Cortical and subcortical diseases: Do true neuropsychological differences exist?

Archives of Clinical Neuropsychology 21 (2006) 29–40

Cortical and subcortical diseases: Do true neuropsychological differences exist?夽 Juan Carlos Arango-Lasprilla a,b,c,∗ , Heather Rogers d , Jean Lengenfelder a,b , John DeLuca a,b , Sonia Moreno c , Francisco Lopera c a

b

Neuropsychology and Neuroscience Laboratory, Kessler Medical Rehabilitation Research and Education Corporation, 300 Execute Drive, Suite 010 West Orange, NJ 07052, USA Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA c Neuroscience Group, University of Antioquia, Medell´ın, Colombia d Uniformed Services University of the Health Sciences, Bethesda, MD, USA Accepted 18 July 2005

Abstract Previous work examining the cortical-subcortical distinction as it relates to cognitive patterns has not typically used genetic confirmation to identify these groups, controlled for age, or used a comprehensive battery to assess specific cognitive abilities. The present study is the first to include only genetically confirmed Familial Alzheimer’s disease (FAD) and Huntington’s disease (HD) patients to evaluate this distinction. Ten patients with FAD, 11 patients with HD, and 17 matched healthy individuals were compared on a comprehensive neuropsychological battery that included tasks of language, memory, attention, visual-spatial, and executive function. The only neuropsychological measures to differentiate the two clinical groups were Animal Fluency and Letter Fluency; performance on all other measures did not differ. Although the neuropsychological battery adequately distinguished between clinical and healthy individuals, it was not useful to further differentiate the cortical or subcortical nature of the disease. FAD and HD appear to have similar neuropsychological profiles; therefore the cortical versus subcortical cognitive distinction may not be clinically meaningful. © 2005 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. Keywords: Alzheimer’s disease; Huntington’s disease; Cortical dementia; Subcortical disease

1. Introduction In the last few decades, researchers have studied the clinical, neuropsychological, neuropathological, neurochemical, and genetic characteristics of degenerating neurological diseases such as Alzheimer’s disease (AD), Pick’s disease, Creutzfeldt-Jacob’s disease, Huntington’s disease (HD) and Parkinson’s disease (PD). In clinical practice, the dementias that result from these diseases are often classified as either cortical or subcortical depending on the brain structures that have been found to be primarily involved in each of the specific disorders. For instance, AD, Pick’s disease, and 夽 The opinions and assertions contained herein are the private views of the authors and are not to be construed as being official or as reflecting the views of the Uniformed Services University of the Health Sciences or the Department of Defense. ∗ Corresponding author. Tel.: +1 973 530 3650; fax: +1 973 736 7880. E-mail address: [email protected] (J.C. Arango-Lasprilla).

0887-6177/$ – see front matter © 2005 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.acn.2005.07.004

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Creutzfeldt-Jacob’s disease are associated with abnormalities primarily in the hippocampus, cortex association areas, and medial temporal lobes (Herzog & Kemper, 1980; Hyman, Van Hoesen, Damasio, & Barnes, 1984). Researchers observed that people with these diseases develop a similar pattern of cognitive decline that mainly included deficits in language, learning, perception, calculation, and praxis (Arango-Lasprilla, Fern´andez, & Ardila, 2003; Tolosa & Alvarez, 1992). This grouping of neuropsychological characteristics became known as a cortical-type dementia. Extra-pyramidal disorders (such as HD, PD, and Supranuclear Palsy [PSP]), on the other hand, are associated with abnormalities in the basal ganglia, thalamus, and brainstem structures (Albert, Feldman, & Willis, 1974). It has been argued that persons with these disorders tend to have disturbances in motivation, mood, attention/concentration, cognitive processing speed, and executive function (Arango-Lasprilla, Iglesias, & Lopera 2003a, 2003b; Cummings & Benson, 1984; Cummings, 1986). This pattern of dysfunction became known as subcortical-type dementia (Cummings, 1993). To determine if this cortical-subcortical distinction is valid for cognitive patterns and useful in a clinical setting, some researchers have administered neuropsychological tests to patients with a prototypic cortical disease (i.e., AD) or a prototypic subcortical disease (i.e., HD). In one study, using a neuropsychological battery comprised of semantic and language measures (Boston Naming Test, Vocabulary, Similarities, Number Information Tests, Verbal Fluency) and episodic memory measures (Buschke-Fuld Selective Reminding Test, modified Visual Reproduction Test), differences in cognitive performance between the two groups emerged (Hodges, Salmon, & Butters, 1990). All subjects were tested initially and then 12 months later. Initially, AD patients displayed poorer performance for visual and verbal delayed recall while HD patients displayed poorer performance on category fluency, copying figures and vocabulary. When examined a year later, the AD patients demonstrated a more rapid decline on measures requiring semantic processing including naming, category fluency, number information, and similarities. In comparison, the HD patients demonstrated a more rapid decline on Letter Fluency. Memory performance was examined in AD, HD, as well as PD patients using the California Verbal Learning Test (Pillon, Deweer, Agid, & Dubois, 1993). While there was no difference in learning between the groups, AD patients demonstrated a greater number of intrusion errors. Additionally, the HD and PD groups had better cued recall and recognition compared to the AD group. A correlation between memory performance and executive functioning was reported for the HD and PD groups, but such a relationship was not evidenced for the AD patients. Patients with HD have also been found to demonstrate greater impairments on measures sensitive to frontal and executive functioning when compared to AD patients (Lange, Sahakian, Quinn, Marsden, & Robbins, 1995). When matched for severity of dementia, HD patients performed poorer on three measures sensitive to frontal lobe dysfunction: Tower of London, spatial working memory, and visual discrimination/attentional set shifting. AD and HD patients have also been compared using the Dementia Rating Scale (Mattis, 1988). Despite matching both groups with respect to their overall total dementia score, the AD patients demonstrated greater impairments on the memory subtest, whereas the HD patients demonstrated greater impairments on the initiation subtest (Salmon, Kwo-on-Yuen, Heindel, Butters, & Thal, 1989). Patterns of cognitive impairment have also been examined using the Mini-mental State Examination (Folstein, Folstein, & McHugh, 1975). Irrespective of degree of dementia, AD patients were more impaired on items assessing memory compared to the HD patients who had greater impairments in calculation (Brandt, Folstein, & Folstein, 1988). Other work has examined category and Letter Fluency in both AD and HD. AD patients were found to have differentially greater impairment on category fluency compared to letter impairment in contrast to the HD patients who demonstrated similar degree of impairment for both category and Letter Fluency (Monsch et al., 1994). The authors suggested that the difference in performance between the two groups was due to HD patient’s problems in initiation while the AD patients demonstrate breakdown in semantic processing. Problems in semantic processing have also been noted in the differential performance between AD and HD patients in naming (Hodges, Salmon, & Butters, 1991). When the two groups were compared on the Boston Naming Test, it was found that HD impairments in naming were primarily due to deficits in perceptual analysis of the items whereas AD patients were due to problems in semantic processing, particularly superordinate and semantic-associative errors. Some researchers have not found significant neuropsychological differences between groups (e.g., Brandt, Corwin, & Krafft, 1992; Barr & Brandt, 1996; Butters, Goldstein, Allen, & Shemansky, 1998; Claus & Mohr, 1996; Granholm & Butters, 1988; Mayeux, Stern, Rosen, & Benson, 1983; Rouleau, Salmon, Butters, Kennedy, & McGuire 1992). Brandt et al. (1992) compared HD and AD subjects on recall and recognition of a word list. The two groups were similar in their free recall performances and overall accuracy on the immediate recognition trial. Rouleau et al. (1992) compared

