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Biomedical subjects

David A Bennett

Publications and source records attributed to David A Bennett.

At least 37 records · Page 2Linked to original sources
PubMed2006

Chronic psychological distress and risk of Alzheimer's disease in old age.

Clinical and pathological data from the Rush Memory and Aging Project were used to test the hypothesis that distress proneness is associated with increased risk of Alzheimer's disease (AD). More than 600 older persons without dementia completed a 6-item measure of neuroticism, a stable indicator of proneness to psychological distress. At annual intervals thereafter, they underwent uniform evaluations that included clinical classification of AD and administration of 18 cognitive tests. Those who died underwent brain autopsy from which composite measures of AD pathology were derived. During a mean of about 3 years of follow-up, 55 people were clinically diagnosed with AD. In analyses that controlled for age, sex, and education, persons with a high level of distress proneness (score = 24, 90th percentile) were 2.7 times more likely to develop AD than those not prone to distress (score = 6, 10th percentile). Adjustment for depressive symptomatology or frequency of cognitive, social, and physical activity did not substantially change this effect. Distress proneness was also associated with more rapid cognitive decline. Among 45 participants who died and underwent brain autopsy, distress proneness was unrelated to diverse measures of AD pathology and was inversely related to cognition after controlling for AD pathology. The results support the hypothesis that distress proneness is associated with increased risk of dementia and suggest that neurobiologic mechanisms other than AD pathology may underlie the association.

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PubMed2006

Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease.

The concept of amnestic mild cognitive impairment (MCI) describes older people who show a decline predominantly in memory function, but who do not meet criteria for dementia. Because such individuals are at high risk for developing Alzheimer's disease, they are of great interest for understanding the prodromal stages of the disease process. The mechanism underlying memory dysfunction in people with MCI is not fully understood. The present study uses quantitative, high-resolution structural MRI techniques to investigate, in vivo, the anatomical substrate of memory dysfunction associated with MCI. Changes in brain structures were assessed with two imaging techniques: (i) whole-brain, voxel-based morphometry to determine regions of reduced white matter volume and (ii) sensitive volumetric segmentation of the entorhinal cortex and hippocampus, gray matter regions that are critically important for memory function. In participants with amnestic MCI, compared with age-matched controls, results showed a significant decrease in white matter volume in the region of the parahippocampal gyrus that includes the perforant path. There was also significant atrophy in both the entorhinal cortex and the hippocampus. Regression models demonstrated that both hippocampal volume and parahippocampal white matter volume were significant predictors of declarative memory performance. These results suggest that, in addition to hippocampal atrophy, disruption of parahippocampal white matter fibers contributes to memory decline in elderly individuals with MCI by partially disconnecting the hippocampus from incoming sensory information.

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PubMed2006

Early involvement of small inhibitory cortical interneurons in Alzheimer's disease.

Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Abeta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.

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PubMed2006

The relation of cigarette smoking to incident Alzheimer's disease in a biracial urban community population.

The relationship between smoking status and incident Alzheimer's disease (AD) was investigated in a random stratified sample of a biracial community in Chicago. Analyses are based on 1,064 persons (of 1,134 evaluated) who had data on smoking status, disease incidence, and key covariates such as apolipoprotein allele status. During a mean of about 4 years of follow-up, 170 persons met criteria for incident AD. Current smoking was associated with increased risk of incident AD (OR = 3.4, 95% CI = 1.4-8.0) compared to persons who never smoked. There was no apparent increase in risk of AD for former smokers compared to persons who never smoked (OR = 0.9, 95% CI = 0.5-1.7). Apolipoprotein E allele status modified this association in that former smokers with a upsilon4 allele were less likely to develop AD (p = 0.04) than those who never smoked. Former smokers also appeared to have a reduced risk of developing AD as their pack-years of smoking increased (p = 0.02)such that the odds of developing AD increased by 50% for every 10 years of smoking cessation (OR = 1.3, CI = 0.9-1.7). The results suggest that older people who currently smoke are more likely to develop AD compared to those who never smoked; the relation between those who used to smoke but quit and the risk of AD is complex and requires further research.

Black or African American↗
PubMed2006

Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease.

