Cerebral metabolic pattern in obsessive-compulsive disorder: Altered intercorrelations between regional rates of glucose utilization

Correlations between normalized regional cerebral metabolic rates for glucose, determined by positron emission tomography with ¹⁸F-2-fluoro-2-deoxy- -glucose, were used to investigate functional associations between pairs of brain regions in 18 adult patients with primary obsessive-compulsive disorder (OCD) of childhood-onset, as compared with 18 age- and sex-matched control subjects. The number of correlations that differed significantly between the two groups exceeded chance, although as many of these correlations were larger in the OCD group relative to controls as were smaller. The two regions that had the largest number of correlations that differed significantly between groups were a left hemisphere superior parietal region and the left hemisphere anterior medial temporal area (which includes principally the amygdala). Correlations involving the caudate nuclei did not differ between the two groups for the most part. Anterior limbic/paralimbic regions had correlations in the OCD group that were significantly larger with frontal areas than in controls, and correlations that were significantly smaller with posterior brain regions. This pattern was especially pronounced for the left hemisphere anterior medial temporal region. These results suggest that the correlation pattern in OCD is not characterized by an overall loss of functional integration but, rather, by functional reorganization.     

Cerebral metabolic pattern in obsessive-compulsive disorder: altered intercorrelations between regional rates of glucose utilization.

Correlations between normalized regional cerebral metabolic rates for glucose, determined by positron emission tomography with 18F-2-fluoro-2-deoxy-D-glucose, were used to investigate functional associations between pairs of brain regions in 18 adult patients with primary obsessive-compulsive disorder (OCD) of childhood-onset, as compared with 18 age- and sex-matched control subjects. The number of correlations that differed significantly between the two groups exceeded chance, although as many of these correlations were larger in the OCD group relative to controls as were smaller. The two regions that had the largest number of correlations that differed significantly between groups were a left hemisphere superior parietal region and the left hemisphere anterior medial temporal area (which includes principally the amygdala). Correlations involving the caudate nuclei did not differ between the two groups for the most part. Anterior limbic/paralimbic regions had correlations in the OCD group that were significantly larger with frontal areas than in controls, and correlations that were significantly smaller with posterior brain regions. This pattern was especially pronounced for the left hemisphere anterior medial temporal region. These results suggest that the correlation pattern in OCD is not characterized by an overall loss of functional integration but, rather, by functional reorganization.     

The cerebral metabolic landscape in autism. Intercorrelations of regional glucose utilization

Correlations between regional cerebral metabolic rates for glucose (rCMRglc), determined by positron emission tomography using 18F-2-deoxy-2-fluoro-D-glucose, provide a measure of the functional associations between brain regions. We compared correlations between ratios of resting rCMRglc to global brain metabolism from 14 healthy autistic men (ages, 18 to 39 years) with those from 14 matched control subjects. The autistic group showed significantly fewer large positive correlations between frontal and parietal regions, particularly those with the left inferior frontal region and its right hemispheric homologue, and significantly lower correlations of the thalamus, caudate nucleus, lenticular nucleus, and insula with frontal and parietal regions, with many correlations negative in the autistic group that were positive in the control group. These results are compatible with functionally impaired interactions between frontal/parietal regions and the neostriatum and thalamus, regions that subserve directed attention.     

Intercorrelations of regional cerebral glucose metabolic rates in Alzheimer''s disease

Patterns of cerebral metabolic correlations were compared between 21 Alzheimer's disease patients and 21 healthy age-matched controls in the resting state. Cerebral metabolic rates for glucose were determined by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. Partial correlation coefficients, controlling for whole brain glucose metabolism, were evaluated between pairs of regional glucose metabolic rates in 59 brain regions. Reliable correlation coefficients were obtained with the 'jackknife' and 'bootstrap' statistical procedures. Compared with healthy controls, the Alzheimer patients had significantly fewer reliable partial correlation coefficients between frontal and parietal lobe regions, and more reliable correlations between the cerebellum and temporal lobe. The number of reliable correlations between many bilaterally symmetric brain regions was reduced in the Alzheimer patients, as compared with controls. These results suggest that in the early stages of Alzheimer's disease there is a breakdown of the organized functional activity between the two cerebral hemispheres, and between parietal and frontal lobe structures.     

