Nature of mental retardation and dementia in down syndrome: Study with PET, CT, and neuropsychology

NeurobiologyofAging.Vol. 13, pp. 723-734, 1992

0197-4580/92 $5.00 + .00 Copyright© 1992PergamonPress Ltd.

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Nature of Mental Retardation and Dementia in Down Syndrome: Study With PET, CT, and Neuropsychology M. B. S C H A P I R O , ' J. V. H A X B Y A N D C. L. G R A D Y

Laboratory o f Neurosciences, Section on Brain Aging and Dementia, National Institute on Aging, Clinical Center, Bethesda, M D 20892 R e c e i v e d 16 April, 1990; Accepted 4 J u n e 1992 SCHAPIRO, M. B., J. V. HAXBY AND C. L. GRADY. Nature of mental retardationand dementia in Down syndrome:Study with PET, CT. and neuropsychology. NEUROB1OL AGING 13(6)723-734, 1992.--Recent evidence suggests that Alzheimer's disease is an etiologically heterogeneous disorder. A human model of Alzheimer's disease exists that avoids such problems of etiologic heterogeneity. Down syndrome (DS), trisomy 21, is a genetic disorder in which an extra portion of chromosome 21 leads to mental retardation, short stature, and phenotypic abnormalities. Prior investigations by others have shown that DS subjects over 40 years of age demonstrate neuropathologie and neurochemical defects postmortem that are virtually indistinguishable from those found in brains of Alzheimer's disease patients and a universal cognitive deterioration more severe in demented than nondemented older DS subjects. In our study, these nondemented older DS subjects show a distinctive pattern of age-related deficits, while a more global pattern is seen in demented older DS subjects. Dementia occurs in 40% of older DS subjects. We find that in older demented DS subjects positron emission tomography (PET) shows identical patterns of abnormal glucose metabolism as those described previously in Alzheimer's disease patients, selectivelyinvolving the phylogenetically newer association areas of parietal and temporal neocortices but sparing primary sensory and motor regions. Further, we find in older demented DS patients quantitative computer-assisted tomography (CT) indicates accelerated neuronal loss and brain atrophy, similar to that previously shown in Alzheimer's disease patients. As a potential use of the DS model, we observed a case of DS with dementia but without mental retardation. This case suggests that expression of dementia in DS may involve genes on chromosome 21 other than in the "obligatory" distal segment of the q arm. Alternatively, differential expression of genes on the q arm of chromosome 21 might cause dementia without phenotypic features and mental retardation. Down syndrome Chromosome 21 Mental retardation Dementia 18FDG Brain metabolism CT scan Neuropsychology

RECENT evidence suggests that Alzheimer's disease is an etiologically heterogeneous disorder and that different causes (including sporadic and heritable forms) exist. For instance, studies of monozygotic twins have shown only a 40-50% concordance rate (65). Such discordance has been shown even in confirmed monozygotic twins using formal cognitive testing, sensitive brain-functional and structural techniques, and longitudinal follow-up of over 10 years (44). Further, Rapoport et al. (65) showed that concordant monozygotic twins were statistically more likely to have a positive family history of Alzheimer's disease and their first-degree relatives more likely to be affected with Alzheimer's disease than discordant monozygotic twins, suggesting a heritable factor in the concordant monozygotic twins and an environmental factor or a nonheritable genetic change (such as a postzygotic somatic cell chromosomal mutation) in the discordant monozygotic twins.

Alzheimer's disease

PET scan

Survey studies have shown a higher risk of Alzheimer's disease in first-degree relatives of Alzheimer's disease probands than in controls (34,35), although it has not been possible to separate a heritable genetic component from a familial clustering of an environmental event (85). Also, pedigree analysis has shown a limited n u m b e r of families with an autosomal dominant pattern of inheritance (23,86). Within these pedigrees of heritable forms of Alzheimer's disease, heterogeneity also may exist, with chromosome 19 implicated in some families (70) and chromosome 21 in others (22,86). Further, on chromosome 21 at least two families with autosomal dominant Alzheimer's disease show a mutation within the gene for the amyloid precursor protein (22), while other families with autosomal dominant show linkage to genetic markers proximal to the gene for the amyloid precursor protein (86). A h u m a n model of Alzheimer's disease exists that circum-

~Requests for reprints should be addressed to Mark B. Schapiro, M.D., Laboratory of Neurosciences, National Institute on Aging, Bldg. 10, Rm. 6C414, National Institutes of Health, Bethesda, MD 20892. 723

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SCHAPIRO, ttAXBXt AND (.;RADXt

vents this problem of etiologic heterogeneity and allows one to study how brain dysfunction occurs due to suboptimal gene expression. Down syndrome (DS), trisomy 21, is a genetic disorder in which an extra portion of chromosome 21 leads to mental retardation, short stature, and other phenotypic abnormalities (63). Further, DS subjects over age 40 years demonstrate neuropathologic (1,53) and neurochemical (98) defects postmortem that are virtually indistinguishable from those found in brains of Alzheimer's disease patients, a universal cognitive deterioration compared to younger DS adults, and a 20-30% prevalence of dementia (78). Other evidence supports a link between the two disorders: A restriction fragment polymorphism from chromosome 21 segregates with early-onset familial Alzheimer's disease (86); the gene coding for the precursor protein offl-amyloid has been assigned to chromosome 21 (21,87); and the expression of the amyloid precursor protein mRNA lacking the protease inhibitor domain is depressed in both aged DS and Alzheimer's disease brains in neocortical association regions (58). The relation of DS and Alzheimer's disease has been considered in prior reports, but many methodological issues were ignored. DS subjects with significant medical illnesses, such as hypothyroidism and congenital heart disease, were included and medications such as psychotropics were not discontinued during testing. Many subjects were recruited from institutions, where educational and training opportunities were limited. Karyotypes were not mentioned. The level and pattern of mental retardation were not characterized, and, most importantly, the presence or absence of dementia often was not described. Because of opportunities available with newer brain imaging techniques, including positron emission tomography (PET) with [~SF]fluoro-2-deoxy-D-glucose (18FDG) to study brain glucose metabolism and quantitative computed-assisted tomography (CT) to study brain anatomy, our laboratory formulated a program in 1983 to address the age changes and mental retardation in DS adults in concert with a study of A1zheimer's disease. Specific questions that were addressed included: What are the cognitive deficits in adults with DS and how does one distinguish dementia from mental retardation: is there brain atrophy in young or older DS adults: are there changes in brain metabolism in young or older adults with DS; do different parts of chromosome 21 determine dementia as opposed to mental retardation in DS: what hypotheses does DS allow one to generate about the pathogenesis and course of Alzheimer's disease? METHOD

To avoid previously mentioned methodological problems, we studied only carefully screened, healthy, noninstitutionalized DS subjects, whose mental status and cognitive deficits could be quantified (76). All subjects (except one subject to be discussed separately) were trisomy 21 karyotype. The DS group included 20 young adults aged 19-34 years and 9 older adults aged 45-63 years (45, 46, 47, 49, 49, 50, 55, 61, and 63 years). Not all subjects were used in all studies. Screening included a review of the medical history, a physical and neurological examination, blood and urine laboratory tests, electrocardiograph (ECG), and chest radiographs. With the exception of thyroid replacement in several subjects and vitamin B.2 injections for celiac sprue in one subject, none was taking medication (75,76). Controls were participants in the National Institute on Aging-Laboratory of Neurosciences Study on Aging (i 4) and were screened with medical, neurological, and laboratory tests.

