Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease

BACKGROUND: Identification of the neuropathological lesions that are most closely associated with the earliest symptoms of Alzheimer disease (AD) is crucial to the understanding of the disease process and the development of treatment strategies to affect its progress. Do the classical neuropathological lesions of AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration? DESIGN AND OUTCOME MEASURES: We examined the extent of neuritic plaque (NP) formation in 5 neocortical regions and the hippocampus, entorhinal cortex, and amygdala in 66 elderly subjects with no dementia, questionable dementia, or mild dementia as assessed using the Clinical Dementia Rating Scale (CDR). SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: Even questionable dementia (CDR, 0.5) was associated with a significant (P = .04) increase in neocortical NP density. The density of NPs increased further with increasing dementia severity in all brain regions examined. However, subjects with questionable dementia or definite but mild dementia did not differ significantly from each other. Density of NPs was nearly maximal in subjects with moderate dementia (CDR = 2.0), suggesting that other neuropathological changes may be responsible for cognitive deficits beyond this level. Dementia severity correlated significantly with the density of NPs in all brain regions examined (r range, 0.47-0.56; P < .001), even when subjects with a CDR of 0 were excluded. CONCLUSIONS: These findings are consistent with the hypothesis that NPs are among the earliest neuropathological lesions in AD. Even very mild or questionable dementia is associated with increased density of neocortical NPs that do not distinguish between clinically questionable vs definite dementia.     

Neuropsychological changes in subjects at risk of inheriting Alzheimer's disease

Subjects from four Mexican families at risk of inheriting Alzheimer's disease (AD) were studied using a complete neuropsychological battery. These tests were repeated and compared 1 year later. Some of the experimental subjects belong to an international protocol on molecular chromosomal study. A control group matched in age and schooling was included. The subjects at risk underwent a complete physical, neurological and neuropsychological assessment. A neuropsychological battery of cognitive domains designed for the the study of dementia syndromes was administered to all subjects. Six of the subjects showed abnormal performance in cognitive functions, memory, visuospatial functions or language which persisted 1 year later. The present work describes the initial findings of a long-term prospective study aimed at delineating the neuropsychological profile of subjects at risk and to validate subtle abnormalities which in some cases could be the incipient changes of AD.     

Atrophy of the corpus callosum in Alzheimer's disease versus healthy aging

OBJECTIVE: To investigate the specificity of atrophic changes in the corpus callosum (CC) compared with the cerebellum and pons in patients with Alzheimer Disease (AD), healthy elderly subjects (HE), and a sample of prospectively studied subjects who have developed cognitive decline or "incipient dementia" (ID). DESIGN: Cross-sectional comparison by age using quantitative MRI. SETTING: Ambulatory research unit. PARTICIPANTS: Sixty HE subjects (mean age 78.2 years; range 66-95), 20 ID subjects (mean age 88.1 years; range 78-98) and 39 AD subjects (mean age 72.2 years; range 52-91) were enrolled in longitudinal studies of healthy aging or AD. The population was selected for optimal health; all were examined to exclude medical, neurological and psychiatric illness. MEASUREMENTS: Brain atrophy by quantitative MRI. RESULTS: AD subjects had smaller CC than HE or ID subjects, who did not differ from each other. All three sectors of the CC were smaller in AD than in HE or ID subjects. The cross sectional area of the cerebellum and pons did not differ between groups. HE and ID subjects showed a significant decline in CC size with age. No age-related decline was found for AD subjects. The regional atrophy of the CC in AD subjects was significantly related to cognitive function but not to disease duration. CONCLUSIONS: Atrophy of the CC differentiates HE and ID from AD subjects and tracks the cognitive decline of this disease. In addition, optimally healthy subjects show an age-related decline in callosum size. The atrophy is specific to the CC, a cortical projection system, and does not occur in cerebellum or pons.     