Decline in cerebral glucose utilisation and cognitive function with aging in Down''s syndrome.

The cerebral metabolic rate for glucose (CMRglc) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in 14 healthy subjects with Down's syndrome, 19 to 33 years old, and in six healthy Down's syndrome subjects over 35 years, two of whom were demented. Dementia was diagnosed from a history of mental deterioration, disorientation and hallucinations. All Down's syndrome subjects were trisomy 21 karyotype. CMRglc also was examined in 15 healthy men aged 20-35 years and in 20 healthy men aged 45-64 years. All subjects were at rest with eyes covered and ears plugged. Mean hemispheric CMRglc in the older Down's syndrome subjects was significantly less, by 23%, than in the young Down's syndrome group; statistically significant decreases in regional metabolism (rCMRglc) also were present in all lobar regions. Comparison of the younger control group with the older control group showed no difference in CMRglc or any rCMRglc (p greater than 0.05). Assessment of language, visuospatial ability, attention and memory showed significant reductions in test scores of the old as compared with the young Down's syndrome subjects. These results show that significant age differences in CMRglc and rCMRglc occur in Down's syndrome but not in healthy controls, and that, although only some older Down's syndrome subjects are demented, significant age reductions in neuropsychologic variables occur in all of them.     

A multicentre study of motor functional connectivity changes in patients with multiple sclerosis

In this multicentre study involving eight European centres, we characterized the spatial pattern of functional connectivity (FC) in the sensorimotor network from 61 right-handed patients with multiple sclerosis (MS) and 74 age-matched healthy subjects assessed with the use of functional magnetic resonance imaging (fMRI) and a simple motor task of their right dominant hand. FC was investigated by using: (i) voxel-wise correlations between the left sensorimotor cortex (SMC) and any other area in the brain; and (ii) bivariate correlations between time series extracted from several regions of interest (ROIs) belonging to the sensorimotor network. Both healthy controls and MS patients had significant FC between the left SMC and several areas of the sensorimotor network, including the bilateral postcentral and precentral gyri, supplementary motor area, middle frontal gyri, insulae, secondary somatosensory cortices, thalami, and right cerebellum. Voxel-wise assessment of FC revealed increased connectivity between the left SMC and the right precentral gyrus, right middle frontal gyrus (MFG) and bilateral postcentral gyri in MS patients as compared with controls. ROI analysis also showed a widespread pattern of altered connectivity, characterized by increased FC between the right MFG, the left insula and the right inferior frontal gyrus in comparison with many regions of the sensorimotor network. These results provide further evidence for increased bihemispheric contributions to motor control in patients with MS relative to healthy controls. They further suggest that multicentre fMRI studies of FC changes are possible, and provide a potential imaging biomarker for use in experimental therapeutic studies directed at enhancing adaptive plasticity in the disease.     

Regional cerebral blood flow in Down's syndrome

Regional cerebral blood flow was measured in 14 patients with Down's syndrome, in 46 patients with Alzheimer's disease and senile dementia of the Alzheimer type, and in 114 age-matched controls, using the xenon 133 inhalation technique. Cerebral blood flow was reduced in 13 of 14 Down's patients by a mean of 16.8 +/- 2.5% from expected age-matched normal values. Degrees of regional cerebral blood flow reduction did not differ among the frontal, temporal, parietal, and occipital regions in both cerebral hemispheres. The regional cerebral blood flow decreases were similar in magnitude and pattern to those in Alzheimer patients. These findings constitute an additional similarity between the two disorders.     

