Diabetes and change in cognitive function.
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Biomedical subjects
D A Bennett
Publications and source records attributed to D A Bennett.
Premorbid reading activity and patterns of cognitive decline in Alzheimer disease.
BACKGROUND: Educational and occupational attainment have been associated with progression of Alzheimer disease in some studies. One hypothesis about this association is that education and occupation are markers for lifelong participation in cognitively stimulating activities like reading. OBJECTIVE: To assess the relation of premorbid reading activity with patterns of cognitive decline in Alzheimer disease. METHODS: During a 4-year period, 410 persons with Alzheimer disease had annual clinical evaluations, which included administration of 17 cognitive function tests from which global, verbal, and nonverbal summary measures were derived. At baseline, a knowledgeable informant was questioned about the affected person's reading frequency and access to reading materials before dementia onset. RESULTS: A composite measure of premorbid reading activity was developed. It had moderately high internal consistency and was positively correlated with education and baseline level of cognitive function. In analyses that controlled for baseline cognitive function, education, and other demographic variables, higher level of premorbid reading activity was associated with more rapid decline on the global cognitive and verbal measures but not on the nonverbal measure. CONCLUSIONS: These results suggest that both the extent and nature of premorbid cognitive experiences may affect how Alzheimer disease pathology is clinically expressed.
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Progression of parkinsonism and loss of cognitive function in Alzheimer disease.
OBJECTIVE: To assess the relation between parkinsonism and cognitive function in Alzheimer disease from cross-sectional and longitudinal perspectives. DESIGN: Prospective cohort study with annual clinical evaluations during a 4-year period. SETTING: Alzheimer disease clinic in an urban medical center. PARTICIPANTS: Four hundred ten persons with clinically diagnosed Alzheimer disease. MAIN OUTCOME MEASURES: Global and specific measures of cognitive function and parkinsonism. RESULTS: Higher levels of parkinsonism at baseline were reliably associated with lower levels of cognitive function at baseline and with more rapid cognitive decline during the 4-year study period. However, the associations were small, with baseline parkinsonism accounting for less than 10% of the variation either in baseline cognitive function or in the rate of cognitive decline. By contrast, rates of change in parkinsonism and cognitive function were strongly correlated, with 70% or more shared variance in the rates of change in many models. The association was observed with diverse measures of cognition and parkinsonism and was not explained by demographic variables or use of neuroleptic medications. CONCLUSION: In Alzheimer disease, progressive worsening of parkinsonism is more strongly associated with cognitive decline than previously recognized. Arch Neurol. 2000.
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Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer's disease.
Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.
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Part I. Epidemiology and public health impact of Alzheimer's disease.
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Age Distribution↗
Part II. Clinical diagnosis and course of Alzheimer's disease.
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Alzheimer Disease↗
Person-specific paths of cognitive decline in Alzheimer's disease and their relation to age.
Change in global and specific measures of cognitive function was studied in a cohort of 410 persons with Alzheimer's disease. Persons completed up to 5 annual evaluations; follow-up participation among survivors exceeded 90%. Average annual decline was 0.57 standard score units (95% confidence interval [CI]: -0.51 to -0.62) on a composite measure based on 17 individual tests and 3.26 points (95% CI: -3.06 to 3.46) on the Mini-Mental State Examination, but substantial heterogeneity was apparent. On both global and specific measures, rate of cognitive decline was reduced in older persons compared with younger persons. A similar effect was observed for estimated age of disease onset. The effect of age was approximately linear and was not attributable to education, sex, race, other conditions that impair cognition, or mortality. The results indicate that person-specific paths of cognitive decline in Alzheimer's disease vary substantially and suggest that in clinical settings some of this variability is related to age.
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The cross-sectional association between blood pressure and Alzheimer's disease in a biracial community population of older persons.