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performances of HD and AD subjects on the Clock Drawing Test and found that both groups were similarly impaired. Using a comprehensive neuropsychological battery (Halstead–Reitan Neuropsychological battery and the Wechsler Adult Intelligence Scale), Butters et al. (1998) investigated the validity and utility of the cortical and subcortical distinction in three groups of patients (AD, HD, and multiple sclerosis). The AD and HD groups did not differ in their performance on the two batteries. Given the mixed results of previous studies evaluating the cortical-subcortical distinction for cognitive patterns, four specific methodological limitations of the prior works will be addressed in the present study. First, many of the previous studies with HD may have included a heterogeneous sample of patients not restricted to HD. Because many of the subcortical–cortical studies were conducted before the genetic mutation for HD was discovered in 1993 (e.g., Granholm & Butters, 1988; Pillon, Dubois, Ploska, & Agid, 1991; Massman, Delis, Butters, Dupont, & Gillin, 1992; Troster, Jacobs, Butters, Cullum, & Salmon, 1989), patients with prototypical subcortical disease were diagnosed with HD based on their clinical characteristic, not a genetic confirmation. Consequently, other individuals with movement disorders but not HD may have been included in this subcortical disease group. The potential heterogeneous nature of this HD group may potentially explain the conflicting findings of earlier studies. It is now possible to extract and analyze the DNA of the subjects recruited for a study on this distinction. In the present study, we compared a subcortical disease group of individuals diagnosed with HD who also possessed the genetic confirmation of the disease with a cortical disease group so that any true differences between groups can emerge. Secondly, previous studies have not included AD patients with genetic confirmation. Traditionally, researchers have studied subjects with prototypical cortical dementia who had dementia of the Alzheimer’s type due to sporadic AD. Because AD can only be definitively diagnosed through autopsy, there is no guarantee that all subjects have AD. In fact, they could possibly have had a different type of dementia altogether. In the last 10 years, advancements in molecular genetics have made it possible to identify genetic markers of AD. It is now known that people with specific autosomal dominant genetic mutations will develop a familial form of AD. Although Familial Alzheimer’s disease (FAD) accounts for less than 5% of total cases of AD and has an earlier age of onset compared to sporadic AD (usually between 40 and 60 years of age), research has shown that the neuropsychological profiles of both types of AD are the same (Arango-Lasprilla, Fern´andaz, & Ardila, et al., 2003; Arango-Lasprilla, Iglesias, et al., 2003a, 2003b; Arango-Lasprilla, Iglesias, Moreno, & Lopera, 2003; Lopera, Pineda, Morena, Durango, Garc´ıa, et al., 1997; Roselli et al., 2000), thus FAD patients can be studied to shed light on the cortical-subcortical cognitive distinction. In the present study, our cortical disease group also possessed the genetic confirmation of their disease (Familial Alzheimer’s disease), thus permitting a direct comparison between two different genetically-verified diseased groups. Third, most of the previous studies have not controlled for age differences in the different dementia groups. Because sporadic AD symptom onset generally occurs after age 65 and individuals with subcortical diseases have decreased longevity, the groups have tended to differ in age by 15–20 years (e.g., Troster et al., 1989a, 1989b). None of the published studies identified in the literature controlled for age methodologically, and very few have controlled for age in the statistical analysis. In the present study, we sampled from a population of individuals with early-onset FAD. These individuals’ young ages allowed us to compare a subcortical disease group of subjects of similar ages, unlike the previous studies. Lastly, some of the previous studies that have examined the cortical-subcortical distinction of cognitive patterns have used neuropsychological tests that evaluate only one area of cognitive functioning (language, memory, or attention, etc.). These studies have confirmed the cortical-subcortical group differences. However, Butters et al. (1998) did use a comprehensive neuropsychological battery and did not find such differences. To address the limitation of not assessing multiple domains of cognitive functioning, in the present study a comprehensive neuropsychological battery that included tasks of language, memory, attention, visual-spatial, and executive function was administered. Given the significant inconsistencies in the literature surrounding this cortical–subcortical distinction of cognitive patterns, the present study attempts to address some of the limitations of previous research. We hope to shed light on this distinction by comparing a cortical pattern of cognitive deficits of a group of individuals with a genetic mutation for Familial Alzheimer’s disease (Arango-Lasprilla, Iglesias, et al., 2003a, 2003b; Arango-Lasprilla, Iglesias, et al., 2003) and a subcortical pattern of deficits of a group of individuals with genetically-confirmed HD (Arango-Lasprilla, Iglesias, et al., 2003). Therefore, the present work has two objectives: (a) to compare two groups with different types of familial genetic disease (either FAD or HD) versus healthy controls using a neuropsychological battery that includes tasks of language, memory, attention, visual-spatial, and executive function, and (b) to compare the pattern cognitive abilities of subjects

