zy Distinct cognitive profiles of cortical and subcortical dementia in advanced illness J.S. Paulsen, PhD; N. Butters, PhD; J.R. Sadek, BS; S.A. Johnson, BS; D.P. Salmon, PhD; N.R. Swerdlow, MD, PhD; and M.R. Swenson, MD zy Article abstract-We administered the Mattis Dementia Rating Scale (DRS) to 120 patients to evaluate the effect of dementia severity on distinct cognitive profiles. Sixty patients with Huntington’s disease (HD) and 60 patients with Alzheimer’s disease (AD) were separated by dementia severity into three groups: mildly demented (DRS mean total = 1291, moderately demented (DRS mean total = 117), and severely demented (DRS mean total = 102). At all levels of dementia severity, HD patients demonstrated greater impairment than AD patients on the Initiatioflerseveration subscale, whereas AD patients demonstrated greater impairment than HD patients on the Memory subscale. At moderate and severe levels of dementia, HD patients demonstrated a n additional impairment in constructional praxis. These profile differences were independent of dementia severity and continued to differentiate between so-called cortical and subcortical dernentias in later stages of dementia severity. NEUROLOGY 1995;45:951-956 Numerous reports have demonstrated differential cognitive impairment between patients with subcortical dementia, such as Huntington’s disease (HD), and cortical dementia, such as Alzheimer’s disease (AD). It is less well known, however, whether distinct cognitive profiles remain in advanced stages of the diseases. In general, subcortical dementia is characterized by bradyphrenia, impaired attention, deficits in problem-solving, and a general retrieval deficit that is evidenced by poor performances on verbal fluency and recall, but not recognition, measures of episodic mem~ry.l-~ In contrast, cortical dementia typically presents with a severe and predominant memory impairment that affects both recall and recognition performance, and with severe deficits in language, problem-solving, and visuospatial a b i l i t i e ~ . ~ - ~ These distinct cognitive profiles are associated with different underlying pathology of the two dementias. For instance, HD is a genetically transmitted disorder that results in a progressive neuronal loss in the caudate nucleus and other basal ganglia structure^.^*^ AD, in contrast, is a neurodegenerative disorder that results primarily in the disruption of frontal, temporal, and parietal cortical association areaslo and the hippocampal formation.ll The use of the distinction between cortical and subcortical dementia in middle and later stages of disease severity, however, is under scrutiny and critical review. One reason for the debate is findings of neuronal degeneration in the cerebral cortex of patients with subcortical disease (HD and Parkinson’s disease) and basal forebrain abnormalities in the brains of patients with cortical diseases (eg, AD), although few studies are able to address which of these neuropathologic changes occur early in the disease process and which changes are associated with late-stage disease. Recently, brief mental status screening instruments have illuminated the differences between HD and AD.lJ2 Salmon et all2 demonstrated that HD and AD patient groups performed differently on the subscales of the Mattis Dementia Rating Scale13 (DRS) despite equivalent scores on the total DRS summary score. HD patients performed worse on the Initiation subscale, whereas AD patients performed worse on the Memory subscale. Brandt et all compared HD and AD patients on the Mini-Mental State Examinati~n’~ (MMSE) items and showed that HD patients demonstrated greater impairment on serial sevens whereas AD patients were more impaired on memory tasks. Moreover, differences between groups on the MMSE remained at middle and severe stages of the diseases. zyx From the University of California at San Diego School of Medicine (Drs. Paulsen, Butters, Salmon, Swerdlow, and Swenson, and J.R. Sadek and S.A. Johnson), and the San Diego Department of Veterans Affairs Medical Center (Drs. Paulsen and Butters, and J.R. Sadek and S.A. Johnson), San Diego, CA. Supported by funds from the Medical Research Service of the Department of Veterans Affairs, the National Institute on Aging grant AG-05131, the National Institute of Mental Health grants MH49671-03, MH45131-06, and MH51200-01A1, the University of California at San Diego, and the National Alliance for Research on Schizophrenia and Depression. Received January 10, 1994. Accepted in final form October 25, 1994. zyxw Address correspondence and reprint requests to Dr. J a n e S. Paulsen, 9-116-A, Department of Psychiatry, UCSD School of Medicine, 3350 La Jolla Village Drive, San Diego, CA 92161. May 1995 NEUROLOGY 45 951 zyxwvutsrqpo zyxwvut zy Table 1. Demographic characteristics and Dementia Rating Scale (DRS) scores of the subject groups” zyxwvutsrqpo Age Education DRS Total 12.9 (2.3) 12.8 (2.1) 12.7 (2.9) 129.3 (3.6) 117.5 (4.2) 102.8 (8.5) 13.6 (4.0) 13.5 (3.7) 13.0 (3.5) 128.2 (4.8) 117.0 (2.9) 101.5 (7.3) Huntington’s disease Mild ject groups. There were no significant differences between the two dementia groups in terms of gender, education, or DRS total at every level of dementia seventy. As expected, the AD patients were significantly older than the HD patients irrespective of dementia severity. Procedures. The DRS13 was administered to individual