol 2001;58:18461851.
44. Hosaka K, Ishii K, Sakamoto S, et al. Voxel-based comparison of regional cerebral glucose metabolism between PSP
and corticobasal degeneration. J Neurol Sci 2002;199:6771.
45. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia
and cortex. Annu Rev Neurosci 1986;9:357381.
46. Kish SJ, Chang LJ, Mirchandani L, Shannak K, Hornykiewicz O. Progressive supranuclear palsy: relationship between
extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol 1985;18:530536.
47. Ruberg M, Javoy-Agid F, Hirsch E, et al. Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann
Neurol 1985;18:523529.
48. Brooks DJ, Ibanez V, Sawle GV, et al. Differing patterns of striatal 18F-dopa uptake in Parkinsons disease, multiple
system atrophy, and progressive supranuclear palsy. Ann Neurol 1990;28:547555.
49. Ilgin N, Zubieta J, Reich SG, Dannals RF, Ravert HT, Frost JJ. PET imaging of the dopamine transporter in progressive
supranuclear palsy and Parkinsons disease. Neurology 1999;52:12211226.
50. Messa C, Volonte MA, Fazio F, et al. Differential distribution of striatal [123I]beta-CIT in Parkinsons disease and pro-
gressive supranuclear palsy, evaluated with single-photon emission tomography. Eur J Nucl Med 1998;25:12701276.
51. Antonini A, Benti R, De Notaris R, et al. 123I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake
in patients with Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy. Neurol Sci 2003;24:
149150.
52. Baron JC, Maziere B, Loch C, et al. Loss of striatal [76Br]bromospiperone binding sites demonstrated by positron
tomography in progressive supranuclear palsy. J Cereb Blood Flow Metab 1986;6:131136.
53. Brooks DJ, Playford ED, Ibanez V, et al. Isolated tremor and disruption of the nigrostriatal dopaminergic system: an
18F-dopa PET study. Neurology 1992;42:15541560.
54. Arnold G, Schwarz J, Tatsch K, et al. Steele-Richardson-Olszewski-syndrome: the relation of dopamine D2 receptor
binding and subcortical lesions in MRI. J Neural Transm 2002;109:503512.
55. Pierot L, Desnos C, Blin J, et al. D1 and D2-type dopamine receptors in patients with Parkinsons disease and progres-
sive supranuclear palsy. J Neurol Sci 1988;86:291306.
56. Shinotoh H, Namba H, Yamaguchi M, et al. Positron emission tomographic measurement of acetylcholinesterase activ-
ity reveals differential loss of ascending cholinergic systems in Parkinsons disease and progressive supranuclear palsy.
Ann Neurol 1999;46:6269.
57. Pappata S, Traykov L, Tavitian B, et al. Striatal reduction of acetycholinesterase in patients with progressive supra-
nuclear palsy (PSP) as measured in vivo by PET and 11C-physiostigmine (11C-PHY). J Cereb Blood Flow Metab
1997;17:687.
58. Suzuki M, Desmond TJ, Albin RL, Frey KA. Cholinergic vesicular transporters in progressive supranuclear palsy.
Neurology 2002;58:10131018.
59. Foster NL, Minoshima S, Johanns J, et al. PET measures of benzodiazepine receptors in progressive supranuclear
palsy. Neurology 2000;54:17681773.
60. Eidelberg D, Dhawan V. Can imaging distinguish PSP from other neurodegenerative disorders? Neurology
2002;58:997998.
62. Sawle GV, Brooks DJ, Marsden CD, Frackowiak RS. Corticobasal degeneration. A unique pattern of regional cortical
oxygen hypometabolism and striatal fluorodopa uptake demonstrated by positron emission tomography. Brain
1991;114:541556.
63. Eidelberg D, Dhawan V, Moeller JR, et al. The metabolic landscape of cortico-basal ganglionic degeneration: regional
asymmetries studied with positron emission tomography. J Neurol Neurosurg Psychiatry 1991;54:856862.
64. Blin J, Vidailhet MJ, Pillon B, Dubois B, Feve JR, Agid Y. Corticobasal degeneration: decreased and asymmetrical
glucose consumption as studied with PET. Mov Disord 1992;7:348354.
65. Nagasawa H, Tanji H, Nomura H, et al. PET study of cerebral glucose metabolism and fluorodopa uptake in patients
with corticobasal degeneration. J Neurol Sci 1996;139:210217.
66. Nagahama Y, Fukuyama H, Turjanski N, et al. Cerebral glucose metabolism in corticobasal degeneration: comparison
with progressive supranuclear palsy and normal controls. Mov Disord 1997;12:691696.
67. Markus HS, Lees AJ, Lennox G, Marsden CD, Costa DC. Patterns of regional cerebral blood flow in corticobasal
degeneration studied using HMPAO SPECT; comparison with Parkinsons disease and normal controls [see com-
ments]. Mov Disord 1995;10:179187.
68. Riley DE, Lang AE, Lewis A, et al. Cortical-basal ganglionic degeneration. Neurology 1990;40:12031212.
69. Laureys S, Salmon E, Garraux G, et al. Fluorodopa uptake and glucose metabolism in early stages of corticobasal
degeneration. J Neurol 1999;246:11511158.
70. Frisoni GB, Pizzolato G, Zanetti O, Bianchetti A, Chierichetti F, Trabucchi M. Corticobasal degeneration: neuropsy-
chological assessment and dopamine D2 receptor SPECT analysis. Eur Neurol 1995;35:5054.
71. Albin RL, Minoshima S, DAmato CJ, Frey KA, Kuhl DA, Sima AA. Fluoro-deoxyglucose positron emission tomog-
raphy in diffuse Lewy body disease. Neurology 1996;47:462466.
72. Minoshima S, Foster NL, Sima AA, Frey KA, Albin RL, Kuhl DE. Alzheimers disease versus dementia with Lewy
bodies: cerebral metabolic distinction with autopsy confirmation. Ann Neurol 2001;50:358365.
PET in Atypical 471
73. Donnemiller E, Heilmann J, Wenning GK, et al. Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD
and 123I-beta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body
disease. Eur J Nucl Med 1997;24:320325.
74. Hu MT, Taylor-Robinson SD, Chaudhuri KR, et al. Cortical dysfunction in non-demented Parkinsons disease patients:
a combined (31)P-MRS and (18)FDG-PET study. Brain 2000;123:340352.
75. Hu XS, Okamura N, Arai H, et al. 18F-fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia
76. Walker Z, Costa DC, Walker RW, et al. Differentiation of dementia with Lewy bodies from Alzheimers disease using
a dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 2002;73:134140.
77. Pirker W, Djamshidian S, Asenbaum S, et al. Progression of dopaminergic degeneration in Parkinsons disease and
atypical parkinsonism: a longitudinal beta-CIT SPECT study. Mov Disord 2002;17:4553.
Current and Future Therapeutic Approaches 473
28
Current and Future Therapeutic Approaches
Elmyra V. Encarnacion and Thomas N. Chase
INTRODUCTION
Approaches to the pharmacotherapy of the atypical parkinsonian or Parkinson plus disorders
have, as yet, met with little success. Drugs attempting to replace or mimic specific neurotransmitters
are relatively ineffective, as evidenced, for example, by the inconsistent response rates to dopamine
(DA) replacement by the administration of levodopa. This variable and modest efficacy contrasts
with the predictable and significant benefit obtained with dopaminomimetics in Parkinsons disease
(PD); in this case, core symptoms arise from the loss of a single transmitter system. By contrast,
clinical disability in the atypical parkinsonian disorders reflects more diffuse neuronal damage and
multiple neurotransmitter involvement. Nigral dopaminergic neurons degenerate, but so do seroton-
ergic, noradrenergic, and cholinergic neurons. Replacing DA thus can improve parkinsonian rigidity
and bradykinesia, but the overall benefit is poor and generally disappears with disease progression.
Studies of drugs targeting cholinergic and other monoaminergic systems have usually reported disap-
pointing results. On the other hand, there is a paucity of well-controlled trials of single transmitter
replacement strategies, and clinical studies that systematically address multiple system deficiencies
are virtually unknown. Indeed, whether a transmitter replacement strategy can be effective in the
symptomatic treatment of the Parkinson plus disorders remains uncertain. However, current neuro-
sciences research is providing rapidly increasing insight into the pathogenesis of PD and atypical
parkinsonian disorders. With this new understanding comes the possibility of discovering interven-
tions that will slow or stop disease progression. Progress in the search for radiologic and biochemical
surrogate markers promises not only earlier and more definitive diagnosis but also efficient and more
reliable therapeutic trials.
For the purpose of this review, the atypical parkinsonian disorders have been categorized as fol-
lows: (a) multiple system atrophy (MSA), further grouped into MSA-C, previously called
olivopontocerebellar atrophy, OPCA; MSA-A, previously called ShyDrager, SD; MSA-P, previ-
ously called striatonigral degeneration SND; (b) progressive supranuclear palsy (PSP); (c) corticobasal
degeneration (CBD); and (d) dementia with lewy bodies (DLB). An initial analysis of current therapeu-
tic approaches, based on clinical trial results published since 1980 and organized by the major neu-
rotransmitter system targeted, will be followed by consideration of possible directions for future
therapeutic research.

473
474 Encarnacion and Chase
PARKINSONISM AND MOVEMENT DISORDERS

Dopaminergic
Since degeneration of the nigrostriatal system occurs in all parkinsonian disorders, drugs targeting
the principal transmitter deficiency, DA, remain the treatment of choice for associated motor dys-
function, especially rigidity and bradykinesia. Positron emission tomography (PET) studies have
shown decreased striatal 18flourodopa uptake and decreased striatal regional blood flow indicative
of the loss of nigral dopaminergic neurons (1,2). Moreover, a preferential loss of postsynaptic DA-D2
receptors in the posterior putamen occurs in relation to levodopa resistance, suggesting the additional
degeneration of striatal spiny neurons (3,4). Similarly, 123I-iodobenzamide (IBZM) single photon
emission computed tomography (SPECT) studies indicate lower mean striatal DA-D2 receptor bind-
ing in patients with atypical parkinsonian disorders than in those with PD (5). A comparison using
[123I]G-CIT SPECT reveals a reduction of striatal DA transporter density in parkinsonian disorders,
including PD (68), but long-term studies have shown a more rapid decline in the atypical disorders;
in MSA and PSP putamen-caudate nucleus ratios are reduced and in CBD there is an increase in
binding asymmetry (9).
In MSA, analyses of 203 pathologically proven cases indicated that although the overall response
to levodopa was poor, some patients might initially respond well (10). Indeed, response rates reported
for levodopa range from 33% up to 68% (11,12). As striatal degeneration occurs, receptor sites for the
postsynaptic activity of DA produced by levodopa treatment declines, and thus clinical efficacy conse-
quently fades, leaving only supportive measures for later-stage patients. Those enjoying good response
may develop levodopa-induced axial, orofacial, and limb dyskinesias of the dystonic or choreiform
type (10,13). In general, DA agonists are no more effective than levodopa, although an open-label
evaluation on apomorphine, the most potent dopamine agonist, suggested some motor benefit in
patients with MSA (14). Uncontrolled studies of bromocriptine (1080 mg) also noted benefit (15),
whereas evaluations of pergolide yielded inconsistent results (16). A controlled trial of lisurude (up
to 2.4 mg per day) observed improvement in one (who was also levodopa responsive) out of seven
patients (17).
In PSP, local cerebral blood flow (LCBF) using xenon-enhanced computed tomography reveal
lower striatal baseline values and no increase following the intravenous administration of levodopa
compared to PD (18). Extensive degeneration of downstream basal ganglia structures may account
for levodopa-unresponsive motor dysfunction (19). Thus, a review of 12 pathologically proven cases
of PSP indicated that one-third of the patients had modest, but nonsustained, improvement while
receiving levodopa with a peripheral decarboxylase inhibitor (20). Similarly, a retrospective review
of clinically diagnosed cases showed that 54% had mild to moderate improvement with levodopa
(21). Reports on dopamine agonists appear to be even more negative. Pramipexole (4.5 mg daily) for
2 mo was not effective (22), and lisuride (mean daily dose of 2.5 mg) provided no overall benefit
when used alone and in combination with levodopa (23). Dyskinesias and other side effects are rare,
with only isolated cases of levodopa-induced oromandibular dystonia, dyskinesia, and apraxia of
eyelid opening (2426).
A review of 14 pathologically proven CBD cases found that virtually all developed asymmetric or
unilateral akinetic-rigid parkinsonism and gait disorder, and that none had a dramatic response to
levodopa therapy (27). A chart review of 147 clinically diagnosed CBD patients from eight major
movement disorders centers noted that 92% received some kind of dopaminergic medication, specifi-
cally levodopa with a peripheral decarboxylase inhibitor (87%), bromocriptine or pergolide (25%),
and selegiline (20%) (28). Overall, clinical improvement occurred in 24% receiving any of these
dopaminergic agents, with levodopa being the most effective drug given at a median dose of 300 mg
and ranging from 100 to 2000 mg. Dopamine agonists (pergolide and bromocriptine) and selegiline
were less successful, producing 6% and 10% benefit, respectively. Parkinsonian signs improved the
most, and dyskinesias were not observed even with high-dose levodopa. Side effects included drug-
associated worsening of parkinsonism, dystonia, myoclonus, and gait dysfunction, whereas nonmotor
side effects included gastrointestinal complaints, confusion, somnolence, dizziness, and hallucina-
tions. A relative failure or lack of efficacy of dopaminergic therapy in a parkinsonian patient with
cortical dysfunction should raise the suspicion of CBD.
Cholinergic
Cholinergic neuronal depletion (29,30) as well as reductions in such enzymatic markers as
cholineacetyltransferase (3133) and acetylcholinesterase (33) occur in the atypical parkinsonian
disorders, although with differences in the degree and distribution of affected neurons. For example,
several cholinergic nuclei undergo degeneration in PSP (32,34,35), whereas immunohistochemical
analyses of autopsy material indicate that in CBD the forebrain cholinergic system is more vulner-
able than the midbrain (36). The generalized loss of striatal cholinergic interneurons accounts for
observed reduction in DA-D2 receptors (37) and thus the ineffectiveness of dopaminergic drugs in
PSP. Unfortunately, cholinergic replacement therapy alone has been no more effective in palliating
symptoms, secondary to the severity of cholinergic deficits and the more widespread impairment of
monoaminergic systems in PSP (38).
In patients with PSP, cholinergic stimulation by intravenous physostigmine had no significant
motor or neurobehavioral effects at any dose, whereas cholinergic blockade by intravenous scopola-
mine, in low and medium doses, impaired memory performance in PSP patients as well as normal
individuals and exacerbated gait disability in some patients (39). Similarly, controlled trials of orally
administered physostigmine failed to benefit any of the motor functions tested (40,41). An open
study of the acetylcholinesterase inhibitor, donepezil, lasting 3 mo also did not appear to improve
cognitive dysfunction or activities of daily living (38). A controlled trial of donepezil in 21 PSP
patients did, however, suggest modest benefit in some cognitive measures but worsened mobility
scores (42). The effect of donepezil on motor dysfunction ranges from none (38) to deleterious (42).
Similarly, the direct cholinergic agonist RS-86 did not improve motor function, eye movements, or
psychometric performance in a controlled trial in 10 PSP patients (43).
In clinically diagnosed CBD cases, 27% received anticholinergics, which briefly benefited some
individuals but were often poorly tolerated (28).
Adrenergic, Serotoninergic, GABAergic, Glutamatergic
Neurotransmitter systems downstream from the degenerating nigrostriatal dopaminergic pathway
have also been targeted therapeutically. The rationale for these pharmacological interventions paral-
lels that for DA replacement, i.e., the restoration of transmitter function, lost as a consequence of the
degenerative process.
Adrenergic system dysfunction occurs in atypical parkinsonian disorders and could contribute to
clinical disability. For example, there is degeneration of the locus ceruleus in PSP, where quantitative
autoradiographic analysis of tissue sections shows a dramatic reduction in F-2 adrenoceptor density
compared to controls (44). Nevertheless, a randomized blinded study revealed that the F-2 adrener-
gic antagonist idazoxan improved balance and manual dexterity in about half of PSP patients (45),
whereas a similarly designed evaluation of efaroxan, another potent F-2 antagonist, did not signifi-
cantly alter any of the assessed measures of motor function (46).
The effect of serotoninergic drugs in the atypicals has not been extensively studied. Open-label
evaluations suggested methysergide, a serotonin 5HT2 receptor antagonist that blocks the facilitatory
effects of raphe stimulation on bulbospinal neurons, affords relief to some PSP patients when used
alone or in combination with antiparkinsonian agents (47,48); marked improvement was reported in
patients with severe dysphagia (48). These studies, however, have not been replicated, and
methysergide is no longer being used owing to its clear side effects (e.g., retroperitoneal fibrosis).
L-Aminobutyric acid (GABA) system function has been assessed in the atypical parkinsonian disor-
ders using PET with [11C]flumazenil. GABA-type A/benzodiazepine receptor binding appears to be
decreased in the brainstem and cerebellum of MSA patients with MSA-C, but not in MSA-A syn-
drome; however, binding still remains largely preserved in the cerebral hemispheres, basal ganglia,
thalamus, and brainstem as well as cerebellum in both MSA groups compared to normal controls
(49). Results from a randomized blinded study of vigabatrin, an irreversible inhibitor of GABA-tran-
saminase, given to patients with MSA-C at a daily oral dose of 24 g for 4 mo, indicate that agents that
increase central GABA concentrations are unlikely to confer symptomatic benefit (50).
In PSP, PET studies revealed a 13% global reduction in [11C]flumazenil binding, particularly in
the anterior cingulate gyrus (51), and a reduced density of GABA neurons was seen in the caudate
nucleus, ventral striatum, and internal and external pallidum (52). A controlled study of zolpidem, a
hypnotic with putative GABA-A receptor agonist activity, at doses of 510 mg, found improvement
in parkinsonian signs (>20% improvement), dysarthria, and eye movements, although sedation
appeared at the highest dose (53). In clinically diagnosed CBD, benzodiazepines, primarily
clonazepam, reportedly improves myoclonus (23%) and dystonia (9%) (28), whereas clinical ex-
perience suggests that baclofen and tizanidine can have a modest beneficial effect on rigidity and
tremor (54).
Possible involvement of glutamatergic systems in the atypical parkinsonian syndromes has been
little explored, although some studies have addressed the therapeutic efficacy of drugs purporting to
inhibit glutamate receptors of the N-methyl-D-aspartate (NMDA) type. For example, an uncontrolled
study of the NMDA antagonist, amantadine, in eight patients with MSA-C lasting on average for
over 40 mo suggested improved performance on measures of reaction and movement time (55). On
the other hand, a short-term pilot study of amantadine at relatively high doses (400600 mg/d) failed
to find consistent benefit (56). Nevertheless, a salutatory response was observed in a blinded and
controlled study involving 30 MSA-C patients that used lower doses of amantadine (200 mg/d) for 3
4 mo (57). Amantadine is neither much used nor very effective in patients with CBD (28).
Others
Tricyclics
A blinded trial of amitriptyline, a norepinephrine and serotonin reuptake blocker, beginning at 25 mg
at bedtime and increasing to 50 mg in a week or two as needed, showed modest benefit in gait (58).
Botulinum Toxin
Dystonia can be a disabling feature in at least a third of CBD cases (28,59) as well as in other
atypical parkinsonian disorders. Open-label studies of botulinum toxin (BTx)-A injections suggest
that the treatment of limb dystonia depends on the severity of the deformity and degree of contractures
(60), temporarily improving hand and arm function in early disease, while reducing pain, facilitating
hygiene, and preventing secondary contractures in more advanced stages (61). BTx-A also report-
edly improved orofacial dystonia using clinical and electromyogram (EMG) examinations as out-
come measures (61), and can be particularly effective in the relief of blepharospasm and
PSP-associated retrocollis (61), and apraxia of eyelid opening (62). Adverse effects are generally
mild and transient, although severe dysphagia has been reported, with onset a few days after treat-
ment and persisting for several months (63).
Neurosurgical Approaches
Stereotactic procedures, such as pallidotomy or pallidal/subthalamic nucleus (STN) stimulation,
have had limited success in the atypical parkinsonian disorders (64), and are not generally recom-
mended. On the other hand, bilateral STN stimulation reportedly benefited rigidity and akinesia in
four MSA patients (65). Neural transplantation approaches are currently being explored in the
atypicals, although beset by the same methodological and ethical issues associated with these proce-
dures in PD. A placebo-controlled study is under way to assess the safety, tolerability, and efficacy of
glial cell-derived neurotrophic factor (GDNF) continuously infused directly into striatum on motor
dysfunction in PSP patients.
Electroconvulsive Therapy (ECT)