Controls had no history of neurological, psychiatric, or syslemic medical disorder. None was taking medication for at least 2 weeks prior to the study. The CT results of young DS adults were compared to results from 16 volunteers aged 2135 years (mean 27.3 years) and the PET results to results from 13 volunteers aged 22-38 years (mean 29.5 years). Neuropathoiogic studies have examined the prevalence of senile plaques and neurofibriltary tangles at different ages in DS. In the report of Mann (51 ), which summarized all previous reported cases, the prevalence of Alzheimer's neuropathology was 15.5% (9/58 cases) at ages 20-29 years and 80.0% (28/35 cases) at ages 30-39 years. These studies of Alzheimer's neuropathology in DS, though, differed markedly in the level of completeness. Studies did not differentiate the presence of senile plaques only vs. the presence of both senile plaques and neurofibrillary tangles, the maturity of the senile plaque, or the density of the lesions. Also, these studies often did not mention the location of the lesions, in particular whether the changes were present in the hippocampus, amygdala, and entorhinal cortex only (where the earliest neuropathologic changes of AIzheimer's disease are noted in DS) (39,52) or in both these limbic regions and the neocortex. Thus, comparison of studies to determine the prevalence of the neuropathologic changes of Alzheimer's disease in DS is difficult. In the largest qualitative study, Matamud (50), although not describing the location, type, or maturity of the lesion, noted that only 5/312 DS brains less than 40 years old had Alzheimer's neuropathology, described as "only occasional and relatively mild changes" (including 1/37 brains 21-30 years old and 3/10 brains 31-40 years old) compared with 35/35 brains over age 40 years. Other qualitative studies, such as those by Burger and Vogel (5) and Haberland (25), noted only primitive plaques without neurofibrillary tangles in the 30- to 40-year age group. In the quantitative neuropathologic study of Wisniewski el al. (97), although 8/8 subjects 31-40 years old were noted to have Alzheimer's neuropathology, mean plaque counts were three to four times larger than neurofibrillary tangle counts. The highest counts of senile plaques and neurofibrillary tangles were after age 50 years. Finally, in a study of the sequence of development of Alzheimer's neuropathologic changes, Mann and Esiri (52) noted that low numbers of primitive plaques were seen only in the hippocampus and amygdala in a 31 year old, that intermediate neuropathologic changes (primitive and mature senile plaques in the hippocampus, amygdala, and neocortex; neurofibrillary tangles in the amygdala, hippocampus, and entorhinal)were seen in subjects aged 37, 38, 40, 41, 42, 43, and 49 years, and that the full spectrum of Alzheimer's neuropathology (large numbers of mature senile plaques and neurofibrillary tangles in both subcortical and neocortical regions) was not present until ages 42, 47, 48, and 50 years. Thus, although it may be argued that, without regard to density, type (senile plaques and/or neurofibrillary tangles), maturity, or location, s o m e DS subjects less than 40 years of age have some degree of senile plaques and/or possibly neurofibriltary tangles, studies show that all subjects over 40 years have some degree of neuropathology, although again the density, type, maturity, and location varies. Therefore, to distinguish mental retardation from dementia DS subjects were divided into those 18-40 years (mentally retarded but relatively free of Alzheimer's neuropathology) and those over 40 years (with definite Alzheimer's neuropathology and possible dementia). In reality, DS subjects in this study at first evaluation ranged in age from 19-34 years in the young group and from 45-63 years in the older group. A battery of neuropsychological tests was employed to mea-

TRISOMY 21: PET, CT, AND NEUROPSYCHOLOGY sure mental age, immediate memory spans, ability to commit new information to long-term memory, and visuospatial and language functions (Table 1). Overall ability was measured using the Stanford-Binet (88) and the Peabody Picture Vocabulary Test--Revised (PPVT) (15). Because visual processing is necessary to interpret the drawings on the latter test, it was considered more a test of overall intelligence than a specific test of language. Immediate memory span was tested with Digit Span, Block Tapping Span, and Object Pointing Span. Block Tapping Span is a modification of Corsi's immediate memory span for spatial locations (56) and Object Pointing Span is a test of immediate verbal memory span that does not require a vocal response

(28). The ability to commit new information to long-term memory was assessed using both the Memory for Object subtest (immediate and delayed) from the Down Syndrome Mental Status Examination (28) and Recognition Memory for Designs (90). Language function was assessed using two tests of expressive ability from the Illinois Tests of Psycholinguistic Ability (42), Grammatic Closure and Manual Expression. The former is a test of the ability to complete sentences with words that have the correct syntactic markers; the latter is a test of the ability to express concepts with manual gestures. In addition, naming, repetition, and comprehension were tested using subtests from the Down Syndrome Mental Status Examination (28). Visuospatial function was tested with the Hiskey Nebraska Block Pattern Subtest (36), the WISC-R Block Design Subtest (93), the Extended Block Design Subtest (28), and the visuo-

725 spatial subtest of the Down Syndrome Mental Status Examination (28). Noncontrast CT imaging was performed using a 8800 CT scanner (General Electric Corp., Milwaukee, WI), for which full width at half m a x i m u m equals 1 mm. Images, obtained parallel to and from 0 to 1 l0 m m above the inferior orbitomeatal (IOM) line, were 10 m m thick with 7-ram interslice spacing. The scanner was standardized daily using an internal program and a water phantom set to a mean CT density of 0 Hounsfield units. Phantoms of differing CT densities were scanned periodically. CT data were stored in digital form on magnetic tape and analyzed on a PDP 11/34 computer (Digital Equipment Corp., Maynard, MA) with a DeAnza Picture Display Monitor (Gould, Inc., Fremont, CA). Using a semiautomated method of analysis, samples each of cerebrospinal fluid (CSF), white matter, and grey matter were visually identified in a standardized manner for each CT slice displayed on the TV monitor. From the mean CT numbers in Hounsfield units obtained for each of these components, representative ranges of CT densities in Hounsfield units were calculated and then used to quantify the numbers ofpixels of CSF, grey matter, and white matter in each CT slice. This CATSEG procedure then determined the total number of intracranial pixels counted for the whole slice and the percentages of the total number of pixeis in each category (12). To minimize the "beam hardening" artifact (13,20), analysis was limited to a 49-mm horizontal volume segment of the brain, starting at the lowest slice that contained the body of the 3rd ventricle (80).

