Neuropsychological functioning in elderly patients with schizophrenia ...

Schizophrenia Research 55 (2002) 217±227

www.elsevier.com/locate/schres

Neuropsychological functioning in elderly patients with schizophrenia and Alzheimer's disease Thomas McBride*, Paul J. Moberg, Steven E. Arnold, Lyn Harper Mozley, Richard N. Mahr, Maureen Gibney, Anand Kumar, Raquel E. Gur Brain Behaviour Laboratory, Department of Psychiatry, 10th Floor, Gates Building, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104 USA Received 30 June 2000; revised 27 March 2001; accepted 28 March 2001

Abstract Cognitive functioning was compared in elderly patients with schizophrenia, elderly patients with probable Alzheimer's disease (AD), and matched healthy controls using a brief neuropsychological battery. Both schizophrenia and AD patients demonstrated marked impairment as compared to controls, with the pro®le of neuropsychological de®cits in both disorders appearing remarkably similar. Only visual confrontation naming, verbal delayed recall, and rate of forgetting (i.e. savings score) signi®cantly differentiated between the two patient groups, with AD patients showing poorer overall recall and more rapid forgetting of verbal information over delay. In addition, schizophrenia subjects showed a signi®cantly greater de®cit in visual confrontation naming than the AD group. The relationship of neuropsychological function and clinical symptoms of schizophrenia subjects was also examined. Results showed that word list learning, delayed recall, and rate of forgetting correlated most strongly with positive and negative symptoms. Recent neuropathological studies have indicated abnormalities in speci®c sub®elds of the hippocampal formation in schizophrenia that are also severely affected in AD. Though the speci®c histopathology of the two disorders differs, abnormalities in the common sites may underlie the common neuropsychological pro®le. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Alzheimer's disease; Aging; Neuropsychological; CERAD

Systematic study of cognitive function over the life-span in schizophrenia has received relatively little attention. Studies of young patients with schizophrenia have found de®cits in abstraction and executive control, attention and vigilance, memory and learning, spatial organization, and motor skills (Blanchard and Neale, 1994; Calev et al., 1987; Ciompi, 1980; Harrow et al., 1997; Heaton and * Corresponding author. Tel.: 11-215-662-6094; fax: 11-215662-7903. E-mail address: [email protected] (T. McBride).

Drexler, 1987; Mirsky and Duncan, 1986; Royall et al., 1993; Saykin et al., 1991, 1994). The pattern of these cognitive de®cits in elderly patients with schizophrenia remains to be elucidated. One issue of interest is whether geriatric patients with schizophrenia exhibit progressive cognitive decline similar to that seen in progressive dementing disorders such as Alzheimer's dementia (AD). Some reports have suggested that cognitive de®cits are evident at the onset of the disorder and remain relatively stable and that cognitive functioning does not decline over time in patients with schizophrenia (Haywood and Modelis, 1963; Klonoff et al., 1970;

0920-9964/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(01)00232-8

218

T. McBride et al. / Schizophrenia Research 55 (2002) 217±227

Martin et al., 1977; Moran et al., 1962; Saykin et al., 1994; Harvey et al., 1995a,b). For example, lack of progressive decline was suggested by Heaton and Drexler (1987) who reviewed 100 cross-sectional and 14 longitudinal studies. They concluded that there was not an increased incidence of cognitive impairments in older compared to younger patients, and that initial neuropsychological de®cits may be partially reversible in many patients, while others show stable de®cits and some have progression. In contrast, several other recent studies report ageassociated differences in cognitive de®cits between geriatric and non-geriatric patients with schizophrenia (Harvey et al., 1997; Putnam and Harvey, 1999). Ciompi (1980), studying 289 surviving probands from an initial sample of 1642 schizophrenia patients, reported more frequent incidence of dementia than in the general population. Compi estimated that at least 25% of the probands suffered moderate to severe cognitive de®cits including memory disturbance and disorientation. Similarly, Cohen et al. (1988) found signi®cant performance differences between young and elderly schizophrenia outpatients on the Mattis Dementia Rating Scale (Mattis, 1973), interpreting the results as supporting a substantive decline of cognitive functioning as patients age, particularly in later life. Fukunishi et al. (1990) using two simpli®ed cognitive batteries (Gottfries et al., 1980; Okabe, 1988), found that 1±21% of the 80 patients studied suffered from moderate to severe dementia. While these early studies are important in further understanding cognitive function in elderly patients with schizophrenia, diagnostic and exclusionary criteria for the selection of subjects were not always clearly de®ned. Moreover, the range of neuropsychological functions assessed typically were limited and their speci®city to schizophrenia was not fully explored. Based on the purported higher incidence of dementia in schizophrenia and the high incidence of psychosis in AD (Burns et al., 1990; Drevets and Rubin, 1989; Merriam et al., 1988; Rubin et al., 1988), a number of investigators have undertaken neuropathological studies attempting to link the two disorders. However, postmortem studies to date have not discovered speci®c neuropathology to account for the dementia in elderly schizophrenia patients (Arnold et al., 1994; Casanova et al., 1992; Powchik et al., 1993; Purohit et al., 1993).