subjects in a standardized manner by trained psychometricians as part of a larger neuropsychological examination. The DRS is a brief measure of cognitive status consisting of 36 common tasks constituting five subscales. The DRS was designed to assess general cognitive function even at lower levels of ability in which traditional assessment procedures typically are bound by floor effects. The DRS tasks are presented in a fured order, generally corresponding to Attention, Initiation, Construction, Conceptualization, and Memory subscales. All test items were administered to every patient in the present study. Because the five DRS subscales are scored on different metrics, all scores were converted to percent of maximum possible score. For example, if a patient earned a score of 24 on the Initiation subscale, his or her score would be 65% (24/37). These values were then averaged across AD and HD patients within each subsample. Moderate Severe 44.5 (13.2) 47.4 (12.6) 53.6 (12.1) Alzheimer’s disease Mild Moderate Severe 75.2 (5.8) 73.1 (7.5) 73.3 (9.2) * Means (SD). zyxw zyxwvutsrq The purpose of the current study is to evaluate whether the DRS, like the MMSE, is useful in differentiating patients with different degrees of dementia severity. Salmon et all2 evaluated patients in the middle stages of disease, but the usefulness of the DRS in the early and later stages of disease is unknown. Given that the DRS is more sensitive than the MMSE with increasing dementia severity,15the DRS may be more appropriate than the MMSE for characterizing dementia in later stages of disease. Methods. Subjects. A total of 120 subjects participated in this study: 60 patients with probable AD and 60 patients with HD. AD patients were participants in the National Alzheimer‘s Disease Research Center of the University of California at San Diego (UCSD). They were diagnosed by two senior staff neurologists according to the criteria for “primary degenerative dementia” in the DSM-III-RIGand by the criteria for “probable Alzheimer’s disease” developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association.17Extensive medical, laboratory, and neuropsychological testing was performed to rule out other possible causes of dementia. HD patients were participants in the Huntington’s Disease Clinical Research Program at UCSD. The diagnosis of HD was made by a senior staff neurologist on the basis of a combination of clinical symptoms of choreoathetosis and neuropsychological deficits, positive family history for the disease, evidence of reduced caudate volume from MRI studies (when available), and dementia according to DSMIII-R.lGThe Chorea scale of the Quantified Neurological Examinationla was performed with each subject to obtain a standardized documentation of clinical features of HD. Exclusion criteria for this study included other serious medical or psychiatric illness, substance abuse in the past year, and history of head trauma with loss of consciousness for greater than 20 minutes. All histories were verified with family members. The p a t i e n t s selected for t h e present s t u d y were matched in terms of their total DRS score on a one-to-one basis (within 2 points). Each patient group was then divided into three equal subsamples based on total DRS score. The “mild” subsample was defined as patients with a DRS total score between 138 and 123 (n = 40). The “moderate” subsample was defined as patients with a DRS total score between 122 and 111(n = 40). The “severe” subsample was defined as patients with a DRS total score between 110 and 80 (n = 40). Table 1 presents the demographic characteristics and total DRS scores for the sub- Results. Mean subscale comparisons. The mean DRS scores of the two patient groups were lower than the near-perfect performance typical of both middle-aged and elderly intact controls.13,19 A two (diagnostic group) by three (level of dementia) by five (DRS subscale) ANOVA revealed a significant three-way interaction (F = 2.79; p < 0.005). Similarly, the group-by-subscale interaction (F = 6.70; p < 0.001) and the level-by-subscale interaction (F = 45.12; p < 0.001) were significant, although-the group-by-level interaction (F = 1.22) was not significant. Two (diagnostic group) by five (DRS subscale) ANOVA conducted at each level of dementia seventy revealed significant group-by-subscale interaction effects at each dementia level (mild, F = 9.42, p < 0.0001; moderate, F = 37.13, p < 0.0001; severe, F = 11.12,p < 0.OOOl). Planned contrasts between HD and AD groups at the mild level of dementia revealed significant differences on two of the five subscales (figure 1). The HD patients performed worse than the AD patients on the Initiation subscale (t[381 = 2.98; p < 0.0061, and the AD patients performed worse than the HD patients on the Memory subscale (t[381 = 4.76; p < 0.0001). By Bonferroni corrections, the patient groups did not differ significantly on the Attention, Conceptualization, or Construction subscales. In the moderately impaired range of the DRS, there remained highly significant differences between HD and AD on the Initiation (t1381 = 6.56; p < 0.0001) and the Memory (ti381 = 7.55; p < 0.0001) subscales. In addition, the HD patients performed worse than the AD patients on the Construction subscale M381 = 3.2; p < 0.003). There were no significant differences between the groups on the Attention or Conceptualization