TABLE 1 NEUROPSYCHOLOGYTESTSCORESFOR YOUNG,NONDEMENTEDOLD, AND DEMENTEDOLD DS GROUPS

Intelligence Peabody Picture Vocabulary Test Age (years) Stanford-Binet Mental Age (years) Attention Digit Span (score) Block Tapping (score) Object Span (score) Language Down Syndrome Mental Status Examination Naming Repetition Comprehension Manual expression Grammatic closure New long-term memory Down Syndrome Mental Status Examination Design Span (score) Visuospatial Down Syndrome Mental Status Examination Visuospatial WISC--R Block Design Subtest Extended Block Design Test Hiskey Nebraska Block Pattern Subtest

YoungDS

NondementedOld DS

DementedOld DS

6.7 _+ 3.2 (20) 5.8 ± 2.0 (20)

4.0_+ 1.7 (5)* 4.2 +_ 1.5 (5)

2.4_+ 0.4 (4)* 2.3 _+ 0.4 (3)*

13.2_+ 3.7 (19) 16.7 _+ 6.9 (20) 12.6+ 4.1 (17)

15.0_+ 3.2(4) 8.8 ± 6.0 (5)* 12.0+_ 3.4(4)

6.3+- 3.0(4)*]" 5.8 -+ 2.4 (4)* 6.3_+ 1.2(3)*t

8.8_+ 2.2(19) 4.4+- 1.4(19) 8.8 + _ 2.2(19) 6.8_+ 2.2(18) 5.4_+ 1.9(18)

6.6+- 4.4(5) 4.6+- 1.5(5) 6.4+_ 1.9(5)* 5.4+_ 1.5(4) 4.8+- 1.2(4)

3.5 + _ 2.6(4)* 1.7_+ 2.1 (3)* 2.7-+ 3.1 (3)* 0 (1) 3.3 (I)

2.9+- 0.2 (19) 5.3 _+ 2.3 (20)

2.0_+ 1.2 (5)* 1.8 _+ 1.9 (5)*

0.3+- 0.6 (3)* 1.3 _+ 0.6 (3)*

6.1_+ 1.1 (19) 7.7+_ 7.5 (19) 14.3_+ 1.6(16) 3.1 _+ 1.3 (20)

4.4+_ 0.5(5)* 1.8+- 4.0(5)* 8.0_+ 4.7(5)* 1.0 ± 1.0 (5)*

3.0 + _ 1.0(3)* 0.0_+ 0.0(3)* 4.3_+ 3.9(4)* 0.3 _+ 0.6 (3)*

Values are mean + SD. Differences between mean values in the three groups were compared with a Friedman test ( l-way ANOVA on ranks). Posthoc comparisons were as follows (t7 < 0.05): Young DS vs. nondemented old DS~young DS vs. demented old DS, and nondemented old DS vs. demented DS. Number for subjects shown in parentheses. *Differs from mean in young DS by Friedman test [ 1-way ANOVA on ranks (p < 0.05)]. t Differs from mean in nondemented old DS by Friedman test [1-way ANOVA on ranks (p < 0.05)].

726 With each contrast-adjusted CT slice displayed on a TV monitor, regions of interest (ROIs) also were outlined using a digitalized graphics tablet and light pen. ROIs for the lateral and 3rd ventricles were outlined on each slice in which the structures were seen. For CT slices outside the 49-ram horizontal volume segment, the areas of the cerebrum and cerebellum plus brainstem were traced by following along the edge of the bone. The number ofpixels in each ROI was computed, Volumes of intracranial structures were derived by summing the number ofpixels of a measure of interest, across slices, and multiplying by pixel area (0.0064 c m 2) and interslice distance (0.7 cm). Volumes were expressed in c m 3 o r as a percent of the intracranial volume in the 49-ram horizontal segment that was examined (starting at the lowest slice that contained the body of the 3rd ventricle) (80). The rate of change of a volume of an intracranial structure or tissue category in cm3/year was derived from the slope of the regression line of that volume (cm 3) on time (years) (78). Regional cerebral metabolic rates for glucose (rCMRglc) were measured in DS subjects and healthy controls in the resting state (eyes patched, ears plugged, no external stimulation) using PET and 18FDG. The procedure has been described in detail elsewhere (14,76). For comparing young DS adults with healthy controls, scanning was carried out with a multislice PET scanner (Scanditronix PC-1024-7B, Uppsala, Sweden) that used a measured attenuation correction. This is a sevenslice machine with a transverse resolution (full width at half maximum) of 6 m m and an axial resolution of 10 mm (76). For comparison of young and old DS subjects, scanning was performed with an ECAT I! PET tomograph (ORTEC, Life Sciences, Oak Ridge, TN), which used a calculated attenuation correction program. Seven serial slices were collected, with transverse and axial resolutions (full width at half maximum) of17 mm (14). Subjects fasted for at least 2 h and refrained from alcohol, caffeine, and smoking for at least 24 h prior to the PET scan. A radial artery catheter was inserted percutaneously for blood sampling and an antecubital venous catheter was inserted in the opposite arm for injection of the isotope. Subjects received 5 mCi 18FDG intravenously and then spent 45 min in a darkened and quiet room. Emission scans were performed after 45 min, parallel to and from 10-100 mm above the IOM line. Arterial blood samples were drawn during the uptake period and the scan itself to obtain plasma for measurements of radioactivity and glucose. From the time courses of plasma radioactivity and glucose concentration, and from brain radioactivity at time of scanning, rCMRglc was calculated in units of mg/100 g/min using Brooks' modification (3) of the operational equation of Sokoloff et al. (82). A value of 0.418 was used for the lumped constant. After comparing PET images with anatomic sections from an atlas of a human brain, a "height above the IOM line" of the slice in the atlas was assigned to each PET slice. Anatomic regions of interest in the PET slices were then identified. Regional metabolic rates for larger anatomic areas were obtained by averaging values in circular regions included in that anatomic area. In addition to determining absolute rCMRglc, global cerebral metabolism (CMRglc) was calculated as the weighted mean of rCMRglc in all grey matter regions, excluding the vermis and midbrain. Two indices of relative metabolism were examined in the young DS group: (a) the ratio of rCMRglc to global CMRglc and (b) an asymmetry index, calculated as 2(R L)/(R + L), where R and L represent right and left rCMRglc values in homologous brain ROIs, respectively. To -

SCHAPIRO, HAXBY ANI) GRAD'~ explore whether metabolism in association neocortex is disproportionately reduc.ed in older DS subjects, the ratio of parietal association rCMRglc to sensorimotor rCMRglc (a region relatively spared neuropathologically in Alzheimer's disease) was calculated. Measurements are presented as mean 2 SD. Means of the neuropsychological test scores of the DS groups were compared using a Friedman test [one-way analysis of variance (ANOVA) on ranks]. For metabolic and CT data, differences between mean values in DS subjects and healthy controls were analyzed with an unpaired t-test (72). Differences between mean values in the young, nondemented old, and demented old DS groups were analyzed with a one-way ANOVA with Bonferroni correction for multiple comparisons. Within groups, right and left regional metabolic values and CT measures were compared with a paired t-test (72). The criterion of statistical significance was p < 0.05. NEUROPSYCHOLOGY

