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Biomedical subjects

David A Bennett

Publications and source records attributed to David A Bennett.

At least 55 records · Page 3Linked to original sources
PubMed2005

The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort.

The long-term objective of the Rush Memory and Aging Project is to identify the postmortem indices linking genetic and environmental risk factors to the development of Alzheimer's disease (AD). The overall study design involves a detailed assessment of risk factors for AD in older persons without known dementia who agree to annual clinical evaluation and organ donation at the time of death. In contrast to other clinical-pathologic studies which are conducted on special populations, the Rush Memory and Aging Project enrolled a cohort with much greater diversity in terms of educational attainment, in addition to gender, race, and ethnicity. From September of 1997 through April of 2005, more than 1,000 older persons without known dementia from more than 30 residential facilities across the Chicago metropolitan area agreed to participate. Their mean age was 81 years, about a third had 12 or fewer years of education, a third were men, and about 10% were members of a racial or ethnic minority group. More than 950 already have completed their baseline clinical evaluation.

Activities of Daily Living↗
PubMed2005

High-resolution serum proteomic profiling of Alzheimer disease samples reveals disease-specific, carrier-protein-bound mass signatures.

BACKGROUND: Researchers typically search for disease markers using a "targeted" approach in which a hypothesis about the disease mechanism is tested and experimental results either confirm or disprove the involvement of a particular gene or protein in the disease. Recently, there has been interest in developing disease diagnostics based on unbiased quantification of differences in global patterns of protein and peptide masses, typically in blood from individuals with and without disease. We combined a suite of methods and technologies, including novel sample preparation based on carrier-protein capture and biomarker enrichment, high-resolution mass spectrometry, a unique cohort of well-characterized persons with and without Alzheimer disease (AD), and powerful bioinformatic analysis, that add statistical and procedural robustness to biomarker discovery from blood. METHODS: Carrier-protein-bound peptides were isolated from serum samples by affinity chromatography, and peptide mass spectra were acquired by a matrix-assisted laser desorption/ionization (MALDI) orthogonal time-of-flight (O-TOF) mass spectrometer capable of collecting data over a broad mass range (100 to >300,000 Da) in a single acquisition. Discriminatory analysis of mass spectra was used to process and analyze the raw mass spectral data. RESULTS: Coupled with the biomarker enrichment protocol, the high-resolution MALDI O-TOF mass spectra provided informative, reproducible peptide signatures. The raw mass spectra were analyzed and used to build discriminant disease models that were challenged with blinded samples for classification. CONCLUSIONS: Carrier-protein enrichment of disease biomarkers coupled with high-resolution mass spectrometry and discriminant pattern analysis is a powerful technology for diagnostics and population screening. The mass fingerprint model successfully classified blinded AD patient and control samples with high sensitivity and specificity.

Alzheimer Disease↗
PubMed2005

White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study.

Diffusion tensor imaging (DTI) can detect, in vivo, the directionality of molecular diffusion and estimate the microstructural integrity of white matter (WM) tracts. In this study, we examined WM changes in patients with Alzheimer's disease (AD) and in subjects with amnestic mild cognitive impairment (MCI) who are at greater risk for developing AD. A DTI index of WM integrity, fractional anisotropy (FA), was calculated in 14 patients with probable mild AD, 14 participants with MCI and 21 elderly healthy controls (NC). Voxel-by-voxel comparisons showed significant regional reductions of FA in participants with MCI and AD compared to controls in multiple posterior white matter regions. Moreover, there was substantial overlap of locations of regional decrease in FA in the MCI and AD groups. These data demonstrate that white matter changes occur in MCI, prior to the development of dementia.

Aged↗
PubMed2005

Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and alpha-synuclein pathology.

Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or alpha-synuclein. In AD, beta-amyloid (Abeta)-associated caspase activation and cleavage of tau at Asp421 (DeltaTau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether DeltaTau accumulates in other diseases not characterized by extracellular Abeta accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied DeltaTau accumulation in DLB cases associated with intracellular alpha-synuclein. DeltaTau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of DeltaTau may represent a common pathway associated with abnormal accumulation of intracellular tau or alpha-synuclein and may be relatively less dependent on the extracellular accumulation of Abeta in non-AD dementias.

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PubMed2005

Implicit memory and Alzheimer's disease neuropathology.