Deformation-based morphometry reveals brain atrophy in frontotemporal dementia

OBJECTIVE: To compare deformation-based maps of local anatomical size between subjects with frontotemporal dementia (FTD) and healthy subjects to identify regions of the brain involved in FTD. DESIGN: Structural magnetic resonance images were obtained from 22 subjects with FTD and 22 cognitively normal, age-matched controls. We applied deformation-based morphometry and compared anatomy between groups using an analysis of covariance model that included a categorical variable denoting group membership and covaried for head size. SETTING: University of California, San Francisco, Memory and Aging Center, and the San Francisco Veterans Affairs Medical Center. PATIENTS: Twenty-two subjects with FTD and 22 cognitively normal, age-matched controls. INTERVENTIONS: Neurological, neuropsychological, and functional evaluations and magnetic resonance imaging. MAIN OUTCOME MEASURE: Deformation maps of local anatomical size. RESULTS: Patients with FTD showed extensive, significant atrophy of the frontal lobes, affecting both gray matter and white matter. Atrophy of similar magnitude but less significance was observed in the anterior temporal lobes. The subcortical and midbrain regions, particularly the thalamus, pons, and superior and inferior colliculi, showed strongly significant atrophy of smaller magnitude. CONCLUSIONS: We confirmed frontal and anterior temporal gray matter atrophy in FTD. The observed white matter loss, thalamic involvement, and midbrain atrophy are consistent with pathological findings in late-stage FTD. Dysfunction of ventral-frontal-brainstem circuitry may underlie some of the unique clinical features of FTD.     

A functional magnetic resonance imaging study of a large clinical cohort of children with Tourette syndrome

There is evidence that cortico-striato-thalamo-cortical pathways are involved in the pathophysiology of Tourette syndrome. During the performance of neuropsychological tests in subjects with Tourette syndrome there are suggestions for increased activity in the sensimotor cortex, supplementary motor areas, and frontal cortex. To replicate findings, the authors examined 22 medication-naive children with Tourette syndrome only, 17 medication-naive children with Tourette syndrome and comorbidity, and 39 healthy controls with functional magnetic resonance imaging (MRI). There were no differences in activation in brain regions between the children with Tourette syndrome (divided according to the presence of comorbidity) and healthy controls after correction for the confounders age, sex, and intelligence. Activation in the cingulated gyrus, temporal gyrus, and medial frontal gyrus was correlated significantly with obsessive-compulsive disorder score. The authors did not find significant correlations between activation patterns and age, sex, duration of disease, intelligence, severity of tics, and attention-deficit hyperactivity disorder (ADHD) score.     

Functional neuroanatomy of visuospatial working memory in fragile X syndrome: relation to behavioral and molecular measures.

OBJECTIVE: Fragile X syndrome is a neurogenetic disorder that is the most common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated. METHOD: Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10-23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, and molecular measures were examined. RESULTS: Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri. CONCLUSIONS: Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression in fragile X syndrome subjects than in normal comparison subjects. The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.     

Abnormalities of the nucleus basalis in Down's syndrome

One of the most striking manifestations of Down's syndrome is profound mental retardation. Furthermore, after 35 years of age, many patients with Down's syndrome develop clinical and pathological features of Alzheimer's disease. Since brains of patients with Alzheimer's disease show significant loss of neurons in the nucleus basalis of Meynert (nbM), we sought to establish normal standards of nbM neurons in persons with Down's syndrome and to determine whether reductions in the number of neurons occur with increasing age. The number and size of neurons in the nbM were measured in selected sagittal sections from 5 patients with Down's syndrome and 5 age-matched controls. The patients (age range, 16 to 56 years) had 29% fewer nbM neurons than controls, and the oldest patient had the lowest cell count of all subjects. The size of nbM neurons did not differ significantly between the two groups. Our results show that the nbM contains fewer neurons in young persons with Down's syndrome than in normal controls and suggest that the number of these nerve cells may be further reduced in older persons with Down's syndrome.     