Although some investigators believe it is difficult to diagnose dementia in mentally retarded subjects, our studies show that such a distinction can be made using specific diagnostic criteria. In our laboratory, the diagnosis of dementia of the Alzheimer type in DS was made using modified criteria from the Diagnostic and Statistical Manual, which specified an acquired, progressive loss of intellectual function, such as loss of daily living and vocational skills, memory impairment, reduced speech and comprehension, and personality change (76). The diagnosis of dementia was based upon interviews with caregivers or employers, clinical examination, and bedside mental status tests. Previous medical and psychological reports were reviewed when available. To evaluate interrater reliability for the diagnosis of dementia in our subjects, a ~-statistic (2) was calculated in a previous study (78). For two physicians independently rating each subject, the ~ was 0.828 (p < 0.001), suggesting that the agreement was better than by chance (78). Extensive neuropathologic changes of Alzheimer's disease (including numerous senile plaques and neurofibrillary tangles in limbic and neocortical regions) were noted at autopsy of three older demented subjects who had been studied in life and are part of this article (55-year-old woman; 47and 66-year-old men). In a previously reported quantitative study of one of these subjects (47 years old), the number of neurofibrillary tangles and extent of neuronal loss was greater than in nondemented age-matched DS subjects, comparable to values in severely demented Alzheimer's disease patients (1). Despite the universal development of some degree of neuropathologic changes of Alzheimer's disease in DS (see above), only a minority of older DS adults demonstrate clinically significant dementia (27,97). Dementia in DS in such studies is usually described in terms of decreased self-help skills, poor memory, loss of speech, and behavioral disorder. In contrast, the early diagnosis of dementia in premorbidly normal subjects is usually made by observing problems in nonroutine activities that require the processing and retention ofnew information. Changes in routine skills, such as those described for the diagnosis of dementia in DS, occur relatively late in the disease in premorbidly normal subjects. Thus, the discrepancy in neuropathology and the diagnosis of dementia in DS may be due to the insensitivity of caregiver reports and of clinical examination to the early behavioral changes of dementia associated with Alzheimer's disease neuropathology, suggesting the necessity of finer instruments (such as standardized neuropsychological testing).

T R I S O M Y 21: PET, CT, A N D N E U R O P S Y C H O L O G Y In fact, previous neuropsychological cross-sectional studies using questionaires (60,95) or neuropsychological test batteries (8,89) in DS have shown that cognitive changes occur with age in DS and are more c o m m o n than dementia. However, these prior studies did not examine patterns of neuropsychoiogical impairment and thus could not determine if similar patterns of impairment existed in older DS adults and premorbidly normal Alzheimer's disease subjects. In the latter, a characteristic pattern of changes occurs, with impaired ability to form new long-term memories the earliest deficit, followed by inability to sustain attention to complex tasks, and later impaired language and visuospatial abilities (31 ). Therefore, we sought to determine whether standardized neuropsychological testing would reveal earlier and more prevalent changes in cognition than standardized clinical criteria for dementia by studying nondemented older DS subjects and comparing them to young and demented older DS groups. Also, by using an extensive battery of neuropsychological tests we sought to determine if patterns of neuropsychological impairment in older DS subjects were similar to the selective pattern of impairment seen in early to moderately demented AIzheimer's disease in premorbidly normal subjects. A battery of neuropsychological tests therefore was designed to examine patterns of age-related neuropsychological changes in older DS adults with and without dementia. Overall ability, as measured with the PPVT (15), was 6.7 _+ 3.2 (mean +_ SD) years in 20 young DS subjects, 4.0 _+ 1.7 years in 5 nondemented old DS subjects, and 2.4 _+ 0.4 years in 4 demented old DS subjects (see above for defining criteria for dementia) (28). Mean mental age on the Stanford-Binet Test (88) was similar. The demented older DS group had lower scores than the young DS group on both measures. However, the nondemented older DS group did not differ from younger subjects on the Stanford-Binet Test. Median mental ages on the Stanford-Binet were 5.3 years in the young DS group, 5.2 years in the nondemented older DS group, and 2.1 years in the demented older DS group. Further, nondemented older DS adults did not differ from young DS adults on several tests of attention or language. This suggests that, as young adults, nondemented older subjects probably had equivalent mental abilities to young DS subjects' current level of function (28). Multiple cognitive areas were specifically evaluated, including immediate memory, long-term memory, language, and visuospatial ability (Table 1). Mean immediate verbal memory spans (i.e., digit and object pointing spans) did not differ significantly between young and nondemented old DS subjects. However, nondemented old DS subjects had lower visuospatial memory spans (i.e., block tapping span) than young DS subjects, suggesting that there is a greater loss of immediate visuospatial memory than immedate verbal memory with aging without dementia in DS. Demented older DS subjects demonstrated poorer performance on both visual and verbal immediate span tests compared to young DS adults. Both nondemented and demented old DS adults differed significantly on tests of new long-term memory and visuospatial construction. Finally, young and nondemented old DS subjects did not differ on tests of language. Demented older subjects in general were not able to perform the language tests; scores from demented older DS subjects were at the lower end or below scores from young DS subjects. As suggested by these findings, cognitive changes, as measured with standardized neuropsychological tests, occur with age in Down syndrome. Our results show that standardized neuropsychological testing can detect these cognitive changes not evident clinically as dementia and that such cognitive

727 changes occur more frequently than dementia. On the other hand, dementia, based upon caregiver reports and clinical examination, occurs only in a fraction of older DS adults. These findings also show that cognitive changes are more severe in demented as compared to nondemented older DS subjects, suggesting two levels of mental deterioration in older DS subjects(28). In addition, in nondemented older DS there is a distinctive pattern of spared abilities (such as immediate verbal memory and language) and diminished abilities (such as long-term memory and visuospatial immediate memory and construction) that resembles the selective pattern of cognitive loss in premorbidly normal subjects with mild Alzheimer's disease. Loss of ability to form new long-term memories is the most consistent loss in these nondemented older DS subjects, similar to the pattern seen in early to intermediate dementia of the Alzheimer type in premorbidly normal subjects where loss of long-term memory is the most prominent and early deficit. A more global pattern of cognitive failure occurs in demented older subjects, suggesting correspondence to severe dementia in premorbidly normal Alzheimer's disease patients (28). It is thought that this distinctive pattern of neuropsychological impairment is not due to normal aging (28). As suggested above, the pattern of changes described is analogous to the pattern seen in early to moderate Alzheimer's disease in premorbidly normal subjects. In both groups, inability to form new long-term memories is the most consistent and earliest deficit. As shown in longitudinal studies ofpremorbidly normal adults with only memory impairment who later met standard criteria for AIzheimer's disease, neocortical nonmemory cognitive functions may show no deficits for several years (24,32). Further, both groups show a selectivity to the pattern of nonmemory deficits that later develop, such as the decreased visuospatial and preserved language in Down syndrome. However, it must be considered that the pattern of cognitive changes in nondemented DS may be analogous to that pattern found in normal aging, where the most prominent changes are in memory and visuospatial function, as well as perceptual motor speed (29,43,91 ). The cause of alterations of cognitive function with aging are unclear. One recent study suggests that a large fraction of normal older adults may have immunocytochemical evidence of #-amyloid protein deposition in their neocortex (9). As suggested by Haxby and Schapiro (33), it may be that some portion of the cognitive changes in normal aging, as well as in nondemented older DS, may be related to some degree of #-amyloid protein deposition. Further longitudinal cognitive studies, as well as supportive serial brain imaging studies (see below), in nondemented older DS subjects will be necessary to determine clearly whether the cognitive changes observed represent a prodrome of Alzheimer's disease (which resembles normal age-related changes) or simply normal agerelated changes. QUANTITATIVE CT