ECT appeared to improved motor signs in five PSP patients after nine treatments, although treat-
ment-induced confusion and prolonged hospitalization limit the usefulness of this technique (66).
AUTONOMIC DYSFUNCTION
Most studies of autonomic dysfunction in atypical parkinsonian disorders focus on MSA, where
this feature is far more common than in CBD, PSP, or DLB. Neuropathological studies reveal neu-
ronal loss in central adrenergic pathways, especially catecholaminergic neuron depletion in the ros-
tral ventrolateral medulla, but not in the sympathetic ganglia (67,68). Asymptomatic orthostatic
hypotension generally does not require treatment in MSA, since autoregulation seems preserved down
to a systolic blood pressure of 60 mmHg, a value well below the 80 mmHg at which autoregulation
fails in normal subjects (69).
For symptomatic orthostatic hypotension, fludrocortisone, acting through expanding plasma vol-
ume and reducing natriuresis, and midodrine, an F-1 adrenoreceptor agonist, generally appear to be
the treatments of choice. A large, randomized, controlled trial showed that midodrine reduced ortho-
static hypotension by increasing peripheral resistance (70). Midodrine can be initiated at 2.5 mg three
times a day, increased up to 10 mg three times a day, if needed, whereas fludrocortisone, which has
never been studied formally, is usually started at .1 mg daily, and increased to a maximum of four
tablets per day in two or three divided doses (62). A placebo-controlled trial in 35 patients comparing
the pressor effects of phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin
(50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg) on seated systolic
blood pressure showed a significant pressor response with phenylpropanolamine, yohimbine, and
indomethacin; comparison of phenylpropanolamine (12.5 mg) and midodrine (5mg) in a subgroup of
patients elicited similar effects (71).
In an uncontrolled, dose-ranging study of L-threo-dihydroxyphenylserine, 100, 200, and 300 mg
twice daily were well tolerated, and the 300-mg dose seemed to offer the most effective control of
symptomatic orthostatic hypotension (72). Similar results were observed when 60 head-up-tilt was
performed after the daily oral administration of 300 mg L-threo-dihydroxyphenylserine for 2 wk (73).
A small, open evaluation of chronic subcutaneous octreotide at 100 g three times a day also sug-
gested functional improvement (74). Furthermore, isolated cases include treatment with vasopressin
in refractory hypotension (75) and erythropoietin in those with anemia (76).
Urinary problems also commonly afflict those with atypical parkinsonian syndromes. F1-adrener-
gic receptors are present in the proximal urethra where impaired relaxation may be responsible for
difficulty voiding and increased residual urine. An uncontrolled study showed that F1-adrenergic
antagonists, prazosin (nonselective) and moxisylyte (selective), reduced residual urine volume,
although side effects related to orthostatic hypotension were common in those with postural hypoten-
sion of more than 30 mmHg (77). An open study suggested that desmopressin at night may reverse
nocturia (78). For incontinence, peripherally acting anticholinergics, such as tolterodine, oxybutynin,
and propiverene, are used, albeit at the expense of causing retention (79). Although no formal studies
have been done on these drugs, recommended doses are tolterodine 24 mg at bedtime or twice daily,
oxybutinin 510 mg at bedtime, or propantheline 1530 mg at bedtime if the pathophysiology
involves detrusor hypereflexia (62).
Other common autonomic disturbances include erectile dysfunction and constipation. A random-
ized controlled study showed that sildenafil citrate (50 mg) is efficacious in the treatment of impo-
tence, but may unmask or exacerbate preexisting hypotension (80); measurement of orthostastic blood
pressure is thus recommended prior to the administration of this drug. General recommendations for
constipation are a high-fiber diet, and over-the-counter laxatives or lactulose. In an open evaluation,
macrogol 3350 was found to diminish constipation (81). Open-label studies have also suggested that
subcutaneous bethanechol chloride, a muscarinic receptor agonist, improves tearing, salivation,
sweating, gastrointestinal, and bladder functions (82), whereas sublingual atropine benefits sialor-
rhea, although with such side effects as delirium and hallucinations (83). Anticholinergics also risk
exacerbating confusion and constipation as well as preexisting prostatism and glaucoma.
COGNITIVE DYSFUNCTION
Cholinergic
Drugs enhancing central cholinergic function provide a rational approach to the treatment of cog-
nitive dysfunction associated with the Parkinson plus disorders. In PSP, however, a controlled trial of
physostigmine showed only borderline changes in long-term memory (41), although improved visual
attention has been reported (92). An open study of donepezil did not appear to ameliorate cognitive
dysfunction (38), whereas a controlled trial suggested modest benefit in some cognitive measures but
worsened mobility scores (42). A controlled trial on the direct cholinergic agonist RS-86 revealed
comparable unsatisfactory results (43).
DLB is attended by brain cholinergic deficits such as an early loss of cholinacetyltransferase activity
(93) as well reductions in hippocampal muscarinic and nicotinic receptors (94). An uncontrolled
assessment of the cholinesterase inhibitor, rivastigmine, suggested improvement after 24 wk of
treatment in cognition, activities of daily living, and behavioral and psychiatric symptoms measured
by the Neuropsychiatric Inventory (95). A subsequent placebo-controlled study observed similarly
benefits with rivastigmine (612 mg daily) on behavior and cognition, with most parameters of cog-
nitive performance returning to pretreatment levels after 3 wk of drug discontinuation (96). Prospec-
tive studies on donepezil, another cholinesterase inhibitor, also found improvement in cognitive and
noncognitive symptoms, without a worsening of motor function (97,98). Cholinergic replacement
therapy should thus be considered in DLB patients.
On the other hand, the use of drugs that possess anticholinergic activity, such as tricyclic antide-
pressants, risk worsening confusion (28).
BEHAVIORAL DYSFUNCTION
Dopaminergic and Serotoninergic
Classical antipsychotic drugs that potently block dopaminergic receptors can ameliorate psychotic
symptoms but worsen parkinsonism, at times seriously enough to require levodopa (84). Better results
in treating psychosis have been obtained with the atypical neuroleptics, possibly owing to their pre-
dominant antiserotoninergic rather than antidopaminergic activity. An extensive chart review revealed
that 90% of DLB patients had partial to complete resolution of psychosis using long-term quetiapine,
although in 27% motor worsening was noted at some point during treatment (85). A large, random-
ized blinded trial found that olanzapine (5 or 10 mg) reduces psychosis without exacerbating parkin-
sonism (86). Relatively small doses of clozapine have also been used successfully for the relief of
paranoid delusions, psychosis, and agitation, albeit at the risk of agranulocytosis (84). Indeed, cau-
tion is generally warranted in using neuroleptics, since sedation, confusion, immobility, postural
instability, and other serious side effects are hardly uncommon (87,88). Neuroleptic malignant syn-
drome (NMS) is a rare but fatal adverse effect more common with typical neuroleptics, such as
haloperidol, owing to potent dopaminergic blockade (84,85). Dopaminomimetic agents (DA agonists
more so than levodopa) are more likely to worsen than improve cognitive and affective function
associated with the atypical parkinsonian disorders. The management of psychosis should thus first
involve lowering the dose of anti-parkinsonian medication in this order: anticholinergics, amantadine,
selegiline, DA agonists, and then levodopa; only if the improvement is inadequate, should a cautious
trial of antipsychotic medication be considered (87). There are isolated reports of improvement in
depression with levodopa (89), or with levodopa combined with L-threodihydroxyphenylserine
and thyroid-releasing hormone (90). The successful use of clozapine in treatment-resistant psy-
Table 1
Most Commonly Recommended Drugs for Each Dysfunction
Motor Levodopa, variable response but best drug
Other dopaminergic agents, less beneficial
Autonomic Orthostatic hypotensionfludrocortisone, midodrine
Urinary incontinencetolterodine, oxybutinin, propantheline
Erectile dysfunctionsildenafil citrate
Cognitive Cholinesterase inhibitors (donepezil, rivastigmine)
Behavioral Psychosisatypical neuroleptics (quetiapine, clozapine)
DepressionSSRI
chotic depression without aggravating neurological disabilities has also been observed (91). In the
absence of formal trials of antidepressants in patients with atypical parkinsonism, serotonin reuptake
inhibitors, such as those used for PD, are generally prescribed.
Others
ECT has been effective in the treatment of depression in the atypical parkinsonian disorders, but
produces inconsistent benefits on motor or cognitive dysfunction (99101).
FUTURE
The atypical parkinsonian disorders present clinically with a myriad of symptoms owing to the
diffuse nature of the underlying neuronal involvement. Current palliative pharmacotherapies, largely
seeking to normalize resultant transmitter system abnormalities, are largely unsuccessful because of
poor efficacy, prominent adverse effects, or both. A variety of factors contribute to this unfortunate
situation. The number of patients afflicted by these disorders is small, insufficient to stimulate spe-
cific pharmaceutical development efforts. Attempts to rigorously assess possible extensions of exist-
ing drugs to the treatment of the atypical parkinsonian syndromes have been uncommon. There are
no reliable means for early and accurate diagnosis, although the National Institutes of HealthPro-
gressive Supranuclear Palsy (NINDSPSP) criteria is specific. There is also a need for validated
animal models, but studies are under way (102105). Finally, most clinical trials have been so limited
and poorly designed as to preclude reliable interpretation. In this setting, physicians have largely
been left to make their own best therapeutic judgments. Treatment remains symptomatic and largely
supportive (Table 1) while awaiting the emergence of neuroprotective strategies to slow or stop dis-
ease progression. Palliative therapies include ambulatory aids and rehabilitation, which are discussed in
another chapter.
Neuroprotection
Notwithstanding the rapid advances in basic neurosciences research, the causes of
neurodegenerative disease remain obscure. Without more detailed etiologic information, the prob-
ability of discovering an effective protective therapy is small. Current research implicates a complex
combination of genetic predispositions and endogenous and/or environmental factors. Oxidative
stress, excitotoxicity, mitochondrial deficiency, microglial activation, apoptotic triggering, and
protein-processing abnormalities have all been suggested as possibly contributory (Table 2).
Recently, the proteins F-synuclein, which interfere with membrane protein function, and tau, a
microtubular-associated protein, which plays an important role in neuronal transport, have received
increasing investigative attention. The discovery of these proteins has prompted classification of the
atypical parkinsonian disorders into F-synucleopathies, specifically MSA (106,107) and DLB (108),
Table 2
Possible Disease Etiologies and Areas to Explore for Neuroprotection
Oxidative stress
Excitotoxicity
Mitochondrial deficiency
Microglial activation
Apoptotic triggering
Protein processing abnormalities (i.e., accumulation of F-synuclein, tau)
and tauopathies, specifically PSP and CBD (109,110). Pathological overlap exists, however, and
colocalization of F-synuclein and tau does occur (111114). A possible role for these proteins in
pathogenesis could also provide a basis for developing surrogate spinal fluid outcome measures to
assist in the clinical evaluation of therapeutic candidates. Stimulation of axonal regeneration through
glial cell-derived neurotrophic factor (GDNF) has already received attention. Neuroradiologic ad-
vances also promise to provide clearer insight into such matters as local cerebral blood flow, trans-
mitter system function, and intracellular metabolic abnormalities, needed to identify the cause of the
selective neurodegenerative processes and to discover successful therapeutic interventions.
REFERENCES
1. Brooks DJ, Ibanez V, Sawle GV, Quinn N, Lees AJ, Mathias CJ, et al. Differing patterns of striatal 18F-dopa uptake in
Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990;28(4):547555.
2. Leenders KL, Frackowiak RSJ, Lees AJ. SteeleRichardsonOlszewski syndrome. Brain energy metabolism, blood
flow and fluorodopa uptake measured by positron emission tomography. Brain 1988;111(Pt 3):615630.
3. Antonini A, Leenders KL, Vontobel P. Complementary PET studies of striatal neuronal function in the differential
diagnosis between multiple system atrophy and Parkinsons disease. Brain 1997;120(Pt 12):21872195.
4. Churchyard A, Donnan GA, Hughes A. Dopa resistance in multiple-system atrophy: loss of postsynaptic D2 receptors.
Ann Neurol 1993;34(2):219226.
5. Hierholzer J, Cordes M, Venz S, Schelosky L, Harisch C, Richter W, et al. Loss of dopamine-D2 receptor binding sites
in Parkinsonian plus syndromes. J Nucl Med 1998;39(6):954960.
6. Pirker W, Asenbaum S, Bencsits G, Prayer D, Gerschlager W, Deecke L, et al. [123I]beta-CIT SPECT in multiple
system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Mov Disord 2000;15(6):11581167.
7. Ransmayrl G, Seppi K, Donnemiller E, Luginger E, Marksteiner J, Riccabona G, et al. Striatal dopamine transporter
function in dementia with Lewy bodies and Parkinsons disease. Eur J Nucl Med 2001;28(10):15231528.
8. Varrone A, Marek KL, Jennings D, Innis RB, Seibyl JP. [(123)I]beta-CIT SPECT imaging demonstrates reduced density
of striatal dopamine transporters in Parkinsons disease and multiple system atrophy. Mov Disord 2001;16(6):10231032.
9. Pirker W, Djamshidian S, Asenbaum S, Gerschlager W, Tribl G, Hoffmann M, et al. Progression of dopaminergic
degeneration in Parkinsons disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study. Mov Disord
2002;17(1):4553.
10. Wenning GK, Tison F, Ben-Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically
proven cases. Mov Disord 1997;12(2):133147.
11. Rajput AH, Rozdilsky B, Rajput A, Ang L. Levodopa efficacy and pathological basis of Parkinson syndrome. Clin
Neuropharmacol 1990;13(6):553558.
12. Colosimo C, Albanese A, Hughes A, de Brun VM, Lees AJ. Some specific clinical features differentiate multiple
system atrophy (stritaonigral variety) from Parkinsons disease. Arch Neurol 1995;52:248294.
try 2002;72(3):300303.
14. Rossi P, Colosimo C, Moro E, Tonali P, Albanese A. Acute challenge with apomorphine and levodopa in parkinsonism.
Eur Neurol 2000;43(2):95101.
15. Goetz CG, Tanner CM, Klawans HL. The pharmacology of olivopontocerebellar atrophy. Adv Neurol 1984;41:143148.
16. Kurlan R, Miller C, Levy R, Macik B, Hamill R, Shoulson I. Long-term experience with pergolide therapy of advanced
parkinsonism. Neurology 1985;35(5):738742.
17. Lees A, Bannister R. The use of lisuride in the treatment of multiple system atrophy with autonomic failure (Shy
Drager syndrome). J Neurol Neurosurg Psychiatry 1981;44(4):347351.
18. Kobari M, Fukuuchi Y, Shinohara T, Nogawa S, Takahashi K. Local cerebral blood flow and its response to intravenous
levodopa in progressive supranuclear palsy. Comparison with Parkinsons disease. Arch Neurol 1992;49(7):725730.
19. Henderson JM, Carpenter K, Cartwright H, Halliday GM. Loss of thalamic intralaminar nuclei in progressive supra-
nuclear palsy and Parkinsons disease: clinical and therapeutic implications. Brain 2000;123(Pt 7):14101421.
20. Kompoliti K, Goetz CG, Litvan I, Jellinger K, Veiny M. Pharmacological therapy in progressive supranuclear palsy.
Arch Neurol 1998; 55(8):10991102.
21. Nieforth KA, Golbe LI. Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin
22. Weiner W J, Minagar A, Shulman LM. Pramipexole in progressive supranuclear palsy. Neurology 1999;52(4):873874.
23. Neophytides A, Lieberman AN, Goldstein M, Gopinathan G, Leibowitz M, Bock J, Walker R. The use of lisuride, a
potent dopamine and serotonin agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosurg Psy-
chiatry 1982;45(3):261263.
24. Defazio G, De Mari M, De Salvia R, Lamberti P, Giorelli M, Livrea P. Apraxia of eyelid opening induced by levodopa
therapy and apomorphine in atypical parkinsonism (possible progressive supranuclear palsy): a case report. Clin
25. Kim JM, Lee KH, Choi YL, Choe GY, Jeon BS. Levodopa-induced dyskinesia in an autopsy-proven case of progres-
sive supranuclear palsy. Mov Disord 2002;17(5):10891090.
26. Tan EK, Chan LL, Wong MC. Levodopa-induced oromandibular dystonia in progressive supranuclear palsy. Clin
Neurol Neurosurg 2003;105(2):132134.
27. Wenning GK, Litvan I, Jankovic J, Granata R, Mangone CA, McKee A, et al. Natural history and survival of 14
patients with corticobasal degeneration confirmed at postmortem examination. J Neurol Neurosurg Psychiatry 1998;
64(2):184189.
28. Kompoliti K, Goetz CG, Boeve BF, Maraganore DM, Ahlskog JE, Marsden CD, et al. Clinical presentation and phar-
macological therapy in corticobasal degeneration. Arch Neurol 1998;55(7):957961.
29. Benarroch EE, Schmeichel AM, Padsi JE. Depletion of mesopontine cholinergic and sparing of raphe neurons in mul-
tiple system atrophy. Neurology 2002;59(6):944946.
30. Benarroch EE, Schmeichel AM, Padsi JE. Preservation of branchimotor neurons of the nucleus ambiguus in multiple
system atrophy. Neurology 2003;60(1):115117.
31. Kish SJ, Robitaille Y, el-Awar M, Deck JH, Simmons J, Schut L, et al. Non-Alzheimer-type pattern of brain
cholineacetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy. Ann Neurol 1989;
26(3):362367.
32. Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, LHeureux R, Hauw JJ, et al. Dopaminergic and cholinergic lesions in
progressive supranuclear palsy. Ann Neurol 1985;18(5):523529.
33. Kish SJ, Chang LJ, Mirchandani L, Shannak K, Hornykiewicz O. Progressive supranuclear palsy: relationship between
extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol 1985;18(5):530536.
34. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in
Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA 1987;84(16):59765980.
35. Juncos JL, Hirsch EC, Malessa S, Duyckaerts C, Hersh LB, Agid Y. Mesencephalic cholinergic nuclei in progressive
supranuclear palsy. Neurology 1991;41(1):2530.
36. Kasashima S, Oda Y. Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive
supranuclear palsy and corticobasal degeneration. Acta Neuropathol (Berl) 2003;105(2):117124.
37. Javoy-Agid F. Cholinergic and peptidergic systems in PSP. J Neural Transm Suppl 1994;42:205218.
38. Fabbrini G, Barbanti P, Bonifati V, Colosimo C, Gasparini M, Vanacore N, et al. Donepezil in the treatment of progres-
sive supranuclear palsy. Acta Neurol Scand. 2001;103(2):123125.
39. Litvan I, Blesa R, Clark K, Nichelli P, Atack JR, Mouradian MM, et al. Pharmacological evaluation of the cholinergic
system in progressive supranuclear palsy. Ann Neurol 1994;36(1):5561.
40. Frattali CM, Sonies BC, Chi-Fishman G, Litvan I. Effects of physostigmine on swallowing and oral motor functions in
patients with progressive supranuclear palsy: a pilot study. Dysphagia 1999;14(3):165168.
41. Litvan I, Gomez C, Atack JR, Gillespie M, Kask AM, Mouradian MM, et al. Physostigmine treatment of progressive
supranuclear palsy. Ann Neurol 1989;26(3):404407.
patients with progressive supranuclear palsy. Neurology 2001;57(3):467473.
and movement in PSP despite effects on sleep. Neurology 1989;39(2 Pt 1):257261.
44. Pascual J, Berciano J, Gonzalez AM, Grijalba B, Figols J, Pazos A. Autoradiographic demonstration of loss of alpha 2-
adrenoceptors in progressive supranuclear palsy: preliminary report. J Neurol Sci 1993;114(2):165169.
45. Cole DG, Growdon JH. Therapy for progressive supranuclear palsy: past and future. J Neural Transm Suppl
1994;42:283290.
46. Rascol O, Sieradzan K, Peyro-Saint-Paul H, Thalamas C, Brefel-Courbon C, Senard JM, et al. Efaroxan, an alpha-2
antagonist, in the treatment of progressive supranuclear palsy. Mov Disord 1998;13(4):673676.
47. Di Trapani G, Stampatore P, La Cara A, Azzoni A, Vaccario ML. Treatment of progressive supranuclear palsy with
methysergide. A clinical study. Ital J Neurol Sci 1991;12(2):157161.
48. Rafal RD, Grimm RJ. Progressive supranuclear palsy: functional analysis of the response to methysergide and
antiparkinsonian agents. Neurology 1981;31(12):15071518.
49. Gilman S, Koeppe RA, Junck L, Kluin KJ, Lohman M, St Laurent RT. Benzodiazepine receptor binding in cerebellar
degenerations studied with positron emission tomography. Ann Neurol 1995;38(2):176185.
50. Bonnet AM, Esteguy M, Tell G, Schechter PJ, Hardenberg J, Agid Y. A controlled study of oral vigabatrin (gamma-
vinyl GABA) in patients with cerebellar ataxia. Can J Neurol Sci 1986;13(4):331333.
51. Foster NL, Minoshima S, Johanns J, Little R, Heumann ML, Kuhl DE, et al. PET measures of benzodiazepine receptors
in progressive supranuclear palsy. Neurology 2000;54(9):17681773.
52. Levy R, Ruberg M, Herrero MT, Villares J, Javoy-Agid F, Agid Y, et al. Alterations of GABAergic neurons in the basal
ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA.
Neurology. 1995;45(1):127134.
53. Daniele A, Moro E, Bentivoglio AR. Zolpidem in progressive supranuclear palsy. N Engl J Med 1999;341(7):543544.
54. Stover NP, Watts RL. Corticobasal degeneration. Semin Neurol 2001;21(2):4958.
55. Botez MI, Botez-Marquard T, Elie R, Le Marec N, Pedraza OL, Lalonde R. Amantadine hydrochloride treatment in
olivopontocerebellar atrophy: a long-term follow-up study. Eur Neurol 1999;41(4):212215.
56. Colosimo C, Merello M, Pontieri FE . Amantadine in parkinsonian patients unresponsive to levodopa: a pilot study. J
Neurol 1996;243(5):422425.
57. Botez MI, Botez-Marquard T, Elie R, Pedraza OL, Goyette K, Lalonde R. Amantadine hydrochloride treatment in
heredodegenerative ataxias: a double blind study. J Neurol Neurosurg Psychiatry 1996;61(3):259264.
58. Newman GC. Treatment of progressive supranuclear palsy with tricyclic antidepressants. Neurology 1985;35(8):
11891193.
59. Vanek ZF, Jankovic J. Dystonia in corticobasal degeneration. Mov Disord. 2001;16(2):252257.
60. Cordivari C, Misra VP, Catania S, Lees AJ. Treatment of dystonic clenched fist with botulinum toxin. Mov Disord
2001;16(5):907913.
61. Muller J, Wenning GK, Wissel J, Seppi K, Poewe W. Botulinum toxin treatment in atypical parkinsonian disorders
associated with disabling focal dystonia. J Neurol 2002;249(3):300304.
62. Mark MH. Lumping and splitting the Parkinson plus syndromes: dementia with Lewy bodies, multiple system atrophy,
progressive supranuclear palsy, and cortical-basal ganglionic degeneration. Neurol Clin 2001;19(3):607627.
63. Thobois S, Broussolle E, Toureille L, Vial C. Severe dysphagia after botulinum toxin injection for cervical dystonia in
multiple system atrophy. Mov Disord 2001;16(4):764765.
64. Lang AE, Lozano Am. Parkinsons disease. Second of two parts. N Engl J Med 1998;339(16):11301143.
65. Visser-Vandewalle V, Temel Y, Colle H, van der Linden C. Bilateral high-frequency stimulation of the subthalamic
nucleus in patients with multiple system atrophyparkinsonism. Report of four cases. J Neurosurg 2003;98(4):882887.
66. Barclay CL, Duff J, Sandor P, Lang AE. Limited usefulness of electroconvulsive therapy in progressive supranuclear
palsy. Neurology 1996;46(5):12841286.
67. Benarroch EE, Smithson IL, Low PA, Parisi JE. Depletion of catecholaminergic neurons of the rostral ventrolateral
medulla in multiple systems atrophy with autonomic failure. Ann Neurol 1998;43(2):156163.
68. Mathias CJ. Autonomic disorders and their recognition. N Engl J Med 1997;336(10):721724.
69. Thomas DJ, Bannister R. Preservation of autoregulation of cerebral blood flow in autonomic failure. J Neurol Sci 1980;
44(23):205212.
70. Wright R, Kaufman HC, Perera R, Opker-Gehring TL, McElligot MA, Cheng KN. A double-blind, dose response study
on midodrine in neurogenic orthostatic hypotension. Neurology 1998;51(1):120124.
71. Jordan J, Shannon JR, Biaggioni I, Norman R, Black BK, Robertson D. Contrasting actions of pressor agents in severe
autonomic failure. Am J Med 1998;105(2):116124.
72. Mathias CJ, Senard JM, Braune S, Watson L, Aragishi A, Keeling JE, et al. L-threo-dihydroxyphenylserine (L-threo-
DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-
ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001;11(4):235242.
73. Yoshozawa T, Fuhita T, Mizusawa H, Shoji S. L-threo-3,4-dihydroxyphenylserine enhances the orthostatic responses
of plasma renin activity and angiotensin II in multiple system atrophy. J Neuro 1999;246(3):193197.
74. Bordet R, Benhadjali J, Destee A, Belabbas A, Libersa C. Octreotide in the management of orthostatic hypotension in
multiple system atrophy: pilot trial of chronic administration. Clin Neuropharmacol 1994;17(4):380383.
75. Vallejo R, DeSouza G, Lee J. ShyDrager syndrome and severe unexplained intraoperative hypotension responsive to
vasopressin. Anesth Analg 2002;95(1):5052.
76. Perrera R, Isola L, Kaufman H. Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary
autonomic failure. Clin Auton Res 1995;5(4):211213.
77. Sakakibara R, Hattori T, Uchiyama T, Suenaga T, Takahashi H, Yamanishi T, et al. Are alpha-blockers involved in
lower urinary tract dysfunction in multiple system atrophy? A comparison of prazosin and moxisylyte. J Auton Nerv
Syst 2000;79(23):191195.
78. Sakakibara R, Matsuda S, Uchiyama T, Yoshiyama M, Yamanishi T, Hattori T. The effect of intranasal desmopressin
on nocturnal waking in urination in multiple system atrophy patients with nocturnal polyuria. Clin Auton Res
2003;13(2):106108.
79. Colosimo C, Pezzella FR. The symptomatic treatment of multiple system atrophy. Eur J Neurol 2002;9(3):195199.
80. Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafil citrate
(Viagra) in parkinsonism due to Parkinsons disease or multiple system atrophy with observations on orthostatic
hypotension. J Neurol Neurosurg Psychiatry 2001;71(3):371374.
81. Eichhorn TE, Oertel WH. Macrogol 3350/electrolyte improves constipation in Parkinsons disease and multiple system
82. Khurana RK. Cholinergic dysfunction in ShyDrager syndrome: effect of the parasympathomimetic agent, bethanechol.
Clin Auton Res 1994;4(12):513.
83. Hyson HC, Johnson AM, Jog MS. Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study. Mov
Disord 2002;17(6):13181320.
84. Geroldi C, Frisoni GB, Bianchetti A, Trabucchi M. Drug treatment in Lewy body dementia. Dement Geriatr Cogn
Disord 1997;8(3):188197.
85. Fernandez HH, Trieschmann ME, Burke MA, Friedman JH. Quetiapine for psychosis in Parkinsons disease versus
dementia with Lewy bodies. J Clin Psychiatry 2002;63(6):513515.
86. Cummings JL, Street J, Masterman D, Clark WS. Efficacy of olanzapine in the treatment of psychosis in dementia with
lewy bodies. Dement Geriatr Cogn Disord 2002;13(2):6773.
2001;16(Suppl 1):S12S18.
88. McKeith I, Fairbairn A, Perry R, Thompson P, Perry E. Neuroleptic sensitivity in patients with senile dementia of Lewy
body type. BMJ 1992;305(6855):673678.
89. Fetoni V, Soliveri P, Monza D, Testa D, Girotti F. Affective symptoms in multiple system atrophy and Parkinsons
disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 1999;66(4):541544.
90. Goto K, Ueki A, Shimode H, Shinjo H, Miwa C, Morita Y. Depression in multiple system atrophy: a case report.
Psychiatry Clin Neurosci 2000;54(4):507511.
91. Parsa MA, Simon M, Dubrow C, Ramirez LF, Meltzer HY. Psychiatric manifestations of olivo-ponto-cerebellar atro-
phy and treatment with clozapine. Int J Psychiatry Med 1993;23(2):149156.
92. Kertzman C, Robinson DL, Litvan I. Effects of physostigmine on spatial attention in patients with progressive supra-
nuclear palsy. Arch Neurol 1990;47(12):13461350.
93. Shiozaki K, Iseki E, Hino H, Kosaka K. Distribution of m1 muscarinic acetylcholine receptors in the hippocampus of
patients with Alzheimers disease and dementia with Lewy bodies-an immunohistochemical study. J Neurol Sci
2001;193(1):2328.
94. Martin-Ruiz C, Court J, Lee M, Piggott M, Johnson M, Ballard C, et al. Nicotinic receptors in dementia of Alzheimer,
Lewy body and vascular types. Nicotinic receptors in dementia of Alzheimer, Lewy body and vascular types. Acta
Neurol Scand Suppl 2000;176:3441.
95. Grace J, Daniel S, Stevens T, Shankar KK, Walker Z, Byrne EJ, et al. Long-Term use of rivastigmine in patients with
dementia with Lewy bodies: an open-label trial. Int Psychogeriatr 2001;13(2):199205.
96. Wesnes KA, McKeith IG, Ferrara R, Emre M, Del Ser T, Spano PF, et al. Effects of rivastigmine on cognitive function
in dementia with lewy bodies: a randomised placebo-controlled international study using the cognitive drug research
computerised assessment system. Dement Geriatr Cogn Disord 2002;13(3):18392.
97. Samuel W, Caligiuri M, Galasko D, Lacro J, Marini M, McClure FS, et al. Better cognitive and psychopathologic
response to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: a preliminary study. Int J
Geriatr Psychiatry 2000;15(9):794802.
98. Shea C, MacKnight C, Rockwood K. Donepezil for treatment of dementia with Lewy bodies: a case series of nine
patients. Int Psychogeriatr 1998;10(3):229238.
99. Hooten WM, Melin G, Richardson JW. Response of the parkinsonian symptoms of multiple system atrophy to ECT.
Am J Psychiatry 1998;155(11):1628.
100. Roane DM, Rogers JD, Helew L, Zarate J. Electroconvulsive therapy for elderly patients with multiple system atrophy:
a case series. Am J Geriatr Psychiatry 2000;8(2):171174.
101. Ruxin RJ, Ruedrich S. ECT in combined multiple system atrophy and major depression. Convuls Ther 1994;10(4):
298300.
102. Feany MB, Bender WW. A Drosophila model of Parkinsons disease. Nature 2000;404(6776):394398.
103. Sahara N, Lewis J, DeTure M, McGowan E, Dickson DW, Hutton M, et al. Assembly of tau in transgenic animals
expressing P301L tau: alteration of phosphorylation and solubility. J Neurochem 2002;83(6):14981508.
104. Giasson BI, Duda JE, Quinn SM, Zhang B, Tojanowksi JQ, Lee VM-Y. Neuronal a-synucleinopathy with severe move-
ment disorder in mice expressing A53T human a-synuclein. Neuron 2002; 34(4):521533.
105. Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, et al. Misfolded proteinase K-resistant
hyperphosphorylated a-synuclein in aged transgenic mice with locomotor deterioration and in human a-synucleinopathies.
J Clin Invest 2002;110(10):14291439.
106. Gai WP, Pountney DL, Power JH, Li QX, Culvenor JG, McLean CA, et al. Alpha-Synuclein fibrils constitute the
central core of oligodendroglial inclusion filaments in multiple system atrophy. Exp Neurol 2003;181(1):6878.
107. Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, et al. Immunohistochemical and biochemical
studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp
Neurol 2000;59(9):830-41.
108. Marui W, Iseki E, Nakai T, Miura S, Kato M, Ueda K, et al. Progression and staging of Lewy pathology in brains from
patients with dementia with Lewy bodies. J Neurol Sci 2002;195(2):153159.
109. Arai T, Ikeda K, Akiyama H, Tsuchiya K, Iritani S, Ishiguro K, et al. Different immunoreactivities of the microtubule-
binding region of tau and its molecular basis in brains from patients with Alzheimers disease, Picks disease, progres-
sive supranuclear palsy and corticobasal degeneration. Acta Neuropathol (Berl) 2003;105(5):489498.
110. Houlden H, Crook R, Dolan RJ, McLaughlin J, Revesz T, Hardy J. A novel presenilin mutation (M233V) causing very
early onset Alzheimers disease with Lewy bodies. Neurosci Lett 2001;313(12):9395.
111. Piao YS, Hayashi S, Wakabayashi K, Kakita A, Aida I, Yamada M, et al. Cerebellar cortical tau pathology in progres-
sive supranuclear palsy and corticobasal degeneration. Acta Neuropathol (Berl) 2002;103(5):469474.
112. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. Colocalization of tau and alpha-synuclein epitopes in Lewy
bodies. J Neuropathol Exp Neurol 2003;62(4):389397.
113. Iseki E, Togo T, Suzuki K, Katsuse O, Marui W, de Silva R, et al. Dementia with Lewy bodies from the perspective of
tauopathy. Acta Neuropathol (Berl) 2003;105(3):265270.
114. Takanashi M, Ohta S, Matsuoka S, Mori H, Mizuno Y. Mixed multiple system atrophy and progressive supranuclear
palsy: a clinical and pathological report of one case. Acta Neuropathol 2002;103(1):8287.
Rehabilitation of Patients With APD 485
29
Rehabilitation of Patients With Atypical Parkinsonian
Disorders
Daniel K. White, Douglas I. Katz, Terry Ellis, Laura Buyan-Dent,

