Curr Top Med Chem. Author manuscript; available in PMC 2010 Jan 12.
Published in final edited form as:
Curr Top Med Chem. 2009; 9(10): 903–912.
PMCID: PMC2804995
NIHMSID: NIHMS158045
Cognitive Impairment and Dementia in Patients with Parkinson Disease
,1,3,5,6 ,3,4 ,2,3,5 ,7 ,7 and 7,*
James B. Leverenz
1 Mental Illness, Oregon Health & Sciences University, Portland, OR
3 Parkinson Disease Research, Education, and Clinical Centers of the Veterans Administration, Oregon Health & Sciences University, Portland, OR
5 Department of Neurology, University of Washington, Seattle, WA
6 Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
Joseph F. Quinn
3 Parkinson Disease Research, Education, and Clinical Centers of the Veterans Administration, Oregon Health & Sciences University, Portland, OR
4 Department of Neurology, Oregon Health & Sciences University, Portland, OR
Cyrus Zabetian
2 Geriatric, Oregon Health & Sciences University, Portland, OR
3 Parkinson Disease Research, Education, and Clinical Centers of the Veterans Administration, Oregon Health & Sciences University, Portland, OR
5 Department of Neurology, University of Washington, Seattle, WA
Jing Zhang
7 Department of Pathology, University of Washington, Seattle, WA
Kathleen S. Montine
7 Department of Pathology, University of Washington, Seattle, WA
Thomas J. Montine
7 Department of Pathology, University of Washington, Seattle, WA
1 Mental Illness, Oregon Health & Sciences University, Portland, OR
2 Geriatric, Oregon Health & Sciences University, Portland, OR
3 Parkinson Disease Research, Education, and Clinical Centers of the Veterans Administration, Oregon Health & Sciences University, Portland, OR
4 Department of Neurology, Oregon Health & Sciences University, Portland, OR
5 Department of Neurology, University of Washington, Seattle, WA
6 Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
7 Department of Pathology, University of Washington, Seattle, WA
* Address correspondence to this author at the Department of Pathology, University of Washington, Seattle, WA 98104; Tel: 206-744-6776; Fax:206-897-5249:
ude.notgnihsaw.u@enitnomt See other articles in PMC that
cite the published article.
Abstract
Parkinson disease (PD) is an already prevalent neurodegenerative disease that is poised to at least double over the next 25 years. Although best known for its characteristic movement disorder, PD is now appreciated commonly to cause cognitive impairment, including dementia, and behavioral changes. Dementia in patients with PD is consequential and has been associated with reduced quality of life, shortened survival, and increased caregiver distress. Here we review clinical presentation and progression, pathological bases, identification of genetic risk factors, development of small molecule biomarkers, and emerging treatments for cognitive impairment in patients with PD.
I. OVERVIEW
Parkinson disease (PD) is an already prevalent neurodegenerative disease that is poised to double over the next 25 years in the US and more than double in developing countries of Asia and South America [1]. It is important to stress that the natural history of PD is variable. If untreated, approximately 80% of patients with subsequently diagnosed definite PD become severely disabled or die 10 to 14 years after onset of disease [2]. Current medical and surgical treatment options have significantly improved quality and length of life for patients with PD. Despite these great advances, PD still typically progresses to diminished responsiveness to dopamine replacement therapies and to development of dyskinesias. Although best known for its characteristic movement disorder, PD is now appreciated also to cause cognitive, psychiatric, autonomic, and sensory disturbances. Indeed, despite James Parkinson’s original claim that intellectual function was preserved in the “shaking palsy” [3], cognitive impairment (CI) is now recognized as a common feature of PD [4]. Cognitive impairments are common in a large fraction of patients with PD at initial diagnosis and afflict a majority of patients as PD progresses. For the sake of clarity we stratify individuals into groups as designated in .