Previous pathologic studies have suggested that brain weight in young DS adults is less than normal, but extreme micrencephaly is rare (84). From such pathologic studies, it is unclear whether cerebral atrophy occurs in young DS patients (5,97). Because CT measures of brain avoid postmortem problems (80), we used quantitative CT to evaluate the dimensions of brain, CSF, and cerebral ventricles in DS subjects (Table 2). As reported previously (74), mean total intracranial volume was significantly less in 18 young DS adults than in 16 young healthy controls (1,067 +_ 90 cm s vs. 1,241 + 120 cm s) (p <

728

SCHAPIRO, HAXBY AND GRA[)~ "FABLE 2 CSF A N D BRAIN M A T T E R VOLUMES FOR YOU NG D O W N S Y N D R O M E ADULTS AND C O N T R O L S OBTAINED BY QUANTITATIVE CT SCANNING Controls

CATSEG analysis CSFvolume (cm 3) % CSF volume* Grey matter + white matter volume (cm 3) % Grey matter + white matter volume* Region of interest analysis Third ventricle (cm 3) Left lateral ventricle (cm 3) Right lateral ventricle (cm 3) % Third ventricle* % Left lateral ventricle* % Right lateral ventricle* Cranial volume Total cranial (cm 3)

DS

18.8 2.4 759 97.6

± 11.4(16) _+ 1.4 + 48 + 1.4

25.9 3.7 664 96.3

_+ 14.0(18) _+2.0 +_40f _+2.0

0.7 8.3 7.8 0.09 1.06 0.99

_+0.4 _+5.6 -+ 4.5 -+0.05 _+0.72 _+0.55

0.7 8.7 11.2 0.10 1.27 1.62

_+0.4 _+4.8 _+6.6 _+0.05 +_0.71 +_0.93

1,241 -+ 120

1,067 _+901

Values are mean _+ SD. Differences between mean values in DS and control groups were compared with an unpaired t-test (p < 0.05). *Normalized to seven-slice cranial volume. TM fDiffers from mean in control by unpaired t-test (p < 0.05).

0.05). Grey matter plus white matter volume also was significantly less in young DS subjects (664 _+ 40 cm 3) compared to controls (759 + 48 cm 3) (p < 0.05) (74). However, after normalization to seven-slice intracranial volume (to correct for the smaller cranial vault in DS) there was no longer any difference between groups in grey matter plus white matter volumes. In addition, CSF and ventricular volumes, either directly or after normalization to seven-slice intracranial volume, did not differ between groups (74). Despite wide variability of mental ages in the young DS group, there was no difference in CT measures between high-functioning (mental age > 8 years) and low-functioning DS subjects, except for an increased third ventricular volume in high-functioning subjects. Although Alzheimer's disease is accompanied by progressive cerebral atrophy on quantitative CT (49), it is not known to what extent demented older DS adults have cortical atrophy. Postmortem studies in older DS subjects have suggested that atrophy usually, although not always, occurs, but it is unclear if brain weight declines with age in DS (5,16,25,37,40,59,79,83,96). We therefore used quantitative CT to study DS adults who had two or more CT scans, in crosssectional and longitudinal analyses, to examine whether differences in brain morphology help distinguish dementia from mental retardation. As shown previously in these cross-sectional studies (78), we found no difference in total intracranial or seven-slice intracranial volume between DS groups. When 5 nondemented older and 12 young adult DS subjects were compared, there was no significant difference in mean volume of CSF, grey matter plus white matter, or ventricles, directly or after normalizing to seven-slice intracranial volume (78). However, significant increases in mean CSF volume and mean third ventricle volumes, directly or after normalizing to seven-slice intracranial volume, were shown between 3 demented older and t2 young DS subjects and between 3 demented and 5 nondemented older subjects. Further, demented older subjects had mean total ventricular volumes that were increased by 85% and 102% as compred to volumes in young and nondemented older groups, respectively (although this failed to reach signif-

icance) (78). Also. demented older subjects had a mean grey matter plus white matter volume (normalized to seven-slice intracranial volume) that was significantly less than in the two DS groups. In longitudinal studies (78), CT scans were separated by an average of 43 months in the 12 young DS subjects, 20 months in the 5 nondemented old DS subjects, and 22 monthsin the 3 demented older DS subjects. A slight increase for rate of change (dilatation) of CSF volume was observed between the nondemented old DS group as opposed to the young DS group (2.50 + 1.81 vs. - 1.32 _+ 1.90 cm~/year, respectively) (p < 0.05) (Table 3). Greater rates of increase of CSF volume were noted between the demented older DS group and young DS group (10.90 -r 4.32 vs. 1.32 z 1.90 cm3/year, respectfully) (p < 0.05) (Table 3). These rates of change for CSF volumein the demented old DS group also differed significantly from those in the nondemented old DS group. Increased rates of change for lateral ventricles also were noted in demented older DS subjects compared to young and nondemented DS subjects (78). Thus, in young adults with DS the smaller brains reflect the smaller stature and smaller cranial vault present in this syndrome. This is similar to findings in male and female controls. where it is established that brain weight is proportional to body height (11). No cerebral atrophy occurs in young DS adults. suggesting that the mental retardation is related to inherent cerebral dysfunction and not to acquired cerebral atrophy. Further, cross-sectional and longitudinal studies using quantitative CT differentiate nondemented and demented older DS subjects, in agreement with two qualitative CT studies (7,48), The results suggest that exaggeratedincreases inCSF and ventricular volumes occur only in older DS subjects who have clinically evident dementia, not in those without dementia. A previous serial quantitative CT scan study in our laboratory showed accelerated rates of ventricular dilatation in Alzheimer's disease as compared to controls (49). Together. that and the current study suggest that rates ofventricular enlargement distinguish demented from nondemented subjects (with or without DS). Thus, demented older DS adults have