Heaton et al. (1994) compared the performance of schizophrenia patients with AD patients on an expanded Halstead-Reitan Battery. Schizophrenia patient's pattern of de®cits differed from AD patients in that AD patients showed less ef®cient learning and more rapid forgetting. It is important to note that the mean ages of the schizophrenia groups in this study were 55.9 (early-onset) and 59.0 (late-onset) years. Using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery, Davidson et al. (1996) compared differences in the speci®c patterns of cognitive performance of patients with AD with a group of elderly patients with schizophrenia. Elderly patients with schizophrenia scored worse than AD patients on tests of naming and constructional praxis, but performed better than AD patients a measure of delayed recall. The current study examined the cognitive performance of a well-characterized sample of chronic elderly schizophrenia and AD patients using the neuropsychological battery developed by the CERAD (Morris et al., 1989). The CERAD battery is more comprehensive than assessment procedures used in the past with elderly schizophrenia patients, and provides a more objective measure of neuropsychological function. Moreover, it enables characterization of the cognitive pro®le of elderly schizophrenia patients by direct comparison with AD patients. Randolph et al. (1993) stated that attempts to de®ne relative impairments in a single group of patients, compared to normal controls is conceptually ¯awed, and that the direct comparison of schizophrenia patients with other patient groups may be the best way to assess any differential de®cits. This type of comparison may reveal differences between patient groups that re¯ect different neurological substrates that may underlie the differential cognitive de®cits in each disorder. Based on our prior investigations of cognitive functioning in elderly schizophrenia patients, we hypothesized that the neuropsychological pro®le would resemble that of AD patients. However, because recent neuropathology studies in elderly patients with schizophrenia have shown a lack of speci®c AD pathology in hippocampal regions, one likely distinguishing de®cit would be memory functions. In characterizing the cognitive pro®le of elderly patients with schizophrenia, it is important to take


219

Table 1 Demographic summary for schizophrenia, Alzheimer, and control groups. (Note: standard deviation in parentheses)

Age Education (years) MMSE Gender Race Missing data

Schizophrenia (n 44)

AD (n 43)

Healthy controls (n 44)

75.5 (^6.7) range 61±88 10.6 (^2.1) range 6±15 19.0 (^6.2) 16 males, 28 females 42 Caucasian 2 African American 1

74.8 (^4.8) range 65±84 11.4 (^2.0) range 6±14 19.1 (^4.9) 16 males, 27 females 42 Caucasian 1 Asian 0

73.7 (^3.2) Range 65±79 13.1 (^2.6) p range 7±20 28.7 (^0.9) p 19 males, 25 females 38 Caucasian 6 African American 0

into account the nature of clinical symptoms in this population. For example, negative symptoms of schizophrenia are highly correlated with cognitive functioning (Addington et al., 1991; Davidson et al., 1995; Harvey et al. 1996a,b). Changes in cognitive functioning with age may be due to improvement or worsening of clinical symptoms in elderly patients. Therefore, in the present study we also examined the relationship of clinical symptoms to neuropsychological function in elderly patients with schizophrenia.

1. Methods and materials 1.1. Subjects Participants included 44 elderly, institutionalized (average length of hospitalization 43.3 years) schizophrenia patients recruited from the geriatric units of two Pennsylvania State psychiatric hospitals, and followed by the Mental Health Clinical Research Center on Schizophrenia at the University of Pennsylvania; 43 outpatients diagnosed with probable AD followed by the Alzheimer's Disease Center of the University of Pennsylvania; and 44 healthy elderly controls. All subjects met strict diagnostic criteria prior to inclusion in the study. Exclusionary criteria for all subjects included: left handedness, ambiguous psychiatric diagnosis (for schizophrenia patients), electroconvulsive therapy, neurologic disorder (epilepsy, stroke, anoxic brain injury, etc.), traumatic brain injury with loss of consciousness, developmental disorder, substance abuse (based on DSM-IV criteria), primary language other than English, and

medical conditions that might alter cerebral function (renal, pulmonary, cardiac, etc.). Schizophrenia patients were selected based on extensive chart review by a physician-led team of clinicians, and met DSM-IV criteria for schizophrenia (American Psychiatric Association, 1987; Arnold et al., 1995). Alzheimer patients met the NINCDS-ADRDA (McKhann et al. 1984) criteria for probable AD and were otherwise medically healthy. These criteria are consistent with those used in earlier reports by our group (Kumar et al. 1994). Controls were recruited from local senior centers, places of worship, and newspaper advertisements. All potential controls, not initially excluded by phone interview, were further screened by the structured clinical interview for DSM-IV (SCID) (Spitzer et al., 1987). Descriptive data for this sample are presented in Table 1. Patients and controls were matched for age (F2; 128 1:46, p 0:23), gender (x2 0:51, df 2, p 0:77), and ethnic background (x2 9:27, df 4, p 0:054). The two patient groups did not differ with regard to global cognitive functioning based on Mini-Mental Status Examination (MMSE: Folstein et al., 1975) scores (t39:2 1:24, p 0:22). The groups, did, however, differ in years of education (F2; 128 13:71, p , 0:001), with controls having more education than both patient groups. The schizophrenia and AD groups, however, did not differ in years of education (F1; 128 2:86, p 0:09). 1.2. Materials Subjects were administered the CERAD neuropsychological assessment battery (Morris et al., 1989). The CERAD battery includes the MMSE; a measure