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with FAD versus those with HD using the same battery in order to evaluate the validity and utility of a cortical–subcortical distinction of quantitative neuropsychological deficits. 2. Methods 2.1. Participants All individuals were Spanish speakers of Hispanic origin from Antioquia, Colombia, South America. Three groups of individuals from three different populations were studied: 10 patients with FAD, 11 patients with HD, and 17 matched healthy individuals. The FAD and HD groups were comprised of individuals from different families reported by Lopera and colleagues whose genetic, clinical and neuropsychological characteristics have been described elsewhere (see Arango-Lasprilla, Fern´andes, et al. 2003; Arango-Lasprilla, Iglesias, et al., 2003a, 2003b; Arango-Lasprilla, Iglesias, et al., 2003; Lopera et al., 1997; Lopera, Pineda, Moreno, Durango, Garc´ıa, Carvajal, et al., 1999). The diagnosis of FAD was made by one neurologist using DSM-IV (APA, 1994) criteria for AD dementia, a neurological examination,and an interview with each individual’s family member. All individuals in the FAD group were carriers of mutation E280A in the preseniline 1 gene. All individuals in the HD group had a medical and genetic diagnosis of HD, a documented positive family history, and presence of choreiform movements. The third group was comprised of healthy individuals who: (a) did not meet the DSM-IV diagnostic criteria for dementia, (b) did not have specific cognitive problems that affected work, social or family life, (c) did not have a history of neurological or psychiatric disorders, and (d) were non-affected family members, and therefore had similar socio-cultural backgrounds as the clinical groups. All the FAD and HD individuals were right-handed, as were 15 of the 17 healthy controls. The mean age at the time of the evaluation was 53.60 ± 7.62 years for the FAD group, 52.45 ± 11.79 years for the HD group, and 49.06 ± 2.63 for the healthy control (HC) group. There was no significant difference in age among the three groups (H = 3.18, p = 0.203). Educational level, as measured by number of years of formal schooling, was low in each of the three groups (FAD = 3.80 ± 3.15, HD = 4.82 ± 1.72, and HC = 4.12 ± 2.03) and there was no significant difference (H = 1.98, p = 0.371). 2.2. Instruments Each individual was administered a battery of neuropsychological tests. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) evaluation battery (Morris et al., 1989) was administered in its entirety, along with additional neuropsychological tests. The version of the CERAD used in this study was a Spanish version that was adapted for the cultural and linguistic characteristics specific to this population. The CERAD battery includes the following measures: 1. Semantic Fluency (Animal Naming): Individuals are requested to name as many animals as they can in 1 min. The dependent variable is the number of unique animals named. 2. Modified Boston Naming Test: This test consists in asking individuals to identify 15 line drawings of increasing complexity (high, medium and low frequency), with a maximum of 10 s for each drawing. One point is awarded for each correct response, giving a total possible score of 15 points. The dependent variable is the total number of correct namings. 3. Mini-mental State: A modified version of the Folstein’s Minimental State Test (Folstein et al., 1975) was used. We excluded the spelling backward subtest because one ability involved in this task (spelling) is not a common skill for Spanish-speaking people. Instead, we replaced it with subtraction by threes, which is more appropriate for this population. The total score of this test was 30 points. The dependent variable was the total number of correct points. 4. Word List Memory: This test assesses the ability to recall newly learned information. Individuals are presented 10 printed words on a card at the rate of one every 2 s. They are immediately asked to recall as many words as possible from the list. This procedure is repeated in three consecutive trials. Maximum number of correct words is 30 for the three trials. The number of correct words identified serves as the dependent variable. 5. Constructional Praxis: Individuals are presented with four line drawings of figures of increasing complexity, one a time, and asked to copy them. Maximum time allowed for copying each figure (circle, rhombus, pentagon and

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cube) is 2 min. Reproductions are scored according to predetermined criteria and the dependent measure is the total score for the four drawings. 6. Word List Recall: This test assesses delayed memory by requesting that the individual recall the list of ten words presented in the Word List Memory task. Maximum time allowed for this recall is 90 s, and 1 point is awarded for each word recalled correctly, with a maximum of 10 points if all the words are recalled. 7. Word List Recognition: This test consists of recognition of the 10 words from the Word List Memory task, presented in a list of 20 words (including 10 additional distractor words). A forced-choice paradigm is used, so that subjects must respond with YES to the words they consider correct (i.e., in the list of words previously read), and NO to the words that were not on that list. One point is awarded for each word correctly recognized. To adjust for chance, the subject’s score is calculated as the total number of correct answers minus 10; if the result is less than 0, a score of 0 is given. 8. Line-Drawing Recall: Individuals are asked to recall the drawings they copied previously and draw them from free recall on a blank sheet of paper. This tests serves to assess visual memory. In addition to the CERAD battery evaluation, the following neuropsychological tests were also administered: 1. Visual “A” Cancellation Test: Individuals are asked to mark, as quickly as possible, all the letter A’s in a series of random letters on a piece of paper. The dependent variables are the number of A’s found and the number of A’s omitted (Ardila, Roselli, & Puente, 1994). 2. The Rey–Osterrieth Complex Figure: Individuals are presented with the complex design card showing a figure that containing 18 elements and asked to copy the figure on blank sheet of white paper. When they finish, the examiner takes away the figure and asks them to reproduce it from memory. It measures memory as well as visual-motor organization (Rey, 1987). Table 1 Overall comparison of neuropsychological variables for FAD, HD, and HC Measure

FAD (mean ± S.D.)

HD (mean ± S.D.)

HC (mean ± S.D.)