729

TRISOMY 21 : PET, CT, AND NEUROPSYCHOLOGY TABLE 3 RATESOF CHANGEOF CEREBROSPINALFLUIDAND BRAINMATTERVOLUMESFOR DOWNSYNDROMEADULTS YoungDS (12) CATSEG analysis CSFvolume Grey matter + white matter volume Region of interest analysis Third ventricle Left lateral ventricle Right lateral ventricle

Nondemented Old DS (5)

DementedOld DS (3)

-1.32 _+ 1.90 -0.17 +_ 5.85

2.50 ± 1.81" 3.28 _+11.63

10.90 +4.32"t 10.41 +3.11

0.027 _+ 0.056 0.52 _+ 0.51 -0.27 ± 0.58

0.115 _+0.232 0.00 + 0.76 0.00 _+0.75

0.131 +0.599 2.18 +_2.99* 3.91 _+2.14"t

Values are mean _+ SD in units of cm3/year. Differences between mean values in DS groups were compared with a one-way ANOVA. Posthoc comparisons using Bonferroni t-tests were as follows (p < 0.05): Young DS vs. nondemented old DS, young DS vs. demented old DS, and nondemented old DS vs. demented DS. *Differs from mean in young DS by Bonferroni t-test (p < 0.05). +Differs from mean in nondemented old DS by Bonferroni t-test (p < 0.05).TM

accelerated brain atrophy, indicating that neuronal loss, in addition to accumulation of senile plaques and neurofibrillary tangles, is critical for dementia in subjects with or without DS. In this regard, although quantitative cross-sectional studies of volumes of postmortem cerebral cortical grey matter and white matter have not been performed in DS, one histological study found fewer pyramidal cells in the hippocampal cortex of a demented DS subject than in brains from five DS subjects without documented dementia ( 1), whereas a second showed fewer neurons in cerebral cortex in old DS in comparison to agematched normals or young DS (although mental state was not described) (51). Because accelerated cerebral atrophy occurs only in demented older DS adults, such results suggest that quantitative CT can help distinguish dementia from the lesser (but nevertheless present) cognitive decline in older DS subjects. Cell counting to detect cell loss, in the postmortem DS brain studied prospectively with neuropsychological testing and documentation of dementia status, also may help distinguish demented from nondemented DS subjects, rather than counting only senile plaques and neurofibrillary tangles.

PET As a reflection of neuronal aetivity, cerebral oxidative metabolism and cerebral blood flow (CBF) have been studied in young adults with DS. No differenee in global eerebral oxygen consumption between young DS subjeets and age-matehed controls was shown using the Kety-Sehmidt nitrous oxide saturation teehnique in two studies (18,46), while no differenee in CBF was shown using 133 Xenon inhalation in another study (67). A seeond study with 133 Xenon showed redueed CBF, although older subjeets were included (55). An initial study with PET and 18FDG showed increased brain glueose metabolism, but a calculated attenuation correction was used that was not valid in DS subjeets due to the smaller eranial eapaeity and thinner skulls (81). We reevaluated brain metabolism using PET and 18FDG to learn i f there are differenees in absolute eerebral metabolic rates for glucose between young DS adults and age-matehed eontrols, as well as to learn i f there are ehanges in patterns of metabolism prior to the development of Alzheimer's neuropathology. As previously reported (75), there was no significant differenee in global or grey matter rCMRgle between young DS and eontrols subjeets. Global CMRgle was 8.76 + 0.76 rag/ 100 g/min (mean ± SD) in 14 young DS adults vs. 8.74 + 1.19

mg/100 g/min in 13 young controls (p > 0.05). Normal rCMRglc was preserved in neocortical association areas, as well as primary motor and sensory cortical areas. Reference ratios (rCMRglc/global CMRglc) also did not differ between groups. In addition, within the DS group subjects with mental ages over 8 years did not differ from those with mental ages less than 8 years for any rCMRglc (75). Thus, young DS adults ( < 4 0 years and without dementia) do not have altered cerebral glucose metabolism, at rest and with reduced sensory input, despite their mental retardation. In addition, reference ratios show no consistent difference in the intrahemispheric distribution of rCMRglc compared to controls. Similar findings also were noted in our subjects with 133 Xenon inhalation studies, which showed no alteration in regional CBF (73). The lack of selective metabolic involvement of neocortex in young DS adults differs from that pattern seen in demented older DS adults (see below). Finally, metabolic differences cannot identify young DS adults "at risk" for Alzheimer's neuropathology, which occurs after age 40 years. Although standard group comparisons did not show differences in rCMRglc between young DS adults and controls, a prior correlational analysis, using resting glucose metabolic data from the ECAT PET scanner, did show disruption in patterns of brain regional interactions in young DS adults (38). In this method of analysis, the correlation coefficient is used as a measure of functional association between brain regions. In comparison to controls, young DS adults had reduced correlations for pairs of regions within and between frontal and parietal lobes. The inferior frontal gyrus that included Broca's area was one region in particular involved (38), consistent with reports of disproportionate language disability in DS (19). Brain metabolism and blood flow also have been studied in older DS adults. Although not specifically looked for, age-related differences in blood flow and metabolism were not shown, and dementia was not examined. In our laboratory, PET with 18FDG was used to determine if there are age-related differences in brain glucose metabolism in DS and if differences in brain metabolism help distinguish dementia from mental retardation in DS adults over 40 years. Table 4 shows representative absolute values of rCMRglc for young, nondemented old, and demented old DS groups. For both association and primary neocortices, nondemented old DS subjects had glucose metabolic values more similar to those in the young DS subjects, as indicated by the lack of significant differences between nondemented old and young DS

SCHAPIRO. HAXBY AN[)GRAD'~

73O TABLE 4 REGIONAL CEREBRAL GLUCOSE METABOLISM IN OI.DFR DS ADULTS (rag/100 g/rain)

Association neocortex Parietal Lateraltemporal Primary neocortex Sensorimotor Occipital

Young DS (15)

Nondemented Old DS (4)

DementedOld DS (3)