A four year prospective study of age-related cognitive change in adults with Down's syndrome

BACKGROUND: While neuropathological studies indicate a high risk for Alzheimer's disease in adults with Down's syndrome, neuropsychological studies suggest a lower prevalence of dementia. In this study, cognitive deterioration in adults with Down's syndrome was examined prospectively over 4 years to establish rates and profiles of cognitive deterioration. METHODS: Fifty-seven people with Down's syndrome aged 30 years or older were assessed using a battery of neuropsychological tests on five occasions across 50 months. Assessments of domains of cognitive function known to change with the onset of Alzheimer related dementia were employed. These included tests of learning, memory, orientation, agnosia, apraxia and aphasia. The individual growth trajectory methodology was used to analyse change over time. RESULTS: Severe cognitive deterioration, such as acquired, apraxia and agnosia, was evident in 28.3% of those aged over 30 and a higher prevalence of these impairments was associated with older age. The rate of cognitive deterioration also increased with age and degree of pre-existing cognitive impairment. Additionally, deterioration in memory, learning and orientation preceded the acquisition of aphasia, agnosia and apraxia. CONCLUSIONS: The prevalence of cognitive impairments consistent with the presence of Alzheimer's disease is lower than that suggested by neuropathological studies. The pattern of the acquisition of cognitive impairments in adults with Down's syndrome is similar to that seen in individuals with Alzheimer's disease who do not have Down's syndrome.     

Elderly patients with schizophrenia exhibit infrequent neurodegenerative lesions

Immunohistochemistry and conventional stains were used to examine the brains of 10 elderly patients with both schizophrenia and dementia to characterize the neuropathology of their cognitive deterioration. Control cases included five nondemented elderly patients with schizophrenia, five age-compatible Alzheimer's disease (AD) patients, and five neurologically normal elderly patients. Only one of the patients with schizophrenia and dementia had AD, another was diagnosed with adult polyglucosan body disease, and the others were devoid of neuropathology that could account for dementia. Quantitation of immunohistochemically detected neurofibrillary tangles and senile plaques revealed similarly low counts for the normal control group and both schizophrenia groups. Typically, the neuropathological causes of dementia can be identified in up to 95% of cases, with AD accounting for 50-60%. The unexpected lack of neuropathological findings to explain the cognitive deterioration in this group of elderly patients with schizophrenia prompts speculation about alternative etiologies.     

Severe pathological changes of parabrachial nucleus in Alzheimer's disease

In the first of a series of studies aimed at mapping brain stem pathological changes in patients with Alzheimer's disease (AD), we report a new finding regarding the parabrachial nucleus (PBN), a unit of paramount importance in the relay and integration of visceral and nociceptive information as well as in homeostatic control. The brains of 20 patients with AD were surveyed. The PBN contained pervasive neuropathological changes in 100% of the brains from those with early-onset dementia and in 80% from those with late-onset dementia. These changes were entirely absent in all 10 normal controls. The pathological changes of PBN, would cause autonomic dysfunction in patients with AD and perhaps contribute to the disproportionate mortality encountered in these patients.     

Influence of education and occupation on the incidence of Alzheimer's disease

OBJECTIVE: Several cross-sectional studies have found an association between Alzheimer's disease (AD) and limited educational experience. It has been difficult to establish whether educational experience is a risk factor for AD because educational attainment can influence performance on diagnostic tests. This study was designed to determine whether limited educational level and occupational attainment are risk factors for incident dementia. DESIGN: Cohort incidence study. SETTING: General community. PARTICIPANTS: A total of 593 nondemented individuals aged 60 years or older who were listed in a registry of individuals at risk for dementia in North Manhattan, NY, were identified and followed up. INTERVENTIONS: We reexamined subjects 1 to 4 years later with the identical standardized neurological and neuropsychological measures. MAIN OUTCOME MEASURES: Incident dementia. RESULTS: We used Cox proportional hazards models, adjusting for age and gender, to estimate the relative risk (RR) of incident dementia associated with low educational and occupational attainment. Of the 593 subjects, 106 became demented; all but five of these met research criteria for AD. The risk of dementia was increased in subjects with either low education (RR, 2.02; 95% confidence interval [Cl], 1.33 to 3.06) or low lifetime occupational attainment (RR, 2.25; 95% Cl, 1.32 to 3.84). Risk was greatest for subjects with both low education and low life-time occupational attainment (RR, 2.87; 95% Cl, 1.32 to 3.84). CONCLUSIONS: The data suggest that increased educational and occupational attainment may reduce the risk of incident AD, either by decreasing ease of clinical detection of AD or by imparting a reserve that delays the onset of clinical manifestations.     