BACKGROUND: Little is known about motor function in mild cognitive impairment (MCI) and its relation to the risk of Alzheimer disease (AD). OBJECTIVE: To examine motor function in persons with MCI and its relation to risk of AD. DESIGN: Longitudinal cohort study. SETTING: More than 40 Catholic religious orders across the United States. PARTICIPANTS: We studied 816 older Catholic clergy members from the Religious Orders Study. At the baseline evaluation, they were classified as having no cognitive impairment (n = 558), MCI (n = 198), or dementia (n = 60). MAIN OUTCOME MEASURES: Motor function was assessed at baseline using performance-based measures of upper and lower extremity function and a modified version of the motor section of the Unified Parkinson's Disease Rating Scale, from which previously established measures of parkinsonian signs were derived. Clinical evaluations for dementia and AD were repeated annually for up to 10 years. All analyses controlled for age, sex, educational level, and possession of at least 1 apolipoprotein E epsilon4 allele. RESULTS: At baseline, individuals with MCI had impaired motor function relative to those without cognitive impairment and superior motor function vs those with dementia. Among those with MCI, baseline levels of lower extremity motor performance, parkinsonian gait, and bradykinesia were inversely related to risk of AD, even after controlling for clinical stroke. Thus, a person with impaired lower limb performance or parkinsonian gait (10th percentile) was 2 to 3 times more likely to develop AD than a person with good lower limb function (90th percentile). CONCLUSIONS: Persons with MCI also have impaired motor function, and the degree of impairment in lower extremity function is related to the risk of AD.

Age Factors↗
PubMed2006

Substantia nigra tangles are related to gait impairment in older persons.

OBJECTIVE: Parkinsonian signs, especially gait impairment, are common and associated with morbidity and mortality in older persons. Our objective was to test the hypothesis that substantia nigra neurofibrillary tangles (NFTs) are related to parkinsonian signs in older persons with and without dementia. METHODS: We studied 86 deceased older Catholic clergy without idiopathic Parkinson's disease from the Religious Order Study, a longitudinal clinical-pathological study. Mean age at death was 85.3 years. Signs of gait disturbance, bradykinesia, rigidity, and tremor were assessed proximate to death using a modified Unified Parkinson's Disease Rating Scale. Forty-micrometer paraffin-embedded sections of substantia nigra were bleached before tau immunohistochemistry and the optical disector was used to count NFTs. We used multivariable linear regression to examine parkinsonian signs as a function of nigra NFTs, controlling for age, sex, education, and cortical NFTs. RESULTS: Substantia nigra NFTs were present in 67 of 86 persons (77.9%). After controlling for age, sex, education, and cortical NFTs, nigra NFTs were related to gait impairment (p < 0.001), but not bradykinesia, rigidity, or tremor. Results were not confounded by dementia, Braak score, neuroleptic medication, cerebral infarcts, or Lewy bodies. INTERPRETATION: NFTs in the substantia nigra are associated with gait impairment in older persons with and without dementia.

Aged, 80 and over↗
PubMed2006

The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study.

BACKGROUND: Few data are available about how social networks reduce the risk of cognitive impairment in old age. We aimed to measure this effect using data from a large, longitudinal, epidemiological clinicopathological study. METHODS: 89 elderly people without known dementia participating in the Rush Memory and Aging Project underwent annual clinical evaluation. Brain autopsy was done at the time of death. Social network data were obtained by structured interview. Cognitive function tests were Z scored and averaged to yield a global and specific measure of cognitive function. Alzheimer's disease pathology was quantified as a global measure based on modified Bielschowsky silver stain. Amyloid load and the density of paired helical filament tau tangles were also quantified with antibody-specific immunostains. We used linear regression to examine the relation of disease pathology scores and social networks to level of cognitive function. FINDINGS: Cognitive function was inversely related to all measures of disease pathology, indicating lower function at more severe levels of pathology. Social network size modified the association between pathology and cognitive function (parameter estimate 0.097, SE 0.039, p=0.016, R(2)=0.295). Even at more severe levels of global disease pathology, cognitive function remained higher for participants with larger network sizes. A similar modifying association was observed with tangles (parameter estimate 0.011, SE 0.003, p=0.001, R(2)=0.454). These modifying effects were most pronounced for semantic memory and working memory. Amyloid load did not modify the relation between pathology and network size. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases. INTERPRETATION: These findings suggest that social networks modify the relation of some measures of Alzheimer's disease pathology to level of cognitive function.