7.14 +0.24 5.65 _+0.18

6.29 _+0.51 5.07 +0.27

4.19 +_0.49"t 3.68 _+0.33"t

7.58 _+0.25 6.43 _+0.21

6.87 _+0.59 6.30 _+0.15

5.21 _+0.56* 4.92 _+0.64*

Values are mean _+ SD in units of mg/100 g/min. Differences between mean values in DS groups were compared with a one-way ANOVA. Posthoc comparisons using Bonferroni t-tests were as follows (p < 0.05): Young DS vs. nondemented old DS, young DS vs. demented old DS, and nondemented old DS vs. demented DS. *Differs from mean in young DS group (p < 0.05). ~-Differs from mean in nondemented old DS group (p < 0.05). subjects. On the other hand, demented older DS subjects had significantly lower values of rCMRglc than young DS subjects, with the greatest reductions in the association neocortices. The demented older group also had significantly lower values of rCMRglc in association neocortices in comparison to nondemented older DS subjects. Thus, decreased brain metabolism is seen only in older DS subjects with dementia. The intrahemispheric distribution of glucose metabolism was examined with the ratio of parietal association cortex to sensorimotor primary cortex. There was no significant difference between 15 young and 4 nondemented older DS subjects (0.94 + 0.01 vs. 0.92 + 0.03)(mean _+ SEM,p > 0.05). However, the ratio in three demented older DS subjects (0.80 _+ 0.01) was significantly less (without overlap) (p < 0.05) than in both young and nondemented older DS subjects. Similar changes were shown for the ratio of temporal association cortex to primary occipital cortex. Thus, glucose metabolism is preserved in older DS subjects without clinical dementia but is reduced in older DS subjects with clinical dementia. However, in the latter the metabolism is not uniformly reduced, with relatively greater involvement of parietal-temporal association neocortices and relative sparing of primary sensorimotor neocortex, cerebellum, thalamus, and caudate and lenticular nuclei. Such a pattern is similar to that seen in patients with Alzheimer's disease who only have a memory deficit (30). In Alzheimer's disease, reduced glucose metabolism in association neocortex occurs early and throughout the course of the disease and indicates that the relatively greater metabolic involvement of parietal-temporal association neocortices occurs with dementia both in subjects with or without DS. As indicated by Rapoport (64), in Alzheimer's disease this regional distribution of metabolic impairment reflects the localization of neuropathology in association regions dominated by interconnecting corticocortical projections rather than in primary neocortex, which are dominated by specific thalamic input (4,47,61,68). Within the association neocortex, neurofibrillary tangles are located in layers that are the source of corticocortical connectivity (layers III and V), as well as corticofugai connections (layer V) to regions outside the neocortex that are functionally related to the association regions. A similar regional (16,51)" and laminar (16,62) distribution of Alzheimer's neuropathology has been described in DS. Such a

pattern of l'unctional and pathologic abnormalities occurs m regions that underwent disproportionate growth during human evolution. It has therefore been argued by Rapoport that Alzheimer's disease in both DS and premorbidly normal subjects is a phylogenic neurodegenerative disease, possibly unique to humans (64). HYPOTHESIS

Despite the universal presence of some type and degree of neuropathologic changes of Atzheimer's disease after age 40 years in DS patients, others have previously noted that only 20-30% of older DS subjects were demented. Explanations for the discrepancy include the difficulty of diagnosing dementia in mentally retarded subjects (57,66), retrospective nature of the studies, delay of age of onset of dementia (94), variable clinical course of dementia (89), or resistance to the development of dementia in a less sensitive brain (94). As in these reports, only a fraction of our older DS subjects were demented despite the likelihood, given their poor performance on standardized neuropsychological tests (which cannot be attributed to normal aging--see above), that all had some neuropathologic changes of Alzheimer's disease. As another explanation of the discrepancy between the presence of neuropathology and dementia; some authors have argued that it is the density, rather than the mere presence of senile plaques and neurofibrillary tangles, that correlates with dementia severity (97), although others disagree (69). In the study of Wisniewski et al. (97), although all 49 brains from subjects over 30 years of age had some degree ofAizheimer's neuropathology only 13 had a history of dementia. Even in those brains with more than 20 senile plaques or neurofibrillary tangles per high-power field, only 13 of 28 subjects had a history of dementia (97). However, in that study 11/13 brains with a history of dementia had both senile plaques and neurofibrillary tangles in large quantities; it was not stated if the other 15 brains had significant accumulations of neurofibrillary tangles. This suggests that an additional factor contributes to the expression of dementia in older DS subjects. This factor may be the additional appearance of large numbers of neurofibrillary tangles and neuronal cell loss in the neocortex, which may occur 10-20 years later than the appearance of large numbers of senile plaques (5,25,52,97). In addition to the retrospective study of Wisniewski et al. (97) noted above, several prospective studies have reliably tested mental status prior to death and correlated such findings with postmortem neuropathology. Both Wisniewski et aL (96) and Lai et al. (45) found that brains of demented DS subjects had marked accumulations of both senile plaques and neurofibrillary tangles in both hippocampal and neocortical areas. In addition, Ball et al. (1) noted that adjusted tangle index in the hippocampus of a prospectively identified demented DS subject was higher than in four of five DS subjects not known to have been demented. Thus, studies that have reliably identified dementia in DS prior to death show large numbers of both senile plaques and neurofibrillary tangles postmortem. In addition to this temporal sequence of changes (large numbers of neurofibrillary tangles after senile plaques), another variable that has not been fully explored is the spatial sequence of the neuropathology. Studies of Mann and Esiri (52), although they did not examine mental status, have shown such a spatial sequence of neuropathologic changes, with the earliest changes occurring in the hippocampus, amygdala, and entorhinal cortex and the latest in the neocortex. In the large studies of pro-

TRISOMY 2 l: PET, CT, AND N E U R O P S Y C H O L O G Y spectively identified demented subjects of Wisniewski et al. (96,97) and Lai et al. (45) (cited above), both senile plaques and neurofibrillary tangles were seen in limbic regions (including the hippocampus) and neocortical regions in DS subjects known to have been demented. In addition to this temporal and spatial sequence of changes, other neuropathologic studies by Mann (51 ) and Ellis (16) suggest that once the full spectrum of neuropathologic changes occurs in DS they are particularly prominent in the association neocortex. On the basis of our findings and previous reports, we suggest that a cognitive decline in older adult DS subjects occurs in two stages that can be separated by as much as 20 years. First, there is a reduction in cognitive performance on standardized neuropsychological tests, perhaps reflective of poorer processing skills. Such cognitive changes are thought to reflect the prodrome of Alzheimer's disease, although it may be possible that these changes represent premature normal aging. This reduction in cognitive function occurs at an age that coincides with the age at which accumulation of marked numbers of senile plaques occurs but prior to the time when neurofibrillary tangle accumulation, cell loss, and atrophy in the neocortex occur to any extent. Our studies of subjects at this stage show absence of a progressive change in CSF and ventricular volumes on quantitative CT scanning and retention of normal patterns of brain metabolism on PET scanning in the nondemented older DS group as compared to the young DS group. In the second stage of cognitive decline, there is additional loss ofoverlearned behaviors, leading to deterioration in social, occupational, and adaptive skills, and a characteristic dementia. Concurrently, it is suggested that accumulations of neurofibrillary tangles and accelerated cell loss become evident, in particular in the phylogenetically newer neocortical association regions. As seen in our demented older DS group, progressive brain atrophy on quantitative CT is suggestive of such cell death, while decreased brain metabolism (in particular in association neocortex) is suggestive of either dysfunctional or dead cells. In another study from our laboratory, we noted that in individual subjects with Alzheimer's disease densities of neurofibrillary tangles, but not of senile plaques, in the neocortex postmortem correlated with the extent of reduction of regional brain metabolism prior to death. Further, neocortical association areas, in general, had the lowest metabolic rates and the highest neurofibrillary counts, emphasizing their selective regional vulnerability in Alzheimer's disease (10). This latter study suggests that decreased brain metabolism in Alzheimer's disease reflects dysfunctional cells (with neurofibrillary tangles a marker of this dysfunction) in the neocortex in Alzheimer's disease. This relatively greater involvement of neocortical association areas further supports the concept that Alzheimer's disease results from dysfunctional pyramidal cells in the association neocortices, the source of the long intracortical and corticofugal fibers. Such a temporal sequence of pathologic changes also has been described in premorbidly normal subjects who were prospectively studied with cognitive tests prior to death: Cognitively impaired yet nondemented subjects had senile plaque accumulation only; demented subjects with the diagnosis of Alzheimer's disease had accumulations of both senile plaques and neurofibrillary tangles (6,41). Although reports exist of demented subjects (in particular older subjects) who have senile plaques without neurofibrillary tangles, the contribution of concurrent vascular disease or loss of subcortical afferents was not quantitated in these cases. Thus, our results suggest that progressive brain atrophy and