A nonlinear mathematical model of electrically stimulated skeletal muscle

Researchers disagree as to whether Lewy body disease (LBD) constitutes a variant of Alzheimer's (AD) or Parkinson's disease (PD), or alternatively, whether it is an independent disease process. The neuropathological, genetic, and clinical characteristics of LBD are reviewed and compared to those of AD and PD. Data for 150 cases of LBD reported in the literature were compiled and grouped according to neuropathological status. Patients with pure LBD (with limited or no concurrent AD pathology) tend to present at a younger age with extrapyramidal signs followed by dementia, whereas patients with mixed LBD-AD (concurrent LB and AD pathology) are somewhat older and tend to present with dementia. The cognitive profile of LBD patients, and the relationships among LBD, AD, and PD remain unclear due to methodological limitations and the paucity of studies comparing the groups directly.     

Naming in dementia secondary to Parkinson's, Huntington's, and Alzheimer's diseases

Confrontation naming problems have been found in patients with dementia secondary to Alzheimer's (AD), Huntington's (HD), and in a subset of Parkinson's disease (PD) patients with dementia. The source of the naming deficit has not been established. The "Perception" and the "Semantic Feature" theories have been proposed to explain this naming dysfunction. Subjects with dementia secondary to AD, HD, and PD were given three tasks to determine which theory best explained the source of confrontation naming problems. The three tasks including picture matching, visual recognition, and confrontation naming were given to 42 subjects with dementia secondary to AD, HD, and PD controlled for severity of dementia, and to age-matched controls. Subjects with dementia did not have significantly more difficulty matching pictures but did have more difficulty associating pictures through semantic features. Subjects with mild dementia secondary to AD and HD had significantly more confrontation naming errors than subjects with mild dementia secondary to PD and normal controls. All subjects with moderate dementia had significantly more confrontation naming errors than normal controls. Statistical power may have been limited due to the small number of subjects in each group. The source of the reduction in confrontation naming performance in subjects with dementia secondary to AD, HD, and PD originated in the deterioration of semantic fields. The perception theory was rejected as findings were consistent with the semantic feature theory.     

Neuropsychological decline in frontotemporal lobar degeneration: A longitudinal analysis.

Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state. A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/naming, and visuoconstruction in 441 patients diagnosed with Alzheimer’s disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD). Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in 'animal' fluency; PNFA patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests. None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal sclerosis contributes to dementia in the elderly

OBJECTIVE: To assess the relevance of hippocampal sclerosis (HS) to dementia in the elderly. BACKGROUND: HS is a prominent pathologic finding in some demented elderly, but the anatomic substrate and cognitive profiles of this dementia have not been well established. DESIGN/METHODS: An autopsy series, including dot-immunobinding assay to estimate neocortical synaptic density, of eight patients (three men, five women) with HS on whom extensive antemortem neuropsychological testing was available. RESULTS: Mean age at onset was 72.0 (+/-9.8) (range, 59 to 89) with a mean duration of symptoms of 6.5 (+/-2.9) years. Patients were only mildly impaired with a mean MMSE of 20.9 (+/-4.9) and a mean DRS of 103.1 (+/-12.5) at presentation. Cardiovascular disease was present in 88%, with a mean Hachinski score of 3.4 (+/-2.2). No patient had a history of seizures. Sixty-three percent had depression or depressive symptoms. Neuropsychologically, most patients presented with prominent memory and language deficits and became progressively demented. Neuropathologically, isolated HS was a rare finding; many patients had either very mild or neocortical "plaque only or plaque predominant" Alzheimer's disease (AD) in addition to HS changes. Midfrontal neocortical synaptophysin counts were significantly reduced in all HS patients compared with controls (p = 0.0006). CONCLUSIONS: In the elderly, HS can be a neuropathologic substrate of dementia. Clinically, it can be associated with a course that is difficult to distinguish from AD although cardiac disease and depression are frequent concomitants. Deterioration of cognitive function in these subjects may relate to other pathologic features such as neocortical synapse loss.     