and Marie H. Saint-Hilaire
INTRODUCTION
Atypical parkinsonism encompasses several disorders that may have disease-specific or individual-
specific characteristics, however common features include akinesia, rigidity, gait difficulties, and
cognitive decline with gradual worsening of the symptoms. These features result in a variety of defi-
cits that affect the patients ability to function in their usual capacity at home, on the job, and within
their community. As in other neurodegenerative disorders, patients with atypical parkinsonian disor-
ders (APDs) become increasingly disabled and have a decline in their quality of life. The rehabilita-
tion teams goal is to improve the patients functional ability and quality of life. Use of a disablement
model provides a conceptual framework helpful in delineating the level at which intervention is best
applied. The team must appreciate the impact of intervention at the pathology, impairment, func-
tional, and disability levels in order to choose the appropriate treatment direction. The evidence sup-
porting rehabilitation in idiopathic Parkinsons disease (PD) can be useful in gaining an appreciation
of the impact of treatment across the different levels in order to help guide rehabilitation direction in
patients with APDs. Treatment direction may encompass both restorative and compensatory strate-
gies to improve function and quality of life and should be considered to supplement pharmacologic
and other medical interventions.
A CONCEPTUAL FRAMEWORK
Rehabilitation teams often use a model of disablement to describe the relationship from disease to
disability and to clearly identify the effects of disease on an individual. A disablement model is
useful in providing a conceptual framework to help focus rehabilitation efforts in an appropriate
direction. A model is also helpful in establishing clear communication among the members of the
rehabilitation team. The Nagi Disablement model, developed by the sociologist, Saad Nagi, is one such
model often adopted by rehabilitation teams. It contains four levels of dysfunction, which include the
pathology, impairment, functional limitation, and disability (1). APDs are examples of pathologies,
which encompass the disease state at the organ level. Impairments refer to the anatomical, physi-
ological, mental, or emotional abnormalities or losses related to structure or function. It is helpful to
distinguish between direct and indirect impairments. Direct impairments are those that arise as a
direct result of the pathology. In APDs, direct impairments may include rigidity, bradykinesia, and
tremor. Indirect impairments may arise from the direct impairments or from adopting a more seden-