Explicit memory failure is the defining cognitive feature of Alzheimer's disease and relates to the hallmark neuropathological features (plaques and tangles) of this illness. However, a pattern of preserved and impaired implicit memory has been found in Alzheimer's disease patients that may be explained by the association between the processing demands of certain implicit tests and the level of regional Alzheimer's disease neuropathology. In this study, we tested the hypothesis that these neuropathological features are related to implicit memory--measured by repetition priming--in a test that emphasized conceptual (or meaning-based) cognitive processing, and that the pathological changes are not related to implicit memory in a repetition priming test that emphasized perceptual (or sensory-based) cognitive processing. Subjects were older nuns, priests and brothers participating in the Religious Orders Study who agreed to annual neurological and neuropsychological evaluation for Alzheimer's disease and common neurological conditions of ageing, and brain autopsy at time of death. Explicit memory was measured by seven tests of episodic recall and recognition and converted to a previously established summary measure. Implicit memory was measured by four repetition priming tests. One test, category exemplar priming, emphasized conceptual, or meaning-based cognitive processing. A second test, word-identification priming, emphasized perceptual, or sensory-based cognitive processing. Two additional priming tests, picture-naming and word-stem completion, invoke both conceptual and perceptual processes. Neuritic and diffuse plaques, and neurofibrillary tangles identified by Bielschowsky silver stain, were quantified from five regions separately (frontal, parietal, temporal, entorhinal cortex and the hippocampus) and converted to a previously established summary measure. In linear regression analyses--controlling for age, sex and education--higher levels of Alzheimer's disease neuropathology were related to lower levels of explicit memory proximate to death. Higher levels of neuropathology were also related to lower levels of priming on the category-exemplar test, but were not related to levels of priming on the word-identification, picture-naming, or word-stem completion tests. The results suggest that hallmark indices of Alzheimer's disease neuropathology are associated with performance on priming tests to the extent that conceptual, but not perceptual, processing resources are required.

Aged↗
PubMed2005

Early life socioeconomic status and late life risk of Alzheimer's disease.

The authors examined the relation of early life socioeconomic status to incident Alzheimer's disease (AD), level of cognition and rate of cognitive decline in old age. For up to 10 years, 859 older Catholic clergy members without dementia at baseline completed annual clinical evaluations as part of the Religious Orders Study. The evaluations included clinical classification of AD and detailed cognitive testing. At baseline, indicators of early life household socioeconomic level (e.g., parental education) and the county of birth were ascertained. Socioeconomic features of the birth county (e.g., literacy rate) were estimated with data from the 1920 US Census. Composite measures of early life household and community socioeconomic level were developed. In analyses that controlled for age, sex and education, higher household and community socioeconomic levels in early life were associated with higher level of cognition in late life but not with risk of AD or rate of cognitive decline. The results suggest that early life socioeconomic level is related to level of cognition in late life but not to rate of cognitive decline or risk of AD.

Aged↗
PubMed2005

Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment.

We determined whether oxidative stress is an early event in the pathogenesis of sporadic Alzheimer disease (AD), and correlated oxidative stress with neuropsychological functions and neurofibrillary pathology in AD and mild cognitive impairment (MCI). Oxidative stress was measured as the percentage of astrocytes expressing heme oxygenase-1 (HO-1) in post mortem temporal cortex and hippocampus after dual HO-1/glial fibrillary acidic protein (GFAP) immunohistochemistry. Glial HO-1 expression in the MCI temporal cortex and hippocampus was significantly greater than in the non-demented group and did not differ from AD values. Astroglial HO-1 expression in the temporal cortex was associated with decreased scores for global cognition, episodic memory, semantic memory and working memory. Hippocampal astroglial HO-1 expression was associated with lower scores for global cognition, semantic memory and perceptual speed. Glial HO-1 immunoreactivity in the temporal cortex, but not hippocampus, correlated with the burden of neurofibrillary pathology. Cortical and hippocampal oxidative stress is a very early event in the pathogenesis of sporadic AD and correlates with the development of specific cognitive deficits in this condition.

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PubMed2005

Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease.

Genes known to contribute to the genetic predisposition to Alzheimer's disease (AD) are active in pathways of neurodegeneration but explain only a minority of the genetic contribution to AD. A protein of importance in cerebral neurodegeneration is the brain-derived neurotrophic factor (BDNF). Variations in two single-nucleotide polymorphisms (SNPs) within the BDNF gene have previously been associated with AD, and one of these SNPs has also been associated with memory loss and affective disorders. We performed a case control study of three BDNF SNPs in 250 neuropathologically confirmed cases of AD and 194 unrelated controls. We did not find a significant association between the three BDNF SNPs studied and AD when evaluated individually or with haplotype analysis. Nor did BDNF genotype appear to affect the APOE epsilon4 association with AD. The three SNPs studied were closely linked (D' = 0.99 across the region). We discuss possible reasons for our failure to confirm the previously reported associations.

Aged↗
PubMed2005

Lack of genetic association of cholesteryl ester transfer protein polymorphisms with late onset Alzheimers disease.