BACKGROUND: The relation of blood pressure to Alzheimer's disease (AD) is complex because both an association of high blood pressure with increased risk of the disease and lower blood pressure as a consequence of the disease are possible. METHODS: We examined the cross-sectional association of blood pressure and AD in the Chicago Health and Aging Project (CHAP), a study of a geographically defined, biracial community. After in-home interviews with 6.162 residents > or =65 years, a stratified random sample of 729 participants was clinically evaluated; 709 had blood pressures measured, and 243 were diagnosed with AD. RESULTS: In logistic regression models adjusted for age, sex, education, and race there was no association between blood pressure measured as a continuous variable and Alzheimer's disease. In categorical analyses, however, prevalence of Alzheimer's disease was significantly higher among persons with low systolic pressure (<130 mmHg) compared with the referent group of 130-139 mmHg (odds ratio [OR] = 2.2, 95% confidence interval [CI]: 1.2,4.1), and with low diastolic pressure (<70 mmHg) compared to the referent of 70-79 mmHg (OR = 1.8, 95% CI: I. 1,3.1). High systolic and diastolic categories were not statistically different from the referent group, although there was some evidence that the associations differed by race. The odds ratios changed little with further adjustment for apolipoprotein E genotype, antihypertensive medications, body mass, stroke, diabetes, and heart disease. CONCLUSION: These findings are consistent with previous studies showing associations between low blood pressure and AD, but longitudinal studies are needed to characterize cause-and-effect associations.
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The prevalence of dizziness and its association with functional disability in a biracial community population.
BACKGROUND: Information regarding the prevalence of dizziness and its association with functional disability among African American and white residents from defined community populations is limited. METHODS: A total of 6,158 persons 65 years and older (78.8% of age-eligible persons) completed in-home interviews that included three common measures of self-reported disability: the Katz Activities of Daily Living (ADL) Scale, the Rosow-Breslau Functional Health Scale, and the Nagi Physical Disability Scale. A stratified random sample of 729 persons underwent a detailed evaluation that included questions on the frequency and severity of dizziness, which was defined as having an episode of dizziness or lightheadedness at least once a month. RESULTS: The overall prevalence of dizziness in this population was 9.6% (95% confidence interval [CI] 7.2-12.0). It increased with age, from 6.6% in those 65-74 years old, to 11.6% in those 75-84 years old, and to 18.4% in those persons > or =85 years old. It was more common in women (odds ratio [OR] 2.03, 95% CI 0.99-4.19) but was not associated with race. After adjusting for age, sex, and race, dizziness was associated with greater disability on the Rosow-Breslau (OR 2.29, 95% CI 1.18-4.46) and Nagi (OR 2.54, 95% CI 1.48-4.36) measures but not on the Katz ADL Scale (OR 1.18, 95% CI 0.64-2.20). CONCLUSIONS: Dizziness is common among older persons and is associated with functional disability.
Activities of Daily Living↗
Decline of language among women and men with Alzheimer's disease.
Previous research raises the possibility that gender differences occur in language function in Alzheimer's disease, but this hypothesis has not been evaluated systematically in longitudinal studies. The authors examined the association of gender with rate of decline in language and other cognitive functions among 410 persons with Alzheimer's disease. Participants were recruited from a dementia clinic and followed for up to 5 annual evaluations. Follow-up participation among survivors exceeded 90%. Decline in a composite score based on 8 language tests was evaluated in random effects models with age, education, and race controlled. Annual decline was 0.71 standard units (95% confidence interval [CI] = 0.62-0.79) for women and 0.74 units (95% CI = 0.61-0.86) for men, not a significant difference. Decline on the individual language tests and on composite measures of memory, perception, and global cognition also indicated no significant association with gender. These results suggest that Alzheimer's disease affects language and other cognitive functions similarly in women and men.
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From healthy aging to early Alzheimer's disease: in vivo detection of entorhinal cortex atrophy.