485
486 White et al.
Fig 1. Disability model with direct and indirect impairment.
tary lifestyle over time. For example, in APDs, the presence of axial rigidity often leads to indirect
impairments such as loss of range of motion into spinal rotation and extension. Indirect impairments
such as poor endurance may evolve because of a decline in activity level as the disease progresses.
Functional limitations include limitations in performance at the level of the whole person such as
walking, moving in bed, rising from a chair, and handwriting. Disability refers to limitations in per-
formance of socially defined roles and tasks including work, travel, and other leisure or recreational
activities. (See Fig. 1.)
The role of the rehabilitation team is to choose and administer the appropriate therapeutic inter-
ventions with the goal of maximizing function and minimizing disability ultimately leading to improv-
ing quality of life. In order to choose the most appropriate interventions, the level of impact must be
defined. The neurologist typically intervenes with pharmacological intervention aimed at the pathology
level. A myriad of medications to optimize availability of dopamine or to replace dopamine are admin-
istered with the goal of reducing severity of impairments such as rigidity, which may lead to im-
provements in mobility at the functional level. However, in patients with APDs, medication
effectiveness is less than optimal and often leads to only modest changes at the impairment and
functional levels. Given the limited effect of pharmacological intervention, rehabilitation may play
an even more important role in maximizing function in patients with APDs than idiopathic PD.
EFFICACY OF REHABILITATION
The efficacy of rehabilitation in patients with APDs is largely unknown, however a number of
studies have investigated the efficacy of physical therapy in addition to medication therapy in indi-
viduals with PD. Most studies reveal positive effects of physical therapy in patients with PD. De Goede
and colleagues conducted a meta-analysis of 12 studies investigating the effects of physical therapy in
addition to medications in individuals with PD (2). All studies included in the analysis were classi-
fied as true or quasi-experiments. The physical therapy interventions varied across studies and
included gait training with external cues, behavioral training to improve activities of daily living
(ADL), exercises to improve mobility, stretching, strengthening, karate, skills training, and educa-
tion. A statistically significant summary effect size was found with regard to ADL (0.40), stride
length (0.46), and walking speed (0.49). The summary effect size with regard to neurological signs
(0.22) was not significant. The authors concluded that individuals with PD benefit from physical
therapy (PT) added to their standard medication. Murphy and Tickle-Degnen conducted a meta-
analysis of 16 studies investigating the effects of occupational therapy (OT)-related treatments for
individuals with PD (3). Studies included contained a variety of experimental designs including ran-
domized controlled trials (RCTs), cohort, pretestposttest, and case-control studies. A statistically
significant summary effect size was found for outcomes classified at the capabilities and abilities level
(0.50), the activities and tasks level (0.54), and on overall outcomes (0.54). The results of this meta-
analysis suggest small to moderate positive effects of OT-related interventions in individuals with
PD. Deane and coauthors concluded in two systematic reviews that there was not enough evidence to
reject or to support the efficacy of PT for patients with PD, however a meta-analytic review was not
conducted (4,5).
A randomized control trial (RCT) (n = 68) investigating the efficacy of PT in patients with PD
revealed significant improvements at the disability level regarding quality of life as it relates to physi-
cal mobility. The most robust findings occurred at the functional level with respect to walking speed
and ADL (6). No significant improvements were found at the impairment level with regard to neuro-
logical signs. Several other investigations support these findings. Formisano et al. investigated the
benefits of a PT program in comparison to a control group and found greater improvements regarding
ADL and a 10-m walking test in the group who had received PT (7). Patti and coauthors investigated
the effects of a multidisciplinary rehabilitation program in an RCT on individuals with idiopathic PD
and found significant increases in walking speed and stride length compared to a nonintervention
control condition (8). In a nonrandomized study, Szekely and coauthors reported significant
improvements in step length and walking speed for a small group of individuals with PD who partici-
pated in a group exercise program (9). Scandalis and colleagues reported significant gains in strength,
stride length, and walking velocity compared to pretreatment values in 14 individuals with PD who
participated an 8-wk course of resistance training (10). Muller et al. randomly assigned 29 patients
with PD to either a control group receiving nonspecific psychological treatment or a behavioral treat-
ment group focusing on strategies to improve initiation and coordination of walking and ADL. The
behavior treatment group showed faster onset of gait initiation and improvements in the Unified PD
Rating Scale (UPDRS) ADL section compared to the control group (11). Thaut et al. investigated the
use of rhythmic auditory stimulation (RAS) as a pacemaker in a 3-wk home-based gait-training pro-
gram for individuals with PD. In comparison to a control group, the patients who trained with RAS
significantly improved gait velocity by 25% and stride length by 12% (12). These studies all provide
evidence supporting the functional gains that occur following PT intervention in the PD population.
These interventions were focused at the functional level targeting walking, balance, and transitional
movements supporting the importance of task-specific training at the functional level.
The impact of rehabilitation on direct impairments stemming from PD appears minimal. The meta-
analysis by deGoede and colleagues and the RCT by Ellis and coauthors revealed no significant
changes in neurological signs (2,6). However, in a randomized crossover study, Comella et al. found
significant improvements in the UPDRS motor scores following participation in a rehabilitation pro-
gram, suggesting a potential impact on neurological signs (13). The impact of rehabilitation on indi-
rect impairments appears stronger. In an RCT, Schenkman and colleagues demonstrated improved
axial mobility and flexibility in individuals with PD who participated in a 10-wk exercise program
(14). Scandalis and coauthors reported strength gains after participation in a resisted strengthening
program in individuals with PD (10). Bridgewater and coauthors reported gains in cardiorespiratory
fitness and habitual activity levels following participation in a 12-wk aerobic-exercise program (15).
488 White et al.
DIRECTING REHABILITATION APPROACHES

Therapists may choose from a variety of treatment approaches and strategy. These include treat-
ments that target problems at the impairment or functional level, and interventions that aim to restore
to a previous level of functioning or compensate for loss of previous healthy functioning. Although
the literature on rehabilitation with patients with PD is not yet adequate to establish comprehensive
evidenced-based guidelines, the growing body of evidence supports the efficacy of rehabilitation and
suggests approaches that rehabilitation teams may use in patients with idiopathic PD and APDs.
Consistent themes that arise from the research in idiopathic PD include improvements in walking
ability and ADL status following rehabilitation targeting these functional areas. Task-specific train-
ing at the functional level appears to be a critical ingredient. Studies of other neurologic disorders
support the notion that performance of tasks improves in relation to direct task practice (16,17).
Furthermore, Lin and colleagues suggest the adult neurological population is more likely to put
effort into purposeful everyday tasks, as opposed to tasks perceived as nonpurposeful or less mean-
ingful (18).
The lack of effect of rehabilitation at the impairment level in patients with PD suggests that reha-
bilitation programs aimed at reducing rigidity, tremor, and other PD impairments are less likely to
lead to changes in functional status. However, indirect impairments such as flexibility, range of mo-
tion, strength and cardiorespiratory status may benefit. Interventions targeting these indirect impair-
ments yield improvements in function and quality of life.
The choice of restorative vs compensatory strategies can vary among individuals, for different
treatment goals and at different times in the progression of the disease. The success of restorative
approaches is in part linked to improvement at the indirect impairment level. For example, as axial
mobility of the spine improves with treatment aimed at increasing range of motion, the patients
ability to get out of bed in a way that resembles premorbid performance of the task also improves. If
underlying impairments do not improve significantly enough to allow successful use of previous move-
ment patterns in the functional task, a compensatory approach may be required to improve function.
For example, if axial mobility remains limited, a new strategy relying less on spinal mobility may be
introduced to compensate for a loss of mobility. In this case, successful completion of the task can
still occur by adopting this new strategy. In idiopathic PD, a combination of restorative and compen-
satory strategies is often implemented to improve function and quality of life. In early PD, when
medications are most effective in treating direct impairments and indirect impairments are most ame-
nable to change with rehabilitation, a restorative approach is often successful. As the disease progresses,
fewer changes at the impairment level are expected and a greater emphasis on compensatory strate-
gies to improve function should be adopted. In APDs, the impact of intervention on impairments is
usually less than that expected in idiopathic PD. The effect of medication on the reduction in direct
impairments, such as rigidity, and indirect impairments, such as spinal mobility, are often less than
what is expected in idiopathic PD. In order to improve function in those with APDs, a compensatory
approach at the functional level is usually necessary. For example, if a patient with an APD is having
difficulty rising from a chair, adopting a strategy using momentum or counting may improve ability
to perform the task. In addition, changing the environmental conditions such as raising the height of
the chair or using a chair with arm rests is often a successful compensatory strategy.
In summary, indirect impairments have the potential to be modified but greater changes would be
expected to occur in the idiopathic PD population compared to the APD population. Frequent reas-
sessment to evaluate the degree of change is necessary to help steer or adjust treatment direction.
Several studies support the effectiveness of task specific practice at the functional level to yield
improvements in functional status in patients with PD. A restorative approach may be successful
when underlying impairments are amenable to improvement; otherwise compensatory approaches in
strategy and environmental constraints may yield the greatest changes in functional status and quality
of life.
OVERVIEW OF A MOVEMENT DISORDERS REHABILITATION PROGRAM

Our institution has developed a specialized inpatient movement disorders program that focuses on
patients with atypical and idiopathic PD and their unique cognitive, motor, and medication-related
issues. The program consists of a team of neurologists, nurses, physical, occupational, and speech
therapists specializing in movement disorders. Upon admission, the initial goals of the team are to
record a patients movement performance and cognitive function throughout the day. This informa-
tion is used to identify particular problems specific to that individual, and establish a working diag-
nosis of the movement disorder to guide treatment decisions. The next goal is to make appropriate
medication adjustments to minimize impairments and optimize functional mobility throughout the
day. During this process patients participate in individual- and group-therapy sessions where team
members treat and monitor movement and cognitive behavior.
Physical and occupational therapists evaluate patients functional status daily with a battery of
short timed tests. Impairment-level assessments are made twice weekly by neurologists examining
tremor, bradykinesia, rigidity, and other impairment-level elements of the UPDRS. Once data are
collected and evaluations are complete, patient cases are discussed at weekly movement disorders
rounds attended by the patients therapy team and the movement disorders team. A brief summary of
any medication side effects or fluctuations of motor or cognitive status is presented to the movement
disorders neurologists, who then direct appropriate medication adjustments. The patients motor and
cognitive function continues to be tracked and presented at the next round to determine the effective-
ness of any medication changes.
A neurologist specializing in movement disorders can play a key role on a rehabilitative team by
assisting in the identification and potential treatment of atypical syndromes. Movement disorder spe-
cialists serve as a resource for new developments, diagnostic criteria, and novel treatments. The input
of the specialist can be particularly valuable since the diagnosis of APD is not straightforward. Fre-
quently, the response or lack of response to dopaminergic medications is key to the diagnosis. The
coordinated efforts of the movement disorders specialist and the rehabilitation team provides a unique
and desirable setting to diagnose APDs and the response to medication.
Rehabilitation team members are able to spend a significant amount of time evaluating and inter-
acting with patients, and if knowledgeable regarding extrapyramidal disorders, can detect subtleties
that may not be available to a neurologist evaluating a patient in the usual clinical setting. For example,
in the typical outpatient office visit, determining the response to medication throughout the day is
largely done by anecdotal information provided by the patient and family. In a medically supervised
setting such as a rehabilitation center, the potential exists for close observation and documentation by
staff specially trained and guided by movement disorders specialists to determine more precisely
what is actually occurring in a patient over time. Acquisition of this kind of information can greatly
improve diagnosis and treatment, which is often a formidable challenge in patients with atypical PD.
Monitoring of Side Effects and Timing of Medication