Table 1
Definitions of clinico-pathologic groups.
| Stratification Terms | Definitions |
|---|
| Level I | II | III | Clinical | Pathologic |
|---|
| Control | | | No neurologic signs or symptoms | No/low ADa; No LRPb |
| Preclinical PD | | | No neurologic signs or symptoms | No/low ADa; Brainstem or olfactory bulb LRPb |
| PD-NCI | | Probable PDc | SN and/or LC LRP |
| PD | PD-CI | PD-CIND | Probable PDc plus CIND | SN and/or LC LRP plus other not yet established |
| PD-D | Probable PDc plus dementia | SN and/or LC LRP plus
Intermediate or high AD, limbic and/or neocortical LRP 1 & 2, or Neither 1 nor 2
|
PD with dementia (PD-D) is consequential. PD-D has been associated with reduced quality of life [5], shortened survival [6], and increased caregiver distress compared to PD with no CI (NCI) [7]. Community-based studies have estimated the point prevalence for dementia in PD to be between 28% and 44% [8–11]. One longitudinal study observed 52% prevalence of dementia with over 4-years follow-up and 60% (95% confidence interval, 54–66%) prevalence of dementia with over 12-years follow up in 233 patients with PD [12]. Another prospective study of 249 patients with PD observed 65% risk of dementia by age 85 years [13]. A third prospective study of 86 patients with PD and 102 age-matched controls estimated the relative risk for dementia equal to 5.1 in patients with PD [10]. Many, but not all, studies have observed more prominent impairment of executive function (EF) in PD-D and its close relative Dementia with Lewy Bodies, than the more prominent amnestic changes observed in Alzheimer’s disease (AD) [14, 15]; although there is clear overlap among the cognitive domains impaired in all three conditions especially at more advanced stages.
While increased prevalence and risk of dementia in patients with PD has been recognized for some time, CI that falls short of diagnostic criteria for dementia (called “CI, no dementia” or CIND) also is common in patients with PD. Mostly, these have included cognitive deficits related to impaired EF: impaired regulation in sorting or planning tasks, defective use of memory stores, and impaired manipulation of internal representation of visuospatial stimuli [16–19]. More recent work has estimated that 19% of newly diagnosed and untreated PD patients had PD-CIND, a twofold increase over other elderly [20]. Another study suggested that 57% of patients with newly diagnosed PD will develop PD-CIND within the next 3 to 5 years [21]. The relationship, if any, between PD-CIND, which is typically manifested as impaired EF, and PD-D, which is typically a more complex derangement of cognitive functions, is not entirely clear, but one study observed that subtle frontal lobe deficits may be of prognostic value in identifying patients who are at risk for PD-D [22], while another has suggested that impairment of cognitive tasks related to more posterior cortical regions are predictive of cognitive decline [21].
Realizing that the actual situation is more complex, we envision at least two caricature pathways for PD-CIND that variably converge in PD-D (). In this hypothetical view, we propose that one path to PD-CIND derives from regional neostriatal or pre-frontal dysfunction that is related to disrupted catecholaminergic or indolaminergic neurotransmission; this form of PD-CIND would be expected to prominently manifest with non-amnestic (CINDn) features like impaired EF, and perhaps is correlated with Lewyrelated pathology (LRP) in limbic and neocortical regions [23]. We propose a second path to PD-CIND derives from the processes of AD intersecting with PD; this form would be expected to prominently manifest with amnestic (CINDa) features and neuropathologic changes of AD. Finally we propose that these two paths converge to varying degrees as disease progresses to produce a spectrum of behavioral and neuropathologic changes like what have been described in patients with PD-D. While is not exhaustive, it does represent testable proposals about genetics, biomarkers, and neuropathologic bases of CI in PD. Fuller understanding of these and other pathways to CI in patients with PD will be critical as disease-specific treatments are developed.
Convergent paths for cognitive impairment and dementia in patients withAbbreviations: a (amnestic), CIND (cognitive impairment, no dementia), D (dementia), IsoPs (isoprostanes), LRP (Lewy-related pathology that includes Lewy bodies and SNCA-immunoreactive filamentous structures as described in [26]), n (non-amnestic), PD (Parkinson disease), P-taus (phosphorylated tau isoforms)
Into this mix of convergent phenotypes, we must mention Dementia with Lewy Bodies, a relatively common cause of dementia that typically presents a combined neuropathologic picture of AD-type changes and widespread LRP. Clinical consensus criteria have been formulated to help systematize the distinction of Dementia with Lewy Bodies from PD-D: dementia precedes or occurs within 12 months of the onset of parkinsonism in Dementia with Lewy Bodies, whereas dementia develops more than 12 months after the onset of parkinsonian signs in PD-D [24–26]. Not surprisingly, controversy persists over whether Dementia with Lewy Bodies and PD-D are the same entity with different initial presentations or two initially distinct entities that converge.