subscales (figure 2). In the most severely impaired groups, there remained significant differences between HD and AD on the Memory (t1381 = 4.50; p < O.OOOl), Initiation (t[381 = 3.14; p < 0.003), and Ccnstruction (tI381 = zyxwvu zyxwvutsrqpo 962 NEUROLOGY 45 May 1995 zyxwvu z zyxwvutsrqp Figure 1. The mean percentage of the maximum possible score obtained on each subscale of the Mattis Dementia Rating Scale (DRS) by the mildly impaired patients with Huntingtonb disease (HD) and Alzheimer’s disease (AD). The asterisk (*) indicates significant differences between the groups (p < 0.01). Figure 3. The mean percentage of the maximum possible score obtained on each subscale of the Mattis Dementia Rating Scale (DRS) by the severely impaired patients with Huntington’s disease (HD) and Alzheimer’s disease (AD).The asterisk (*) indicates significant differences between the groups (p < 0.01). cific response to other items on the orientation task received a score of 219, or 22%. When assumptions of normality of distribution and homogeneity of variance among the groups were met, comparisons were made between each pair of groups by a priori orthogonal t tests. When assumptions were not met, groups were compared by the Mann-Whitney U test. At all levels of dementia severity, the AD patients were more impaired than the HD patients on the orientation and sentence recall tasks (allp’s c 0.001) of the Memory subscale. Differences between groups on the remaining memory tasks did not reach statistical significance. On the Initiation subscale, HD patients were significantly worse than the AD patients on the double alternating movements task at all levels of dementia severity (all p’s < 0.01). The HD patients were also significantly worse than the AD patients on the fluency for supermarket items task in the moderate stage of dementia (p c 0.01), but this difference was not significant at the mild or severe levels of dementia severity. Post-hoc analyses. To determine whether differences between groups on the Construction subscale of the DRS were due to abnormal involuntary movements in the HD group, we conducted a bivariate correlation between DRS total Construction subscale scores and the maximum Chorea scale total from the Quantified Neurological Examination.18 There was no significant relationship between Chorea scale and DRS Construction subscale performance. To further examine differences between groups on the Initiation subscale, performance on the fluency for supermarket items task was qualitatively anaRelyzed as suggested by previous investigators.20s21 sults demonstrated no significant differences on any qualitative fluency variable between HD and AD patients at the mild or severe levels of dementia severity. In contrast, the moderately impaired AD patient zy zyxwvutsrq zyxwvutsrq Figure 2. The mean percentage of the maximum possible score obtained on each subscale of the Mattis Dementia Rating Scale (DRS) by the moderately impaired patients with Huntington’s disease (HD) and Alzheimer$ disease (AD). The asterisk (*) indicates significant differences between the groups (p < 0.01). 2.89; p < 0.006) subscales. There were no significant differences in the Attention subscale, although the Conceptualization subscale approached significance ( p = 0.034) (figure 3). Mean item comparisons. The performances of the HD and AD patients on the individual items constituting the Initiation and Memory subscales were considered in terms of the percentage of the maximum possible score that could be achieved on each item. For example, a subject who produced eight items on the supermarket fluency task received a score of 8/20, or 40%. Similarly, a subject who produced the correct month and year but not the spe- zy zyxw May 1995 NEUROLOGY 45 953 zyxwvutsr zyxwvu Table 2. The Unstandardized Canonical Discriminant Function Coefficients, by level of dementia Subscale Coefficient HD versus AD (mild) Attention Memory Construction Conceptualization Constant -9.88 7.80 2.43 9.91 -8.21 HD versus AD (moderate) Memory Construction Conceptualization Constant 8.95 -2.56 4.97 -8.42 HD versus AD (severe) Attention Memory Construction Constant -4.46 5.71 -1.37 1.65 HD versus AD (all levels) Attention Memory Initiation Conceptualization Constant -3.16 5.39 -3.49 2.57 -0.60 HD Huntington’s disease. AD Alzheimer’s disease. entiate so-called cortical from subcortical dementias remain viable in the advanced stages in which neuropathologic changes are expected to cause diffuse and generalized cognitive impairment. That is, HD patients could be discriminated from AD patients with 93% accuracy in the mild and moderate stages of the disease process, and the discriminative utility of the DRS remained well above chance (75%) even in the most advanced stages of the diseases. HD and AD patients, who were precisely matched in terms of their total DRS scores, differed markedly in the pattern of cognitive impairment associated with these scores. The HD patients performed significantly poorer than the AD patients on the Initiation subscale, particularly on the alternating movement items. In contrast, the AD patients were significantly more impaired on the Memory subscale (particularly orientation and sentence recall) than were the HD patients. This differential pattern of performance is consistent with previous reports1J2 t h a t demonstrated greater impairment on the initiation and