In addition to carrying out daily motor and cognitive assessments, therapists and nursing staff are
knowledgeable of the indications and potential side effects of the dopaminergic medications used in
the treatment of extrapyramidal movement disorders. Issues regarding administration of these medi-
cations with respect to meals and activities are emphasized. The nursing staff is focused on keeping
to dosage schedules, often challenging in patients with frequent dosing of multiple medications. The
staff recognizes the importance of accurate documentation of actual times medications are received
so there is reliable information to guide further medication adjustments.
The rehabilitation team monitors medication effects and side effects. Educational inservices are
given to assure correct identification of parkinsonian signs and side effects including tremor, freez-
ing, wearing-off phenomena, dyskinesias, hallucinations, and orthostasis. Clinical responses are docu-
mented and tracked in relation to medication dosing. These observations are key for medication
adjustment decisions.
490 White et al.
Cognitive Performance Measures

The primary measure used to track cognitive performance is the Mini Mental Status Exam (MMSE)
(19). The MMSE is an 11-item test examining five areas of cognitive function including orientation,
registration, attention, calculation, language, and recall. This is performed at least once during admis-
sion to obtain baseline information or may be used for comparison in future admissions. Scores may be
used to monitor cognitive decline after medication changes. If cognitive difficulty is a significant
problem, neuropsychology may provide further assessment. Behavioral problems are managed using
the combined expertise of the rehabilitation team, with input from psychology, neuropsychology,
and neurology.
Motor Performance Measures

The therapy staff records motor performance measures to objectively track a patients response to
a medication regimen. When selecting a test, therapists attend to the particular areas of functional
mobility that fluctuate throughout the day and choose a physical measure that incorporates this par-
ticular motor task, such as turning, ambulating, or transitioning from sitting to standing. The motor
test should be administered around the patients medication schedule accounting for peak (on) and
trough (off) times. Subsequent retests should be carried out at similar times to help distinguish
random fluctuations in motor behavior from those related to medication dosing. Again, strict timing
of administration of medications is emphasized to ensure motor performance can be related to a
possible medication effect.
Physical-performance measures that have been found to be valid and reliable in idiopathic PD
population include the 2-min walk, the timed up and go (TUG), and the timed supine to stand and
stand to supine (20,21). The results of these tests is documented in the chart for team members to
track changes over time and in relation to medication interventions.
The 2-Min Walk
The 2-min walk involves measuring the distance a patient can ambulate at a comfortable pace in
2 min. The test should be carried on a flat level surface with two cones or markers delineating the
repeated walking path. The distance between the markers should be kept consistent between tests to
improve reliability. The patient can use an assistive device during the test if necessary. This test has
been shown to identify the loss of walking endurance in those with idiopathic PD compared to healthy
controls (20). The 2-min walk is more appropriate than a 6- or 12-min walk test in patients with
APDs. The test requires two practice walks followed by one recorded walk to control for learning
effects. An example of how to administer this test is included on the CD-ROM.
The Timed Up and Go
The TUG is a simple test that can be quickly administered. The TUG records the time it takes to
stand up from a chair with armrests, walk 3 m, turn, return to the chair, and sit down. The patient can
use an assistive device such as a walker or cane during the test. The TUG has been shown to have
excellent interrater reliability (ICC = 0.99) and intrarater reliability (ICC = 0.99) (22). The test also
has been found to correlate moderately with gait speed, balance, and functional capacity (22). The
TUG has been shown to be responsive to changes in motor performance in individuals with idio-
pathic PD. The test is performed twice with a practice first trial and a recorded second trial. An
example of how to administer this test is included on the CD-ROM.
The Timed Supine to Stand and Stand to Supine
This test records the amount of time it takes for a patient to transfer from a supine to standing
position and separately records time to transfer from standing to supine. The timed supine to stand and
stand to supine test has been found to be a stable measure with good testretest reliability (ICC = 0.77
for supine to stand, and 0.80 for stand to supine) (21). As with the TUG, this test incorporates functional
elements that patients with APDs usually have difficulty with. In the clinic, the test can be modified
to a sitting position instead of a standing position for those patients unable to stand unassisted, how-
ever the patient must be able to transfer unassisted. Patients perform one practice trial and the aver-
age of two subsequent test trials yields the time that is recorded. An example of how to administer
this test is included on the CD-ROM.
Intervention Approaches
Both restorative and compensatory approaches are implemented in the inpatient movement disor-
ders program at our institution. Whereas most patients demonstrate some potential for change of
indirect impairments, the majority respond best to interventions aimed at functional-level tasks. Some-
times both strategies are combined through the collaborative efforts of physical or occupational
therapy.
For example, axial rigidity, a common direct impairment, results in the indirect impairment of
limited range of motion in spinal rotation and extension. To address these indirect impairments, a
physical therapist can have patients pass a therapy ball laterally from side to side in a seated or
standing position. Patients can achieve more axial extension through increasing the height at which
the therapy ball is passed. Increased axial rotation can be achieved through seating the patients more
perpendicular to one another.
Both of these indirect impairments can be further treated within a functional context using mean-
ingful tasks, such as meal preparation, upper- or lower-body dressing, or grooming. PT and OT can
employ these activities in constructing tasks to address loss of axial range of motion (ROM). For
instance, placing canned goods in overhead cabinets during meal preparation activities improves
spinal ROM. Patients can reach for food items positioned laterally to facilitate spinal rotation and
place the items in an overhead cabinet facilitate spinal extension. For most patients, compensatory
techniques will be appropriate to accomplish this task in the home environment, and can be intro-
duced through educating patients to place items on lower shelves to compensate for limited axial
extension. Patients can then actively practice utilizing this compensatory strategy in the functional
kitchen environment.
A video illustrating an example of one approach aimed at the indirect impairment level followed
by the functional level can be found on the CD-ROM.
CASE STUDY
The following case study illustrates some of the essential components of our movement disorders
program at our institution for a patient with an APD.
MG is an 89-yr-old male who reported progressive worsening of gait and increased frequency of
falls. He was started on L-dopa/carbidopa several months prior to admission by his primary neurolo-
gist, who suspected the patient had idiopathic PD. It was not clear that medication produced an
improvement in function. His past medical history was significant for hypertension, coronary artery
disease, chronic anemia, and a coronary artery bypass graft. Upon admission MG had no frank
rigidity, but mild cogwheeling (left greater than right), and a mild to moderate symmetric bilateral
action tremor. Functionally, the patient was able to walk with a minimal amount of assistance for
distances of 100 ft with a rolling walker. His gait was characterized by an overall slow cadence,
short step length, and a decreased base of support. On admission the patient was receiving one and
a half tabs of L-dopa/carbidopa 25/100 three times a day. Given the patients questionable response
to L-dopa/carbidopa and his cardiovascular risk factors, the initial working diagnosis of the move-
ment disorders team was APD.
Since MG was able to ambulate with a minimal amount of assistance, the patient was appropriate
for functional testing using the TUG and 2-min walk. The supine to stand test was not appropriate
since MG required assistance with bed mobility upon admission. After baseline measures were col-
492 White et al.
Fig. 2. Case study: timed up and go.
Fig. 3. Case study: 2-min walk.

lected, L-dopa/carbidopa was tapered and discontinued because of the lack of evidence that it pro-
vided clear benefit. To ensure the patient had no negative effects from the medication taper, func-
tional measures were collected after each medication change. Figures 2 and 3 describe performance
on functional measures regarding medication changes.
At discharge the patients functional measures were improved, about 10 s faster with the TUG and
26 ft farther with the 2-min walk from initial measures. The improvement in functional measures
despite tapering L-dopa/carbidopa suggested that the improvement was the result of rehabilitation
interventions. At discharge, the patient returned to assistive living.
This case illustrates several important contributions a movement disorders rehabilitation team can
provide patients with atypical PD. Aside from the benefits of rehabilitation interventions, the team
provided systematic objective measures of function to accurately conclude that MG did not benefit
from pharmacological intervention.
CONCLUSION
Patients with atypical PD present numerous unique challenges to the health care team and their
families. Rehabilitation can play an important role in improving function and quality of life espe-
cially for treatment of this patient population since current medical and surgical therapies are limited
for treating this patient population. Although the efficacy of rehabilitation in patients with APD has
not been adequately studied, themes emerge from the rehabilitation literature in idiopathic PD, which
may be helpful in the treatment of individuals with APD. Rehabilitation may focus at an impairment
or functional level and may employ restorative or compensatory strategies. Research evidence is
strongest for rehabilitative treatment at a functional level but some combination of strategies, em-
ploying a variety of activities and the combined efforts of multiple disciplines may be most effective.
Rehabilitation efforts need to be closely coordinated with medication adjustments. A multidisciplinary
team with expertise in the treatment of patient with movement disorders can facilitate such a coordi-
nated effort using standardized protocols to track progress, response to medication, and side effects.
FUTURE RESEARCH DIRECTIONS FOR REHABILITATION

OF PATIENTS WITH APDS
Additional randomized control trials are needed to determine the efficacy of rehabilitation
across the short and long term.
An investigation of the relationship between functional gains and the impact on quality of life
is needed.
The relationship between impairment-level gains and change in function needs to be examined.
The critical aspects of treatment that lead to improved function and quality of life need to be
identified.
Guidelines are needed to categorize which patients are responders or non-responders to
rehabilitation and which patients benefit from a compensatory vs a restorative approach.
VIDEO LEGENDS
File Functional Tests APD
Timed Up and Go
Demonstration of the Timed up and Go with a patient with PD.
2-Min Walk
Demonstration of the 2-Min walk test with a patient with PD.
494 White et al.
Timed Supine to Stand and Stand to Supine

Demonstration of the Timed Supine to Stand and Stand to Supine with a patient with PD.
File MD Program Treatment
Movement Disorders Program Axial Rotation
Demonstration of intervention directed at the indirect impairment level for two patients with PD.
Movement Disorders Program Kitchen Activity
The first section is of a higher-level patient performing a kitchen activity to improve axial
rotation and extension. The second section is of a lower-level patient performing the same task,
but modified for his level of function.
REFERENCES
1. Verbrugge LM, Jette AM. The disablement process. Soc Sci Med 1994;38(1):114.
2. de Goede CJ, Keus SH, Kwakkel G, Wagenaar RC. The effects of physical therapy in Parkinsons disease: A research
synthesis. Arch Phys Med Rehabil 2001;82:509515.
3. Murphy S, Tickle-Degnen L. The effectiveness of occupational therapy-related treatments for persons with Parkinsons
disease: a meta-analytic review. Am J Occup Ther 2001;55(4):385392.
4. Deane KH, Ellis-Hill C, Jones D, Whurr R, Ben-Shlomo Y, Playford ED, et al. Systematic review of paramedical
therapies for Parkinsons disease. Mov Disord 2002;17(5):984991.
5. Deane KH, Jones D, Ellis-Hill C, Clarke CE, Playford ED, Ben-Shlomo Y. Physiotherapy for Parkinsons disease: a
comparison of techniques (Cochrane Review). In: The Cochrane library, Issue 3, 2002. Oxford: Update Software.
6. Ellis T, deGoede CJT, Feldman RG, Wolters ECH, Kwakkel G, Wagenaar RC. Efficacy of a physical therapy program
in patients with Parkinsons disease: a randomized controlled trial. Neurology Report 2002;26(4):191.
7. Formisano R, Pratesi L, Modarelli FT, Bonifati V, Meco G. Rehabilitation and Parkinsons disease. Scand J Rehabil
Med 1992;24(3):157160.
8. Patti F, Reggio A, Nicoletti F, Sellaroli T, Deinite G, Nicoletti Fr. Effects of rehabilitation therapy on Parkinsonians
disability and functional independence. J Neurol Rehabil 1996;10:223231.
9. Szekely BC, Kosanovich NN, Sheppard W. Adjunctive treatment in Parkinsons disease: physical therapy and compre-
hensive group therapy. Rehabil Lit 1982;43(3-4):7276.
10. Scandalis TA, Bosak A, Berliner JC, Helman LL, Wells MR. Resistance training and gait function in patients with
Parkinsons disease. Am J Phys Med Rehabil 2001;80(1):3843; quiz 4446.
11. Muller V, Mohr B, Rosin R, Pulvermuller F, Muller F, Birbaumer N. Short-term effects of behavioral treatment on
movement initiation and postural control in Parkinsons disease: a controlled clinical study. Mov Disord
1997;12(3):306314.
12. Thaut MH, McIntosh GC, Rice RR, Miller RA, Rathbun J, Brault JM, Rhythmic auditory stimulation in gait training for
Parkinsons disease patients. Mov Disord 1996;11(2):193-200.
13. Comella CL, Stebbins GT, Brown-Toms N, Goetz CG. Physical therapy and Parkinsons disease: a controlled clinical
trial. Neurology 1994;44(3 Pt 1):376378.
14. Schenkman M, Cutson TM, Kuchibhatla M, Chandler J, Pieper CF, Ray L, et al. Exercise to improve spinal flexibility and
function for people with Parkinsons disease: a randomized, controlled trial. J Am Geriatr Soc 1998;46(10):12071216.
15. Bridgewater KJ, Sharpe MH. Trunk muscle performance in early Parkinsons disease. Phys Ther 1998;78(6):566576.
16. Wagenaar RC. Effects of stroke rehabilitation. In: Kaufman T, ed. Rehabilitation of the Geriatric Patient. New York:
Churchill Livingstone, 2000:130134.
17. Richards CL, Malouin F, Wood-Dauphinee S, Williams JI, Bouchard JP, Brunet D. Task-specific physical therapy for
optimization of gait recovery in acute stroke patients. Arch Phys Med Rehabil 1993;74(6):612620.
18. Lin K, Wu C, Tickle-Degnen L, Coster W. Enhancing occupational performance through occupationally embedded
exercise: A meta-analytic review. Occupational Therapy Journal of Research 1997;12:2547.
19. Folstein M, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients
for the clinician. J Psychiatr Res 1975;12(3):189198.
20. Light K, Behrman A, Thigpen M, Triggs M. The 2-minute walk test: A tool for evaluating walking endurance in clients
with Parkinsons disease. Neurol Rep 1997;21(4):136139.
21. Schenkman M, Cutson TM, Kuchibhatla M, Chandler J, Pieper C. Reliability of impairment and physical performance
measures for persons with Parkinsons disease. Phys Ther 1997;77(1):1927.
22. Podsiadlo D, Richardson S. The timed Up & Go: A test of basic functional mobility for frail elderly persons. J Am
Geriatr Soc 1991;39(2):142148.
Atypical Parkinsonism 495
30
Atypical Parkinsonism
Andrew Lees
Diagnosis is a system of more or less accurate guessing in which the end point achieved is a name.
These names applied to disease come to assume the importance of specific entities, whereas they are
for the most part no more than insecure and temporary conceptions.
Sir Thomas Lewis (1931)
Despite its imprecision, atypical parkinsonism is a useful clinical term. It unites a group of disor-
ders linked by the predominant presence of bradykinesia, but where additional clinical features
exclude Parkinsons disease (PD; hence the analogous but currently less-favored term Parkinsons
plus). In most cases, disease progression is rapid and relentless and the response to dopaminergic
drugs minimal or temporary. Multiple system atrophy (MSA) is the most common example among
the primary neurodegenerations, but a substantial number of cases are found at autopsy to have neu-
rofibrillary tangle degeneration, or a combination of neocortical and subcortical Lewy bodies. Exten-
sive subcortical cerebrovascular disease without additional neurodegenerative pathological change is
another relatively common cause, but one that presents considerable diagnostic difficulties in clinical
practice. Because so many of these pathologies carry a grim and hopeless prognosis, the delicate
nuance of uncertainty implicit within the term atypical parkinsonism may be preferable to a more
precise alternative clinical label. Nonetheless, names given to neurological disorders assume great
importance, both within the medical profession and for those individuals who acquire them: giving
a name to the enemy, however baleful, is often greeted, at least initially, with a sense of relief
better the devil you know!
Division into more precise nosological entities is also essential for research. MSA is a
synucleinopathy whereas progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)
are four-repeat primary tauopathies. Erroneous inclusion of cases of vascular Parkinsons syndrome
could invalidate a genetic study on MSA or an epidemiological study of PSP.
Recent clinico-pathological studies of Parkinsons syndromes have led to an increased awareness
among neurologists of MSA of the parkinsonism type (MSA-P, striatonigral degeneration, Shy
Drager syndrome), vascular Parkinsons syndrome, and a motley collection of conditions united by
the abnormal accumulation of hyperphosphorylated tau protein in the brain and subcortical neu-
rofibrillary degeneration. The best-recognized conditions in this group are PSP, CBD, and fronto-
temporal dementia with parkinsonism (FTDP). Much rarer, but of great contemporary interest, are
the inherited heavy-metal storage disorders including HallervordenSpatz disease and HARP syn-
drome (recessively inherited and caused by mutations in pantothenate kinase 2 [PANK 2] on chromo-
some 20), neuroferritinopathy (dominantly inherited and caused by a light ferritin chain mutation on