II. NEUROPATHOLOGY OF PD AND PD-D
Although our appreciation for the breadth of systems affected by PD is growing [27], PD still is characterized by prominent loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) in relatively early stages of the disease, depletion of striatal dopamine (DA), and the presence of intraneuronal inclusions called Lewy bodies (LBs) [28, 29]. PD is the most common idiopathic cause of parkinsonism. Other diseases involving the nigrostriatal DAergic system, which also produce parkinsonism, include progressive supranuclear palsy, multiple system atrophy (a syndrome consisting of extrapyramidal, cerebellar, and/or autonomic features), corticobasal degeneration, and Dementia with Lewy Bodies.
The neuropathological hallmark of PD is accumulation of LBs in the SNpc or locus ceruleus (LC) [30, 31]. This association is so strong that incidental LB disease, which occurs in about 7–10% of older individuals [32], is regarded by many investigators as a preclinical stage of PD. However, autopsy findings in individuals who die of PD not only include LB accumulation in SNpc and LC with extensive neurodegeneration at these sites, but also degenerative changes in other regions of the brain including the dorsal motor nucleus of the glossopharyngeal and vagal nerves, some subnuclei of the reticular formation and the raphe system, the magnocellular nuclei of the basal forebrain, and many subnuclei of the thalamus and amygdala [33]. In addition, cases with severe damage usually show neurodegeneration and LBs in neocortical regions [34, 35]. Braak and colleagues conducted elegant studies using autopsied brain from PD patients and neurologically normal controls [33, 36]. They concluded that pathological changes in PD follow a stereotypical course as the disease progresses. Braak Stages 1 and 2 show LB pathology and associated neuronal degeneration confined to the medulla oblongata and olfactory bulb, where many nuclei are involved, including the spindle-shaped projection neurons of the dorsal IX/X motor nucleus and, in some instances, in projection cells of the intermediate reticular zone. Braak Stages 3 and 4 define PD cases with involvement chiefly confined to the lower and upper brain stem, e.g., SNpc, in the absence of cortical lesions or with initial involvement of the anteromedial temporal mesocortex. Finally, Braak Stages 5 and 6 indicate severe involvement of brain, including neocortical areas such as parietal and frontal cortex. Others have largely confirmed these studies in patients with PD [37].
Numerous clinico-pathologic studies have sought the structural bases of cognitive impairment in patients with PD. It is important to realize that these studies are seriously confounded by a strong bias to late-stage disease when different processes likely have merged into a complicated picture. Nevertheless, a broad summary of these many studies shows that dementia in PD-D is commonly associated with limbic or neocortical (L/N) LRP to the exclusion of other consensus pathologic criteria for dementia (Path 1) [23, 38–40] with AD pathologic changes to the exclusion of other consensus pathologic criteria for dementia (Path 2) [41–43] with both L/N LRP and AD (convergent phenotype), or without reaching pathologic consensus criteria for dementing illness [44–47]. The prevalence of PD-D without L/N LRP or AD is not entirely clear and has been estimated in several autopsy series to be essentially none [48], 24% [49], or 55% [50] of patients. This wide-ranging difference is likely related to methodologic differences in these studies. Appropriate clinical diagnosis and assessment of cognitive function, use of more sensitive SNCA antibodies for LB detection, and the scheme used for pathologic staging of AD are all important issues to consider in evaluating these clinicopathological studies of PD-D [51]. Indeed, this category of PD-D seems to be progressively contracting as methods improve.
The possibility that there is a substantial number of patients with PD-D but no obvious explanation of their dementia motivated several groups to examine ventral medial midbrain DA neuron loss in patients with PD-D; the midbrain region where DA meso-frontal neurons have been proposed to be concentrated [41, 44, 47]. However, while these projections may be important in PD-D, localization of their neuron cell bodies to the ventral medial midbrain has been severely challenged by recent data from non-human primates that displayed widespread distribution of mesofrontal DA neurons in the substantia nigra [52].
The neuropathologic correlates of CI in PD-CIND are not yet clarified, although five different projections from the basal nuclei or brain stem have been proposed to be relevant.