731 reduced brain metabolism occur only in demented old DS subjects and quantitative CT and PET scanning with 18FDG can help distinguish dementia from lesser cognitive decline in older DS subjects. MOSAIC/TRANSLOCATION DOWN SYNDROME

When dementia was described previously in DS, subjects first had been already mentally retarded. Thus, the relation of mental retardation and dementia has not been defined. We had the opportunity to study and report a case of DS who developed dementia without mental retardation (77). A 45-year-old woman presented with a 2-year history of dementia. As an infant, her physician suggested that she might have DS but this was not followed up. She attended regular classes and graduated from public high school with average grades. For the next 25 years, she was employed as a teller and clerk-typist until onset of her dementia. Cognitive decline then continued over the next 2.5 years until presentation to us. Examination showed normal stature and head circumference. Stigmata of DS included brachycephaly, midfacial hypoplasia, bilateral clinodactyly, and a right Simian crease. There were no Brushfield spots, small ears, enlarged tongue, or heart murmur. Analysis of peripheral blood karyotype with Giemsa-trypsin showed a single cell ( 1/ 100) with an absent chromosome 21 and an atypical small metacentric chromosome with banding consistent with a t(21;21) rearrangement. In the other cells with 46 chromosomes, there appeared to be two normal 21 chromosomes and no abnormalities of the other autosomes or sex chromosomes. A repeat methotrexate-synchronized highresolution study of peripheral blood was normal. Two subsequent blood studies detected the translocation in a low percentage of cells. One of two fibroblast cultures from a skinpunch biopsy showed a 46,XX, - 21, + t(21 ;21 ) translocation trisomy 21 karyotype in all cells. In the other fibroblast culture, there were two normal-appearing number 21 chromosomes, and a normal chromosome count of 46 in all cells. Additional skin-punch biopsies yielded cell lines with 0-20% trisomic cells. Peripheral blood karyotypes of both parents were normal. Initial neuropsychological assessment showed a WAIS Verbal IQ score (92) of 85, within the normal range. On the other hand, her initial score on the Mattis Dementia Scale (54) was 121 (normal > 136), indicative of mild dementia. Subsequent neuropsychological assessment showed decline in cognitive abilities. Further, similar to Alzheimer's disease, she had dilated ventricles on quantitative CT scanning and reduced parietal and temporal glucose metabolism on PET scanning with 18FDG. Thus, Alzheimer's disease in DS may occur without mental retardation (71,77). In light of the normal body growth, absence of mental retardation, and minimal physical stigmata of DS in this case, it is suggested that the typical phenotypic expression of DS is not necessary for the late expression of dementia in DS. Development of dementia in DS may involve genes in regions of chromosome 21 other than the so-called "obligatory" DS region (q22.2 or q22.3) (63) given the relative lack of phenotypic expression of DS in this case. Our chromosomal findings in this case suggest that this region is not on the short arm of chromosome 21 and could be proximal to the q22.2 band. This is supportive of the studies by St. GeorgeHyslop et al. (86) suggesting that there is a locus for susceptibility to familial Alzheimer's disease on the proximal portion of the q arm of chromosome 21 near the centromere, as well as

732

SCHAPIRO, HAXBY AND GRAI)Y

the studies o f G o a t e et al. (22) suggesting a mutation within the gene for the amyloid precursor protein. Alternatively, in this case where only a portion of somatic cells carry the translocation differential expression of genes on the long arm of chromosome 21 might cause the dementia without the phenotypic features and mental retardation of DS. For example, Neve et al. (58) showed in fetal DS brains that amyloid protein precursor m R N A is increased 4.6 times compared to normal, rather than the expected increase of 1.5 times, which has been shown for genes near the critical DS region (17). Finally, because our subject's dementia developed at the age at which subjects with DS develop the neuropathology of Alzheimer's disease one may assume that cells in her brain are trisomic for chromosome 21 (26). Although the degree of trisomy of her brain cells is uncertain, mosaicism, rather than full trisomy 21, in the brain is suggested by the peripheral mosaicism of blood and skin fibroblasts and, perhaps, by her lack of mental retardation (26). This suggests that only a portion of cells in the brain need to be trisomic for the development of Alzheimer's disease. It is possible that once a portion of cells are afflicted with Alzheimer's disease a cascade effect develops and the disease explodes with the resulting characteristic type and sequence of morphological changes and pattern of distribution of neuropathology. The development of such a cascade may require a threshold of cells to develop, localization of the Alzheimer's changes in a critical location (i.e., limbic or neocortical association), or involvement of certain cortical systems or subsets of brain cells (i.e., pyramidal neurons that furnish corticocortical or corticofugal projections to functionally and anatomically related regions).

('ON('LtlSIONS

In Down syndrome, an extra portion of chromosome 2i results in a dementia syndrome phenotypically identical to Alzheimer's disease in premorbidly normal individuals. The diagnosis of dementia can be made reliably in Down syndrome despite the mental retardation. However, more sensitive formal neuropsychological tests are needed to detect lesser cognitive decline in nondemented older DS subjects. Both quantitative CT and PET scanning with 18FDG can distinguish dementia from the lesser cognitive decline that also occurs in older DS subjects. Identical patterns of abnormal glucose metabolism, selectively involving association areas of parietal and temporal neocortices, are present in older DS subjects with dementia and Alzheimer's disease patients. Further, progressive brain atrophy is present in demented DS as well as Alzheimer's disease patients. Finally, dementia in DS can occur without mental retardation, suggesting that expression of dementia may involve genes on chromosome 21 other than in the obligatory distal segment of the q arm. A limitation of our work is that the older DS groups include only limited numbers of subjects. Such small group sizes may reduce the statistical power of our data analyses and thus limit the generalizability of the results. Therefore, it is crucial that our findings be repeated with larger sample sizes. Such research should continue to show the importance of chromosome 21 for the study of Alzheimer's disease and how abnormal excess or differential expression of different genes on this chromosome leads to different features, such as mental retardation or dementia.

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