495
496 Lees
chromosome 19),Wilsons disease (recessively inherited and caused by mutations of copper-trans-

porting P-type ATPase on chromosome 13), and acaeruloplasminaemia (recessively inherited and
caused by mutations of the caeruloplasmin gene on chromosome 3).
As concepts of what constitutes the clinical picture of PD continue to evolve, our definition of
atypical Parkinsonism will also be modified. For example, early autonomic failure, early severe demen-
tia, a negative response to 1000 mg per day of L-dopa for at least 6 wk, and more than one affected first-
degree relative have been considered red flags for atypical parkinsonism, and yet all of these have
been linked with Lewy body pathology in clinico-pathological studies (1). On the other hand, mini-
mal change MSA with an excellent sustained response to L-dopa may be indistinguishable from PD
throughout the whole course of the illness (2).
A 46 Hz pill-rolling rest tremor remains the single best clinical marker for PD (3) but a few
patients never notice one; in others it may be slight and unobtrusive, and some lose their rest tremor
completely as the clinical picture evolves (4) Greater attention to olfaction in the clinical examina-
tion may become important as preliminary data indicate that the majority of patients with PD and
dementia with Lewy bodies (DLB) have hyposmia, whereas olfactory discrimination in vascular
Parkinsons, PSP, CBD, and parkin mutations is usually normal (5). Formed visual hallucinations,
which occur commonly in PD and DLB, are extremely rare in MSA, PSP, and CBD and may be
another rather neglected red flag for PD especially in the absence of any associated dementia.
PSP (SteeleRichardsonOlszewski disease) is usually included as an important cause of atypical
parkinsonism, but Richardson in his seminal descriptions emphasized the marked clinical differences
between PSP and PD, although he later conceded that the phenomenology of PSP was likely to
broaden with greater clinical awareness and further pathological study (6). L-Dopa-unresponsive sym-
metrical bradykinesia with prominent axial involvement, preserved downgaze, and extensive subcor-
tical neurofibrillary tangle formation is now recognized as one of the more common causes of atypical
parkinsonism, but it is questionable whether this should be included as a clinical variant of Steele
RichardsonOlszewski disease (7,8). CBD, a much rarer clinico-pathological entity, is also included
in the list of neurodegenerative disorders presenting with parkinsonism. Despite this, a presentation
with predominant parkinsonism must be extraordinarily rare as unilateral myoclonus, jerky tremor,
rigidity, cortical sensory loss, dyspraxia, and dystonia usually dominate the clinical picture.
Much interest is at present focused on the parkinsonian signs seen in DLB. This clinical syndrome
first described by Kosaka and other Japanese colleagues presents with prominent cognitive decline,
delirium, and visual hallucinations, usually in the seventh and eighth decades of life, but the histo-
pathological findings cannot be reliably distinguished in an individual case from those found in PD.
Many of these cases also have extensive additional neocortical neurofibrillary tangles, hence the
alternative name Lewy body variant of Alzheimers disease. However, there is a very interesting
group of young patients with pure diffuse cortical and subcortical Lewy body pathology who present
with rapidly progressive dementia, behavioral disturbance, and atypical parkinsonism (9). Parkin-
sonism is seen at some stage in most cases of DLB and it has been reported that the therapeutic
response to L-dopa is poorer and rest tremor less frequent and intrusive than in PD (10). However, it
is my clinical impression that the L-dopa response is also less striking in many elderly PD patients
especially when there is associated cognitive impairment (11)and it is now accepted that rest tremor
may disappear in the later stages of PD. It seems justified on clinical grounds to distinguish PD and
DLB, but from a molecular biological perspective both are likely to share very similar if not identical
pathological processes.
In comparison with PD the atypical Parkinsons syndromes are all uncommon, at least in Cauca-
sians. There are some very preliminary data to suggest that atypical features, including a poorer
response to L-dopa, may be more common in Africans and Indians with presumed PD, and that an
increased frequency of comorbid cerebrovascular disease or associated diabetes mellitus does not
account for this difference (12,13). In one South London movement disorder clinic survey, the
percentage of atypical parkinsonism was found to be 22% in black African and African/Caribbean
patients and 20% in South Asian patients compared to 7% in whites (14) This raises the interesting
possibility that the phenotype of PD may vary somewhat from race to race, but pathological diagno-
sis is needed to take this interesting possibility further. A higher incidence of atypical parkinsonism
has also been reported among the Chamorros of the Mariana Islands (bodig) (15), the Afro-Caribbean
population of the French Antilles (16) and the indigenous population of New Caledonia. For example
in Guadeloupe, of 220 consecutive patients examined at the CHU Pointe a Pitre, 26.5% fulfilled
National Institute of Neurological Disorders and Stroke (NINDS) criteria for PSP and 43.8% were
unclassifiable using available published clinical criteria for the recognized parkinsonian syndromes
(17). The possibility that cycad or annonacae toxicity may explain these geographic clusters of atypi-
cal parkinsonism has been proposed: however, genetic factors may also be important and it is now
recognized that spinocerebellar ataxia (SCA) 2 and SCA 3 may present with atypical parkinsonism
particularly in Afro-Caribbean and Oriental populations (1820).
Huntingtons disease is another autosomal dominantly inherited disorder that occasionally pre-
sents with atypical parkinsonism in middle age (21).
Neuroleptic-provoked Parkinsons syndrome, which is often clinically indistinguishable from PD
in the elderly, remains a much more common condition than MSA, PSP, or DLB, although it seems
likely that more judicious use of the older antipsychotic drugs and employment of the newer drugs
with reputedly fewer extrapyramidal side effects may have reduced its frequency a little. There is a
poor or negligible response to L-dopa (22), so if the history of neuroleptic intake is overlooked these
cases may be misdiagnosed as MSA or PSP (23). A proportion of elderly-onset cases do not improve
even a year after neuroleptic withdrawal, indicating that the drug has probably unmasked latent PD.
The clinical diagnosis of vascular Parkinsons syndrome remains at best an insecure one. Most
neurologists now recognize the syndrome of lower half parkinsonism with a broad-based, shuffling
gait and freezing, with only minimal hand bradykinesia, hypomimia, and often normal speech. Dif-
fuse cerebrovascular disease, especially if there is a history of hypertension, is the most common
pathological finding. Striatal cerebrovascular disease is, however, a relatively common associated
pathological finding in the elderly parkinsonian patient (1) and it is probable that in some patients
this modifies the clinical picture. Parkinsonism following a stroke is less well accepted, but there are
a number of reported cases in the literature with supportive neuroimaging or pathological confirma-
tion (24,25).
In the absence of specific biological or genetic markers for any of the neurodegenerative processes
associated with atypical Parkinsons syndromes, their diagnosis and differentiation depend primarily
on scrupulous history taking and a full clinical examination. Diagnosis of the established classical
presentation of MSA or PSP is straightforward but overlap syndromes, atypical presentations,
and early incomplete clinical pictures are frequent, and pose formidable challenges. A recent cross-
sectional survey in two tertiary university hospital referral centers for movement disorders in West-
ern Europe revealed that at any one time there were about 5% of atypical parkinsonian patients who
could not be more precisely categorized using currently available clinical diagnostic criteria (26). A
clinico-pathological study of the first 100 patients diagnosed as PD by UK neurologists 20 yr ago
coming to autopsy at the Queen Square Brain Bank for Neurological Disorders (QSBB) in London
revealed that 24% did not have severe nigral and locus coeruleus neuronal loss with Lewy bodies in
surviving neurones. However, retrospective application of the QSBB criteria for the clinical diagno-
sis of PD by a movement disorder specialist blinded to the pathological diagnosis improved the accu-
racy of clinical diagnosis retrospectively to 86%. The most common pathology in the misdiagnosed
cases was extensive subcortical neurofibrillary tangles (27). Conversely 12% of 100 cases fulfilling
operational criteria for the pathological diagnosis of PD were found to have clinical signs that would
have excluded a diagnosis of PD using QSBB operational criteria (1). Ten years later, using identical
ascertainment and methodology, diagnostic accuracy had risen to 90% and did not improve further
with retrospective application of the QSBB criteria; on this second review MSA-P had taken over as
the commonest cause for misdiagnosis. This improvement is likely to reflect a greater clinical aware-
498 Lees
ness among UK neurologists of the wide spectrum of atypical parkinsonian disorders and the publi-
cation of sets of consensus criteria to aid clinical diagnosis (28).
A recent review of 60 cases diagnosed clinically with PSP who came to autopsy at the QSBB
showed that the clinical diagnosis was accurate in 47 (78%). Sources of diagnostic error included
DLB, MSA, tauopathies, and motor neuron disease (MND)-ubiquitin inclusion dementia. Retrospec-
tive application of the NINDS and Society for PSP Consensus criteria marginally improved the accu-
racy of initial clinical diagnosis, but none of the existing diagnostic criteria for PSP could significantly
improve accuracy of the final clinical diagnosis (29). A similar methodological study with MSA
revealed that 51 of 59 clinically suspected cases were confirmed pathologically in the QSBB, with
PD as the most common false positive; this study showed a high diagnostic accuracy for the clinical
diagnosis of MSA. Retrospective application of either the Quinn or Consensus criteria for MSA
further improved clinical diagnosis in the early stages, but not at the time of the last hospital visit
before death (30). In an earlier study from the QSBB, Wenning et al. found that one-third of patho-
logically confirmed cases carried an alternative clinical diagnosis at deathusually PD (31). Litvan
and colleagues (32) using material derived from a number of brain banks, found that only 50% of
cases with pathologically proven MSA had been accurately diagnosed by their primary neurologist,
whereas retrospective analysis by movement disorder specialists improved the accuracy to around
70%. Several studies have compared the clinical features of pathologically proven MSA with idio-
pathic PD and developed scoring systems weighted for different clinical features (33). These have
produced sensitivities of 90%. However, application of these scoring systems in prospective clinical
series is likely to be less impressive, as they are internally derived and may overestimate their true
performance.
In an attempt to see whether greater accuracy of clinical diagnosis could be achieved by move-
ment disorder specialists working in a university hospital setting, the detailed case notes of 143 patho-
logical cases of parkinsonism thoroughly investigated at the National Hospital for Neurology, Queen
Square, by at least one staff movement disorder expert between 1990 and 1999 were scrutinized. The
positive predictive value of a clinical diagnosis of MSA was 85.7 (30 out of 35), and the sensitivity
was 88.2% (30 out of 34). For PSP, comparable figures were positive predictive value 80% (16 out of
20) and sensitivity 84.2% (16 out of 19). The positive predictive value for PD in this study was
extremely high at 98.6% (72 out of 73) with a sensitivity of 91.1%, owing to seven false-negative
cases. This suggests that neurologists with special training in movement disorders can expect to
achieve around a 90% overall diagnostic accuracy rate for Parkinsons syndromes in the late stages of
disease (34).
For more than a century the semiology of the Parkinsons syndromes has been based on a com-
bination of the clinical picture and the neuropathological findings. Even with this traditional two-
dimensional classification, new nosological entities continue to be described. Recent advances in
genetics and molecular pathology have led to reappraisal of what constitutes a disease: disorders with
very different clinical features are linked through identical histopathological changes and patients
carrying the same genetic mutation may have very different physical signs. Further confusion stems
from the finding that patients fulfilling operational clinical diagnostic criteria for a particular
Parkinsons syndrome are sometimes found to have incompatible pathological lesions, and that dual
or even multiple pathologies are commonly found at postmortem examination of the elderly. Our
conception of PD has been under modification ever since James Parkinsons seminal description of
the shaking palsy: his original description was embellished by the 19th-century neurologists, particu-
larly Charcot and Gowers, and the pathological discoveries of Lewy and Tretiakoff provided sub-
stance for the notion that it was a distinct entity. However, not long after, following the pandemic of
von Economos disease and the realization that syphilis, head trauma, and cerebrovascular disease
could additionally produce parkinsonism, the very existence of the shaking palsy (PD) was called
into question. In the 1960s a cluster of previously unrecognized clinico-pathological entities with
bradykinesia as a prominent feature were delineated and neuroleptic drugs started to replace posten-
cephalitic parkinsonism as the most common cause of secondary parkinsonism. Attempts to distin-
guish these atypical cases from PD have led to the development of operational exclusion criteria and
supportive red flags to aid diagnostic accuracy of brainstem Lewy body PD.
It has always been recognized that PD is protean in its clinical manifestations and natural history
which has led to proposals for tremulous, akinetic-rigid, young-onset, senile, and benign and malig-
nant subtypes. Widespread acknowledgement of the maladys clinical heterogeneity has also led to
calls for abolition of the term PD in favor of idiopathic Parkinsonism. The cloning of at least four
gene mutations in familial Parkinsons syndromein which the clinical picture closely resembles
classical sporadic PDhas further led to a reconsideration of clinical terminology. Some molecular
pathologists link PD, DLB, and MSA because all three are associated with the abnormal misfolding
and aggregation of alpha-synuclein. PSP, corticobasal ganglionic degeneration, and some rare famil-
ial cases of frontotemporal degeneration, on the other hand, have been embraced under the rubric of
primary tauopathy.
The paradigm for treatment of neurodegenerative disease has largely hinged on the success of L-
dopa in PD and the clinico-biochemical/pathological correlate linking bradykinesia with dopam-
inergic lesions in the pars compacta of the substantia nigra. However, the success of this approach
has served to hide its shortcomings: as neurologists record the constellation of symptoms and signs in
a patient with atypical parkinsonism and speculate on why specific brain regions appear selectively
vulnerable at postmortem examination, they should not forget Sir Thomas Lewiss cautionary words
to his cardiological colleagues 70 yr ago, that what were then considered discrete entities would in
time prove to be no more than ephemeral conceptions. In fact what we often perceive as entities are
really processes, each made up of a finite number of specific events.
Neurodegeneration results from a limited number of pathological events each of which engenders
biochemical consequences at cellular level. These are modified by genetic and environmental factors
and may result in nerve cell death by apoptosis or necrosis. What determinesin an atypical
parkinsons casewhy a particular neurone takes the tau/tangle or synuclein/Lewy body/glial cyto-
plasmic inclusion route to cell death may depend on many factors, including the particular chemistry
of that neuron, the timing of the event, and the influence of supporting glia. Greater understanding of
the mechanisms that cause these destructive biochemical cascades will shed light on the causes of the
atypical Parkinson syndromes and, with luck, lead to effective new disease-modifying treatments.
The words of LHermitte and Cornil from 1921 remain as relevant today as then:
We must either admit that there exists in addition to multiple Parkinsonian syndromes, an authentic
Parkinsons disease with particular lesions and a characteristic evolution and symptomatology or
we must say that there is no Parkinsons disease just as there is no hemiplegic disease or pseudo-
bulbar disease.
As we evolve from the traditional clinico-pathological concept of disease entities to a more dynamic
consideration of pathological processes, it may be more useful for neurologists in future to describe
patients who fulfill a definition of parkinsonism (bradykinesia plus rigidity and/or rest tremor) in
terms of their associated physical signs (e.g., dementia, autonomic failure, supranuclear downgaze
palsy), functional and physical disability (as quantified by rating scales), disease duration, response
to dopaminergic therapy, and genetic profile, rather than attempting to guess the associated histo-
pathological findings on the basis of pattern recognition. In the meantime, however, we must use the
crumbs of knowledge we have gathered by clinical observation and research about these brutal clini-
cal syndromes to inform and relieve suffering in our patients.
REFERENCES
Neurol 1993;50(2):140148.
500 Lees
2. Wenning GK, Quinn N, Magalhaes M, Mathias C, Daniel SE. Minimal change multiple system atrophy. Mov Disord
1994;9(2):161166.
3. Stadlan EM, Yahr MD. The pathology of parkinsonism. Proceedings of the 5th International Congress of Neuropathol-
ogy 1965;100:569571.
4. Winogrodzka A, Wagenaar RC, Bergmans P, et al. Rigidity decreases resting tremor intensity in Parkinsons disease: a
(123)beta-CIT SPECT study in early, non-medicated patients. Mov Disord 2001;16:10331040.
5. Hawkes C. Olfaction in neurodegenerative disorder. Mov Disord 2003;18(4):364372.
6. Steele J, Richardson J, Olszewski J. Progressive supranuclear palsy. Arch Neurol 1964;10:333359.
7. Daniel SE, de Bruin VM, Lees AJ. The clinical and pathological spectrum of SteeleRichardsonOlszewski syndrome
(progressive supranuclear palsy): a reappraisal. Brain 1995;118(Pt 3):759770.
8. Morris HR, Gibb G, Katzenschlager R, et al. Pathological, clinical and genetic heterogeneity in progressive supra-
nuclear palsy. Brain 2002;125(Pt 5):969975.
9. Gibb WR, Esiri MM, Lees AJ. Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body
dementia). Brain 1987;110(Pt 5):11311153.
10. Levy G, Tang MX, Cote LJ, et al. Motor impairment in PD: relationship to incident dementia and age. Neurology
2000;55(4):539544.
11. Burn DJ, Rowan EN, Minett T, et al. Extrapyramidal features in Parkinsons disease with and without dementia and
dementia with Lewy bodies: A cross-sectional comparative study. Mov Disord 2003;18(8):884889.
12. Chaudhuri KR, Hu MT, Brooks DJ. Atypical parkinsonism in Afro-Caribbean and Indian origin immigrants to the UK.
Mov Disord 2000;15(1):1823.
13. Schrag A, Bhatt M, Soonawala N, Quinn NP, Bhatia KP. Occurrence of atypical parkinsonism in Indians and Cauca-
sians. Acta Neurol Scand 2004;109(2):155156.
14. Hu M. Cortical and Striatal Function in a Cross-Racial Parkinsons Disease Population. London: Guys, Kings and St.
Thomass School of Medicine, 2000. PhD thesis, University of London.
15. Hirano A, Kurland L, Krooth R, Lessell S. Parkinsonism-dementia complex, an endemic disease on the island of Guam.
1. Clinical Features. Brain 1961;84:642661.
of tropical plants: a case-control study. Caribbean Parkinsonism Study Group. Lancet 1999;354(9175):281286.
17. Caparros-Lefebvre D, Sergeant N, Lees A, et al. Guadeloupean parkinsonism: a cluster of progressive supranuclear
palsylike tauopathy. Brain 2002;125(Pt 4):801811.
18. Subramony SH, Hernandez D, Adam A, et al. Ethnic differences in the expression of neurodegenerative disease:
MachadoJoseph disease in Africans and Caucasians. Mov Disord 2002;17(5):10681071.
19. Furtado S, Farrer M, Tsuboi Y, et al. SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET
findings. Neurology 2002;59(10):16251627.
20. Payami H, Nutt J, Gancher S, et al. SCA2 may present as levodopa-responsive parkinsonism. Mov Disord
2003;18(4):425429.
21. Reuter I, Hu MT, Andrews TC, Brooks DJ, Clough C, Chaudhuri KR. Late onset levodopa responsive Huntingtons
disease with minimal chorea masquerading as Parkinson plus syndrome. J Neurol Neurosurg Psychiatry
2000;68(2):238241.
22. Hardie RJ, Lees AJ. Neuroleptic-induced Parkinsons syndrome: clinical features and results of treatment with levodopa.
J Neurol Neurosurg Psychiatry 1988;51(6):850854.
23. Tolosa E, Coelho M, Gallardo M. DAT imaging in drug-induced and psychogenic parkinsonism. Mov Disord
2003;18(Suppl 7):S28S33.
24. Tolosa ES, Santamaria J. Parkinsonism and basal ganglia infarcts. Neurology 1984;34(11):15161518.
25. Ziljmans J, Daniel SE, Hughes AJ, Revesz T, Lees AJ. Clinico-Pathological Investigation of Vascular Parkinsonism(VP)
Including Clinical Criteria for the Diagnosis of VP. Mov Disord, published online, March 16, 2004.
26. Katzenschlager R, Cardoso A, Tolosa E, Lees A. Unclassifiable parkinsonism in two European tertiary referral centres
for movement disorders. Mov Disord 2003;18:11231131.
27. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinsons disease: a clinico-
pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55(3):181184.
28. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinsons disease. Neurology
2001;57(8):14971499.
29. Osaki Y, Ben-Shlomo Y, Lees AJ, et al. Accuracy of Clinical Diagnosis of Progressive Supranuclear Palsy. Mov
Disord 2004;19:181189.
30. Osaki Y, Wenning GK, Daniel SE, et al. Do published criteria improve clinical diagnostic accuracy in multiple system
atrophy? Neurology 2002;59(10):14861491.
31. Wenning GK, Ben-Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinicopathological study of 35 cases of multiple
system atrophy. J Neurol Neurosurg Psychiatry 1995;58(2):160166.
clinicopathologic study. Arch Neurol 1997;54(8):937944.
33. Colosimo C, Albanese A, Hughes AJ, de Bruin VM, and Lees AJ. Some specific clinical features differentiate multiple
system atrophy (striatonigral variety) from Parkinsons disease. Arch Neurol 1995;52(3):294298.
movement disorder service. Brain 2002;125(Pt 4):861870.
Index 503
Index
A limb-kinetic apraxia, 201, 202

