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David A Bennett

Publications and source records attributed to David A Bennett.

At least 73 records · Page 4Linked to original sources
PubMed2005

Hallucinations and mortality in Alzheimer disease.

OBJECTIVE: The authors tested the relationship of hallucinations and delusions to mortality in Alzheimer disease (AD). METHODS: A group of 407 persons with clinically diagnosed AD completed a uniform clinical evaluation, after which vital status was monitored for a mean of 3.7 years. At the initial evaluation, a previously established, structured, informant interview was used to ascertain the presence of hallucinations and delusional thinking. The evaluation also included a structured medical history, inspection of all medications, and detailed assessment of cognitive functioning and parkinsonian signs. RESULTS: At study onset, hallucinations were present in 41.0% of participants and delusions in 54.4%. During follow-up, 146 deaths occurred. In a proportional-hazards model adjusted for age, sex, race, and education, hallucinations were associated with a 78% increase in risk of death. The association was not substantially altered in subsequent analyses that controlled for level of cognitive impairment, severity of parkinsonism, use of antipsychotic medications, and the presence of chronic medical conditions. Risk of death was more than doubled in those with both auditory and visual hallucinations. By contrast, we did not find evidence of an association of delusions with mortality. CONCLUSION: Hallucinations are associated with an increased risk of death in AD.

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PubMed2005

Early and late life cognitive activity and cognitive systems in old age.

Little is known about the relative benefits of cognitively stimulating activities at different points in the lifespan. In a cohort of 576 older persons without dementia, we assessed current and past (childhood, young adulthood, middle age) frequency of cognitive activity; availability of cognitively stimulating resources in the home in childhood and middle age; and 5 domains of cognitive function. Past cognitive activity and cognitive resources were positively correlated with both current cognitive activity and current cognitive function. The association with cognitive function was reduced after controlling for current cognitive activity, however. Current cognitive activity was associated with better cognitive function, especially semantic memory and perceptual speed, even after controlling for past activity. The results suggest that past cognitive activity contributes to current cognition principally through its association with cognitive activity in old age.

Activities of Daily Living↗
PubMed2004

Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.

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PubMed2004

Decreases in soluble alpha-synuclein in frontal cortex correlate with cognitive decline in the elderly.

Alpha-synuclein (ASN) is a presynaptic protein and major component of Lewy bodies. It is considered important in the pathogenesis of Alzheimer's disease (AD), but its relevance to progressive cognitive decline in aging is largely unknown. To address this issue, ASN immunoreactivity was measured in frontal cortex of elderly individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI) and early AD using a Western blot technique and a polyclonal antibody to ASN. ASN immunoreactivity was significantly lower in AD than in MCI and NCI, but there was no difference between MCI and NCI. The ASN immunoreactivity correlated with CERAD diagnosis, as well as Mini-Mental State Exam (MMSE) score, global neuropsychologic z-score and some, but not all, frontal neuropsychology measures. Clinical correlations were stronger for ASN than synaptophysin immunoreactivity assessed in a similar manner. The correlation with MMSE was robust when NCI cases were considered separately, suggesting that decreases in soluble ASN may be an early feature of cognitive decline in aging and AD.

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PubMed2004

Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials.

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

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PubMed2004

Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function.

OBJECTIVE: To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles. DESIGN: Longitudinal clinicopathologic cohort study. PARTICIPANTS AND SETTING: Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death. METHODS: The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition. MAIN OUTCOME MEASURES: Clinically diagnosed AD and level of global cognitive function proximate to death. RESULTS: In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001). When a term for tangles was added to the regression model with amyloid, the association of amyloid load with clinical disease was reduced by more than 60% and was no longer significant, whereas the association of tangles with clinical disease was essentially unchanged. Similar results were found in analyses of global cognitive function. CONCLUSION: These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.

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PubMed2004

Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function.

BACKGROUND: Few prospective studies have assessed diabetes mellitus as a risk factor for incident Alzheimer disease (AD) and decline in cognitive function. OBJECTIVE: To evaluate the association of diabetes mellitus with risk of AD and change in different cognitive systems. DESIGN: Longitudinal cohort study. PARTICIPANTS: For up to 9 years, 824 older (those >55 years) Catholic nuns, priests, and brothers underwent detailed annual clinical evaluations. MAIN OUTCOME MEASURES: Clinically diagnosed AD and change in global and specific measures of cognitive function. RESULTS: Diabetes mellitus was present in 127 (15.4%) of the participants. During a mean of 5.5 years of observation, 151 persons developed AD. In a proportional hazards model adjusted for age, sex, and educational level, those with diabetes mellitus had a 65% increase in the risk of developing AD compared with those without diabetes mellitus (hazard ratio, 1.65; 95% confidence interval, 1.10-2.47). In random effects models, diabetes mellitus was associated with lower levels of global cognition, episodic memory, semantic memory, working memory, and visuospatial ability at baseline. Diabetes mellitus was associated with a 44% greater rate of decline in perceptual speed (P =.02), but not in other cognitive systems. CONCLUSIONS: Diabetes mellitus may be associated with an increased risk of developing AD and may affect cognitive systems differentially.