220


Fig. 1. Mean z-transformed scores of schizophrenia and AD patients on the CERAD neuropsychological battery. WLTOT word list recall total number correct trials 1±3, WLSDE total number correct on word list short delay, SAVING total words on delayed recall divided by number of words on word list trial 3, INTRU total number of intrusions on word list trials 1±3, BNT Boston Naming Test, total number correct, AN total word count on Animal Naming, CETOT drawing praxis.

of semantic word-list generation (Animal Naming); a modi®ed Boston Naming procedure; a word-list learning, free recall, and recognition procedure; and an assessment of drawing praxis. A subset of subjects with schizophrenia were also administered the Scale of the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms. (SAPS) (Andreasen, 1984). The SANS can be divided into ®ve subscales: affective ¯attening; alogia; avolition-apathy; Anhedoniaasociality; attention. The SAPS can be divided into four subscales: hallucinations, delusions, bizarre behavior, positive formal thought disorder. SANS and SAPS subscale scores were obtained by summing the scores for all of the items within each subscale. 1.3. Procedure The CERAD battery was administered and scored according to standard procedures and criteria (Morris et al., 1989). Neuropsychological testing was performed by experienced clinical neuropsychologists under the supervision of the neuropsychology faculty. All data and scoring were checked by independent examiners. In order to compare neuropsychological functioning across tests in the three groups, the raw scores on each neuropsychological test were rescaled to standard score equivalents (z-scores) using the means and standard deviations of the control group. The control group mean is represented by the zero line

with S:D: 1 for all variables. Testing for signi®cant multivariate effects were followed by univariate analyses examining group differences on each of the neuropsychological measures. 2. Results Multivariate analysis of variance (MANOVA) was employed to evaluate cognitive performance on tests of the CERAD battery. The mean CERAD test scores for each group are shown in Fig. 1. Results of MANOVA revealed a large overall difference in performance between diagnostic groups, with both patient groups scoring lower than healthy controls (F2; 125 69:51, p , 0:0001). There was no main effect for sex or interaction with diagnosis and sex. A signi®cant diagnosis by neuropsychological function interaction was, however, observed (F12; 750 21:47, p , 0:0001). Comparison of the two patient groups with diagnosis as the independent variable and neuropsychological function as the within-groups factor revealed a signi®cant interaction effect for diagnosis and neuropsychological measure (F6; 492 4:31, p , 0:0002). The neuropsychological measures that distinguished between the two patient groups at the univariate level were Boston Naming Test total score (t85 22:43, p , 0:01) and delayed verbal recall (t85 2:58, p , 0:01) with AD patients performing


221

Fig. 2. Correlation of negative symptoms with neuropsychological variables.

better on Boston Naming and worse than schizophrenia patients on delayed recall of verbal information. While AD patients tend to produce more intrusions on the word list recall test than the schizophrenia patients, this difference failed to reach signi®cance (t85 21:97, p , 0:052). For easier visual comparison, the mean number of intrusions during list learning for each group in Fig. 1 was multi-

plied by 21. This procedure put all measures on the same scale, showing that the performance for these tests for the patient groups was lower than that of the controls. Since AD patients have been reported to have more rapid forgetting compared to persons with subcortical dementias (i.e. Huntington's and Parkinson's disease), `savings' score for the word-list memory

Fig. 3. Correlation of positive symptoms with neuropsychological variables.

222


task were calculated. Savings score (percent retention) was calculated by dividing each patient's score on the delayed recall of the word-list memory task by his/her recall on trial three of the word-list learning task and multiplying the product by 100. Thus, the lower the savings score, the greater the rate of forgetting. The results of this analysis indicated that schizophrenia patients had signi®cantly better savings scores than the AD patients (t85 2:08, p , 0:03); that is, AD patients showed a more rapid rate of forgetting. Figs. 2 and 3 show the correlations between cognitive variables, and SANS and SAPS scores for the patients with schizophrenia. The mean SANS total score was 38.25 and the mean SAPS total score was 16.81. Animal Naming, word list, word list delay, and Boston Naming test scores correlated signi®cantly with negative symptoms. A more detailed analysis of SANS subscales revealed that the affective ¯attening, Alogia, and attention subscales had the highest correlations with these measures. Word list delay scores correlated signi®cantly with all SANS subscales with the exception of the Anhedonia scale. In addition, signi®cant negative correlations were found between the Avolition subscale and Boston Naming. The Boston Naming test also correlated signi®cantly with the Anhedonia-asociality subscale. Word list total, word list delayed recall scores and rate of forgetting on the word list test correlated signi®cantly with positive symptoms. The hallucination and delusion subscales of the SAPS correlated most strongly with word list total and word list delayed recall scores. Rate of forgetting was also found to correlate signi®cantly with the hallucinations subscale, as did Animal Naming scores. A single composite index of cognitive functioning was created by averaging the individual z-scores for each of the cognitive variables. The correlation between the composite cognitive score and the SANS total score was signi®cant (r 20:61, p , 0:001) as was the correlation between the composite cognitive score and the SAPS total score (r 20:495, p , 0:01). 3. Discussion Results of the current study indicated that both AD