prospects for study, 206
AD, see Alzheimers disease
Parkinsons disease, 204, 205
Agitation, definition and identification, 162
progressive supranuclear palsy, 204
F (alpha)-Synuclein, see Synucleins
whole body apraxia, 202
ALS, see Amyotrophic lateral sclerosis
Argyrophilic grain disease, neuropathol-
Alzheimers disease (AD)
ogy, 119, 123
coexistence with Dementia with Lewy
Ataxia telangiectasia, eye movements, 245
bodies, 140, 141
Autonomic reflexes
Lewy bodies, 116, 117
assessment, 419, 420
neuropathology, 47
dysautonomia clinical evaluation, 157
tau pathology, 124
dysfunction management, 349351, 477,
Amyotrophic lateral sclerosis (ALS), par-
478
kinsonism dementia complex of
multiple system atrophy function testing
Guam, 47
bladder function, 341, 342
Anxiety, definition and identification, 162
cardiovascular function, 341
Apathy, definition and identification, 162,
185 B
Aphasia, see Speech and language distur- Botulinum toxin, dystonia management,
bances 476
ApoE4, dementia with Lewy bodies risks, Bradykinesia, clinical evaluation, 154, 410
141, 142 Brainstem reflexes, see Eye movements;
Apraxia, see also Speech and language Neurophysiological assessment
disturbances Brain tumors, parkinsonism induction, 403,
comparison in parkinsonian disorders, 404
205
computer modeling of abnormal kine- C
matics during pointing movement Carbon monoxide, parkinsonism induc-
and errors in praxis tion, 397
bread-slicing gesture simulations, 104 CBD, see Corticobasal degeneration
cortical networks, 101 Charcot, Jean-Martin, Parkinsons disease
finger-to-nose test simulations, 102, research contributions, 1113
103 Childhood onset parkinsonism, causes, 400
tasks, 99 Cholinesterase inhibitors, dementia with
corticobasal degeneration, 202204 Lewy bodies management, 368, 369
definition, 195 Computed tomography (CT)
eyelid opening, 202 progressive supranuclear palsy, 298, 440
face apraxia, 202 vascular parkinsonism, 443
limb apraxia Computer modeling, basal ganglia disor-
assessment, 196, 197 ders
diseases, 195 abnormal kinematics during pointing
error patterns, 197, 198 movement and errors in praxis
ideational apraxia, 199 bread-slicing gesture simulations, 104
ideomotor apraxia, 199201 cortical networks, 101
503
504 Index
finger-to-nose test simulations, 102, neuropsychological symptoms

103 evaluation, 170172, 188, 189, 312, 316
tasks, 99 management, 176
behavioral operating characteristics, 95 progression, 3
hypokinetic disorders n Parkinsons research prospects, 330
disease, 9799 speech and language disturbances
limitations, 105, 106 clinical management, 259
neuropathology considerations, 96, 97 language disturbances, 258, 259, 324
overview, 95, 96 neuroanatomy, 257
paradigm of neural network modeling, speech disturbances, 257, 258, 324
95, 96 syndromic features, 327
prospects, 104, 105 tau pathology, 145, 329
Constipation, management, 477, 478 typical versus atypical forms, 122
Corticobasal degeneration (CBD) visuospatial disorders, 221, 222
cholinergic defects and therapeutic tar- Web resources, 331
geting, 475 Creutzfeldt-Jacob disease, eye movements,
classification within parkinsonian disor- 243
ders, 1, 2, 5, 6, 309, 498 CT, see Computed tomography
clinical features Cyanide, parkinsonism induction, 397
alien limb phenomenon, 311
D
cognitive features, 312
cortical sensory loss, 311 Dementia, evaluation, 184
dementia, 312 Dementia with Lewy bodies (DLB)
dystonia, 311 classification within parkinsonian disor-
levodopa nonresponsiveness, 312, ders, 1, 2, 5, 6, 498
329 coexistence with Alzheimers disease,
mirror movements, 311 140, 141
myoclonus, 311 cognitive dysfunction management, 478
progressive asymmetric rigidity and diagnosis
apraxia, 310, 311 accuracy, 365
tremor, 312 criteria, 5, 361, 362
yes/no reversals, 312 differential diagnosis, 365367
clinicopathologic heterogeneity, 327, 328 epidemiology, 361
diagnosis extrapyramidal syndrome, 363, 364
accuracy, 328, 329 eye movements, 243, 365
criteria, 313316 falls, 365
dopaminergic defects and therapeutic familial disease, 140
targeting, 474, 475 genetic risk factors, 141, 142
epidemiology, 310 management
eye movements, 242, 313 antidepressants, 370
functional neuroimaging, 317, 465, 466 cholinesterase inhibitors, 368, 369
historical description, 18, 309 overview, 368
laboratory findings, 313, 316 prospects, 370
limb apraxia, see Apraxia sleep disturbances, 370
magnetic resonance imaging, 316, 317, neuroimaging
440, 442 magnetic resonance imaging, 366, 442
management, 329, 330 positron emission tomography, 366,
neuropathology, 41, 43, 44, 119121, 123, 466, 467
317, 321 scintigraphy, 368
Index 505
single photon emission computed Erectile dysfunction, management, 477

tomography, 366, 368, 466, 467 Ethanol, parkinsonism induction, 397, 398
neuropathology, 36, 37, 140, 361 Euphoria, definition and identification,
neurophysiological studies, 368 162
neuropsychological symptoms Executive function, evaluation, 185
evaluation, 168, 169, 189, 190, 362, 363 Eye movements
fluctuating cognition, 362, 363 bedside examination, 156, 157
management, 175, 176 brainstem reflex testing, 412415
progression, 3, 364 clinical examination in parkinsonism,
sleep studies, 365 233, 234
speech and language disturbances Huntingtons disease, 243, 244
clinical management, 265 idiopathic Parkinsons disease
language disturbances, 264 clinical findings, 238
neuroanatomy, 263, 264 effects of disease course and treat-
speech disturbances, 264 ment, 240
visuospatial disorders, 223 laboratory findings
Depression, definition and identification, saccades, 238, 239
162 smooth pursuit, 239
Developmental parkinsonism, causes, 400, vestibular responses, 239
401 laboratory studies, 234236
Disinhibition, definition and identification, MPTP toxicity, 240, 243
162, 185 progressive supranuclear palsy
DLB, see Dementia with Lewy bodies clinical findings, 240, 241
Drug-induced parkinsonism differential diagnosis, 241243
clinical features, 399, 400, 499 effects of disease course and treat-
drugs, 200 ment, 240
Dysarthria, see Speech and language dis- laboratory findings
turbances saccades, 241
Dysautonomia, clinical evaluation, 157 smooth pursuit, 241
Dystonias vestibular responses, 241
clinical evaluation, 157, 158 research prospects, 245, 246
management, 381, 382
F
syndrome clinical features
DYT3, 382384 Fahrs disease
DYT5, 382, 383 eye movements, 243
DYT12, 383 features, 399
DYT14, 383 Familial Parkinsons disease
dystonia syndromes, 381384
E
gene loci, 39
ECT, see Electroconvulsive therapy Huntingtons disease, 384
Electroconvulsive therapy (ECT), atypical mitochondrial abnormalities, 388
parkinsonism management, 477, 479 PARK locus defects and phenotypes, 376
Electromyography (EMG), see also Neuro- Perry syndrome, 384386
physiological assessment spinocerebellar ataxias, 380, 381
needle recording of sphincter muscles, Wilsons disease, 387
420 Fludrocortisone, orthostatic hypotension
surface recording of abnormal move- management, 477
ments, 417, 418 fMRI, see Functional magnetic resonance
EMG, see Electromyography imaging
506 Index
Frontotemporal dementia with parkin- HIV, see Human immunodeficiency virus

sonism linked to chromosome 17 HPHA, see Hemiparkinsonismhemiatro-
(FTDP-17) phy
classification within parkinsonian disor- Hr-QoL, see Health-related quality of life
ders, 1, 2, 5, 6 Human immunodeficiency virus (HIV),
clinical features, 378, 380 parkinsonism induction, 398
genetics, 375, 378 Huntingtons disease (HD)
neuropathology, 46 features, 146, 384, 499
tau pathology, 127, 143, 144 neuropathology, 47, 49
transgenic mouse models, 6971 Hyperparathyroidism, parkinsonism in-
FTDP-17, see Frontotemporal dementia duction, 399
with parkinsonism linked to chromo- Hypokinesia, neurophysiological assess-
some 17 ment, 410
Functional magnetic resonance imaging Hypothyroidism, parkinsonism induction,
(fMRI) 399
applications and advantages, 452, 456 Hypoxic ischemic injury, parkinsonism
principles, 451, 452 induction, 399
G I
Gait disorders, clinical evaluation, 155 Idiopathic Parkinsons disease
Genetic testing, atypical parkinsonian dis- eye movements
orders, 388, 389 clinical findings, 238
effects of disease course and treat-
H
ment, 240
Hallervoden-Spatz disease, see laboratory findings
Neurodegeneration with brain iron saccades, 238, 239
accumulation smooth pursuit, 239
Hallucinations, clinical evaluation, 157 vestibular responses, 239
HD, see Huntingtons disease features, 3336, 497, 498, 501
Health-related quality of life (Hr-QoL) lesion topography, 109, 112
assessment neuropathology, 112, 113
development and validation of mea- Instrumental function, evaluation, 185
sures, 276
L
instrument types and selection, 277
Parkinsons disease-specific instru- Language, see Speech and language distur-
ments, 277279 bances
preference-based outcome measures, LBs, see Lewy bodies
277 Levodopa
rationale, 276 corticobasal degeneration
caregiver burden, 282, 283 nonresponsiveness, 312, 329
definition, 275, 276 multiple system atrophy management,
parkinsonism impact 350, 351
multiple system atrophy, 280, 282 progressive supranuclear palsy respon-
Parkinsons disease, 280 siveness, 300
progressive supranuclear palsy, 280, 282 responsiveness variability in atypical
quality of life domains affected, 281 parkinsonism, 473
research prospects, 283 Lewy bodies (LBs)
Hemiparkinsonismhemiatrophy (HPHA), Alzheimers disease, 116, 117
clinical features, 401, 403 brain distribution, 116
Index 507
clinico-pathological correlations, 117 eye movements in parkinsonism, 240,

comparative neuropathology of parkin- 243
sonism, 35, 36 parkinsonism induction, 52, 396
components, 114, 115 synuclein knockout mouse resistance, 79
historical description, 113 Midodrine, orthostatic hypotension man-
spectrum of disorders, 37, 39, 146 agement, 477
F-synuclein and Lewy body diseases MND, see Motor neuron disease
inherited Lewy body diseases, 82, 83 Motor neuron disease (MND), neuropa-
PARK1 locus, 79, 138, 139 thology, 47
PARK4 locus, 139 MPTP, see 1-Methyl-4-phenyl-1,2,3,6-
sporadic Lewy body diseases, 8082 tetrahydropyridine
Limb apraxia, see Apraxia MRI, see Magnetic resonance imaging
MRS, see Magnetic resonance spectroscopy
M
MS, see Multiple sclerosis
Magnetic resonance imaging (MRI), see MSA, see Multiple system atrophy
also Functional magnetic resonance Multiple sclerosis (MS), parkinsonism in-
imaging duction, 404
corticobasal degeneration, 316, 317, 440, Multiple system atrophy (MSA)
442 animal models, 348, 349
dementia with Lewy bodies, 366, 442 autonomic function testing
diffusion-weighted imaging, 454, 455 bladder function, 341, 342
manganese-induced parkinsonism, 443 cardiovascular function, 341
morphometry, 455, 456 case-control studies of environmental
multiple system atrophy factors, 28, 30
cerebellar type, 435, 437 cerebrospinal fluid findings, 340
overview, 342, 343 classification within parkinsonian disor-
parkinsonian type, 432, 433, 435 ders, 1, 2, 5, 6
Parkinsons disease, 431, 432 diagnostic criteria, 4, 5, 336338
progressive supranuclar palsy, 298, 437, dopaminergic defects and therapeutic
438, 440 targeting, 474
research prospects, 443, 445, 447 epidemiology
vascular parkinsonism, 395 analytical epidemiology, 336
vascular parkinsonism, 443 incidence, 23, 26, 336
Magnetic resonance spectroscopy (MRS) prevalence, 2326, 335, 336
phosphorous study in multiple system risk factors, 26, 2830, 142, 143, 336
atrophy, 454 eye movements, 242, 243
principles, 452 GABAergic defects and therapeutic tar-
proton studies of atypical parkinsonism, geting, 475, 476
453 health-related quality of life, 280, 282
research prospects, 443, 445, 447 historical description, 1820
Manganese, parkinsonism induction and hormone testing, 340, 341
features, 396, 397, 443 imaging
Medical history, interview in parkin- magnetic resonance imaging
sonism, 153, 154 cerebellar type, 435, 437
Memory overview, 342, 343
evaluation, 184, 185 parkinsonian type, 432, 433, 435
spatial, see Visuospatial cognition magnetic resonance spectroscopy, 454
1-Methyl-4-phenyl-1,2,3,6- positron emission tomography, 343,
tetrahydropyridine (MPTP) 344, 460463
508 Index
single photon emission computed needle recording of sphincter