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PubMed2006

Cognitive decline in old age: separating retest effects from the effects of growing older.

Repeated administration of cognitive tests improves test performance, making it difficult for researchers to gauge the true extent of age-related cognitive decline. The authors examined this issue using data from the Rush Religious Orders Study and linear mixed-effects models. At annual intervals for up to 8 years, more than 800 older Catholic clergy members completed the same set of 19 cognitive tests from which previously established composite measures of cognitive domains were derived. Retest effects on some measures were substantial and continued to accumulate even after 8 annual test readministrations, but effects on other measures were minimal. Across cognitive measures, retest effects were not related to age, sex, or education. Individual differences in retest effects were substantial but not consistent across cognitive measures. The results suggest that retest-based improvement in cognitive test performance can be substantial and persistent.

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PubMed2006

Personality and incident disability in older persons.

OBJECTIVE: to examine the relation of personality to the development of disability in old age. METHODS: participants are 813 older Catholic nuns, priests and brothers without dementia or disability at study onset. As part of a uniform baseline evaluation, they completed standard measures of the five principal dimensions of personality. Disability was assessed at baseline and annually thereafter with the Katz scale. The relation of each trait to incident disability was assessed in proportional hazard models controlled for age, sex, education and selected clinical variables. RESULTS: during a mean of about 6 years of observation, 255 persons (31%) became dependent on at least one activity of daily living. Risk of becoming disabled was 85% [95% confidence interval (CI) = 80.5-89.6%] lower in persons with high (90th percentile) compared to low (10th percentile) extraversion and 50% (95% CI = 46.6-54.2%) lower in those with high compared to low conscientiousness, and controlling for chronic medical conditions, depressive symptoms or social and cognitive activity did not substantially affect these associations. By contrast, neuroticism had a marginal association with disability risk that was eliminated after controlling for depressive symptomatology, and openness and agreeableness were unrelated to disability risk. CONCLUSIONS: The results suggest that higher levels of extraversion and conscientiousness may be associated with a reduced risk of incident disability in old age.

Activities of Daily Living↗
PubMed2006

Blood pressure and lower limb function in older persons.

BACKGROUND: Factors contributing to gait difficulties in elderly persons are considered to be multifactorial and are not well understood. The purpose of this study was to examine the association of blood pressure (BP) with change in lower limb function in older persons. METHODS: Eight hundred eighty-eight older Catholic clergy members without baseline dementia or Parkinson's disease were recruited from about 40 groups across the United States. At baseline, BP was measured, the presence of vascular diseases and diabetes was recorded, cognitive function was assessed, and medications were inspected. At baseline and subsequent annual visits, gait and balance were assessed using performance-based tasks from which a previously established composite measure of lower limb function was derived. RESULTS: In a general estimating equation analysis controlling for age, education, and gender, a 10 mmHg increment in systolic blood pressure (SBP) was associated with greater decline in lower limb function (estimate of interaction = -6.35 x 10(-3), standard error = 2.49 x 10(-3), p =.011). Thus, on average, lower limb function declined 28.7% faster in persons with an SBP of 160 mmHg than in persons with an SBP of 120 mmHg. This effect was unchanged after controlling for baseline vascular diseases, diabetes, or cognition. However, censoring individuals who developed stroke during the study made the relationship between SBP and change in lower limb function nonsignificant. CONCLUSIONS: SBP may be associated with decline in lower limb function in older persons.

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PubMed2006

Childhood adversity and psychosocial adjustment in old age.