and schizophrenia patient groups show signi®cant de®cits across a wide range of neuropsychological functions relative to controls. The pattern of neuropsychological de®cits on the CERAD in elderly patients with schizophrenia is remarkably similar to that observed in AD patients. However, AD patients demonstrated greater impairment on delayed recall of a word list as well as greater loss of memory information over a short delay (37% retention for AD vs. 63% retention for schizophrenia). Research has shown that healthy controls, on an average, perform at the level of 80% retention over delay. These data support the notion that while both AD and schizophrenia groups showed forgetting over time, the loss in AD patients was much greater. Welsh et al. (1991) found that delayed verbal recall was the most sensitive CERAD test in discriminating between patients with even very mild AD and normal elderly subjects. Previous research has consistently pointed to the importance of rate of forgetting in distinguishing AD from other dementing processes such as Huntington's disease and Korsakoff's syndrome (Butters et al. 1988; Kramer et al., 1989; Squire, 1981). Based on the ®ndings in this study, rate of forgetting also appears to distinguish AD from cognitive impairment associated with schizophrenia. Troster et al. (1993) reported that while indices of forgetting tend to distinguish AD from HD patients in the earlier stages of dementia, they appear to have limited utility at the more advanced stages of the disease process (i.e. moderate to severe range). It is noteworthy that, though the mean MMSE scores for both AD and schizophrenia groups in the current study would place subjects in the moderately demented range (mean MMSE score 19.0 for schizophrenia and 19.1 for AD), the savings score continued to be a signi®cant discriminator between the two groups. This ®nding is also consistent with that of Heaton et al. (1994) who found that AD patients were signi®cantly more impaired than elderly schizophrenic patients on measures on retention for stories and ®gures. The ®nding that AD patients performed better than patients with schizophrenia on a test of visual confrontation naming (BNT), is consistent with the ®ndings that chronically institutionalized, poor outcome, geriatric patients with schizophrenia show cognitive impairment in neuropsychological functions


that are usually spared in younger patients with schizophrenia (Davidson et al., 1996). The average length of hospitalization in our sample of patients with schizophrenia was 43.3 years (S:D: 15:1 years). As in our sample, Davidson et al. (1996) found that the poor outcome patients scored better than AD patients on delayed verbal recall, equivalently to AD patients on serial verbal learning, and worse than AD patients on naming. Putnam and Harvey (1999) speculated that this pro®le, manifested by poor outcome patients with schizophrenia, represents impairment in both cortical and subcortical memory functions. The poorer BNT performance of patients with schizophrenia may also be due to qualitative differences in the types of errors committed by each group. For example, a number of authors have suggested that the naming de®cit in AD may largely re¯ect de®cits in the retrieval of semantic information. In contrast, there is evidence that young thought disordered patients with schizophrenia show diffuse activation and disruption of their semantic network (see Spitzer, 1997 for a review). It seems possible that in elderly schizophrenia patients, these disrupted patterns of semantic activation, in combination with retrieval problems, produce a greater level of naming de®cit. Future studies detailing the nature and pattern of errors made in both AD and schizophrenia patients may probe this hypothesis. The relationship between the severity of positive and negative symptoms and cognitive de®cits in schizophrenia was also examined in our sample. Consistent with previous research, elderly patients had greater severity of negative symptoms than positive symptoms (Davidson et al. 1995). Results also showed signi®cant negative correlations between negative symptoms of elderly patients with schizophrenia and cognitive impairments on word list learning, delayed word list recall, semantic word list generation (Animal Naming), and confrontation naming (BNT). Harvey et al. (1995a,b) found that negative symptom severity was correlated with each of the cognitive measures of the CERAD battery. Cognitive impairments were also found to be more stable over time, but did not predict the severity of negative symptoms over time. Similarly, Harvey et al. (1999) reported that baseline severity of positive and negative symptoms did not correlate with cognitive

223

decline in geriatric patients with schizophrenia. Therefore, it appears that cognitive impairments and clinical symptoms are related, but discriminable features in schizophrenia. The present ®ndings support previous research which found that negative symptoms were more likely to be associated with cognitive performance on tests of memory (Tamlyn et al. 1992; Addington et al., 1991) and general intellectual ability, particularly verbal ability and verbal ¯uency (Addington et al., 1991). Positive symptoms have been shown to be associated with de®cits on verbal tests and with de®cits in selective attention (Cornblatt et al., 1985; Green and Walker, 1985). Analysis of the SANS subscales revealed that affective ¯attening, attention, and Alogia showed the strongest correlations with verbal ¯uency, and word list learning and delay. While one would expect the attention subscale to show a relationship to cognitive function, the relationship between affective ¯attening and Alogia requires some elaboration. Based on previous literature, the correlation of the affective ¯attening and Alogia subscales with verbal memory and semantic ¯uency is not unexpected. For example, Keefe et al. (1992) proposed a three-factor model to describe negative symptoms in schizophrenia. The ®rst dimension, diminished expression, was made up primarily of items from the affective ¯attening subscale and the Alogia subscale of the SANS. In our sample, verbal ¯uency correlated signi®cantly with affective ¯attening and Alogia subscales of the SANS. The second factor, social dysfunction, includes items from the Anhedonia-asociality and Avolition subscales of the SANS. The third factor, disorganization, included one item from the Alogia subscale, and inappropriate affect from the affective ¯attening scale. Bilder et al. (1985) found that symptoms re¯ecting disorganization, such as inappropriate affect correlated signi®cantly with use of language and ability to concentrate. This is consistent with our ®nding that Alogia and affective ¯attening were related to verbal ¯uency. A previous study of elderly patients with schizophrenia by Davidson et al. (1995) reported strong correlations between cognitive impairment, as measured by the MMSE and negative symptoms but not positive symptoms (as measured by the Positive and Negative Syndrome Scale, PANSS). In the