Using quantitative structural MRI protocols, we examined the effects of age on alterations in entorhinal cortex (EC) volume. The left EC was found to be smaller than the right in both young and healthy aged subjects. More importantly, the right EC, but not the left, was significantly smaller in elderly participants compared to young controls. In an attempt to determine the earliest sites of involvement in mild and incipient Alzheimer's disease (AD), we compared entorhinal and hippocampal volume in (1) healthy elderly controls, (2) patients with very mild AD, and (3) elderly patients who were evaluated for cognitive complaints, but did not meet criteria for dementia. Both patient groups differed from controls in EC volume, but not from each other. In contrast, the two patient groups differed in hippocampal volume from controls, as well as from each other, with the mild AD cases showing the greatest atrophy. These results suggest that degeneration of the EC and hippocampal formation occurs before the onset of overt dementia. In fact, follow-up clinical evaluations available on 23 of 28 nondemented patients indicated that 12 of 23 had converted to AD. Converters could be best differentiated from nonconverters on the basis of entorhinal volume.
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Hallucinations, delusions, and cognitive decline in Alzheimer's disease.
OBJECTIVES: To examine the occurrence of hallucinations and delusions in Alzheimer's disease over a 4 year period and their association with rate of cognitive decline. METHODS: A cohort of 410 persons with clinically diagnosed Alzheimer's disease underwent annual clinical evaluations over a 4 year period. Participation in follow up exceeded 90% in survivors. Evaluations included structured informant interview, from which the presence or absence of hallucinations and delusions was ascertained, and detailed testing of cognitive function. The primary cognitive outcome measure was a composite cognitive score based on 17 individual performance tests. The mini mental state examination (MMSE) and summary measures of memory, visuoconstruction, repetition, and naming were used in secondary analyses. RESULTS: At baseline, hallucinations (present in 41%) and delusions (present in 55%) were common and associated with lower cognitive function. In analyses that controlled for baseline level of cognitive function, demographic variables, parkinsonism, and use of antipsychotic medications, hallucinations, but not delusions, were associated with more rapid cognitive decline on each cognitive measure. In the primary model, there was a 47% increase in the average annual rate of decline on a composite cognitive measure in those with baseline hallucinations compared with those without them. This effect was mainly due to a subgroup with both auditory and visual hallucinations. CONCLUSION: These findings suggest that the presence of hallucinations is selectively associated with more rapid cognitive decline in Alzheimer's disease.
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Novel method to quantify neuropil threads in brains from elders with or without cognitive impairment.
Pathological alterations in dendrites and axons (i.e., neuritic pathologies) occur in the normal aging brain as well as in brains from elders with mild cognitive impairment and neurodegenerative dementia. These alterations may correlate with clinical measures of cognitive abilities, but the contribution of neuropil threads (NTs), which constitute 85-90% of cortical tau pathology, has not been clear because of the lack of quantitative methodologies. We combined quantitative fractionation and image analysis to devise a strategy for measuring the burden of tau-rich NTs in the entorhinal and perirhinal cortex of brains from elders with and without cognitive impairment, including dementia due to Alzheimer's disease (AD). On the basis of data presented here using this novel strategy, we conclude that this quantitative imaging technique will facilitate efforts to determine the behavioral correlations of neuritic lesions in AD and other brain disorders.
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Applying biomarker research.
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Biomarkers↗
Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer's disease.
Immunocytochemistry for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) was used to examine the expression of these linked cholinergic markers in human basal forebrain, including cases with early stages of Alzheimer's disease (AD). Previous neurochemical studies have measured decreased ChAT activity in terminal fields, but little change or even increased levels of VAChT. To determine total cholinergic neuron numbers in the nucleus basalis of Meynert (nbM), stereologic methods were applied to tissue derived from three groups of individuals with varying levels of cognition: no cognitive impairment (NCI), mild cognitive impairment (MCI), and early-stage Alzheimer's disease (AD). Both markers were expressed robustly in nucleus basalis neurons and across all three groups. On average, there was no significant difference between the number of ChAT- (210,000) and VAChT- (174, 000) immunopositive neurons in the nbM per hemisphere in NCI cases for which the biological variation was calculated to be 17%. There was approximately a 15% nonsignificant reduction in the number of cholinergic neurons in the nbM in the AD cases with no decline in MCI cases. The number of ChAT- and VAChT-immunopositive neurons was shown to correlate significantly with the severity of dementia determined by scores on the Mini-Mental State Examination, but showed no relationship to apolipoprotein E allele status, age, gender, education, or postmortem interval when all clinical groups were combined or evaluated separately. These data suggest that cholinergic neurons, and the coexpression of ChAT and VAChT, are relatively preserved in early stages of AD.