Alzheimer Disease↗
PubMed2004

Subregional analysis of GABA(A) receptor subunit mRNAs in the hippocampus of older persons with and without cognitive impairment.

We employed in situ hybridization and quantitative densitometry techniques to examine hippocampal mRNA expression of GABA(A) receptor subunits alpha1 and alpha5 in human subjects with progressing cognitive impairment. Included in this study were 17 participants of the Religious Order Study (ROS), who were categorized into three groups based upon degree of cognitive impairment: no cognitive impairment (n = 6); moderate cognitive impairment (n = 5); and probable Alzheimer's disease (AD) (n = 6). While the levels of each specific subunit mRNA were relatively homogeneously distributed throughout the five hippocampal subregions analyzed (CA1-4, and the granule cell layer of the dentate gyrus), mRNA expression of the alpha1 receptor subunit was found to be 20% reduced in the moderate cognitive impairment group as compared to the no cognitive impairment group. In addition, alpha1 mRNA expression was 25% reduced in the probable Alzheimer's disease group compared to the group with no cognitive impairment. Similarly, alpha5 subunit mRNA was reduced 32% between no cognitive impairment and moderate cognitive impairment groups, and 35% between no cognitive impairment and probable Alzheimer's disease groups. No significant reductions were found between moderate cognitive impairment and probable Alzheimer's disease groups for either subunit. Collectively, our data provide evidence for modest reductions in GABA(A) receptor subunit mRNAs, and suggest these changes occur very early in the progression of Alzheimer's disease cognitive impairment.

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PubMed2004

Contribution of changes in ubiquitin and myelin basic protein to age-related cognitive decline.

The structural substrates for age-associated cognitive and motor slowing are not known, but age-related white matter changes, such as ubiquitin (UBQ)-immunoreactive granular degeneration of myelin, might contribute to this slowing. To address this hypothesis we measured immunoreactivity for UBQ and myelin basic protein (MBP) in frontal white matter of age-, sex- and postmortem interval-matched cases with no cognitive impairment (NCI; N=12), mild cognitive impairment (MCI; N=14) and Alzheimer disease (AD; N=12). There were no significant correlations between UBQ in white matter and cognitive measures, but MBP was significantly lower in AD compared with NCI and MCI. MBP correlated with overall cognition as assessed by neuropsychological summary scores, as well as with timed cognitive tests and those that reflect frontal functions. An age-related decrease in MBP immunoreactivity was detected in NCI cases (r=0.71). These results support the hypothesis that white matter pathology may contribute to age-associated decline in cognition.

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PubMed2004

A longitudinal study of implicit and explicit memory in old persons.

Decline in explicit memory with advancing age is a common finding, but it is unclear whether implicit memory (repetition priming) declines or remains stable. Meta-analyses of studies that examined differences between extreme groups (young-old), typically at a single point in time and on a single test, suggest that a mild reduction in priming occurs with advancing age. The authors examined explicit memory and priming, on multiple tests over 4 annual data-collection waves, in a large group of older persons without dementia at baseline. Explicit memory declined significantly, but priming remained stable. Findings indicate that explicit memory and priming are dissociable on the basis of age-related change and that mildly reduced priming is not an inevitable consequence of growing older.

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PubMed2004

A longitudinal study of parkinsonism and disability in a community population of older people.

BACKGROUND: Parkinsonian signs in patients without Parkinson's disease are often undetected but occur frequently in older people, and are often considered benign. We measured the association between parkinsonism and subsequent disability. METHODS: We conducted a prospective, longitudinal, community-based population study in East Boston, Massachusetts, using a stratified random sample of 455 community residents, aged 65 years and older. Four categories of parkinsonian signs were measured at baseline: bradykinesia, gait disturbance, rigidity, and tremor. Parkinsonism was defined as the presence of two or more categories of parkinsonian signs, and cases of Parkinson's disease were excluded from analyses. Disability was assessed annually over a mean of 4.7 years using the Katz, Rosow-Breslau, and Nagi disability measures. RESULTS: Parkinsonism at baseline strongly predicted subsequent disability as assessed with the three disability measures (on the Katz measure, beta = -1.30, p < .001). On average, a person with parkinsonism had a disability level at follow-up equal to that of a comparable person approximately 16.7 years for men and 8 years for women. The rate of developing disability for persons with parkinsonism increased each year; on the Katz measure, participants with parkinsonism declined on average 16.4% faster than those without. Gait impairment and bradykinesia strongly predicted subsequent disability; tremor and rigidity did not. The effect of parkinsonism was attenuated but still persistent in persons with coexistent moderate-to-severe cognitive impairment or stroke. CONCLUSIONS: Parkinsonism strongly predicts progressive disability in the older community population and has a marked aging effect on disability level.

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PubMed2004

Predictors of depressive symptoms in persons with Alzheimer's disease.