224


present study, severity of positive symptoms correlated signi®cantly with cognitive de®cits. Speci®cally, severity of positive symptoms was inversely associated with Animal Naming, word list learning, word list delayed recall scores, and the related measure, rate of forgetting on word list delay. Analysis of the individual subscales revealed that the hallucination and delusion scales correlated most strongly with these measures. The difference between the present ®ndings and those of Davidson et al. (1995) may be due to the fact that, in addition to the MMSE, the CERAD battery was used to assess cognitive function in the present study. The MMSE is a screening instrument and may not be as sensitive to the cognitive impairments in schizophrenia. The present ®ndings are consistent with the reported associations of positive symptoms in younger patients with schizophrenia and performance on verbal tests and tests involving selective attention (Cornblatt et al. 1985). While the present study examined this relationship only in patients with schizophrenia, negative symptoms such as disengagement, apathy, diminished emotional responsiveness, loss of volition, and decrease initiative are also present in individuals with AD (White and Cummings, 1996). Alzheimer's patients also exhibit positive symptoms, which resemble those observed in schizophrenia. For example, delusions with persecutory content are often observed in individuals with AD. Evidence from pharmacological research suggests that a distorted dopaminergic/cholinergic balance could result in psychotic symptoms in both schizophrenia and AD. It would, therefore, be informative to investigate the relationship between positive and negative symptoms and cognitive impairment in Alzheimer's patients. Such data would provide useful information in comparing the relationship of cognitive de®cits and symptoms in the two disorders and help elucidate the relationship between the underlying neurological causes of positive and negative symptoms in the two disorders. Neuropathological studies, to date, have found little or no evidence of Alzheimer pathology (neuro®brillary tangles, senile plaques) in elderly patients with schizophrenia and dementia (Arnold et al., 1994; Powchik et al. 1993; Purohit et al. 1993; Casanova et al., 1992; Berg, 1988; Khachaturian, 1985).

These studies can be criticized, however, because the level of cognitive impairment (dementia) was determined by a review of clinical records and interviews with caregivers instead of formal psychometric testing. Indeed, Harvey et al. (1992) found that reliance on chart review alone, without contact with the patient or caregiver, resulted in systematic bias toward overestimation of the severity of dementia. Recent cytoarchitectural, neuronal morphometric, and immunohistochemical studies, however, have indicated overlap in sites of pathology, if not process of pathology, between schizophrenia and AD. Cytoarchitectural studies have found aberrant arrangement of neurons in the entorhinal cortex and hippocampus (Arnold et al., 1991a,b,c; Conrad et al., 1991; Jakob and Beckmann, 1986; Kovelman and Scheibel, 1984) suggesting abnormal neurodevelopment. We have also observed more speci®c abnormalities in neuron size and neuronal cytoskeletal protein expression in super®cial layers of the entorhinal cortex and in the subiculum (Arnold et al., 1994). These are the same areas of the hippocampal formation that show the greatest vulnerability to accumulation of neuro®brillary tangles in AD (Arnold et al., 1991a,b; Braak and Braak, 1986). Because the hippocampal formation (hippocampus, subiculum, entorhinal cortex) has such extensive cortical and subcortical connections, its dysfunction would likely have important and wide-ranging neuropsychological sequelae. Thus, overlap in cognitive de®cits between schizophrenia and AD patient groups on the CERAD would not be unexpected. Therefore, similarities and differences in memory functions between the two patient groups may re¯ect the similarities and differences in the underlying sites and processes of neuropathology. Both patient groups showed impaired memory performance relative to controls, which re¯ect overlap in the site of pathology including the hippocampus. However, the greater impairment of the AD patients on verbal recall and retention of information may be related to the more extensive pathology observed in the hippocampus in this group (i.e. neuro®brillary tangles and senile plaques). Several caveats are worth noting. First, the CERAD battery, while representing an improvement over previous cognitive examinations for dementia in schizophrenia, may not be sensitive enough to other


speci®c differences between elderly schizophrenics and AD patients. A more comprehensive battery may uncover other de®cits speci®c to schizophrenia or AD, such as de®cits in praxis. Secondly, just as examination of the savings score in the current protocol was useful in better understanding the memory impairment in these two groups, such `®ner-grained' analysis of other de®cits may be useful in differentiating the two groups. For example, it may be that schizophrenia patients make errors distinct from those made by AD patients on various tests, such as confrontation naming (Hodges et al., 1991). Thirdly, while our schizophrenia and AD patients were matched for demographics and MMSE, the schizophrenia patients, nevertheless, represented a very chronic subgroup. We are currently expanding our studies of elderly patients with schizophrenia to include outpatient samples. Fourth, because of existing demographics in institutionalized patient populations, our schizophrenia subjects did not include other ethnic backgrounds (e.g. African Americans, Asians, etc.). The ®ndings, therefore, may not necessarily be representative of elderly schizophrenia patients in the general population. Lastly, while the current results do suggest that the cognitive pro®le of elderly patients with schizophrenia differs from that observed in younger patients, and is similar to AD, longitudinal studies will be important to document such a decline in individual patients. For example, Harvey et al. (1995a,b) found that in contrast to what was observed in progressive dementing conditions such as AD, there was no decline in MMSE scores of elderly schizophrenia patients after one and two year follow-up. Nor was there a decline in performance on the CERAD battery after a one-year follow-up (Harvey et al., 1996a,b). Taken together, the results of these studies suggest that chronic schizophrenia patients differ from AD patients in the progressive course of impairment. It will be important to document the course of other cognitive measures in elderly patients with schizophrenia. Acknowledgements The authors wish to thank Eric Zarahn, Dan Walsh, Laurie Burke, and Helen Mitchell-Sears, B.A. for