conceptual tracking tasks for HD patients and greater impairment on memory items for AD patients. These findings a r e consistent with t h e neuropathologic changes usually associated with early HD and AD. Given the prominent hippocampal pathology in ADll (and not in HD), that the Memory subscale is the most sensitive cognitive variable for the discrimination of early AD from HD is not surprising. Given the prominence of basal ganglia pathology in early HDs,9(and not in AD), t h a t deficits on a motor task such as alternating sequences are more distinctive in HD than in AD is also not surprising. The patterns of relatively spared and impaired cognitive abilities at different disease stages may also be consistent with the temporal progression of the neuropathologic changes of HD and AD. The neuronal loss in HD first involves the striatal enkephalid GABAergic neurons that innervate the external globus pallidus (GPe) and substantia nigra pars reticulata, and it is not until the more advanced stages of the illness that significant loss occurs in substance P/GABAergic striatal neurons projecting to the internal globus pallidus (GPi) and substantia nigra pars compacta.22One implication of these findings, as described elsewhereZ3 is that early striatal loss in HD primarily or exclusively involves elements of the “indirect” striatal efferent system, which links the striatum, GPe, and subthalamic nucleus, and that the “direct” striatal-GF’i-thalamic projection remains spared until late in the disease. Thus, deficits of initiation/ perseveration and perhaps even those of constructional praxis noted in this study in mild or moderately impaired HD patients may be temporally linked with dysfunction in the indirect striatal-GPe-subthalamic circuit. Alternatively, it is possible that the present measures are sufficiently sensitive to detect early damage in the direct substance P/GABAergic striatalGPi projection, prior to a point that can be detected by immunohistologic analysis of postmortem tissue. Consistent with this notion, loss of this direct output is zy zyxwvutsr group sampled a greater number of categories and produced more words per category sampled (all p’s < 0.01) than the moderately impaired HD patient group. Mean comparisons within dementia groups demonstrated that mildly impaired HD patients performed significantly better on all measures than moderately and severely impaired HD patients, who were not different from one another. In contrast, mildly and moderately impaired AD patients were not significantly different from each other but performed significantly better than the severely impaired group (allp’s < 0.01). Classification analyses. Linear discriminant function analyses were performed in order to determine if patients could be classified as HD or AD with equivalent sensitivity at the different levels of dementia severity (table 2). At every level of dementia severity, highly significant discriminant functions were obtained (allp’s < 0.001; canonical r’s = 0.64 to 0.87). Although the overall classification accuracy was 83% for the entire sample, classification accuracy ranged from 75% at the severe level of dementia (80% for HD and 70% for AD) to 93% at the moderate level of dementia (95% for HD and 90% for AD). Classification accuracy in the mildest group of patients was intermediate at 90% (90%for both groups). A more conservative jackknifed classification procedure performed equally well at all levels of dementia. Discussion. The results of the present study demonstrate that a 20-minute mental status examination can reliably differentiate subcortical from cortical dementia patients, even in later stages of the diseases. The distinct cognitive profiles that differ954 NEUROLOGY 45 May 1995 zyxwv associated with the appearance of bradykinesia and ridigity22and the deficits of initiation noted in the present sample. This pattern of cognitive and verbal correlates of impaired motor initiation in evolving bradykinesia is similar to that noted in patients with Parkinson's disease.24Damage to both the direct and indirect striatal projections, as well as damage reported in dorsolateral prefrontal cortex layers 111, v, and VI in advanced HD,25b26 may be responsible for the constructional deficits noted in the present study in the more severely impaired HD sample. Several recent studies suggest that the hippocampus and related structures are affected early in the course of AD, whereas the association cortices become increasingly involved with disease prog r e s ~ i o n . l ' , Based ~ ~ - ~ ~on these neuropathologic findings, we would expect memory tests to be most sensitive to early AD changes (eg, hippocampal dysfunction) and construction, language, and problemsolving tests to be more sensitive in later disease stages (ie, as the association cortices become more involved). Indeed, our findings show that Construction, Initiation, and Conceptualization DRS subscales worsen with AD progression, although the Memory subscale remains the most sensitive discriminator of cortical from subcortical dementia syndromes on this brief mental status examination. Thus, memory measures may continue to be the best way to discriminate so-called cortical dementia syndromes from other, more subcortical syndromes throughout the course of the d i s e a ~ e , ~whereas ',~~ other cognitive tests sensitive to cortical pathology (eg, semantic memory33or