Kruskal–Wallis Test H

P

19.80 10.40 6.10 9.60

± ± ± ±

1.32 3.63 4.56 2.99

21.18 6.64 2.40 8.09

± ± ± ±

2.96 2.84 2.41 2.12

28.59 15.59 7.76 12.53

± ± ± ±

1.97 3.12 2.93 1.66

26.98 20.90 15.96 17.10

0.000 0.000 0.000 0.000

Memory Recall Intrusions Delay recall Delay intrusions Recognition

7.90 2.70 1.80 0.80 5.20

± ± ± ± ±

2.51 3.40 1.23 0.15 2.93

7.73 2.45 2.64 0.45 4.00

± ± ± ± ±

4.29 4.01 1.63 0.70 3.52

15.71 1.18 5.88 0.47 9.70

± ± ± ± ±

3.02 1.29 1.22 0.72 0.58

22.29 1.60 26.96 0.000 24.44

0.000 0.448 0.000 1.00 0.000

Praxias Copy Recall

6.50 ± 2.68 2.40 ± 2.37

4.4.5 ± 4.06 1.64 ± 2.66

9.18 ± 1.29 7.06 ± 3.07

12.60 18.00

0.002 0.000

TMT A Correct Errors Time

14.33 ± 10.48 7. 56 ± 8.99 104.85 ± 61.05

20.43 ± 8.16 3.57 ± 8.16 215.57 ± 43.73

23.31 ± 2.75 0.69 ± 2.75 58.00 ± 23.49

8.98 9.83 15.27

0.011 0.007 0.000

Cancellation A Correct Omissions

10.71 ± 4.27 5.29 ± 4.27

7.90 ± 4.93 8.10 ± 4.93

14.44 ± 1.71 1.56 ± 1.71

12.51 12.51

0.002 0.002

Rey Figure Copy Recall Reading of words

7.44 ± 7.85 2.94 ± 7.26 10.00 ± 0. 00

4.95 ± 5.50 1.18 ± 1.45 9.09 ± 3.02

22.85 ± 7.20 9.44 ± 5.20 10.00 ± 0.00

22.50 16.64 2.45

0.000 0.000 0.293

MMSE Animal Fluency Letter Fluency Naming

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3. Letter Fluency: This tests asks individuals to generate as many words as possible beginning with the letter F, excluding proper names or derivatives (diminutives, etc.), in 1 min. The dependent variable is the total number of correct words in one minute (Ardila et al., 1994). 4. Trail Making Test (Part A): Individuals have to connect circles in ascending order (1 trough 25) as quickly as possible. The dependent variables are the number of correct connections, the number of errors, and the total time needed to complete the test. 2.3. Procedure All participants provided consent for participation, in accordance with the protocol of informed consent approved by the ethics committee of the University of Antioquia’s Medical School (in Medell´ın, Colombia). For those individuals diagnosed with dementia, a close family member (spouse or adult) also gave informed consent. Each participant was then administered the CERAD battery (Morris et al., 1989) followed by the additional neuropsychological tests. Each entire evaluation was administered by the same neuropsychologist in one 90-min session. 2.4. Data analyses The neuropsychological data were analyzed using the statistical package SPSS version 10.0. All three groups were compared using the Kruskal–Wallis Test in order to determine the variables yielding overall differences among groups. Non-parametric statistics were chosen because of the small sample sizes and large variances within groups. All dependent measures significant at the p < 0.05 level were further analyzed using the Mann–Whitney U for independent samples (FAD versus HC, HD versus HC, and FAD versus HD) with alpha set at 0.05.

Table 2 Comparison of neuropsychological variables for FAD and HD vs. HC Mann–Whitney U-Test FAD vs. HC

Mann–Whitney U-Test HD vs. HC

U

P

U

P

Minimental State Fluency (Animals) Letter Fluency Naming

0.000 23.00 47.50 36.50

0.000 0.002 0.058 0.014

4.500 3.500 12.00 7.000

0.000 0.000 0.000 0.000

Memory Recall Delay recall Recognition

2.500 0.000 13.00

0.000 0.000 0.000

15.50 6.000 3.500

0.001 0.000 0.000

Praxias Copy Recall

35.00 20.50

0.011 0.001

27.50 17.00

0.002 0.000

TMT A Correct Errors Time

18.00 28.50 19.00

0.003 0.002 0.004

36.00 36.00 2.500

0.043 0.043 0.000

Cancellation A Correct Omissions

22.00 22.00

0.021 0.21

19.50 19.50

0.001 0.001

Rey Figure Copy Recall

11.50 24.50

0.000 0.005

4.500 14.00

0.000 0.000

Measure

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3. Results 3.1. Neuropsychological measures The results of the neuropsychological test comparisons among the three groups are provided in Table 1. The three groups (FAD, HD, and HC) differed with respect to most of the neuropsychological variables, except intrusions (H = 1.60, p = 0.448), delay intrusions (H = .000, p = 1.00), and reading of words (H = 2.45, p = 0.29). Each of the two clinical groups (FAD and HD) were then individually compared to the healthy individuals (HC) using the Mann–Whitney U-Test (see Table 2). The FAD group had significantly poorer performance than the HC on all of the neuropsychological variables except Letter Fluency, which, although not statistically significant, indicated a trend towards significance (U = 47.50, p = 0.06). The HD group demonstrated significantly poorer performance than the HC on all of the neuropsychological variables. Finally, the FAD and HD groups were directly compared using the Mann–Whitney U-Test (see Table 3). These two groups performed similarly on all neuropsychological measures except for significant differences in Animal Fluency (U = 22.50, p = 0.021) and Letter Fluency (U = 16.50, p = 0.010). One key neuropsychological variable in determining the cortical and subcortical distinction is retrieval failure. Specifically, retrieval failure has been found to be a defining cognitive deficit in subcortical diseases (Cummings & Benson, 1984). To examine this concept in the present data set, a post-hoc comparison between the FAD and HD groups was conducted to specifically examine whether retrieval failure could be observed in the HD group relative to the FAD group. Retrieval was assessed using a savings score on the CERAD Word List Memory Test. The savings score was defined per subject as delayed recall divided by immediate recall × 100. This analysis resulted in no significant difference in savings between the FAD group and the HD group (19.8% versus 35.2%, U = 35.0, p = 0.16).