(i) Meso-frontal DA projections
Because of prominent impairment of EF in PD, PD-D, and other diseases characterized by LRP, such as Dementia with Lewy Bodies, many have proposed that meso-striatal DA degeneration leads to motor impairments in PD while meso-frontal DA degeneration leads to cognitive impairment [19, 41, 44, 47]. Recent functional MRI studies from patients with PD or PD-CIND support this model [53, 54], but a recent clinical trial does not [55]. Given the difficulties in defining which nigral DA neurons are part of the meso-frontal circuit in primates [52], the most direct test of this proposal seems to be quantification of PFC DA. Yet we are aware of only one study that quantified concentrations of DA and its metabolites in PFC of patients with PD; these investigators concluded that there was a selective reduction in PFC DA in PD [56]. This 24-year-old study did not distinguish among PD, PD-CIND, or PD-D because these concepts were not yet considered. Thus, it remains unclear if reduction in PFC DA is present in all forms of PD or restricted to those with PD-CIND or PD-D.
(ii) Meso-anterior neostriatal (head of caudate nucleus) DA projections
The regional distribution of dopaminergic degeneration in the neostriatum may be a critical contributor to cognitive impairment in patients with PD. Meso-striatal dopaminergic degeneration in the postero-lateral neostriatum disrupts the corticalstriatal- pallidal-thalamic motor circuit to produce the initial movement abnormalities of PD. By analogy, we and others have proposed that meso-striatal dopaminergic degeneration in the anterior neostriatum disrupts the dorsolateral PFC and lateral orbitofrontal circuits to produce impaired EF in PD-CIND and PD-D [57, 58]. Recent positron emission tomography (PET) studies support the proposal that decreased anterior neostriatal activity is a feature of early cognitive impairment in PD [59]. Others measured neuronal activity during a verbal mental-operation task with H215O PET to evaluate brain activity change without the influence of motor deficits in non-demented patients with PD (off medication). Their results showed that, in contrast to controls, patients with PD lacked an increase in the anterior striatal activity, whereas the medial premotor cortex showed an increase proportional to healthy controls [60]. Another group used 18F-fluorodopa PET in patients with PD and variable degree of cognitive impairment [61]. Uptake was reduced 36% in the putamen, 61% in the head of the caudate nucleus, and 45% in PFC in patients with PD compared with controls. Importantly, reduced 18F-fluorodopa uptake in the head of the caudate nucleus and PFC was related to impairment in EF in PD-CIND and PD-D. We are aware of one study that mapped neostriatal DA loss in PD patients [62]. Like the study of PFC neurotransmitters in patients with advanced PD, this 19-yearold study cannot answer the critical questions about the clinical relevance of regionally restricted dopaminergic neurodegeneration in PD-CIND and PD-D because cognitive performance data were not collected. Thus, it remains unknown if the regionally selective reduction in neostriatal DA observed by this group is a feature of all PD patients or restricted to PD-CIND or PD-D.
(iii) Ponto-frontal and -hippocampal NE projections
The same study that measured PFC DA in controls and patients with PD but unspecified cognitive function also measured PFC (A9) and hippocampal (A34) NE levels, and showed > 50% reduction of NE in both regions of brain from patients with PD [56]. A recent study of 4 patients with PD and 4 controls described variable degeneration of noradrenergic neurons in the locus ceruleus (LC) [63]. Importantly, both aged human and non-human primate studies have failed to observe any significant reduction in PFC NE. Thus, PFC noradrenergic degeneration is a potential candidate for PFC-dependent cognitive impairments, such as reduced EF, in PD. In contrast to DA, there is no detectable NE in the human neostriatum [56].
(iv) Pontomedullary-frontal, –hippocampal, and striatal 5HT projections
The same two studies cited for NE in the preceding section also investigated 5HT. PFC (A9), caudate (region unspecific), and hippocampus (A34); all showed a significant reduction in 5HT in patients with PD compared to those without a known history of neurologic disease [56]. The same study cited above describing variable degeneration of noradrenergic neurons in LC in PD also reported extensive serotonergic neuron loss in the pontine and medullary raphe nuclei [63].
(v) Basal nuclei-frontal and -hippocampal ACh projections
Results from one autopsy series concluded that ChAT activity is reduced in frontal and temporal cortex as well as hippocampus of patients who died from PD compared to controls, and that these reductions in PFC correlated with cognitive impairment assessed during life [64]. Another larger autopsy series concluded that PFC depletion of ChAT activity distinguished diseases characterized by LRP (PD or Dementia with Lewy Bodies) without AD changes from those with AD changes [65]. This finding was supported by a relatively small PET neuroimaging study that showed greater reduction in cerebral cortical (excluding lateral temporal lobe) ChAT activity in patients with PD-D compared to PD, and relative preservation in patients with AD [66]. Consistent with these findings, a large clinical trial demonstrated modest therapeutic benefit from a cholinesterase inhibitor on cognitive impairments and behavior in patients with PD-D [67].