tomography, 343, 344, 460463 muscles, 420
management surface recording of abnormal move-
autonomic failure, 349351 ments, 417, 418
cerebellar ataxia, 352 evoked potentials, 421, 422
overview, 350 hypokinesia, 410
parkinsonism, 351, 352 progressive supranuclar palsy, 299, 300
prospects, 352 research prospects, 423, 424
neuropathology, 39, 41, 97, 117, 118, rigidity, 410412
345347 spinal reflexes, 417
neuropsychological symptoms transcranial magnetic stimulation, 421
evaluation, 172, 173, 187 Neuroprotection, therapeutic prospects,
management, 176 479, 480
onset and progression, 337, 339 Neuropsychological evaluation
progression, 3 basal ganglia neuropsychiatry, 163, 164
speech and language disturbances batteries, 163, 184
clinical management, 263 behavioral dysfunction management,
language disturbances, 263 478, 479
neuroanatomy, 261, 262 corticobasal degeneration, 170172, 188,
speech disturbances, 262, 263 189
F-synuclein deposits, 8385, 142 dementia with Lewy bodies, 168, 169,
visuospatial disorders, 223, 224 189, 190
Mycoplasma, parkinsonism induction, 399 diagnostic value in parkinsonian disorders
Myoclonus, clinical evaluation, 158 methodological considerations, 165
168
N
overview, 190
NBIA, see Neurodegeneration with brain multiple system atrophy, 172, 173, 187
iron accumulation Parkinsons disease, 186, 187
Neurodegeneration with brain iron accu- progressive supranuclear palsy, 169, 170,
mulation (NBIA) 187, 188
classification within parkinsonian disor- research prospects, 190
ders, 1, 2, 5, 6 symptoms
clinical presentation, 387 definition and identification, 162, 184,
gene mutations, 146, 148, 387 185
neuropathology, 49, 50 epidemiology and implications in
Neurofibrillary tangles (NFTs), comparative parkinsonian disorders, 164, 165
neuropathology of parkinsonism, 35 management
Neurophysiological assessment corticobasal degeneration, 176
autonomic reflexes, 419, 420 dementia with Lewy bodies, 175,
bradykinesia, 410 176
brainstem reflexes multiple system atrophy, 176
eye and eyelid movements, 412415 Parkinsons disease, 173175
facial reflexes, 415 progressive supranuclear palsy,
prepulse inhibition, 417 176
startle reaction, 415417 measurement, 163, 184, 185
dementia with Lewy bodies, 368 Neurosurgery, atypical parkinsonism man-
differential diagnosis of atypical parkin- agement, 476
sonism, 422, 423 NFTs, see Neurofibrillary tangles
electromyography Niemann-Pick disease, eye movements, 245
Index 509
O corticobasal degeneration, 465, 466

Ocular motor assessment, see Eye move- dementia with Lewy bodies, 366, 466,
ments 467
Organic solvents, parkinsonism induction, multiple system atrophy
397 dopaminergic dysfunction, 461, 462
Orthostatic hypotension, management, 477 metabolic changes, 460
microglial activation, 463
P opioid dysfunction, 462
Pale bodies, comparative neuropathology overview, 343, 344, 460
of parkinsonism, 35 principles, 459
Parkinson, James, Parkinsons disease re- progressive supranuclar palsy
search contributions, 11 cholinergic, opioid, and ligand bind-
Parkinsonism dementia complex of Guam, ing, 464
tau pathology, 125, 126 dopaminergic system, 464
Parkinsons disease (PD), see also Idio- metabolic studies, 463, 464
pathic Parkinsons disease overview, 298
causes, 33, 34, 112 research prospects, 467, 468
definition, 33 tracers, 459, 460
diagnostic criteria, 499, 500 Postencephalitic parkinsonism (PEP)
health-related quality of life, 280 epidemiology, 51
limb apraxia, see Apraxia neuropathology, 51, 52
magnetic resonance imaging, 431, 432 tau pathology, 124, 125
neuropsychological symptoms Postural reflexes, clinical evaluation, 154
evaluation, 186, 187 Praxis, see Apraxia
management, 173175 Progressive supranuclar palsy (PSP)
PARK locus defects and phenotypes, 376 adrenergic defects and therapeutic tar-
posttraumatic parkinsonism, 52 geting, 475
visuospatial disorders, 218, 219 case-control studies of environmental
PD, see Parkinsons disease factors, 28, 30
PEP, see Postencephalitic parkinsonism cholinergic defects and therapeutic tar-
Perry syndrome, clinical features, 384386 geting, 475
PET, see Positron emission tomography classification within parkinsonian disor-
Physical examination ders, 1, 2, 5, 6, 297, 498
bradykinesia, 154 clinical features
dysautonomia, 157 behavioral and cognitive frontal fea-
dystonia, 157, 158 tures, 291
eye movements, bedside examination, differential diagnosis, 289
156, 157 extrapyramidal signs, 291
gait disorders, 155 postural instability and falls, 287, 289
guidelines, 158, 159 pyramidal signs, 292
myoclonus, 158 speech and swallowing, 291, 292
postural reflexes, 154 diagnosis
rigidity, 154 accuracy and difficulty, 292, 293
tremor, 154 criteria, 4, 290
utilization and imitation behaviors in dopaminergic defects and therapeutic
frontal syndrome, 155, 156 targeting, 474
Picks disease, definition, 126, 127 eye movements
Positron emission tomography (PET) clinical findings, 240, 241, 291
corticobasal degeneration, 317 differential diagnosis, 241243
510 Index
effects of disease course and treat- patient education, 300

ment, 240 prospects, 301, 302
laboratory findings typical versus atypical forms, 122
saccades, 241, 291, 297, 298 visuospatial disorders, 219221
smooth pursuit, 241 PSP, see Progressive supranuclar palsy
vestibular responses, 241 Pure akinesia, eye movements, 242
vertical supranuclear gaze palsy, 290
Q
GABAergic defects and therapeutic tar-
geting, 476 Quality of life, see Health-related quality
health-related quality of life, 280, 282 of life
historical description, 1517
R
imaging
computed tomography, 298, 440 Rehabilitation therapy
magnetic resonance imaging, 298, 437, case study of idiopathic Parkinsons
438, 440 disease, 491, 493
positron emission tomography, 298, cognitive performance measures, 490
463465 conceptual framework, 485, 486
single photon emission computed directing rehabilitation approaches, 488
tomography, 463465 efficacy, 486, 487
incidence, 23, 26, 293 intervention approaches, 491
limb apraxia, see Apraxia medication side effect monitoring and
neuropathology, 44, 97, 119121, 287, timing, 489
293 motor performance measures, 490, 491
neurophysiological studies, 299, 300 overview for movement disorders, 489
neuropsychological symptoms prospects, 493
evaluation, 169, 170, 187, 188, 298 Rigidity
management, 176 clinical evaluation, 154
prevalence, 2326, 293 neurophysiological assessment, 410412
progression, 3, 293
S
research prospects, 302, 303
risk factors Saccades, see Eye movements
environmental factors, 295297 SCA, see Single photon emission computed
genetics, 294 tomography
inflammation, 295 Scintigraphy, dementia with Lewy bodies,
overview, 26, 28, 29 368
oxidative injury, 295 Senile plaque (SP), comparative neuropa-
serotininergic defects and therapeutic thology of parkinsonism, 35
targeting, 475 Single photon emission computed tomog-
speech and language disturbances raphy (SPECT)
clinical management, 261 corticobasal degeneration, 317, 465, 466
language disturbances, 260, 261 dementia with Lewy bodies, 366, 368,
neuroanatomy, 259, 260 466, 467
speech disturbances, 260 multiple system atrophy
tau pathology, 144, 145 dopaminergic dysfunction, 461, 462
transgenic mouse models, 72, 73 metabolic changes, 460
treatment microglial activation, 463
levodopa responsiveness, 300 opioid dysfunction, 462
neurotransmitter replacement, 301 overview, 343, 344, 460
palliative measures, 301, 302 principles, 459
Index 511
progressive supranuclar palsy classification within parkinsonian disor-

cholinergic, opioid and ligand bind- ders, 1, 2, 5, 6
ing, 464 familial parkinsonism with ataxia, 380,
dopaminergic system, 464 381
metabolic studies, 463, 464 features, 146
research prospects, 467, 468 neuropathology, 49
tracers, 459, 460 Subacute sclerosing panencephalitis, par-
vascular parkinsonism, 395 kinsonism, 398
Sleep studies Sydenhams chorea, eye movements, 245
dementia with Lewy bodies, 365 Synucleins
progressive supranuclar palsy, 299 assembly studies using recombinant
SP, see Senile plaque filaments, 85, 86
Spasmodic torticollis, eye movements, 245 fatty acid binding, 78
SPECT, see Single photon emission com- knockout mouse phenotypes and MPTP
puted tomography resistance, 79
Speech and language disturbances Lewy body diseases and F-synuclein
aphasia types and features, 270, 271 inherited Lewy body diseases, 82, 83
apraxia types and features, 271 PARK1 locus, 79, 138, 139
clinical assessment, 255, 273, 274 PARK4 locus, 139
comparative features by diagnostic sporadic Lewy body diseases, 8082
group, 256 multiple system atrophy and F-
corticobasal degeneration synuclein deposits, 8385
clinical management, 259 phosphorylation, 79
language disturbances, 258, 259 research prospects, 89, 90
neuroanatomy, 257 rotenone neurotoxicity models of F-
speech disturbances, 257, 258 synucleinopathies, 89
definitions structure, 77, 78
language, 253 F-synuclein functions and role in dis-
speech, 253 ease, 138, 479
dementia with Lewy bodies tissue distribution, 77, 78
clinical management, 265 transgenic animal models of F-
language disturbances, 264 synucleinopathies
neuroanatomy, 263, 264 Caenorhabditis elegans, 88
speech disturbances, 264 Drosophila, 88
dysarthria types and features, 271, 272 mice, 8688
multiple system atrophy viral vector-mediated gene transfer,
clinical management, 263 88
language disturbances, 263 types, 77
neuroanatomy, 261, 262
T
speech disturbances, 262, 263
neuroanatomical correlates, 253255 Tardive dyskinesia, eye movements, 245
progressive supranuclear palsy Tau
clinical management, 261 Caenorhabditis elegans model of dys-
language disturbances, 260, 261 function, 72
neuroanatomy, 259, 260 clinical features of specific mutations,
speech disturbances, 260 379
research prospects, 265267 Drosophila model of dysfunction, 72
Spinal reflexes, assessment, 417 fish model of dysfunction, 72
Spinocerebellar ataxia (SCA) function and role in disease, 143
512 Index
gene structure, 65 neuropathology, 52, 393, 394

inherited tauopathies, 143, 144 research prospects, 404
isoforms, 65, 118, 119 subgroups, 394
transgenic mouse models Visuospatial cognition
frontotemporal dementia with par- assessment, 224, 225
kinsonism linked to chromo- disorders in disease
some 17, 6971 corticobasal degeneration, 221, 222
isoform expression studies, 6769 dementia with Lewy bodies, 223
overview, 65, 66 multiple system atrophy, 223, 224
phosphorylation status studies, 65, 67 Parkinsons disease, 218, 219
progressive supranuclear palsy, 72, 73 progressive supranuclear palsy, 219
prospects, 72, 73 221
TMS, see Transcranial magnetic stimula- research prospects, 224, 225
tion size perception, 215
Tourrette syndrome, eye movements, 245 spatial imagery, 217, 218
Transcranial magnetic stimulation (TMS), spatial memory
investigations, 421 long-term, 217
Tremor short-term, 216, 217
clinical evaluation, 154 spatial perception
peripherally induced tremor and parkin- depth perception, 212, 213
sonism, 400 perception of line orientation, 212
Tricyclic antidepressants, atypical parkin- stimulus localization, 212
sonism management, 476 topographical orientation disorders,
218
U
visuomotor coordination, 213
Urinary incontinence, management, 477 visuospatial attention, 213215
V W
Vascular parkinsonism Wasp sting, parkinsonism induction, 404
clinical features, 394, 395 Whipples disease, eye movements, 242
historical description, 393 Wilsons disease
imaging, 395, 443 clinical features, 387
laboratory testing, 395 eye movements, 244, 245
management, 396 neuropathology, 54

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Atypical Parkinsonian Disorders

CURRENT CLINICAL NEUROLOGY

Atypical Parkinsonian Disorders: Clinical and Research Aspects, edited by Irene

Yves Agid, MD, PhD

This publication is printed on acid-free paper. h

Cover design by Patricia F. Cleary

Photocopy Authorization Policy:

Series Editors Introduction ............................................................................................................. v

16 Characterizing and Assessing Speech and Language Disturbances .......................... 253

Index ................................................................................................................................................. 503

ALEXANDER GERHARD, MD MRC Clinical Sciences Centre and Division of Neuroscience,

From: Current Clinical Neurology: Atypical Parkinsonian Disorders

Quinn (54) Litvan et al.

CLASSIFICATION OF ATYPICAL PARKINSONIAN DISORDERS

Studying archetypes is a fundamental task in nosography. Duchenne de Boulogne practiced it instinc-

From: Current Clinical Neurology: Atypical Parkinsonian Disorders

EARLY CONCEPTS OF ATYPICAL PARKINSONS DISEASE

Parkinsonism Without Prominent Rest Tremor

Parkinsonism With Atypical Postures

Hemiplegic Parkinsons Disease

HISTORICAL DESCRIPTIONS OF ATYPICAL PARKINSONIAN

Multiple System Atrophy

Adam Zermansky and Yoav Ben-Shlomo

THE PREVALENCE AND INCIDENCE OF PSP AND MSA

From: Current Clinical Neurology: Atypical Parkinsonian Disorders

Prevalence of PSP and MSA

PSP Prevalence MSA Prevalence

MSA and PSP

*Estimated from paper

Incidence of PSP and MSA

Implications From Prevalence and Incidence Data

RISK FACTORS FOR PSP AND MSA

Risk Factors for PSP

Risk Factors for MSA

Implications From Case-Control Studies of PSP and MSA

IDIOPATHIC PARKINSONS DISEASE

From: Current Clinical Neurology: Atypical Parkinsonian Disorders

DEMENTIA WITH LEWY BODIES

THE SPECTRUM OF LB DISORDERS

FAMILIAL PARKINSONS DISEASE

MULTIPLE SYSTEM ATROPHY

PROGRESSIVE SUPRANUCLEAR PALSY

ALS/PARKINSONISM DEMENTIA COMPLEX OF GUAM

OTHER NEURODEGENERATIVE CONDITIONS

Fig. 6. ALS/parkinsonism/dementia complex of Guam. (A,B) Numerous neurofibrillary tangles in CA1

Jada Lewis and Michael Hutton

MICE EXPRESSING TRANSGENES THAT ALTER TAU KINASE

From: Current Clinical Neurology: Atypical Parkinsonian Disorders

TRANSGENIC MICE EXPRESSING WILD-TYPE TAU TRANSGENES

TRANSGENIC MICE EXPRESSING FTDP-17-ASSOCIATED P301L MUTANT

TRANSGENIC MICE EXPRESSING OTHER FTDP-17-ASSOCIATED

OTHER ANIMAL MODELS OF TAU DYSFUNCTION

Michel Goedert and Maria Grazia Spillantini

THE SYNUCLEIN FAMILY

From: Current Clinical Neurology: Atypical Parkinsonian Disorders

LEWY BODY DISEASES

F-Synuclein and Sporadic Lewy Body Diseases

F-Synuclein and Inherited Lewy Body Diseases

MULTIPLE SYSTEM ATROPHY