Dysregulation of cholesterol homeostasis may be associated with the pathogenesis of coronary artery disease (CAD) and Alzheimers disease (AD). Recently, several single nucleotide polymorphisms (SNPs) in cholesteryl ester transfer protein (CETP) were associated with altered plasma CETP concentrations, cholesterol concentrations and CAD. Hence, these CETP SNPs represent excellent candidates for evaluating association with AD. To date, one study has evaluated the association between a single CETP SNP and AD. In this study, we examined three CETP SNPs to evaluate the genetic association of CETP with late onset AD on two study cohorts: the Religious Orders Study (ROS) series, including 85 AD and 70 non-AD individuals, and the University of Kentucky (UKY) series, including 78 AD and 84 non-AD individuals. Significant association between CETP genotypes or haplotypes and late onset AD was not detected in these two study cohorts. Moreover, the CETP genotypes and haplotypes were not significantly associated with AD when the populations were stratified for the presence or absence of apolipoprotein E4 (apoE4). In summary, CETP genetic variants were not associated with AD in two series.

Aged↗
PubMed2005

Reduction of choline acetyltransferase activity in primary visual cortex in mild to moderate Alzheimer's disease.

BACKGROUND: Cholinergic deficits in the primary visual cortex (PVC) may underlie some of the abnormalities in visual processing and global cognitive performance in Alzheimer's disease (AD). OBJECTIVE: To correlate measures of general cognition (Mini-Mental State Examination and Global Cognitive Score) and visuospatial function with choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities, and nerve growth factor protein levels in the PVC. DESIGN: The ChAT and AChE enzyme assays and a nerve growth factor protein enzyme-linked immunoabsorbent assay were performed on PVC tissue samples from subjects clinically diagnosed as having mild cognitive impairment (MCI), AD, or no cognitive impairment (NCI). SETTING AND PATIENTS: Nuns, priests and brothers enrolled in the Religious Order Study, with annual premortem records of neuropsychological testing. RESULTS: Significant differences in ChAT activity, but not in AChE activity or nerve growth factor protein levels, were found among diagnostic groups (P = .049). The ChAT activity was lower in AD than in MCI or NCI (P<.01); MCI was not different from NCI. The PVC ChAT activity correlated with measures of overall cognitive function (Mini-Mental State Examination and Global Cognitive Score), but less so with a composite measure of visuospatial function. CONCLUSIONS: The reduction in ChAT activity in the PVC of mild to moderate AD, but not in MCI, might serve to distinguish between clinical and preclinical forms of the disease. It appears that this change relates to generalized cognitive abnormalities but not specifically to visuospatial function.

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PubMed2005

Sex differences in the clinical manifestations of Alzheimer disease pathology.

CONTEXT: Sex differences in risk of clinically diagnosed Alzheimer disease (AD) have been studied extensively, but little is known about the relation of the pathologic indices of AD to the clinical manifestations of the disease in men compared with women. OBJECTIVE: To test whether the relation of AD pathology to the clinical manifestations of the disease differs in men and women. DESIGN: Longitudinal, clinicopathologic cohort study. PARTICIPANTS AND SETTING: Analyses were conducted on 141 older Catholic clergy members who underwent detailed annual clinical evaluations and brain autopsy at death. The number of neuritic plaques, diffuse plaques, and neurofibrillary tangles in a 1-mm2 area sampled from 4 cortical regions was counted, and a global measure of AD pathology (range, 0-2.98 U) and specific measures of each pathology were derived. MAIN OUTCOME MEASURES: Clinical diagnosis of probable AD and level of global cognitive function at the last evaluation before death. RESULTS: Women had more global AD pathology than did men (P = .04), due primarily to more neurofibrillary tangles (P = .02). At the last evaluation before death, 57 persons met clinical criteria for probable AD (34 [60%] of them women). In logistic regression models, sex was not related to odds of clinical AD (odds ratio [OR], 1.35; 95% confidence interval [CI], 0.56-3.25), but the relation of global AD pathology to clinical diagnosis differed for men and women. Each additional unit of AD pathology was associated with a nearly 3-fold increase in the odds of clinical AD in men (OR, 2.82; 95% CI, 1.03-7.65) compared with a more than 20-fold increase in the odds of clinical AD in women (OR, 22.67; 95% CI, 5.11-100.53). Results were unchanged after controlling for potential confounders or using level of cognition as the outcome. CONCLUSION: These data suggest that AD pathology is more likely to be clinically expressed as dementia in women than in men.

Aged↗
PubMed2005

Genetic association of low density lipoprotein receptor and Alzheimer's disease.