The proposal that dysfunction of medium spiny neurons (MSNs) may result from dopamineergic degeneration with unopposed cerebral cortical and thalamic glutamatergic input has been around for more than a decade, and is widely hypothesized as one mechanism underlying the response fluctuation and dyskinesias that eventually compromise DA replacement strategies in patients with PD [58, 68, 69]. Increasing evidence suggests that augmented synaptic efficacy of striatal ionotropic GLU receptors contributes to the appearance of these motor complications [70]. Indeed, several groups demonstrated that drugs that block either NMDA or AMPA receptors, or glutamate release, diminish motor complications in parkinsonian models in rodents and non-human primates [71–77]. Neurophysiological observations suggest that these actions likely involve the modulation of excitatory transmission in MSNs and downstream nuclei [78, 79]. Some groups have attempted to extend this research to patients with PD with mixed results [80–82]. Recently, an L-type calcium ion channel has been identified in rodent models as a therapeutic target for protection of striato-pallidal MSN dendrites following dopaminergic denervation with toxins [83]. We have proposed that regionally restricted DA degeneration in neostriatum may be linked to spinodendritic degeneration of MSNs, and that this may contribute to impaired EF.
III. GENETICS
Human genetic studies have begun to shed light on the molecular events that lead to neuronal injury and death in PD. Through the study of rare multigenerational pedigrees in which PD segregates in a Mendelian pattern, five “causal” genes (SNCA [α-synuclein], LRRK2 [leucine-rich repeat kinase 2], PARK2 [parkin], PINK1 [PTEN induced putative kinase 1], and PARK7 [DJ-1]) have been identified over the last decade [84–89]. These genes have implicated dysregulation of diverse cellular processes (e.g., mitochondrial respiratory chain function, kinase signaling, ubiquitin-mediated protein degradation) as potentially pathogenic in PD and opened new avenues of research [90–93].
It is important to stress that causal mutations in these five genes account for no more than 2% (combined) of PD in populations of European ancestry. Thus, there have been many hundreds of studies conducted to determine whether common sequence variants (i.e., those with a minor allele frequency [MAF] ≥ 5%) alter PD susceptibility. The vast majority of this work has consisted of case-control association studies on “candidate” genes that have yielded conflicting results. However, recent large-scale collaborative studies have now implicated common variants in two genes, SNCA and MAPT [microtubule-associated protein tau] as susceptibility factors in PD [94, 95]. The latter data are particularly intriguing because common variants in MAPT also modify risk for AD, progressive supranuclear palsy, and corticobasal degeneration, suggesting the possibility of a shared pathophysiological mechanism among neurodegenerative diseases. There also is substantial emerging evidence that mutations in the glucocerebrosidase (GBA) gene increase risk for both PD and Dementia with Lewy Bodies [96–102].
Relatively little work has been conducted on identifying genetic risk factors for CI in PD. This gap in knowledge has arisen from a combination of several factors, including the extremely limited availability of DNA samples from large cohorts of PD patients who have undergone rigorous psychometric assessments, a lack of consensus criteria on the evaluation and definition of CI in PD, and variation in the psychometric instruments used to assess patients across studies.
In summary, the discovery of genetic risk factors for PD has uncovered a wealth of information that has been used to create new experimental models, to identify promising targets for therapeutic intervention, and to select subgroups of patients and at-risk subjects appropriate for specific clinical trials. Similar work to discover genetic risk factors for CI in PD is equally promising but has lagged behind, largely because of limited availability to appropriately characterized patient populations.
IV. BIOMARKERS
The clinical diagnosis of PD is difficult because its signs and symptoms overlap with other forms of parkinsonism, its progression can vary substantially among patients, and as yet there is no robust ante mortem biomarker or diagnostic imaging protocol that has been validated and widely accepted, although many are under research and development [103–121]. The clinical diagnosis of PD is based on identification of cardinal motor feature and their responsiveness to DA replacement therapies. Currently, the clinical diagnosis of possible or probable PD is based on clinical criteria alone [122–124]. Neuropathologic examination (see next section)is required for the diagnosis of definite PD in patients with the clinical diagnosis of possible or probable PD.