Abnormal superior temporal connectivity during fear perception in schizophrenia

Patients with schizophrenia have difficulty in decoding facial affect. A study using event-related functional neuroimaging indicated that errors in fear detection in schizophrenia are associated with paradoxically higher activation in the amygdala and an associated network implicated in threat detection. Furthermore, this exaggerated activation to fearful faces correlated with severity of flat affect. These findings suggest that abnormal threat detection processing may reflect disruptions between nodes that comprise the affective appraisal circuit. Here we examined connectivity within this network by determining the pattern of intercorrelations among brain regions (regions of interest) significantly activated during fear identification in both healthy controls and patients using a novel procedure CORANOVA. This analysis tests differences in the interregional correlation strength between schizophrenia and healthy controls. Healthy subjects' task activation was principally characterized by robust correlations between medial structures like thalamus (THA) and amygdala (AMY) and middle frontal (MF), inferior frontal (IF), and prefrontal cortical (PFC) regions. In contrast, schizophrenia patients displayed no significant correlations between the medial regions and either MF or IF. Further, patients had significantly higher correlations between occipital lingual gyrus and superior temporal gyrus than healthy subjects. These between-group connectivity differences suggest that schizophrenia threat detection impairment may stem from abnormal stimulus integration. Such abnormal integration may disrupt the evaluation of threat within fronto-cortical regions.     

Comparative coherence studies in healthy volunteers and Down's syndrome patients from childhood to adult age.

Within the scope of the Munich Pediatric Longitudinal Study, EEG coherence was studied in 212 Down's syndrome patients and 342 healthy controls aged from 6 months up to 30 years. The digitalized EEG records were subjected to spectral analysis. Frequency band-related coherences were calculated to reveal age-specific differences in the functional relationship between two brain areas in Down's syndrome patients and controls. The results show that in the "eyes-open" state the intra-hemispheric coherence in the alpha band was significantly lower (P less than 0.05) in the Down's syndrome patients than in the controls whereas that in the delta bands it was generally higher. The intra-hemispheric coherence in the "eyes-closed" state was generally higher in the Down's syndrome groups than in the controls; however, significant differences could be detected only in some age groups. The age-specific development of coherence in the inter-hemispheric parieto-occipital region was almost identical in Down's syndrome children as in controls, both with open and closed eyes. The most distinct differences were found in the fronto-central inter-hemispheric coherence (P less than 0.01), while the coherence deficiencies in the Down's syndrome group became more prominent with increasing age from school age onwards. These electrophysiological results are compared with the results of neuropathological and neurophysiological studies of other authors. It can be suggested that there are correlations with a significantly small number of dendritic spines in Down's syndrome patients, which was determined in neuropathological examinations. A neuronal model of interpretation is presented which explains the increasing developmental deficit with age in Down's syndrome children.     

大脑静息葡萄糖代谢改变与情绪障碍的相关性

目的前瞻性分析大脑静息葡萄糖代谢改变在初诊肺癌患者情绪障碍发病中的临床意义。方法实验组来自临床拟诊肺癌并拟行全身(脑+躯干)18F-氟脱氧葡萄糖(18F-FDG)正电子发射断层显像/计算机体层摄影(PET/CT)检查的患者,对照组来自健康体格检查者。所有被试者在18F-FDG PET/CT检查前接受哈密尔顿抑郁量表(HAMD)及焦虑量表(MAS)评定,对比分析大脑静息葡萄糖代谢改变、情绪障碍评分以及两者之间的相关性。结果最终纳入155例肺癌患者(实验组)及152例健康体检者(对照组),实验组HAMD评分及MAS评分均高于对照组(t=1.020.P=0.04;t=0.09,P=0.03);实验组脑PET显像存在以双侧额、颞叶为主的多个脑区葡萄糖代谢减低,且受累脑区平均标准化摄取值(SUV)在双侧额叶及左侧颞叶分别与HAMD评分呈负相关(r=0.68、0.60、0.55),在左侧额叶及左侧颞叶分别与MAS评分呈负相关(r=0.59、0.58)。结论大脑静息葡萄糖代谢改变与情绪障碍在肺癌患者中具有显著相关性,且以额叶为著。脑葡萄糖代谢改变可能是肺癌患者情绪障碍发病的神经病理基础,有望作为神经生物学标记用于临床评估。     

Disturbed Functional Connectivity of Cortical Activation during Semantic Discrimination in Patients with Schizophrenia and Subjects at Genetic High-risk