construction abilities) may be more sensitive to within-disease staging of AD over time. Several studies have described severe verbal fluThe ency impairments in both AD and HD.2,21,34-36 DRS supermarket fluency item did not provide equivalent discrimination between the HD and AD groups at all levels of dementia severity. Although verbal fluency tasks offered adequate discrimination between groups in the middle stages of disease progression, there were no significant differences between cortical and subcortical groups in the early and late stages of disease; this pattern remained when we analyzed qualitative data.20s21 Given that both AD and HD patients showed impairments in verbal fluency, some tasks can offer better discriminative utility when data are analyzed in a qualitative fashion as suggested by Monsch et aP6 or Chan et al.37These recent papers provide methods of evaluating the semantic network underlying verbal fluency performance. For instance, Monsch et a136suggested the most robust differentiation of AD and HD when using fluency tasks is provided by examining differential performances in semantic and phonemic fluency. Although AD patients demonstrated greater difficulty with semantic fluency tasks, HD patients demonstrated equivalent difficulty with semantic and phonemic fluency tasks. The impaired fluency performance of HD patients is considered secondary to primary retrieval and search strategy deficits, whereas the fluency impairments of AD patients may be due to the bottom-up deterioration of semantic k n ~ w l e d g e .It ~ ~should - ~ ~ be noted, however, that qualitative analyses of DRS fluency data in the current study did not clearly differentiate between the processes underlying the fluency deficits of HD and AD patients at all levels of dementia severity. The observed difference between HD and AD patients' performance on the Initiation subscale of the DRS was largely due to the HD patients' specific deficit in double alternating movements. These tasks require the patient to conduct repetitious motor sequences alternating between the right and left hands. HD patients' impairments on these tasks are consistent with recent studies demonstrating impairments on tasks that involve the programming of motor sequences. For instance, HD patients were unable to demonstrate normal learning on a pursuit rotor task38or a prism adaptation task39that were easily mastered by AD patients. Several investigators have interpreted these deficits as evidence that the corticostriatal system is critical for the acquisition and implementation of motor sequence^.^^,^^ In addition to differences between HD and AD patients on the Memory and Initiation subscales previously reported by Salmon et a1,12 the present findings demonstrated that these patient groups also differed in the Construction subscale of the DRS at moderate and severe levels of dementia. With disease progression, HD patients showed increased impairment on the copying of simple geometric line drawings. Previous research has demonstrated visuoperceptual and constructional impairments in both AD and HD patient^,^,^^ although the underlying mechanisms of the deficits may be different.42 AD patients' visuoconstructional errors were largely due to conceptual difficulties or a loss of the semantic associations evoked by the figural stimuli. In contrast, HD patients' performance was characterized by graphic deficits and planning problems in spatial layout. Given the differential impairment of HD and AD patients on the Construction subscale of the DRS, successful completion of the DRS items may rely more heavily on planning and graphic abilities compromised in the later stages of HD than on conceptual and semantic abilities compromised in AD. Moreover, both the current data and previous datax8 show that chorea severity is not associated with disease progression. In addition, chorea severity did not correlate with constructional impairment in our sample of HD. Thus, the differential construction impairment of moderately and severely impaired HD patients is probably not secondary to abnormal involuntary movements. Rather, our findings suggest that HD patients show greater evidence of constructional impairments due to planning deficits in middle and late stages of the disease. The discriminative power of brief mental status examinations has clinical relevance for late-stage patients when care facility staff and family members often treat patients in a uniform manner irrespective of diagnosis. In the later stages of many neurodegen- zyxwvutsrqp zyxwvuts zyxw May 1995 NEUROLOGY 45 955 erative illnesses (ie, HD, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis), motor agility, including expressive language, is commonly affected. This specific limitation in “initiation” limits interactions and can produce a perception of generalized “dementia” or loss of capability. 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Neurology 1995;45;951-956 DOI 10.1212/WNL.45.5.951 This information is current as of May 1, 1995 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/45/5/951.full.html Citations This article has been cited by 7 HighWire-hosted articles: http://www.neurology.org/content/45/5/951.full.html##otherarticles Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright Copyright 1995 by Advanstar Communications Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.