Table 3 Comparison of neuropsychological variables for FAD vs. HD Measure

Mann–Whitney U-Test FAD vs. HD U

P

MMSE Fluency (Animals) Letter Fluency Naming

38.00 22.50 16.50 44.00

0.227 0.021 0.010 0.428

Memory Recall Delay recall Recognition

49.50 36.00 43.00

0.687 0.169 0.393

Praxias Copy Recall

38.00 40.50

0.227 0.279

TMT A Correct Errors Time

14.50 21.50 29.50

0.328 0.268 0.831

Cancellation A Correct Omissions

23.50 23.50

0.258 0.258

Rey Figure Copy Recall

42.00 22.50

0.400 0.532

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4. Discussion There are inconsistent findings in the literature regarding the validity of the cortical–subcortical cognitive distinction. Methodological issues, in part, may be responsible for some of these inconsistencies. Many of the previous studies examining this distinction have not used genetic confirmation to identify these groups, have not controlled for differences in age, or used a comprehensive neuropsychological battery to assess cognitive abilities. The present study has addressed some of the methodological limitations of past work by (a) using a comprehensive neuropsychological evaluation battery that covers a wide range of cognitive abilities (including memory, language, attention, praxis, and executive functions), (b) including individuals with genetically-confirmed HD, (c) including individuals with Familial Alzheimer’s disease instead of the sporadic form of the disease, thus obtaining a younger sample more similar to the HD group’s ages, (d) selecting samples of similar educational levels, and (e) comparing groups whose genetic, clinical, and neuropsychological characteristics have been previously identified and published. Because the FAD and HD groups had similar results in almost all areas of cognitive functioning, the results of the present study do not support the existence of a “typical” cortical or subcortical neuropsychological profile as has been purported by the literature. In fact, the data shown in Table 3 comparing the FAD and HD groups suggest a number of similarities in cognitive performance on this comprehensive battery of tests. In addition, the present results do not provide support for retrieval failure in the subcortical group as a key distinctive feature between cortical and subcortical diseases. Other studies have failed to demonstrate quantitative differences in cognitive functioning between individuals with cortical and subcortical diseases. For example, many studies have examined general cognitive abilities (Mayeux et al., 1983), verbal fluency (Epker Lacritz & Cullum, 1999), memory of words (Granholm & Butters, 1988), intelligence (Butters et al., 1998), visuo-constructive capacity (Rouleau et al., 1992), and attention (Claus & Mohr, 1996) and reported no significant differences between groups. Taken together, the data from the present study as well as several published reports seriously question the construct validity of the cortical and subcortical cognitive distinction. A closer look at the results reveals that only the two measures of verbal fluency were able to successfully differentiate the FAD group and the HD group. Specifically, the HD group scored lower than the FAD group on both the letter and categorical fluency tasks. The finding of poorer performance on Letter Fluency by the HD groups concurs with results from others studying these populations (e.g., Hodges et al., 1990; Monsch et al., 1994) and may be explained by the neuropathological differences that underlie each disease. Fluency tasks are commonly used to differentiate cognitive patterns of cortical and subcortical deficits in dementia patients. In particular, the phonological (letter) verbal fluency test is typically administered as a measure of executive functioning, as it is implicated in initiation/retrieval processes and has been found to be sensitive to left prefrontal cortex dysfunction (Pendleton, Heaton, Lehman, & Hulihan, 1982). The prefrontal cortex has reciprocal connections with subcortical structures. It is thought that those with HD may score low on this test because the fronto-subcortical nature of their disease decreases their ability to initiate/retrieve words (Cummings, 1993). The frontal lobes of AD patients, on the other hand, remain intact until the moderate and severe stages of the illness, thus they are able to retrieve words and therefore perform better than those with HD on this task (Braak & Braak, 1996). The semantic (categorical) fluency task is often used by neuropsychologists to index the integrity of the structure of semantic knowledge. The temporal neocortex has been postulated to be the anatomical substrate of semantic knowledge (Martin & Fedio, 1983; Randolph, Braun, Goldberg & Chase, 1993) and AD is characterized by neuropathologcal alterations of the temporal lobe. This hypothesis predicts that those with AD would show a corresponding deficit in semantic fluency and perform worse than those with HD on this task. Previous studies with these populations have confirmed this prediction (e.g. Monsch et al., 1994). However, the results of this study show exactly the opposite: the AD group scored better than the HD group on both types of fluency tests. The neuropsychological battery used in the present study does not permit a clear conclusion as to why the HD group performed significantly worse than the AD group on the semantic fluency tasks. It is possible that the AD patients had initation and retrieval difficulties in addition to deficits in semantic knowledge and that the HD patients had deficits in sematic knowledge beyond their initiation and retrieval difficulties. Another possiblity is that level of education influenced the results. Future studies of these two groups examining semantic knoweldge and executive function are warrented in order to understand the nature of the deficits observed in this study and clarify the pattern of cognitive differences between these diseases. Some researchers (i.e., Rouleau et al., 1992) suggest that although quantitative difference may not exist, there may be qualitative variations in task completion that differ between AD and HD groups that do not become apparent by simply analyzing their reported scores and group means. Although the Alzheimer’s and Huntington’s groups showed