Neuropathological assessment of the lesions of significance in vascular dementia

OBJECTIVES: To better define the neuropathology of vascular dementia. METHODS: The neuropathological findings in 18 elderly, undemented subjects free of cerebrovascular disease were compared with 19 elderly undemented subjects who had cerebrovascular disease (many of whom had had a "stroke") and 24 elderly demented subjects who had cerebrovascular disease, but no other pathology to account for dementia. Cases in all groups were selected for absence or no more than very mild Alzheimer type pathology. RESULTS: Microvascular brain damage in the form of severe cribriform change and associated subcortical white matter damage and microinfarction were correlated with a history of dementia. Severe cribriform change was much more common and microinfarction somewhat more common in the demented group with vascular disease than the undemented group with vascular disease (P=0.0006 and P=0.031 respectively). Other findings of note were that congophilic angiopathy had a greater prevalence in the vascular dementia group than the control group, single cerebral infarcts were more common in the group who were undemented with vascular disease than in the group with dementia and vascular disease (P=0.0028), and the last group lacked evidence of macroscopic infarction more often than the first (P=0.034). There was a non-significant trend for the ratio of infarcted:uninfarcted tissue in one cerebral hemisphere to be higher in the group with dementia and vascular disease than in the group with vascular disease but no dementia. CONCLUSIONS: Microvascular disease, not macroscopic infarction, was the chief substrate of vascular dementia in this series of cases.     

Effects of sequential neuropsychological testing of an elderly community-based sample

The magnitude and importance of changes in scores of neuropsychological tests on retest in the elderly, especially over long time periods, is not well established. Three neuropsychological tests and one mental status test were initially administered to screen for potential dementia and were readministered to 380 of the surviving individuals 2.4 years later who either failed the screening examination or were an age matched control. Of the 380 women and men aged 65 and older, 56 were diagnosed as having Alzheimer disease (AD), 82 as at risk for developing AD, and 242 as having normal cognition. The present report focuses on changes in test scores between the two visits. In the normal and at risk groups, significant improvements were seen on retest of the Visual Reproduction Test (VRT), the Trails B test, and the Mini-Mental Status examination; verbal fluency decreased, and savings score of the VRT showed small variations. On most tests, scores of the AD group decreased. Practice effects, biases, and other variables may have played a role in the improvements seen in those labeled normal and at risk. If these results are confirmed, savings score of the VRT (which remained stable over time in normals and individuals at risk and decreased in patients with dementia) and verbal fluency (which decreased in all groups) may be better measures of true cognitive performance than the other tests that we evaluated.     

Re-evaluating the role of vascular changes in the differential diagnosis of Alzheimer's disease and vascular dementia

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common causes of dementia, and much effort has been devoted to their differential diagnosis. However, current epidemiological, clinical and neuropathological evidence points to a substantial overlap between AD and VaD and suggests that vascular pathology, the traditional cornerstone of the differential diagnosis between the two entities, may not represent as clear a line of demarcation as originally believed. It may be time to reevaluate the dichotomy between AD and VaD.     

Comparison of neuropsychological functioning in Alzheimer's disease and frontotemporal dementia

Neuropsychological changes distinguishing mild Alzheimer's disease (AD) from frontotemporal dementia (FTD) have been described, but empirical verification of differential cognitive characteristics is lacking. Archival neuropsychological data on 15 FTD patients, 16 AD patients, and 16 controls were compared. Controls outperformed both patient groups on measures of verbal and nonverbal memory, executive ability, and constructional skill, with AD patients showing more widespread memory decline. No differences were found between the 3 groups in confrontation naming, recognition memory, or basic attention. Patient groups differed only in nonverbal memory, with FTD patients performing significantly better than AD patients. However, patient groups also differed in pattern of performance across executive and memory domains. Specifically, AD patients exhibited significantly greater impairment on memory than executive tasks, whereas the opposite pattern characterized the FTD group. These findings suggest that examination of relative rankings of scores across cognitive domains, in addition to interpretation of individual neuropsychological scores, may be useful in differential diagnosis of FTD versus AD.     