The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) LDLR modulates the homeostasis of cholesterol, which itself appears associated with AD. Therefore, we evaluated whether LDLR haplotypes alter the odds of AD by performing an association study examining three LDLR single nucleotide polymorphisms (SNPs) in 118 AD patients and 133 non-AD subjects. LDLR genotypes were obtained by TaqMan allelic discrimination assays. Although individual LDLR SNPs were not associated with AD, analyses of unambiguous haplotypes suggested the hypothesis that the 211 LDLR haplotype was associated with reduced odds of AD. We then evaluated this hypothesis in a second study cohort, i.e., the Religious Orders Study. These results supported the hypothesis that the 211 LDLR haplotype is associated with reduced odds of AD. Moreover, these data suggested further associations between LDLR variants and AD. Thus, LDLR variants appear significantly associated with AD and merit additional study.

Aged↗
PubMed2005

Distress proneness and cognitive decline in a population of older persons.

The association between distress proneness and cognitive decline was examined in older residents of a biracial community in Chicago. At baseline, participants completed four cognitive tests that yielded a global measure (baseline mean=101.2; standard deviation (SD)=7.8), and a brief measure of the tendency to experience negative emotions (mean=16.5; SD=6.7) based on the Neuroticism scale of the NEO Five-Factor Inventory. Cognitive testing was repeated twice at three-year intervals. In mixed models that controlled age, sex, race, and education, for each point on the distress proneness scale, global cognitive score was 0.12 unit lower at baseline (p<0.001) and annual rate of decline increased by 0.01 unit (p=0.002), or about 2%. Thus, cognitive decline was about 30% faster in a person highly prone to distress (score=24, 90th percentile) compared to the one low in distress proneness (score=9, 10th percentile). This effect was unchanged after controlling for level of cognitive activity or excluding people with cognitive impairment at baseline, but it was reduced to a trend (p=0.059) after controlling for depressive symptoms. The results suggest that the tendency to experience psychological distress is associated with increased cognitive decline in old age.

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PubMed2005

Parkinsonian signs and cognitive function in old age.

Studies have shown that parkinsonian signs are related to cognitive function in aging. What remains unclear is whether this association is stronger for some cognitive domains than it is for others, and precisely how much variability in global and specific cognitive functions is explained by the motor signs. We examined the associations between four parkinsonian signs (gait, rigidity, bradykinesia, tremor) and five cognitive domains (episodic memory, semantic memory, working memory, perceptual speed, visuospatial ability) in a large cohort of older persons who were free of Parkinson's disease and dementia and were participating in the Rush Memory and Aging Project. In a series of regression equations that controlled for age, sex, and education, higher levels of three signs (gait, rigidity, and bradykinesia) were related to lower levels of cognitive function, but they accounted for less than 5% of the variance in most measures. The results did not change when the presence of depressive symptoms, diabetes, and hypertension were added to the models. The cross-sectional association between parkinsonian signs and cognitive function did not vary substantially across specific cognitive domains or specific cognitive tests. The results suggest that parkinsonian signs have a modest, but statistically reliable, association with level of cognitive function in old age.

Aged↗
PubMed2005

Repetition priming and recognition memory in younger and older persons: temporal stability and performance.

The dissociation between intact priming and reduced explicit memory in aging has been called into question on the basis of limited information that suggests that priming measures are less reliable than explicit memory measures. No aging study to date, however, has offered a comprehensive examination of the reliability of these measures. Age-related performance and test-retest stability coefficients for multiple priming and explicit memory tasks were compared. Age effects were found on some tasks but not others, and stability was not related to task performance. Stability was similar for implicit versus explicit task instructions, younger versus older persons, and studied versus unstudied items. Results indicate that dissociations between priming and explicit memory performances cannot be accounted for by differential reliability of the measures.

Adult↗
PubMed2005

The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment.

Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI.

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PubMed2005

Assessment of cognitive decline in old age with brief tests amenable to telephone administration.

The adequacy with which brief cognitive tests suitable for telephone administration can assess cognitive decline due to aging and Alzheimer's disease is uncertain. The authors examined these issues with data from the Religious Orders Study, which involves annual clinical evaluations and brain donation at death. Participants are 996 older Catholic clergy members. Analyses focused on seven cognitive tests which can be administered in person or by telephone in less than 15 min. Composite measures of global cognition and of episodic, semantic and working memory were formed. During a mean of 5.8 years of follow-up, performance on each composite measure declined in persons with and without dementia at baseline. Among those without dementia, possession of the apolipoprotein E epsilon4 allele was associated with more rapid cognitive decline, especially in episodic and working memory. Level of performance on each cognitive measure proximate to death was inversely related to the level of cortical plaques and tangles in the brain. In a subset of persons who were given the tests by telephone, there was no evidence that performance differed from in-person administration. The results suggest that briefly assessing cognition with tests amenable to telephone administration may prove useful in longitudinal epidemiologic studies of older persons.

Age Factors↗