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impairment, the neuropsychological processes affected at a qualitative level in each group of subjects are likely to be different (Hodges et al., 1991). Future research should address such qualitative issues and underlying deficits because this may be the only way to provide the neuropsychological evidence to support a cortical–subcortical cognitive distinction. From a neuroanatomical/neuropathological perspective, the distinction between cortical and subcortical disease is not always clear either. In some cases, a person with cortical dementia (i.e., AD) may also have abnormalities in their subcortical structures and vice versa (Boller, Mizutani, Roessmann, & Gambetti, 1980; Braak, Del Tredici, Rud, & de Vos, 2003; Bruyn, Bots, & Dom, 1979; Hakim, & Mathieson, 1979; Kassubek et al., 2004; Macdonald & Halliday, 2002; Mazurek, Garside, & Beal, 1997). Studies of individuals with AD have found additional subcortical structure abnormalities in the thalamus, the amygdala, nucleus basalis of Meynert (Herzog, & Kemper, 1980; McDuff & Sumi, 1985; Whitehouse, Price, Clark, Coyle, & DeLong, 1981; Whitehouse et al., 1982) and especially the substantia innominata, the locus ceruleus and raphe nuclei (Bondareff, Mountjoy, & Roth, 1982). Meanwhile, studies of individuals with HD have found additional cortical structure abnormalities, including changes to the hippocampus and loss of pyramidal neurons in the angular gyrus and frontal lobe (Aylward et al., 1998; Macdonald Halliday, Trent, & McCusker, 1997; Spargo, Everall, & Lantos, 1993). PD, like HD, is also classified as a subcortical disease. Between 18 and 25% of people with AD manifest pathological changes and clinical characteristics typically associated with PD (Adams & Victor, 1989). Other studies have found that individuals with HD and PD have neuropathological and neurochemical alterations typically associated with AD, e.g., senile plaques, neurofibrillary tangles, tau pathology changes (Bruyn & Roos, 1990; Jackson et al., 1995; Jellinger, 1998; McIntosh Jameson, & Markesbery, 1978; Whitehouse et al., 1986). Taken together, these disparate results suggest a controversy regarding the existence of “true” cortical and subcortical disorders from a neuroanatomical/neuropathological perspective. The FAD, HD, and HC group all had similar ages and educational levels, yet, there were significant differences among them on all of the neuropsychological test variables in the comprehensive battery except intrusions, delay intrusions, and reading of words. It is not surprising that reading of words performance was similar for these particular groups of individuals. Those with FAD have been reported to conserve their capacity to read aloud (Pe˜na, 1999), even when their understanding of language maybe compromised (Chui, 1989; Cummings Houlihan, & Hill, 1986; Huppert & Tym, 1986; Gonzalez, Del Ser Quijano, & Bermejo, 1990). Those with HD do not normally manifest reading problems either, and any difficulties in this area are typically secondary to other deficits such as dysarthria or disruption of perceptual analysis, which are common in advanced stages of the disease (Podoll, Caspary, Lange, & Noth, 1988). However, the findings of similar performance among groups on the intrusions and delay intrusions measures of the memory test contradict Jacobs, Salmon, Troster, and Butters (1990) findings after evaluating the memory capacities of these same groups. The type of test used to evaluate this cognitive domain may be one possible explanation for this discrepancy. In the present study, a verbal memory test was used, while Jacobs and colleagues (1990) administered a figural memory test. This inconsistent performance may depend on the type of stimulus, and, although intrusion errors do not seem to represent a general characteristic of these individuals’ memories, further research to replicate and explain these differences (if they exist) is warranted. When FAD and HD groups were individually compared to the healthy individuals, the results verify that the FAD and HD groups in the present study did indeed have neuropsychological alterations in language, memory, attention, praxis, information processing speed, and executive function consistent with those shown in previous literature (Brandt & Butters, 1986; Brantjes & Bouma, 1991; Daum, Riesch, Sartori, & Birbaumer, 1996; Rosser & Hodges, 1994; Zakzanis, 1998). The present study also has a number of limitations that should be addressed in future research. For example, larger sample sizes would have increased the robustness of the findings, qualitative evaluation of the individuals’ cognitive performances would have shed light on potential differences between groups that escape quantitative analysis, and additional tests that measure executive function would have provided more conclusive results as to the quantitative differences between subjects with AD and HD in this specific area of cognitive function. Because individuals in this study had a low educational level, the findings of this study might have limited generalizability to those who are more educated. It should be recognized that the low educational levels of participants in this study is indeed representative of the dementia population in Colombia. Finally, because FAD represents a small subset of AD, the results of the current study may not be able to be generalized to the larger AD population. However, prior studies have found that the cognitive profile in AD is the same that FAD (Arango-Lasprilla, Iglesias, et al., 2003a; Lopera et al., 1997; Roselli et al., 2000), suggesting fairly strong external validity in this case.

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In conclusion, although the comprehensive neuropsychological battery adequately distinguished between those individuals with a dementia/disease and those without (the healthy controls), it was not useful to further differentiate the particular cortical or subcortical cognitive pattern of an individual’s disease. The quantitative results of the present study suggest that people with FAD and HD have similar neuropsychological profiles. The cortical versus subcortical cognitive distinction may not be clinically meaningful in light of the current evidence. More research with these groups is needed, especially in the area of executive functioning, in order to correctly identify the neuropsychological strengths and weaknesses of each person (regardless of his/her disease) so that effective rehabilitation plans can be designed and implemented. Acknowledgment This research was supported by CODI, 2005–2006 sustainability program to the Neuroscience Group, University of Antioquia, Medellin, Colombia. References Adams, R. D., & Victor, M. (1989). Principles of neurology (4th ed.). New York: McGraw Hill. Albert, M. L., Feldman, R. G., & Willis, A. L. (1974). The “subcortical dementia” of progressive supranuclear palsy. Journal of Neurology, Neurosurgery, and Psychiatrydkjdot, 37, 121–130. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Arango-Lasprilla, J. C., Fern´andez, S., & Ardila, A. (2003). La enfermedad de Alzheimer. In J. C. Arango Lasprilla, S. Fern´andez, & A. Ardila (Eds.), Las demencias: Aspectos cl´ınicos, neuropsicol´ogicos y tratamiento (pp. 191–208). D.F. Mexico: Manual Moderno. Arango-Lasprilla, J. C., Iglesias, J., & Lopera, F. (2003). Caracter´ısticas cl´ınicas y neuropsicol´ogicas de la enfermedad de Huntington: Una revisi´on. Revista de Neurolog´ıa. 37, 758–765. Arango-Lasprilla, J. C., Iglesias, J., & Lopera, F. (2003). Neuropsychological study of familial Alzheimer’s disease caused by mutation E280A in the presenilin 1 gene. American Journal of Alzheimer’s Disease and Other Dementias, 18, 137–146. Arango-Lasprilla, J. C., Iglesias, J., Moreno, S., & Lopera, F. (2003). Estudio neuropsicol´ogico de la enfermedad de Huntington en familias de Antioquia-Colombia. Revista de Neurolog´ıa, 37, 7–13. Ardila, A., Roselli, M., & Puente, A. (1994). Neuropsychological. Evaluation of the Spanish Speaker. New York: Plenum Press. Aylward, E. H., Anderson, N. B., Bylsma, F. W., Wagster, M. V., Barta, P. E., Sherr, M., et al. (1998). Frontal lobe volume in patients with Huntington’s disease. Neurology, 50, 252–258. Barr, A., & Brandt, J. (1996). Word list generation deficits in dementia. Journal of Clinical and Experimental Neuropsychology, 6, 810– 822. Boller, F., Mizutani, T., Roessmann, U., & Gambetti, P. (1980). Parkinson disease, dementia, and Alzheimer disease: Clinicopathological correlations. Annals of Neurology, 7, 329–335. Bondareff, W., Mountjoy, C. A., & Roth, M. (1982). Loss of neurons of origin of adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology, 32, 164–168. Braak, H., & Braak, E. (1996). Evolution of the neuropathology of Alzheimer’s disease. Acta Neurologica Scandinavia, 165, 3–12. Braak, H., Del Tredici, K., Rub, U., de Vos, R. A., Jansen Steur, E. N., & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 24, 197–211. Brandt, J., & Butters, N. (1986). The neuropsychology of Huntington’s disease. Trends in Neuroscience, 9, 118–120. Brandt, J., Corwin, J., & Krafft, L. (1992). Is verbal recognition memory really different in Huntington’s and Alzheimer’s disease? Journal of Clinical and Experimental Neuropsychology, 14, 773–784. Brandt, J., Folstein, S. E., & Folstein, M. F. (1988). Differential cognitive impairment in Alzheimer’s disease and Huntington’s disease. Annals of Neurology, 23, 555–561. Brantjes, M., & Bouma, A. (1991). Qualitative analysis of the drawings of Alzheimer patients. Clinical Neuropsychology, 5, 41–52. Bruyn, G. W., Bots, G., & Dom, R. (1979). Huntington’s chorea: Current neuropathological status. Advances in Neurology, 23, 83–93. Bruyn, G. W., & Roos, R. A. (1990). Senile plaques in Huntington’s disease: A preliminary report. Clinical Neurology and Neurosurgery, 92, 329–331. Butters, M. A., Goldstein, G., Allen, D. N., & Shemansky, W. J. (1998). Neuropsychological similarities and differences among Huntington’s disease, multiple sclerosis, and cortical dementia. Archives of Clinical Neuropsychology, 13, 721–735. Chui, H. (1989). Dementia: A review emphasizing clinicopathologic correlation and brain-behavior relationships. Archives of Neurology, 46, 806–814. Claus, J. J., & Mohr, E. (1996). Attentional deficits in Alzheimer’s, Parkinson’s, and Huntington’s disease. Acta Neurologica Scandinavia, 93, 346–351. Cummings, J. L. (1986). Subcortical dementia: Neuropsychology, neuropsychiatry, and pathophysiology. British Journal of Psychiatry, 149, 682–697. Cummings, J. L. (1993). Frontal-subcortical circuits and human behavior. Archives of Neurology, 50, 873–880. Cummings, J. L., & Benson, D. F. (1984). Subcortical dementia: Review of an emerging concept. Archives of Neurology, 41, 874–879.