OBJECTIVE: The objective of this study was to test the hypothesis that higher level of childhood adversity is associated with lower level of psychosocial adjustment in old age. METHOD: Participants are 253 older persons (mean age: 79.8, standard deviation: 2.1; 73.9% women) from the Rush Memory and Aging Project, a clinicopathologic study of common chronic conditions of old age. Childhood adversity was assessed with a 16-item measure based on portions of the Childhood Trauma Questionnaire and other inventories. Psychosocial adjustment was assessed with multiple measures of neuroticism (i.e., proneness to negative emotions) and social engagement. RESULTS: Based in part on a factor analysis, composite measures of total adversity, emotional neglect, parental intimidation, parental violence, family turmoil, and financial need were developed. In a series of linear regression models adjusted for age, sex, own education, and parental education, the composite measure of childhood adversity was associated with all facets of neuroticism and accounted for more than 13% of the variance in the composite neuroticism measure. Emotional neglect and parental intimidation had the strongest associations with neuroticism. Childhood adversity was not related to frequency of participation in social activities, but more adversity was associated with having a smaller network (accounting for 3% of the variance) and feeling more emotionally isolated (accounting for 7% of the variance). CONCLUSION: Childhood adversity is associated with less adaptive psychosocial functioning in old age.

Aged↗
PubMed2005

Odor identification and decline in different cognitive domains in old age.

The authors examined the association of odor identification with rate of decline in different cognitive systems. Participants are 481 older persons from the Rush Memory and Aging Project. At baseline, the Brief Smell Identification Test was administered. At annual intervals for up to 3 years, a battery of 19 cognitive tests was administered from which previously established composite measures of 5 cognitive domains were derived. In mixed-effects models adjusted for age, sex, and education, lower odor identification score was associated with lower function at baseline in each cognitive domain. Lower score was also associated with more rapid decline in perceptual speed (estimate=0.015, SE=0.006, p=0.013) and episodic memory (estimate=0.012, SE=0.006, p=0.030) but not with rate of decline in semantic memory, working memory, or visuospatial ability. Thus, on average, a person with a low odor identification score (6, 10th percentile) declined more than twice as rapidly in perceptual speed and episodic memory as a person with a high score (11, 90th percentile). Results were unchanged in subsequent analyses that controlled for cigarette smoking or clinically diagnosed stroke. The results indicate that impaired odor identification in old age is associated with impaired global cognition and more rapid decline in perceptual processing speed and episodic memory.

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PubMed2005

The amyloid pathology progresses in a neurotransmitter-specific manner.

Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

Acetylcholine↗
PubMed2005

Change in cognitive function in Alzheimer's disease in African-American and white persons.

Few studies have examined the association of race with change in cognitive function in Alzheimer's disease (AD). We studied the rate of decline in global and specific measures of cognitive function in a cohort of 410 older African-Americans and whites with clinically diagnosed AD. Persons were examined annually for an average of 3.5 years, and follow-up participation among survivors exceeded 90%. In mixed-effects models that controlled for age, gender, education, and premorbid reading activity, African-Americans scored lower than whites at baseline on a composite measure of global cognition and on specific measures of visuoconstruction and naming. However, they experienced less rapid decline in episodic memory (p < 0.01), with similar but not quite significant effects for global cognition (p = 0.06), perceptual speed (p = 0.07) and naming (p = 0.08). The results suggest that the rate of cognitive decline in AD is slower in African-Americans compared with whites, particularly for episodic memory.

Aged↗
PubMed2005

Relation of blood pressure to risk of incident Alzheimer's disease and change in global cognitive function in older persons.

PURPOSE: To examine the relation of systolic and diastolic blood pressure to incident Alzheimer's disease (AD) and rate of cognitive change. METHODS: Longitudinal cohort study with annual clinical evaluations. At baseline, blood pressure was measured, apolipoprotein E (APOE) genotyping was performed, and medications were reviewed. RESULTS: 824 older Catholic clergy members without baseline dementia were recruited from across the United States. During a mean of about 6 years of observation, 151 persons developed AD. In a proportional hazards model adjusted for age, sex and education, neither systolic (relative risk = 0.995; 95% CI: 0.986, 1.004, p = 0.249) nor diastolic (relative risk = 1.000; 95% CI: 0.985, 1.015, p = 0.975) blood pressure was related to AD incidence. In mixed effects models, neither systolic nor diastolic blood pressure was related to level or to annual rate of change on a global measure of cognition. These results did not change in subsequent models that accounted for the use of medications with antihypertensive properties or for the possession of an APOE epsilon4 allele. CONCLUSIONS: In a cohort of older persons with a majority taking medications with antihypertensive properties, we did not find a relationship between blood pressure and risk of AD or cognitive decline.

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