Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down's syndrome: implications for the prodromal phase of Alzheimer's disease.

OBJECTIVE: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. METHOD: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume. RESULTS: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. CONCLUSIONS: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.     

Temporal lobe anatomy and psychiatric symptoms in velocardiofacial syndrome (22q11.2 deletion syndrome)

OBJECTIVE: To investigate the association between mesial temporal lobe morphology, ratios of prefrontal cortex to amygdala and hippocampus volumes, and psychiatric symptomatology in children and adolescents with velocardiofacial syndrome (VCFS). METHOD: Scores on behavioral rating scales and volumetric measures of the amygdala, hippocampus, and prefrontal cortex based on high-resolution magnetic resonance imaging were compared among 47 children with VCFS, 15 of their siblings, and 18 community controls. RESULTS: After covarying for whole brain volume, children with VCFS exhibited 11% greater volume of the left amygdala (p =.002) and 8% greater volume of the right amygdala (p =.01). Children with VCFS exhibited smaller volumes of the hippocampus, but not disproportionately to reductions in whole brain volume. Children with VCFS exhibited smaller volumetric ratios of prefrontal and orbitofrontal cortex to amygdala, but not prefrontal cortex to hippocampus. For children with VCFS, but not for the comparison sample, larger volumes of the amygdala and smaller ratios of prefrontal cortex to amygdala were associated with higher scores on the Internalizing, Externalizing, Anxiety, and Aggression scales of the Child Behavior Checklist and on the parent version of the Young Mania Rating Scale. CONCLUSIONS: These findings suggest that the prefrontal cortex-amygdala circuit that underlies emotional processing is disrupted in children with VCFS and may be an important neurobiological substrate of psychiatric disorder in these children.     

Neuroanatomy of Down's syndrome: a high-resolution MRI study

OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.     

MRI brain changes in subjects with Down syndrome with and without dementia

Individuals with Down syndrome (DS), a disorder of known genetic etiology (trisomy of chromosome 21), exhibit several types of structural brain abnormalities that are detectable pathologically and by MRI. In addition, in middle age, individuals with DS develop histological and, in some cases, clinical features of Alzheimer's disease (AD). Abnormalities in MRI scans of 50 adults with DS, 11 of whom had clinical dementia, are described and compared with those of 23 cognitively normal, healthy subjects who were matched for age, sex, and race. Qualitative visual analogue scale (VAS) ratings on MRI hard copies for all subjects and computer-aided volume measures for a subsample of subjects were carried out. On VAS, subjects with DS had larger lateral ventricles, a higher frequency of posterior fossa arachnoid cysts/megacisterna magna and fewer scans rated as normal compared with controls. Quantitatively, total brain and gray-matter volumes were reduced in DS, as were the volumes of the left hippocampus and amygdala; ventricle volumes were larger. Post hoc comparisons of subjects with DS with and without dementia revealed that on VAS the former had more generalized atrophy for age, mesial temporal shrinkage, and third ventricular enlargement. Similarly, total train, left hippocampus, and left amygdala volumes were reduced quantitatively in subjects with DS with dementia, while ventricular volumes were increased.     

A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems

MRI was used to measure amygdalar and hippocampal volumes in 14 nondemented depressed patients who persistently complained of "memory" difficulties and in 14 control subjects. Mild neuropsychological impairment had been detected in 5 patients before the study but had later improved. The volume of the left amygdala was smaller in depressed subjects, and there was a trend for smaller left hippocampus in the 5 patients who had exhibited mild cognitive impairment. The authors conclude that subjective memory complaints in depressed patients do not translate into a clinical picture of dementia, but that abnormalities in the amygdala and hippocampus may be relevant in explaining affective and cognitive symptoms.     

Amygdalar and hippocampal MRI volumetric reductions in Parkinson's disease with dementia.

Parkinson's disease (PD) involves neuropathological changes in the limbic system that lead to neuronal loss and volumetric reductions of several nuclei. We investigated possible volumetric reductions of the amygdala and hippocampus associated to PD. We carried out magnetic resonance imaging (MRI) volumetric studies in 16 patients with PD and dementia (PDD), 16 patients with PD without dementia (PD), and 16 healthy subjects. The general analysis of variance (ANOVA) showed a significant group effect (for the amygdala, P = 0.01; for the hippocampus, P = 0.005). A post-hoc test demonstrated that the differences were due to PDD and control group comparisons for the amygdala (P = 0.008) and for the hippocampus (P = 0.004). In nondemented PD subjects, we observed an 11% reduction in the amygdala and a 10% reduction in the hippocampus compared with that in controls. In summary, demented PD patients have clear amygdalar and hippocampal atrophy that remains statistically significant after controlling for global cerebral atrophy. Nondemented PD patients also showed a degree of volumetric reduction in these structures although the differences were not statistically significant.     

MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults

OBJECTIVE: To determine whether volumes of hippocampus and amygdala are abnormal in people with autism. BACKGROUND: Neuropathologic studies of the limbic system in autism have found decreased neuronal size, increased neuronal packing density, and decreased complexity of dendritic arbors in hippocampus, amygdala, and other limbic structures. These findings are suggestive of a developmental curtailment in the maturation of the neurons and neuropil. METHODS: Measurement of hippocampus, amygdala, and total brain volumes from 1.5-mm coronal, spoiled gradient-recalled echo MRI scans in 14 non-mentally retarded autistic male adolescents and young adults and 14 individually matched, healthy community volunteers. RESULTS: Amygdala volume was significantly smaller in the autistic subjects, both with (p = 0.006) and without (p = 0.01) correcting for total brain volume. Total brain volume and absolute hippocampal volume did not differ significantly between groups, but hippocampal volume, when corrected for total brain volume, was significantly reduced (p = 0.04) in the autistic subjects. CONCLUSIONS: There is a reduction in the volume of amygdala and hippocampus in people with autism, particularly in relation to total brain volume. The histopathology of autism suggests that these volume reductions are related to a reduction in dendritic tree and neuropil development, and likely reflect the underdevelopment of the neural connections of limbic structures with other parts of the brain, particularly cerebral cortex.     

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.     

Amygdala and hippocampus volumes in pediatric major depression.

BACKGROUND: The purpose of this study was to measure amygdala and hippocampus volumes in pediatric major depressive disorder (MDD) and to address the question of neuroanatomical continuity with adult-onset depression. METHODS: We studied 20 children and adolescents with MDD (17 female subjects) and 24 healthy comparison subjects (16 female subjects) using 1.5 Tesla magnetic resonance imaging. Group differences in left and right amygdala and hippocampus volumes were examined using repeated measures analyses of covariance, adjusting for age, gender, and whole brain volume. RESULTS: Depressed children had significant reductions of left and right amygdala volumes compared with healthy subjects. Hippocampus volumes did not differ between the groups. No significant correlations were found between amygdala volumes and depressive symptom severity, age at onset, or illness duration. CONCLUSIONS: Smaller amygdalas are present early in the course of pediatric depression and may predispose to the development of this disorder or perhaps more generally of childhood mood disorders. Future research should examine the longitudinal course and functional correlates of amygdala volume abnormalities in childhood-onset depression, including their possible moderation by gender.     

The natural history of dementia in Down's syndrome

In a prospective longitudinal study with death as the end point in 17 middle-aged patients with Down's syndrome, dementia was clinically diagnosed in 15 patients, by means of careful observations in daily circumstances. Autopsies were performed in 10 cases: 8 demented patients and 2 nondemented patients. Neuropathologically, Alzheimer-type abnormalities were demonstrated in 9 patients, both demented and nondemented, and combined Alzheimer-type abnormalities with infarctions were demonstrated in 1 patient. In the 14 demented patients who did not show evidence of cerebrovascular or systemic vascular disease, dementia had an early onset and was rapidly progressive (mean age at onset, 51.3 years in the moderately retarded patients and 52.6 years in the severely retarded patients; mean duration of symptoms, respectively, 4.9 and 5.2 years). Cognitive and behavioral decline corresponded to symptoms of dementia of the Alzheimer's type in patients without Down's syndrome, but often were not recognized early. In the present group of patients, there was a remarkably high incidence of gait and speech deterioration. Also, the incidence of epileptic seizures and myoclonus was about eightfold, as compared with dementia of the Alzheimer's type in patients without Down's syndrome.     

Hippocampal volume reduction in major depression

OBJECTIVE: Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. The purpose of this study was to measure hippocampal volume in patients with depression. METHOD: Magnetic resonance imaging was used to measure the volume of the hippocampus in 16 patients with major depression in remission and 16 case-matched nondepressed comparison subjects. RESULTS: Patients with depression had a statistically significant 19% smaller left hippocampal volume than comparison subjects, without smaller volumes of comparison regions (amygdala, caudate, frontal lobe, and temporal lobe) or whole brain volume. The findings were significant after brain size, alcohol exposure, age, and education were controlled for. CONCLUSIONS: These findings are consistent with smaller left hippocampal volume in depression.     

Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer's disease: Correlation with memory functions

Summary We studied the usefulness of measuring volumes of the hippocampus, amygdala and frontal lobes with coronal magnetic resonance imaging (MRI) scans in the diagnosis of early Alzheimer's disease (AD). We examined 32 patients diagnosed according to the NINCDS-ADRDA criteria of probable AD and 16 age-matched healthy cognitively normal controls. The AD patients had mild dementia with a mean score of 22.8 in the Mini-Mental Status Examination (MMSE). We used a 1.5T magnetic resonance imager and normalized the volumes for brain area. The AD patients had significantly smaller volumes of the right and the left hippocampus (–38%) (ANOVA, p<0.001) and the left frontal lobe (–16%, p<0.05) compared to controls. The reductions in volumes of the right frontal lobe (–13%), the right amygdala (–14%) or the left amygdala (–18%) were not statistically significant. In the discriminant function analysis which included the volumes of the hippocampus, amygdala, and the frontal lobes and age, the volumes of the left and right hippocampus, the left and right frontal lobe, and the right amygdala entered the model and we could correctly classify 92% of the subjects into AD and control groups (Chi-square 42.6, df 5, p<0.0001). By using the volumes of the hippocampus, the frontal lobes or the amygdala on their alone, the correct classification was achieved in 88%, 65% and 58% of the subjects, respectively. In addition, in AD patients the volumes of the left hippocampus correlated significantly with the MMSE score and with immediate and delayed verbal memory; the smaller the volume the more impaired was their performance. Our data indicate that measurements of volumes of the hippocampus might be useful in diagnosis of early AD.     

Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort

Structural brain differences have been reported in many studies with schizophrenia, but few have involved a general population birth cohort. We investigated differences in volume, shape and laterality of hippocampus and amygdala in patients with schizophrenia, all psychoses and comparison subjects within a large general birth cohort sample, and explored effects of family history of psychosis, perinatal risk and age-at-onset of illness. All subjects with psychosis from the Northern Finland 1966 birth cohort were invited to a survey including MRI scan of the brain, conducted in 1999-2001. Comparison subjects not known to have psychosis were randomly selected from the same cohort. Volumes of hippocampus and amygdala were measured in 56 subjects with DSM-III-R schizophrenia, 26 patients with other psychoses and 104 comparison subjects. Small hippocampal volume reductions in schizophrenia (2%) and all psychoses (3%) were not significant when adjusted for total brain volume. The shape of hippocampus in schizophrenia did not differ significantly from comparison subjects. Right hippocampus and amygdala were significantly larger than the left in all groups. Mean amygdala volume in schizophrenia or all psychoses did not differ from comparison subjects. Patients with family history of psychosis had larger hippocampus than patients without. Neither perinatal risk nor age-at-onset of illness had any effect on hippocampal or amygdala volumes. Small hippocampal volume reduction in schizophrenia and all psychoses was not disproportionate to reduced whole brain volume in this population-based sample. Perinatal events that have been suggested as of etiological importance in structural pathology of psychosis had no effect.     

Reduced amygdala and hippocampal volumes in patients with methamphetamine psychosis

The similarity between psychotic symptoms in patients with schizophrenia such as hallucinations and delusions and those caused by administration of methamphetamine has been accepted. While the etiology of schizophrenia remains unclear, methamphetamine induced psychosis, which is obviously occurred by methamphetamine administration, had been widely considered as a human pharmaceutical model of exogenous psychosis. Although volume reductions in medial temporal lobe structure in patients with schizophrenia have repeatedly been reported, those in patients with methamphetamine psychosis have not yet been clarified. Magnetic resonance images (MRI) were obtained from 20 patients with methamphetamine psychosis and 20 age, sex, parental socio-economic background, and IQ matched healthy controls. A reliable manual tracing methodology was employed to measure the gray matter volume of the amygdala and the hippocampus from MRIs. Significant gray matter volume reductions of both the amygdala and hippocampus were found bilaterally in the subjects with methamphetamine psychosis compared with the controls. The degree of volume reduction was significantly greater in the amygdala than in hippocampus. While the total gray, white matter and intracranial volumes were also significantly smaller-than-normal in the patients; the regional gray matter volume reductions in these medial temporal structures remained statistically significant even after these global brain volumes being controlled. The prominent volume reduction in amygdala rather than that in hippocampus could be relatively specific characteristics of methamphetamine psychosis, since previous studies have shown significant volume reductions less frequently in amygdala than in hippocampus of the other psychosis such as schizophrenia.     

Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder

BACKGROUND: The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples. OBJECTIVE: To investigate amygdala and hippocampal volume in adults and adolescents with BD.Setting and PARTICIPANTS: Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults).Design and MAIN OUTCOME MEASURES: Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state. RESULTS: For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P =.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected. CONCLUSIONS: These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample.     

Hippocampus and amygdala volumes in patients with vaginismus

AIM: To compare hippocampus and amygdala volumes of patients with vaginismus with those of healthy control subjects. METHODS: Magnetic resonance imaging was performed on ten patients with vaginismus and ten control subjects matched for age and gender. Volumes of the hippocampus and amygdala were blindly measured. RESULTS: We found that the mean right amygdala volume of patients with vaginismus were smaller than that of the healthy controls. With regard to hippocampus volumes, the mean left and right hippocampus volumes were smaller than those of the healthy controls. CONCLUSION: Our present findings suggest that there have been hippocampus and amygdala structural abnormalities in patients with vaginismus. These changes provide the notion that vaginismus may be a fear-related condition.     

Hippocampal size and dementia in stroke patients: the Sydney stroke study

BACKGROUND: Hippocampal atrophy is an early feature of Alzheimer's disease (AD) but it has also been reported in vascular dementia (VaD). It is uncertain whether hippocampal size can help differentiate the two disorders. METHODS: We assessed 90 stroke/TIA patients 3-6 months after the event, and 75 control subjects, with neuropsychological tests, medical and psychiatric examination and brain MRI scans. A diagnosis of VaD, vascular mild cognitive impairment (VaMCI) or no cognitive impairment (NCI) was reached by consensus on agreed criteria. T1-weighted MRI was used to obtain total intracranial volume (TICV), gray and white matter volume, CSF volume, hippocampus and amygdala volumes, and T2-weighted scans for white matter hyperintensity (WMH) ratings. RESULTS: Stroke/TIA patients had more white matter hyperintensities (WMHs), larger ventricle-to-brain ratios and smaller amygdalae than controls, but hippocampus size and gray and white matter volumes were not different. WMHs and amygdala but not hippocampal volume distinguished stroke/TIA patients with VaD and VaMCI and without NCI and amygdala volumes. Right hippocampus volume significantly correlated with new visual learning. CONCLUSIONS: Stroke/TIA patients and patients with post-stroke VaMCI or mild VaD do not have hippocampal atrophy. The amygdala is smaller in stroke/TIA patients, especially in those with cognitive impairment, and this may be accounted for by white matter lesions. The hippocampus volume relates to episodic memory, especially right hippocampus and new visual learning. A longitudinal study of these subjects will determine whether hippocampal atrophy is a late development in VaD.     

High brain myo-inositol levels in the predementia phase of Alzheimer's disease in adults with Down's syndrome: a 1H MRS study

OBJECTIVE: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome. METHOD: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects. RESULTS: Concentrations of myoinositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group. CONCLUSIONS: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myoinositol levels in symptomatic Alzheimer's disease.     

Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease.

BACKGROUND: The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression. DESIGN AND MAIN OUTCOME MEASURES: We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR). SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved. CONCLUSIONS: Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.     

Small cerebral hemispheres in adults with Down's syndrome: contributions of developmental arrest and lesions of Alzheimer's disease

Morphometric analysis was used to measure cross-sectional areas of cerebral structures in middle-aged patients with Down's syndrome (N = 5) for comparison with data obtained from individuals with senile dementia of the Alzheimer type (N = 16) and neuropathologically normal controls (N = 14). Down's syndrome was distinguished from Alzheimer's disease by the 19% lower mean brain weight which was associated with more pronounced reductions in the areas of both cortex and white matter. However, the differences were most striking in the anterior frontal and anterior temporal regions where the effects of arrested neurodevelopment are grossly evident. In addition, in Down's syndrome the amygdala was significantly smaller than in Alzheimer's disease. In both Down's syndrome and Alzheimer's disease, shrinkage of the cortical ribbon was associated with abundant neuritic plaques and neurofibrillary tangles, while white matter atrophy was associated with histopathological evidence of axonal degeneration. These findings suggest that in Down's syndrome the reduction in volume in the posterior portion of the cerebrum relative to controls is largely due to acquired lesions of Alzheimer's disease, whereas anteriorly and within certain subcortical nuclei, the effects of both Alzheimer's disease and arrested neurodevelopment are manifested. Moreover, the finding of white matter lesions in Down's syndrome corroborates the notion that white matter degeneration is a fundamental component of the Alzheimer's disease process.