J.C. Arango-Lasprilla et al. / Archives of Clinical Neuropsychology 21 (2006) 29–40

39

Cummings, J. L., Houlihan, J., & Hill, M. (1986). The pattern of reading deterioration in dementia of the Alzheimer type: Observation and implications. Brain and Language, 29, 315–323. Daum, I., Riesch, G., Sartori, G., & Birbaumer, N. (1996). Semantic memory impairment in Alzheimer’s disease. Journal of Clinical and Experimental Neuropsychology, 18, 648–665. Epker, M., Lacritz, L., & Cullum, M. (1999). Comparative analysis of qualitative verbal fluency perfomance in normal elderly and demented populations. Journal of Clinical and Experimental Neuropsychology, 21, 425–434. Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189–198. Gonzalez, J., Del Ser Quijano, T., & Bermejo, F. (1990). Demencia: Lenguaje e inteligencia previa. Archivos de Neurobiolog´ıa, 53, 163–170. Granholm, E., & Butters, N. (1988). Associative encoding and retrieval in Alzheimer’s and Huntington’s disease. Brain Cognition, 7, 335–347. Hakim, A. M., & Mathieson, G. (1979). Dementia in Parkinson disease: A neuropathologic study. Neurology, 29, 1209–1214. Herzog, A. G., & Kemper, T. L. (1980). Amygdaloid changes in aging and dementia. Archives of Neurology, 37, 625–629. Hodges, J. R., Salmon, D. P., & Butters, N. (1990). Differential impairment of semantic and episodic memory in Alzheimer’s and Huntington’s diseases: A controlled prospective study. Journal of Neurology, Neurosurgery, and Psychiatry, 53, 1089–1095. Hodges, J. R., Salmon, D. P., & Butters, N. (1991). The nature of the naming deficit in Alzheimer’s and Huntington’s disease. Brain, 114, 1547–1558. Huppert, F., & Tym, E. (1986). Clinical and neuropsychological assessment of dementia. British Medical Bulletin, 42, 11–18. Hyman, B. T., Van Hoesen, G. W., Damasio, A. R., & Barnes, C. L. (1984). Alzheimer’s disease: Cell specific pathology isolates the hippocampal formation. Science, 225, 1168–1170. Jackson, M., Gentleman, S., Lennox, G., Ward, L., Gray, T., Randall, K., et al. (1995). The cortical neuritic pathology of Huntington’s disease. Neuropathology and Applied Neurobiology, 21, 18–26. Jacobs, D., Salmon, D. P., Troster, A., & Butters, N. (1990). Intrusion errors in the figural memory of patients with Alzheimer’s and Huntington’s disease. Archives of Clinical Neuropsychology, 5, 49–57. Jellinger, K. A. (1998). Alzheimer-type lesions in Huntington’s disease. Journal of Neural Transmission, 105, 787–799. Kassubek, J., Juengling, F. D., Kioschies, T., Henkel, K., Karitzky, J., Kramer, B., et al. (2004). Topography of cerebral atrophy in early Huntington’s disease: A voxel based morphometric MRI study. Journal of Neurology, Neurosurgery, and Psychiatry, 75, 213–220. Lange, K. W., Sahakian, B. J., Quinn, N. P., Marsden, C. D., & Robbins, T. W. (1995). Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degree of dementia. Journal of Neurology, Neurosurgery, and Psychiatry, 58, 598–606. Lopera, F., Ardila, A., Mart´ınez, A., Madrigal, L., Arango-Viana, J. C., Lemere, C. A., et al. (1997). Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. Journal of the American Medical Association, 277, 793–799. Lopera, F., Pineda, N., Moreno, S., Durango, L., Garc´ıa, F., Carvajal, L., et al. (1999). Enfermedad de Huntington en familias antioque˜nas. Acta Neurol´ogica Colombiana, 15, 87–96. Macdonald, V., & Halliday, G. (2002). Pyramidal cell loss in motor cortices in Huntington’s disease. Neurobiology of Disease, 10, 378– 386. Macdonald, V., Halliday, G. M., Trent, R. J., & McCusker, E. A. (1997). Significant loss of pyramidal neurons in the angular gyrus of patients with Huntington’s disease. Neuropathology and Applied Neurobiology, 23, 492–495. Martin, A., & Fedio, P. (1983). Word production and comprehension in Alzheimer’s disease: The breakdown of semantic knowledge. Brain and Language, 19, 124–141. Massman, P. J., Delis, D. C., Butters, N., Dupont, R. M., & Gillin, J. C. (1992). The subcortical hypothesis of memory deficits in depression: Neuropsychological validation in a subgroup of patients. Journal of Clinical and Experimental Neuropsychology, 14, 687–706. Mattis, S. (1988). Dementia rating scale (DRS). Odesa, FL: Psychological Assessment Resources. Mayeux, R., Stern, Y., Rosen, J., & Benson, F. (1983). Is “subcortical dementia” a recognizable clinical entity? Annals of Neurology, 14, 278–283. Mazurek, M. F., Garside, S., & Beal, M. F. (1997). Cortical peptide changes in Huntington’s disease may be independent of striatal degeneration. Annals of Neurology, 41, 540–547. McDuff, T., & Sumi, S. M. (1985). Subcortical degeneration in Alzheimer’s disease. Neurology, 35, 123–126. McIntosh, G. C., Jameson, H. D., & Markesbery, W. R. (1978). Huntington disease associated with Alzheimer disease. Annals of Neurology, 3, 545–548. Monsch, A. U., Bondi, M. W., Butters, N., Paulsen, J. S., Salmon, D. P., Brugger, P., et al. (1994). A comparison of category and Letter Fluency in Alzheimer’s Disease and Huntington’s Disease. Neuropsychology, 8, 25–30. Morris, J. C., Heyman, A., Mohs, R. C., Hughes, J. P., van Belle, G., Fillenbaum, G., et al. (1989). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 39, 1159–1165. Pendleton, M. G., Heaton, R. K., Lehman, R. A., & Hulihan, D. (1982). Diagnostic utility of the Turstone word fluency test in neuropsychiatric evaluations. Journal of Clinical Neuropsychology, 4, 307–317. Pe˜na, J. (1999). Enfermedad de Alzheimer - Del diagn´ostico a la terapia: Conceptos y hechos. Barcelona: Fundaci´on La Caixa. Pillon, B., Deweer, B., Agid, Y., & Dubois, B. (1993). Explicit memory in Alzheimer’s, Huntington’s, and Parkinson’s Diseases. Archives of Neurology, 50, 374–379. Pillon, B., Dubois, B., Ploska, A., & Agid, Y. (1991). Severity and specificity of cognitive impairment in Alzheimer’s, Huntington’s, and Parkinson’s diseases and progressive supranuclear palsy. Neurology, 41, 634–643. Podoll, K., Caspary, P., Lange, H. W., & Noth, J. (1988). Language functions in Huntington’s disease. Brain, 111, 1475–1503. Randolph, C., Braun, A., Goldberg, T. E., & Chase, T. N. (1993). Semantic fluency in Alzheimer’s, Parkinson’s and Huntington’s disease: Dissociation of storage and retrieval failures. Neuropsychology, 1, 82–88. Rey, A. (1987). Test de copia de una figura compleja de Rey. Madrid: TEA Ediciones.