225

their assistance during various phases of this project. We also extend special thanks to Albert Didario, M.S.W., Edith Krohn, M.A. and the staff at Norristown State Hospital and Harrisburg State Hospital for the help they provided in this study. This study was supported in part by grants from the Alzheimer's Disease Center Core, NIA-AG 10124, NIMH Training grant MH19112 and MHCRC grant MH43880. References Addington, J., Addington, D., Maticka-Tyndale, D., 1991. Cognitive functioning and positive and negative symptoms in schizophrenia. Schizophr. Res. 5, 123±134. American Psychiatric Association, 1987. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders, Third EditionRevised. American Psychiatric Association, Washington DC. Andreasen, N.C., 1984. Scale for the Assessment of Positive and Negative Symptoms. Arnold, S.E., Hyman, B.T., Flory, J., Damasio, A.R., Van Hoesen, G.W., 1991a. The topographical and neuroanatomical distribution of neuro®brillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1, 103±116. Arnold, S.E., Hyman, B.T., Van Hoesen, G.W., Damasio, A.R., 1991b. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. Arch. Gen. Psychiatry 48, 625±632. Arnold, S.E., Lee, V.M.-Y., Gur, R.E., Trojanowski, J.Q., 1991c. Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in speci®c sub®elds of the hippocampal formation in schizophrenia. Proceedings of the National Academy of Science (USA) 88, 10850±10854. Arnold, S.E., Franz, B.R., Gur, R.C., Gur, R.E., Shapiro, R.M., Moberg, P.J., Trojanowski, J.Q., 1994. Decreased neuron size in hippocampal sub®elds that mediate cortical-hippocampal interactions in schizophrenia. Am. J. Psychiatry 152, 738±748. Arnold, S.E., Gur, R.E., Shapiro, R.M., Fisher, K.R., Moberg, P.J., Gibney, M.R., Gur, R.C., Blackwell, P., Trojanowski, J.Q., 1995. Prospective clinicopathological studies of schizophrenia: Accrual and assessment. Am. J. Psychiatry 152, 731±737. Berg, L., 1988. Clinical dementia rating (CDR). Psychopharmacol. Bull. 24 (4), 637±639. Bilder, R.M., Mukherjee, S., Reiter, R.O., Pandurangi, A.K., 1985. Symptomatic and neuropsychological components of defect states. Schizophr. Bull. 11, 409±419. Blanchard, J.J., Neale, J.M., 1994. The neuropsychological signature of schizophrenia: Generalized or differential de®cit? Am. J. Psychiatry 151 (1), 40±48. Braak, H., Braak, E., 1986. Ratio of pyramidal cells versus nonpyramidal cells in the human frontal isocortex and changes in ratio with aging and Alzheimer's disease. Progress in Brain Res. 40, 185±212. Burns, A., Jacoby, R., Levy, R., 1990. Psychiatric phenomena in

226


Alzheimer's disease. I. Disorders of thought content. Br. J. Psychiatry 157, 72±76. Butters, N., Salmon, D.P., Cullum, C.M., Cairns, P., Troster, A.I., Jacob, D., Moss, M., Cermak, L.S., 1988. Differentiation of amnesic and demented patients with the Wechsler memory scale-revised. Clin. Neuropsychologist 2, 133±148. Calev, A., Korin, Y., Kugelmass, S., Lerer, B., 1987. Performance of chronic schizophrenics on matched word and design recall tasks. Biol. Psychiatry 22, 699±709. Casanova, M.F., Zito, M., Altshuler, L., Weinberger, D.R., 1992. Normal nucleolar size of entorhinal cortex cells in schizophrenia. Psychiatry Rev. 44, 79±82. Ciompi, L., 1980. Catamnestic long-term study on the course of life and aging of schizophrenics. Schizophr. Bull. 6, 606±618. Cohen, C.I., Stasny, P., Perlick, D., Samuelly, I., Horn, L., 1988. Cognitive de®cits among aging schizophrenic patients residing in the community. Hosp. Community Psychiatr. 39, 557±559. Conrad, A.J., Abebe, T., Austin, R., Forsythe, S., Scheibel, A.B., 1991. Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch. Gen. Psychiatry 48, 413±417. Cornblatt, B.A., Lenzenweger, M.F., Dworkin, R.H., ErlenmeyerKimling, L., 1985. Positive and negative schizophenic symptoms, attention and information processing. Schizophr. Bull. 11, 387±408. Davidson, M., Harvey, P.D., Powchik, P., Parrella, M., White, L., Knobler, H.Y., Losonczy, M.F., Keefe, R., Katz, S., Frecska, E., 1995. Severity of symptoms in chronically institutionalized geriatric schizophrenic patients. Am. J. Psychiatry 152, 197± 2076. Davidson, M., Harvey, P.D., Welsh, K., Powchik, P., Putnam, K.M., Mohs, R.C., 1996. Cognitive functioning in late-life schizophrenia: A comparison of elderly schizophrenic patients and patients with Alzheimer's disease. Am. J. Psychiatry 153, 1274±1279. Drevets, W.C., Rubin, E.H., 1989. Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type. Biol. Psychiatry 25, 39±48. Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. ªMini-Mental Stateº: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatry Res. 12, 189±198. Fukunishi, I., Okabe, S., Nakagawa, T., Hosokawa, K., 1990. The assessment of intelligence function of aged chronic schizophrenia. Japanese J. Psychiatry Neurol. 44, 503±509. Gottfries, C.G., Brane, G., Gullberg, B., Steen, G., 1980. A new rating scale for dementia syndromes. Arch. Gerontology and Geriatrics 1, 311±330. Green, M., Walker, E., 1985. Neuropsychological performance and positive and negative symptoms in schizophrenia. J. Abnorm. Psychol. 94, 460±464. Harrow, M., Marengo, J., Pogue-Geile, M., Pawelski, T.J., 1997. Schizophrenic de®cits in intelligence and abstract thinking: In¯uence of aging and long-term institutionalization. In: Miller, N.E., Cohen, G.D. (Eds.), Schizophrenia and Aging. Guilford Press, New York, pp. 133±144. Harvey, P.D., Davidson, M., Powchik, P., Parrella, M., White, L., Mohs, R.C., 1992. Assessment of dementia in elderly schizophrenics with structured rating scales. Schizophr. Res. 7, 85±90.