Schizophrenia has a strong genetic component that is relevant to the understanding of the pathophysiology of the syndrome. Thus, recent investigations have shifted from studies of diagnosed patients with schizophrenia to examining their unaffected relatives. Previous studies found that during language processing, relatives thought to be at genetic high-risk for the disorder exhibit aberrant functional activation in regions of language processing, specifically in the left inferior frontal gyrus (Broca’s area). However, functional connectivity among the regions involved in language pathways is not well understood. In this study, we examined the functional connectivity between a seed located in Broca’s area and the remainder of the brain during a visual lexical decision task, in 20 schizophrenia patients, 21 subjects at genetic high risk for the disorder and 21 healthy controls. Both the high-risk subjects and patients showed significantly reduced activation correlations between seed and regions related to visual language processing. Compared to the high-risk subjects, the schizophrenia patients showed even fewer regions that were correlated with the seed regions. These results suggest that there is aberrant functional connectivity within cortical language circuitry in high-risk subjects and patients with schizophrenia. Broca’s area, which is one of the important regions for language processing in healthy controls, had a significantly reduced role in the high-risk subjects and patients with schizophrenia. Our findings are consistent with the existence of an underlying biological disturbance that begins in genetically at risk individuals and progresses to a greater extent in those who eventually develop schizophrenia.     

Levels of phospholipid catabolic intermediates, glycerophosphocholine and glycerophosphoethanolamine, are elevated in brains of Alzheimer's disease but not of Down's syndrome patients

Concentrations of glycerophosphocholine and of glycerophosphoethanolamine, the metabolites of two major membrane phospholipid classes, phosphatidylcholine and phosphatidylethanolamine respectively, were determined post-mortem in cortical areas 20 and 40 and in cerebellum and caudate nucleus of brains obtained at autopsy from patients with Alzheimer's disease, Down's syndrome and age-matched control subjects. Glycerophosphocholine concentrations in all of the brain regions examined were higher by 67-150% in Alzheimer's disease than in control brains and 81-104% higher in Alzheimer's disease than in Down's syndrome. Glycerophosphoethanolamine concentrations were 21-52% higher in Alzheimer's disease than in controls, and 27-92% higher in Alzheimer's disease than Down's syndrome. Levels of glycerophosphocholine and of glycerophosphoethanolamine did not differ significantly between Down's syndrome and control brains. These data indicate that abnormal phospholipid metabolism in brain is characteristic of Alzheimer's disease but not Down's syndrome and suggest that this abnormality may be a central pathophysiological feature of Alzheimer's disease because levels of glycerophosphocholine and of glycerophosphoethanolamine are elevated in brain regions with and without manifestations of histopathology.     

Comparison of positron emission tomography, cognition, and brain volume in Alzheimer''s disease with and without severe abnormalities of white matter.

OBJECTIVES--To examine cerebral metabolism, cognitive performance, and brain volumes in healthy controls and two groups of patients with probable Alzheimer's disease, one group with severe abnormalities of white matter (DAT+) and the other group with none, or minimal abnormalities (DAT-). METHODS--Neuropsychological tests, CT, MRI, quantitative MRI, and PET studies were carried out to allow comparison between the DAT+ and DAT- groups and the healthy controls. RESULTS--Compared with the healthy controls, both demented groups had significantly reduced global and regional cerebral metabolism, significant brain atrophy, and significantly lower scores on neuropsychological testing. The DAT- patient group showed a pattern of parietal-temporal cerebral metabolic reductions and neuropsychological performance deficits typical of Alzheimer's disease. In addition, metabolism in the association neocortex (AD ratio) and measures of neuropsychological task performance were significantly correlated in the DAT- patient group. Comparison of DAT+ with DAT- patients showed a significantly higher ratio of parietal to whole brain glucose utilisation for the DAT+ group. Moreover, when comparing group z score differences from the healthy controls, the DAT+ group had, on average, smaller differences from controls in the frontal, parietal, and temporal regions than did the DAT- group. Discriminant analysis using metabolic ratios of the frontal, parietal, and temporal regions showed cerebral metabolic patterns to be significantly different among the DAT+, the DAT-, and the healthy controls. These differences were due primarily to relatively higher frontal, parietal, and temporal metabolic ratios in the DAT+ group which resulted in discriminant scores for the DAT+ group between the healthy controls and the DAT- group. Group mean scores on tests of neuropsychological performance were not significantly different between the DAT- and DAT+ patients. By contrast with the DAT- group, however, no significant correlations between the AD ratio and any neuropsychological task were seen in the DAT+ group. Multiple regression analysis showed significant between group differences in the relation between the AD ratio and neuropsychological scores on three tasks. The slopes of the relations between the AD ratio and memory scores (memory and freedom from distractability deviation quotient of the Wechsler adult intelligence scale (WMDQ)) also were significantly different for the two groups. CONCLUSIONS--Although multiple causes for abnormalities of white matter exist in patients with Alzheimer's disease, these data suggest that the presence of severe abnormalities of white matter indicate a second pathological process in the DAT+ patients. The DAT- patients showed the parietal-temporal metabolic deficits and correlations between association neocortical metabolism and neuropsychological task performance typical of patients with Alzheimer's disease. By contrast, the DAT+ group had a pattern of cerebral metabolism significantly different from healthy controls and DAT+ patients, as well as no significant correlations between metabolism in the association neocortex and neuropsychological performance. These differences probably reflect the superimposed pathology of the abnormalities of white matter which may exert their affect through disruption of long corticocortical pathways.     