In a 4-year longitudinal study, we evaluated factors related to the development of depressive symptoms in 410 persons with Alzheimer's disease. We measured depressive symptoms annually by using the 17-item Hamilton Rating Scale, which we completed by using structured interviews with family members. On the basis of informant ratings of premorbid personality, we associated neuroticism with a higher rate of depressive symptoms, particularly mood disturbances. We associated greater cognitive impairment with a small reduction in mood symptoms and a modest increase in somatic symptoms. Among demographic variables, somatic symptoms were more common in men and mood symptoms were inversely related to age. Depressive symptoms in Alzheimer's disease appear to follow a more predictable pattern of expression than previously described.

Activities of Daily Living↗
PubMed2004

Personality and mortality in old age.

We examined the relation of personality to mortality in 883 older Catholic clergy members (69% women). At baseline, they completed the NEO Five-Factor Inventory, which assesses the five principal dimensions of personality. They were followed for a mean of 5.1 years, during which 182 deaths occurred. Risk of death was nearly doubled in those with a high neuroticism score (90th percentile) compared with a low score (10th percentile) and was approximately halved in those with a high conscientiousness score compared with a low score. Findings for extraversion were mixed, and neither agreeableness nor openness was strongly related to mortality. The results suggest that personality is associated with mortality in old age.

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PubMed2004

Racial differences in perceived discrimination in a community population of older blacks and whites.

OBJECTIVES: To examine the prevalence of perceived discrimination in an older biracial population and to examine its correlation with depressive symptoms. METHODS: The sample consisted of 2,652 Blacks and 1,630 Whites, 68 years old and older, from the Chicago Health and Aging Project (CHAP). Perceived discrimination was measured with a nine-item scale developed by Williams, Yu, Jackson, and Anderson (1997). RESULTS: A factor analysis of the discrimination scale revealed two subscales, unfair treatment and personal rejection. Blacks scored higher on both subscales as compared with Whites. In linear regression models, race was significantly associated with higher levels of unfair treatment and personal rejection, controlling for demographic variables and socioeconomic status (SES). Each subscale was also positively related to depressive symptoms, and these effects did not vary by race. DISCUSSION: These findings suggest that older Blacks perceive more discrimination than do older Whites. This may have important implications for health differences between older Blacks and Whites.

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PubMed2003

Negative affect and mortality in older persons.

The authors examined the relation of negative affect to mortality in the Religious Orders Study, a longitudinal cohort study of older persons, between 1994 and 2002. Participants were 851 Catholic clergy members without dementia at baseline (mean age, 75.4 (standard deviation, 6.9) years; 68% women). They completed standard measures of depressive symptoms, proneness to anxiety and anger, and patterns of anger expression at baseline and then underwent annual clinical evaluations for a mean of 4.7 (standard deviation, 2.7) years. The association of each scale with mortality was examined in proportional hazards models adjusted for age, sex, education, measures of cognitive function, lower limb function, chronic illness, smoking, alcohol, and obesity. During follow-up, 164 persons died. Measures of internally experienced negative affect, such as depressive symptoms and suppressed anger, were related to mortality, but measures of externally directed negative affect, such as the tendencies to be angry with others and to express anger overtly, were not. Persons with a high score (90th percentile) on a summary measure of internally experienced negative affect were nearly twice as likely to die as persons with a low score (10th percentile). The results suggest that negative affect in older persons, especially internally experienced distress, is associated with an increased mortality risk.

Affect↗
PubMed2003

Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status.

CONTEXT: Few studies compare Alzheimer disease (AD) incidence among black and white subjects. OBJECTIVE: To estimate incidence and the effect of the apolipoprotein E (APOE) epsilon4 allele in these races. DESIGN: Population-based study of disease incidence using a random, stratified sample. SETTING: A geographically defined community of 3 adjacent neighborhoods in Chicago, Ill. PARTICIPANTS: A total of 6158 persons (78.7% overall; 80.5% of the black subjects and 74.6% of the white subjects) participated; 4.1 years later, persons initially free of AD were sampled for clinical evaluation for disease incidence (overall 842 persons [74.8%] participated; 67.6% of the black subjects and 81.9% of the white subjects). INTERVENTIONS: None. MAIN OUTCOME MEASURE: Incident, clinically diagnosed AD. RESULTS: The effect of the APOE epsilon4 allele on the risk of AD differed strongly for black and white subjects. Among white subjects, the presence of the APOE epsilon4 allele was associated with a 2.73-fold (95% confidence interval [CI], 1.40-5.32) increase in risk while among black subjects there was no increase in risk (odds ratio, 1.02; 95% confidence interval, 0.39-2.68). Black race was associated with a nonsignificantly increased risk of AD with an odds ratio of 1.84 (95% CI, 0.73-4.66) if APOE and its interaction with race are considered, and an odds ratio of 1.28 (95% CI, 0.54-2.98) if they are not. The incidence of AD was 1.45% (95% CI, 0.89%-2.01%) per year among persons 65 to 74 years old, 4.73% (95% CI, 3.83%-5.64%) among those 75 to 84 years old, and 9.11% (95% CI, 7.36%-10.9%) among those 85 years and older. CONCLUSION: Apolipoprotein E epsilon4 led to increased risk of AD among white subjects but not black subjects.

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