Intermediate TCR cells can induce graft-versus-host disease after allogeneic bone marrow transplantation

In this study we compared memory performances of 29 probable patients with AD (17 mildly and 12 moderately demented) with those of 39 healthy young subjects, 36 elderly subjects (matched with the AD group for age and years of schooling), and 19 healthy very old subjects. In most of the memory tasks used in the present study, a progressive decline in performance was observed passing from the Young to the Elderly to the Very Old to the AD group. However, patients with AD were selectively impaired in the backward reproduction of verbal and spatial span sequences and in the semantic encoding of verbal material. These data are consistent with the hypothesis of not only quantitative but also a qualitative discontinuity between the process of normal aging and the dementia syndrome.     

Neuropsychological asymmetry in Alzheimer's disease: verbal versus visuoconstructional deficits across stages of dementia

The incidence of clinically apparent asymmetric profiles of neuropsychological deficits in Alzheimer's disease (AD) patients similar to those reported in the PET literature is currently unclear. This study investigated lateral neuropsychological asymmetry using principal component factor analysis in a sample of 153 patients diagnosed with probable AD. Using factor scores, patients were classified into groups exhibiting asymmetric or symmetric profiles of neuropsychological deficits. In the analysis of lateral asymmetry, 27.5% of patients were classified as asymmetric (10% verbally and 17% visuospatially). Consistent with reports of continued asymmetry beyond the mild dementia stage, asymmetry was exhibited in the mild, moderate, and severely demented groups. These findings of neuropsychological asymmetry across stages of dementia are consistent with the picture of significant neuropsychological heterogeneity in AD that has been emerging in the decade.     

Visuoconstructional problems in dementia: Contribution of executive systems functions.

Visuoconstructional ability was assessed by asking patients diagnosed with Alzheimer's disease (AD), ischaemic vascular dementia (IVD), and Parkinson's disease (PD) and a normal control group (NC) to copy a modification of the Rey–Osterrieth Complex Figure (M–ROCF). The drawings of the NC group were superior to all dementia participants. AD patients generally outperformed LVD and PD patients; however, there were few differences between LVD and PD groups. Nonetheless, the drawings of LVD and PD patients were very fragmented and contained numerous perseverations and omissions. Despite these errors, patients with LVD and PD obtained higher delayed recognition memory scores than AD patients. Correlational analyses among dementia patients between neuropsychological tests and the copy of the M–ROCF found that accurate figure copy was most consistently correlated with tests of working memory, that is, tests requiring patients to monitor their behavior and sustain a complex mental set while performing mental manipulations. By contrast, no relationship between executive function tests related to measures of response selection/inhibition or other domains of neuropsychological functioning was found. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Quantitative analysis of neuropathologic changes in the cerebral cortex of centenarians

1. The quantitative distribution of neurofibrillary tangles and senile plaques was studied in the brains of 65 elderly patients aged from 96 to 104 years by immunohistochemistry. 2. According to the clinical and neuropathological diagnoses, three groups of cases were considered: 19 patients with Alzheimer's disease, 22 patients with mixed dementia (vascular and degenerative) and 24 patients with no or very mild cognitive impairment. 3. Moderate to high neurofibrillary tangle densities were always present in the hippocampus and entorhinal cortex. The inferior temporal cortex was very frequently affected in demented and non-demented cases whereas the superior frontal cortex was spared in the majority of cases independently of the clinical diagnosis. Quantitatively, Alzheimer's disease cases showed significantly higher NFT densities than cases with no clinical findings of dementia only in the CA1 field of the hippocampus. 4. The hippocampus and entorhinal cortex were often devoid of senile plaques in non-demented cases while the vast majority of Alzheimer's disease cases had few SP in these regions. The frontal and temporal cortex were more frequently involved than the limbic structures in both non-demented and Alzheimer's disease cases. The SP densities in layers II and III of the inferior temporal and superior frontal cortex were significantly higher in Alzheimer's disease than in non-demented cases. 5. These observations suggest that the dementing process in nonagenarians and centenarians may differ to that described in younger demented individuals in that neurofibrillary tangles involve principally the hippocampal formation with relative sparing of the neocortex. Furthermore, they indicate that both the neurofibrillary tangle densities in the CA1 field and senile plaque densities in the superficial layers of the neocortex must be considered for the neuropathological diagnosis of Alzheimer's disease in this age group.