Harvey, P.D., Powchik, P., Mohs, R., Davidson, M., 1995a. Memory impairment in geriatric chronically institutionalized schizophrenic patients: a neuropsychological study. J. Neuropsychiatry Clin. Neurosci. 7, 207±212. Harvey, P.D., White, L., Parrella, M., Putnam, K.M., Kincaid, M.M., Powchik, P., Mohs, R.C., Davidson, M., 1995b. The longitudinal stability of cognitive impairment in schizophrenia: Mini-Mental State scores at one- and two-year follow-ups in geriatric in-patients. Br. J. Psychiatry 166, 630±633. Harvey, P.D., Lombardi, J., Leibman, M., White, L., Parrella, M., Powchik, P., Davidson, M., 1996a. Cognitive impairment and negative symptoms in geriatric chronic schizophrenic patients: a follow-up study. Schizophr. Res. 22, 223±231. Harvey, P.D., Lombardi, J., Leibman, M., White, L., Parrella, M., Powchik, P., Mohs, R., Davidson, M., 1996b. Performance of chronic schizophrenic patients on cognitive measures sensitive to dementia. Int. J. Geriatric Psychiatry 11, 621±627. Harvey, P.D., Lombardi, J., Leibman, M., Parrella, M., White, L., Powchik, P., Mohs, R., Davidson, M., Davis, K.L., 1997. Agerelated differences in formal thought disorder in chronically hospitalized schizophrenic patients: a cross sectional study across nine decades. Am. J. Psychiatry 154 (2), 205±210. Harvey, P.D., Silverman, J.M., Mohs, R.C., Parrella, M., White, L., Powchik, P., Davidson, M., Davis, K.L., 1999. Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients. Biol. Psychiatry 45 (1), 32±40. Haywood, H.C., Modelis, I., 1963. Effect of symptom change on intellectual function in schizophrenia. J. Abnorm. Soc. Psychol. 67, 76±78. Heaton, R.K., Drexler, M., 1987. Clinical neuropsychological ®ndings in schizophrenia and aging. In: Miller, N.E., Cohen, G.D. (Eds.), Schizophrenia and Aging. Guilford Press, New York, pp. 145±161. Heaton, R., Paulsen, J.S., McAdams, L.A., Kuck, J., Zisook, S., Braff, D., Harris, J., Dilip, J.V., 1994. Neuropsychological de®cits in schizophrenia: Relationship to age, chronicity, and dementia. Arch. Gen. Psychiatry 51, 469±476. Hodges, J.R., Salmon, D.P., Butters, N., 1991. The nature of the naming de®cit in Alzheimer's and Huntington's disease. Brain 114, 1547±1558. Jakob, H., Beckmann, H., 1986. Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J. Neural Transmission 65, 303±326. Keefe, R., Harvey, P.D., Lenzenweger, M.F., Davidson, M., Apter, S.H., Schmeidler, J., Mohs, R., Davis, K.L., 1992. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: negative symptoms. Psychiatry Res. 44, 153± 165. Khachaturian, Z.S., 1985. Diagnosis of Alzheimer's disease. Arch. Neurol. 42, 1097±1105. Klonoff, H., Fibiger, C.H., Hutton, G.H., 1970. Neuropsychological patterns in chronic schizophrenia. J. Nerv. Ment. Dis. 150, 291± 300. Kovelman, J.A., Scheibel, A.B., 1984. A neurohistologic correlate of schizophrenia. Biol. Psychiatry 19, 1601±1621. Kramer, J.H., Levin, B.E., Brandt, J., Delis, D.C., 1989.