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Change in cognitive function in older persons from a community population: relation to age and Alzheimer disease.
OBJECTIVE: To examine change in cognitive function in older persons sampled from a community population, and its relation to age and Alzheimer disease. DESIGN: Prospective cohort study with an average of 3.5 years of follow-up. SETTING: East Boston, Mass--a geographically defined, urban, working-class community. PARTICIPANTS: A stratified, random sample of persons 65 years and older underwent uniform, structured clinical evaluation for Alzheimer disease. The 388 persons (89.2% of those eligible) who completed at least 1 annual follow-up evaluation were studied: 97 had Alzheimer disease at baseline; 95 developed Alzheimer disease during the study; and 196 were unaffected. OUTCOME MEASURES: Eight cognitive performance tests were administered, then converted to population-weighted z scores and averaged to create a composite summary measure of cognitive function. Initial level of and change in this score were the outcome measures. RESULTS: In the population as a whole, many persons experienced a decline in cognitive performance, and age was related to both initial level and rate of decline. Analyses were conducted in 3 subgroups: persons with Alzheimer disease at baseline, those who developed Alzheimer disease during the study, and those who remained unaffected. In both Alzheimer disease subgroups, substantial cognitive decline was observed, but neither initial level nor rate of decline was related to age. In unaffected persons, little cognitive decline was evident, and there was a small, inverse association of age with initial level of cognitive function. CONCLUSION: In a general population sample, there was little evidence of cognitive decline during a 3.5-year period among persons who remained free of Alzheimer disease.
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Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment.
The deposition of beta-amyloid within the entorhinal cortex (EC) may play a key role in the development of mild cognitive impairment (MCI) in the elderly. To examine the relationship of beta-amyloid deposition to MCI, EC tissue immunostained for this protein was quantitated from a cohort of aged Catholic religious clergy with a clinical diagnosis of MCI and compared to those with no cognitive impairment (NCI) and Alzheimer's disease (AD). beta-amyloid staining was seen in 12 of the 20 NCI, in 10 of 12 MCI, and in all 12 AD cases within the EC. beta-amyloid immunoreactivity displayed two patterns within the EC: (1) a crescent-shaped band within layers 3-4 or (2) bilaminar staining mainly within layers 2-3 and 5-6. Ten cases failed to display any detectable beta-amyloid imunoreactivity. Despite the heterogeneity of beta-amyloid loads within the clinical groups, decomposing an analysis of variance revealed a significant difference across groups in mean beta-amyloid load within the EC based upon a linear trend analysis. Multiple comparisons testing revealed that NCI individuals had a significantly lower mean beta-amyloid load (1.32) than AD individuals (4.55). The MCI individuals had a mean intermediate (2.60) load between NCI and AD, but not statistically distinguishable from the mean for either NCI or AD. Spearman rank correlation showed a trend for decreasing MMSE with increasing amyloid load that failed to reach statistical significance. Since many NCI cases displayed beta-amyloid loads equal to or greater than that seen in some MCI and some AD cases, it is mostly likely that deposition of this protein is not the sole pathogenic event underlying cognitive impairment in the elderly.
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Word-stem completion priming in healthy aging and Alzheimer's disease: the effects of age, cognitive status, and encoding.
There are many conflicting results concerning the effects of age and Alzheimer's disease (AD) on word-stem completion priming. To examine potential sources of this variability, the authors examined the influences on such priming of age, cognitive status, and encoding in a large sample of young, old, and AD individuals. At study, words were processed aloud by reading, reading and rating likeability, or generating from definition. Old participants had less priming than young participants and more priming than AD patients. For the healthy old participants, priming decreased with advancing age and with cognitive loss following generation only. For AD patients, priming decreased as dementia severity increased; patients with the mildest dementia did not differ from healthy old participants. Thus, age, cognitive status, and encoding differentially influenced the magnitude of priming in healthy aging and AD.
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