40

J.C. Arango-Lasprilla et al. / Archives of Clinical Neuropsychology 21 (2006) 29–40

Roselli, M., Ardila, F., Moreno, S., Standish, V., Arango-Lasprilla, J. C., et al. (2000). Cognitive decline in patients with familial Alzheimer’s disease associated with E280a presenilin-1 mutation: A longitudinal study. Journal of Clinical and Experimental Neuropsychology, 22, 483–495. Rosser, A. E., & Hodges, J. R. (1994). Initial letter and semantic category fluency in Alzheimer’s disease, Huntington’s disease, and progressive supranuclear palsy. Journal of Neurology, Neurosurgery, and Psychiatry, 57, 1389–1394. Rouleau, I., Salmon, D. P., Butters, N., Kennedy, C., & McGuire, K. (1992). Quantitative and qualitative analyses of clock drawings in Alzheimer’s and Huntington’s disease. Brain Cognition, 18, 70–87. Salmon, D. P., Kwo-on-Yuen, P. F., Heindel, W. C., Butters, N., & Thal, L. J. (1989). Differentiation of Alzheimer’s Disease and Huntington’s Disease with the Dementia Rating Scale. Archives of Neurology, 46, 1204–1208. Spargo, E., Everall, I. P., & Lantos, P. L. (1993). Neuronal loss in the hippocampus in Huntington’s disease: A comparison with HIV infection. Journal of Neurology, Neurosurgery, and Psychiatry, 56, 487–491. Tolosa, E. S., & Alvarez, R. (1992). Differential diagnosis of cortical vs. subcortical dementing disorders. Acta Neurologica Scandinavia, 139, 47–53. Troster, A. I., Jacobs, D., Butters, N., Cullum, M., & Salmon, D. P. (1989). Differentiating Alzheimer’s Disease from Huntington’s Disease with the Wechsler Memory Scale—Revised. Clinical Geriatric Medicine, 5, 611–632. Troster, A. I., Salmon, D. P., McCullough, D., & Butters, N. (1989). A comparison of the category fluency deficits associated with Alzheimer’s and Huntington’s disease. Brain and Language, 37, 500–513. Whitehouse, P. J., Martino, A. M., Marcus, K., Mayeux, R., Davis, L., & Kellar, K. J. (1986). Reductions in cortical nicotinic receptor in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. Neurology, 36(Suppl.), 224. Whitehouse, P. J., Price, D. L., Clark, A. W., Coyle, J. T., & DeLong, M. R. (1981). Alzheimer’s disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis. Annals of Neurology, 10, 122–126. Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., & DeLong, M. R. (1982). Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science, 215, 1237–1239. Zakzanis, K. K. (1998). The subcortical dementia of Huntington’s disease. Journal of Clinical and Experimental Neuropsychology, 20, 565–578.