Although experts in movement disorders have greater accuracy in the initial diagnosis of PD [125, 126], several clinico-pathologic studies have observed that the diagnostic accuracy for PD with current criteria is about 65% at initial evaluation, and this improves to about 80% as patients progress [127–129]. Therefore, despite advancements in diagnostic techniques, as many as one in five persons are misclassified clinically. For example, in one autopsy series [128] 59 patients with parkinsonism were seen by a single neurologist, and the diagnosis of PD was made initially when patients had at least 2 of the 3 non-postural cardinal signs (bradykinesia, rigidity, and resting tremor). No other identifiable cause of parkinsonism or clinical evidence of widespread central nervous system (CNS) lesions were found in these patients. The final clinical diagnosis of PD was reduced to 41 patients on follow-up; of these patients,31 (76%) were confirmed as definitive PD at autopsy. In another series of 100 patients with the clinical diagnosis of PD [129] the diagnosis was confirmed neuropathologically in 76 patients (76%). Diagnostic specificity can be increased by requiring all three cardinal features (tremor, rigidity, and bradykinesia) for the clinical diagnosis of PD, but in the aforementioned study this reduced sensitivity, since only65% of patients with pathologically confirmed PD exhibited these criteria [130]. Furthermore, response to levodopa is not specific to PD. For example, 22% to 35% of patients with progressive supranuclear palsy respond to levodopa, at least temporarily [131, 132]. Levodopa responsiveness is also reported in 69% to 75% of patients with autopsy-confirmed multiple system atrophy [131, 133], and although the response diminishes over time in most patients, 7% to 35%of patients remain at least partially responsive to levodopa throughout their illness [133, 134]. Finally, in patients with Dementia with Lewy Bodies who present with parkinsonian features, 70% to 87% respond to levodopa [130–135]. Furthermore multiple system atrophy and progressive supranuclear palsy patients are at least partially responsive to newer DA agonists [136, 137].
Clearly, this is an area of clinical management that would benefit greatly from validated biomarkers of Path 1 and Path2 to PD-D. Indeed, there are validated CSF biomarkers of AD that have recently been demonstrated for the pre-clinical stage of disease. Recently published studies of older adults showed that CSF tau and Aβ42 levels that were determined when individuals were neurologically normal could be used to predict subsequent development of amnestic Mild Cognitive Impairment (MCI), a syndromic classification that closely reflects prodromal AD [138, 139]. Studies of CSF tau in PD without dementia have consistently found levels closer to control subjects than to AD subjects, supporting the impression that this marker may be useful for distinguishing PD subjects with and without concomitant AD pathology [140, 141].
CSF F2-isoprostanes (IsoPs) are quantitative in vivo biomarkers of oxidative damage to the brain that when combined with CSF tau and Aβ42 levels, can increase the sensitivity and specificity of a laboratory diagnosis of mild AD [142]. Others have shown that CSF F2-IsoPs are elevated in individuals with amnestic MCI [143, 144]. We and others have shown in longitudinal studies that CSF F2-IsoPs increase as AD progresses [143–145]. Autopsy and limited CSF data do not support their use as biomarkers of LBD or parkinsonism from multiple system atrophy [146–148]. Therefore, CSF F2-IsoPs may be useful as biomarkers of Path 2.
We know of no validated biomarker of latent or prodromal PD, PD-D, or the form of Dementia with Lewy Bodies that lacks co-morbid changes of AD [142, 149–158], although this also is an area of intense research and we are hopeful that candidates will advance from ongoing studies.
SUMMARY
PD is an already prevalent disease among older individuals that is poised to become a much greater public health problem here and elsewhere around the globe in the coming decades. Although not traditionally appreciated as a facet of PD, recent research has underscored that a substantial number of patients with PD have CI early in their disease process, and that the majority will have CI or dementia at some point in the course of their illness. We envision at least two pathways to progressive CI in patients with PD. The significance is that these two pathways likely differ not only in their etiology, pathogenesis, genetic risk, and biomarker profile, but also response to therapeutics.
Acknowledgments
This work was supported by VA Merit Review Awards, grants from the NIH (P50AG05136 and P50NS062684), the C-M Shaw Endowment, and the Nancy and Buster Alvord Endowment.
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