T. McBride et al. / Schizophrenia Research 55 (2002) 217±227 Differentiation of Alzheimer's Huntington's, and Parkinson's disease patients on the basis of verbal learning characteristics. Neuropsychology 3, 111±120. Kumar, A., Newberg, A., Alavi, A., Moberg, P.J., Berlin, J., Miller, D., Souder, E., Gur, R.E., Gottlieb, G., 1994. MRI volumetric studies in Alzheimer's disease: relationship to clinical and neuropsychological variables. Am. J. Geriatric Psychiatry 2, 21±31. Martin, J.P., Friedmeyer, M.H., Sterne, A.L., Brittain, H.M., 1977. IQ de®cit in schizophrenia: A test of competing theories. J. Clin. Psychol. 33, 667±672. Mattis, S., 1973. Dementia Rating Scale: Professional Manual. Psychological Assessment Resources, Odessa, Florida. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34, 939±944. Merriam, A.E., Aronson, M.K., Gaston, P., Wey, S., Katz, I., 1988. The psychiatric symptoms of Alzheimer's disease. J. Am. Geriatric Soc. 36, 7±12. Mirsky, A.F., Duncan, C.C., 1986. Etiology and expression of schizophrenia: neurobiological and psychosocial factors. Ann. Rev. Psychol. 37, 291±319. Moran, L.J., Gorham, D.R., Holtzman, W.H., 1962. Vocabulary knowledge and usage of schizophrenic subjects: a six year follow-up. J. Abnorm. Soc. Psychol. 61, 246±254. Morris, J.C., Heyman, A., Mohs, R.C., Hughes, J.P., van Belle, G., Fillenbaum, G., Mellits, E.D., Clark, C., 1989. The consortium to establish a registry for Alzheimer's disease. Part I. Clinical and neuropsychological assessment of Alzheimer's disease (CERAD). Neurology 39, 1159±1164. Okabe, S., 1988. Simpli®ed intelligence scale. Jpn J. Clin. Psychiatry 17, 55±61. Powchik, P., Davidson, M., Nemeroff, C.B., Haroutunian, V., Purohit, D., Losonczy, M., Bissette, G., Perl, D., Ghanbari, H., Miller, B., Davis, K.L., 1993. Alzheimer's-disease-related protein in geriatric schizophrenia patients with cognitive impairment. Am. J. Psychiatry 150 (11), 1726±1727. Purohit, D.P., Davidson, M., Perl, D.P., Powchik, P., Haroutunian, V.H., Bierer, L.M., McCrystal, J., Losonczy, M., Davis, K.L., 1993. Severe cognitive impairment in elderly schizophrenic patients: a clinicopathological study. Biol. Psychiatry 33, 255±260.

227

Putnam, K.M., Harvey, P.D., 1999. Memory performance of geriatric and nongeriatric chronic schizophrenic patients: a cross-sectional study. J. Int. Neuropsychol. Soc. 5, 494±501. Randolph, C., Goldberg, T.E., Weinberger, D.R., 1993. The neuropsychology of schizophrenia. In: Heilman, K.M., Valenstein, E. (Eds.), Clinical Neuropsychology, 3rd. Oxford University Press, New York, pp. 499±522. Royall, D.R., Mahurin, R.K., True, J.E., Anderson, B., Brock, I.P., Freeburger, L., Miller, A., 1993. Executive impairment among the functionally dependent: Comparisons between schizophrenic and elderly subjects. Am. J. Psychiatry 150 (12), 1813± 1819. Rubin, E.H., Drevets, W.C., Burke, W.J., 1988. The nature of psychotic symptoms in senile dementia of the Alzheimer type. J. Geriatric Psychiatry and Neurology 1, 16±20. Saykin, A.J., Gur, R.C., Gur, R.E., Mozley, D., Mozley, L.H., Resnick, S.M., Kester, B., Sta®niak, P., 1991. Neuropsychological function in schizophrenia: Selective impairment in memory and learning. Arch. Gen. Psychiatry 48, 618±624. Saykin, A.J., Shtasel, D.L., Gur, R.E., Kester, D.B., Mozley, L.H., Sta®niak, P., Gur, R.C., 1994. Neuropsychological de®cits in neuroleptic naive, ®rst episode schizophrenic patients. Arch. Gen. Psychiatry 51, 124±131. Spitzer, M., 1997. A cognitive neuroscience view of schizophrenic thought disorder. Schizophr. Bull. 23, 29±50. Spitzer, R.L., Williams, J.B., Gibbon, M., 1987. Instruction Manual for the Structured Clinical Interview for DSM-III-R (SCID). Biometrics Research Department, New York State Psychiatric Institute, New York. Squire, L.R., 1981. Two forms of human amnesia: an analysis of forgetting. J. Neurosci. 1 (6), 635±640. Tamlyn, D., McKenna, P.J., Mortimer, A.M., Lund, C.E., Hammond, S., Baddeley, A.D., 1992. Memory impairment in schizophrenia: its extent, af®liations and neuropsychological character. Psychol. Med. 22, 101±115. Troster, A.I., Butters, N., Salmon, D.P., Cullum, C.M., Jacobs, D., Brandt, J., White, R.F., 1993. The diagnostic utility of savings scores: differentiating Alzheimer's and Huntington's diseases with the logical memory and visual reproduction tests. J. Clin. Exp. Neuropsychol. 15 (5), 773±788. Welsh, K., Butters, N., Hughes, J., Mohs, R., Heyman, A., 1991. Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures. Arch. Neurol. 48, 278±282.