Quantitative CT analysis of brain morphometry in adult Down's syndrome at different ages

Quantitative CT demonstrated that healthy adults with Down's syndrome (DS) have smaller brains and smaller intracranial volumes than controls. Normalized volumes of CSF, ventricles, and brain parenchyma did not differ in patients and controls. Both DS subjects and controls showed similar significant age-related increments in volumes of CSF and ventricles. Of seven older DS subjects, one was demented, whereas the group as a whole showed reductions in cognitive test scores as compared with younger DS subjects. The results demonstrate cognitive decline in older DS subjects, but no brain atrophy other than that expected with aging.     

Thalamofrontal circuitry and executive dysfunction in recent-onset juvenile myoclonic epilepsy

Purpose:   Thalamofrontal abnormalities have been identified in chronic primary generalized epilepsy, specifically in juvenile myoclonic epilepsy (JME). These regions also underlie executive functioning, although their relationship has yet to be examined in JME. This study examined the relationship between thalamic and frontal volumes and executive function in recent-onset JME compared to healthy control subjects and recent-onset benign childhood epilepsy with centrotemporal spikes (BCECTS), a syndrome not typically associated with thalamocortical or executive dysfunction.
Methods:   Twenty children with recent-onset JME were compared to 51 healthy controls and 12 children with BCECTS using quantitative magnetic resonance imaging (MRI) and measures of executive abilities. Quantitative thalamic and frontal volumes were obtained through semi-automated software. Subtests from the Delis–Kaplan Executive Function System (D-KEFS) and the Behavior Rating Inventory of Executive Function (BRIEF) were used to measure executive function.
Results:   Executive functions were impaired in JME subjects compared to control and BCECTS subjects. Subjects with JME had significantly smaller thalamic volumes and more frontal cerebrospinal fluid (CSF) than control and BCECTS subjects. Thalamic and frontal volumes were significantly related to executive functioning in the JME group, but not in the other two groups.
Discussion:   Children with JME have significant executive dysfunction associated with significantly smaller thalami and more frontal CSF. Children with recent-onset BCECTS do not display the same pattern. Frontal and thalamic volumes appear to mediate the relationship between executive functioning and brain structure in JME.     

Reduced D-[3H]aspartate binding in Down's syndrome brains

The binding of D-[3H]aspartate to glutamate uptake sites was measured in post-mortem brains from subjects with Down's syndrome (DS) and age-matched controls. DS brains had substantially reduced D-[3H]aspartate binding in the frontal and temporal cortex, hippocampus and caudate nucleus. There was no correlation between the numbers of Alzheimer-like plaques and tangles or clinically-assessed dementia and D-[3H]aspartate binding in DS brains. The binding of [3H]N-(1-[2-thienyl]cyclohexyl)piperidine ([3H]TCP) to postsynaptic N-methyl-D-aspartate sites was normal in DS brains. This study suggests that the reduction in glutamate uptake sites in DS is more substantial and widespread than in Alzheimer's disease.