Neelum T. Aggarwal

Natural history of mild cognitive impairment in older persons

Background Cognitive abilities of older persons range from normal, to mild cognitive impairment, to dementia. Few large longitudinal studies have compared the natural history of mild cognitive impairment with similar persons without cognitive impairment. Methods Participants were older Catholic clergy without dementia, 211 with mild cognitive impairment and 587 without cognitive impairment, who underwent annual clinical evaluation for AD and an assessment of different cognitive abilities. Cognitive performance tests were summarized to yield a composite measure of global cognitive function and separate summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. The authors compared the risk of death, risk of incident AD, and rates of change in global cognition and different cognitive domains among persons with mild cognitive impairment to those without cognitive impairment. All models controlled for age, sex, and education. Results On average, persons with mild cognitive impairment had significantly lower scores at baseline in all cognitive domains. Over an average of 4.5 years of follow-up, 30% of persons with mild cognitive impairment died, a rate 1.7 times higher than those without cognitive impairment (95% CI, 1.2 to 2.5). In addition, 64 (34%) persons with mild cognitive impairment developed AD, a rate 3.1 times higher than those without cognitive impairment (95% CI, 2.1 to 4.5). Finally, persons with mild cognitive impairment declined significantly faster on measures of episodic memory, semantic memory, and perceptual speed, but not on measures of working memory or visuospatial ability, as compared with persons without cognitive impairment. Conclusions Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Depressive symptoms, cognitive decline, and risk of AD in older persons

Background:Cross-sectional and retrospective case-control studies suggest an association of depression symptoms with cognitive impairment and AD, but there have been few prospective studies and their results have been inconsistent. Methods:Participants are Catholic clergy members who were aged ≥65 years and who did not have clinical evidence of AD. During a 7-year period, they underwent annual clinical evaluations that included clinical classification of AD and detailed cognitive function testing from which global and specific measures of cognition were derived. Number of depressive symptoms was assessed at baseline with a modified, 10-item Center for Epidemiologic Studies Depression Scale (CES-D). The association of CES-D score with incident AD, using proportional hazards models, and cognitive decline, using random effects models, was examined. Results:At baseline, participants reported an average of about one depressive symptom on the CES-D scale (range, 0 to 8). During the 7 years of follow-up, 108 persons developed AD. In analyses that controlled for selected demographic and clinical variables including baseline level of cognitive function, CES-D score was associated with both risk of AD and rate of cognitive decline. For each depressive symptom, risk of developing AD increased by an average of 19%, and annual decline on a global cognitive measure increased by an average of 24%. Conclusions:The results raise the possibility that depressive symptoms in older persons may be associated with risk of developing AD.

Cognitive activity and incident AD in a population-based sample of older persons

Background: Participation in cognitively stimulating activities is hypothesized to be associated with risk of AD, but knowledge about this association is limited. Methods: A biracial community in Chicago was censused, persons aged 65 years and older were asked to participate in an interview, and 6,158 of 7,826 (79%) eligible persons did so. As part of the interview, persons rated current frequency of participation in seven cognitive activities (e.g., reading a newspaper) and nine physical activities (e.g., walking for exercise) from which composite measures of cognitive and physical activity frequency were derived. Four years later, 1,249 of those judged free of AD were sampled for a detailed clinical evaluation of incident disease and 842 (74% of those eligible) participated. Results: The composite measure of cognitive activity ranged from 1.28 to 4.71 (mean 3.30; SD 0.59), with higher scores indicating more frequent activity. A total of 139 persons met National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for AD on clinical evaluation. In a logistic regression model adjusted for age, education, sex, race, and possession of the APOE ε4 allele, a one-point increase in cognitive activity score was associated with a 64% reduction in risk of incident AD (OR 0.36; 95% CI 0.20 to 0.65). By contrast, weekly hours of physical activity (mean 3.5; SD 5.1) was not related to disease risk (OR 1.04; 95% CI 0.98 to 1.10). Education was associated with risk of AD and a similar trend was present for occupation, but these effects were substantially reduced when cognitive activity was added to the model. Conclusion: Frequency of participation in cognitively stimulating activities appears to be associated with risk of AD and may partially explain the association of educational and occupational attainment with disease risk.

The Neuropathology of Older Persons with and Without Dementia from Community versus Clinic Cohorts

Community-based cohorts of older persons may differ neuropathologically from clinic-based cohorts. This study investigated age-related pathologies in persons with and without dementia and included autopsied participants from two community-based cohorts, the Rush Religious Orders Study (n=386) and the Memory and Aging Project (n=195), and one clinic-based cohort, the Clinical Core of the Rush Alzheimers Disease Center (n=392). Final clinical diagnoses included no cognitive impairment (n=202), mild cognitive impairment (MCI) (n=150), probable Alzheimers disease (AD) (n=474), possible AD (n=88), and other dementias (n=59). Postmortem diagnoses included pathologic AD, cerebral infarcts, and Lewy body disease. Community-based persons with clinical AD had less severe AD pathology (p<0.001) and had more cerebral infarcts (p<0.001) compared to clinic-based persons. Additionally, community-based persons with MCI had more infarcts compared to clinic-based persons. Overall, there was a higher proportion of Lewy bodies and atypical pathologies in the clinic-based compared to the community-based cohorts (p<0.001). Community-based persons with probable AD show less severe AD pathology and more often have infarcts and mixed pathologies; those with MCI more often have infarcts and mixed pathologies. Overall, clinic-based persons have more Lewy bodies and atypical pathologies. The spectrum of pathologies underlying cognitive impairment in clinic-based cohorts differs from community-based cohorts.

Decision rules guiding the clinical diagnosis of Alzheimer's disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study

We developed prediction rules to guide the clinical diagnosis of Alzheimer’s disease (AD) in two community-based cohort studies (the Religious Orders Study and the Rush Memory and Aging Project). The rules were implemented without informant interviews, neuroimaging, blood work or routine case conferencing. Autopsies were performed at death and the pathologic diagnosis of AD made with a modified version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria. We compared the positive predictive value of the clinical diagnosis in the two community-based studies to the positive predictive value of the clinical diagnosis of AD made by standard clinical practice in a clinic-based cohort study using AD pathology as the gold standard. Of 306 clinic cases with probable AD, 286 (93.5%) met CERAD neuropathologic criteria for AD; the results were comparable for those with possible AD (51 of 54, 94.4%). Of 141 study subjects with probable AD, 130 (92.2%) met CERAD neuropathologic criteria for AD; the results were lower but acceptable for those with possible AD (26 of 37, 70.3%). The results were similar in secondary analyses using alternate neuropathologic criteria for AD. The clinical diagnosis of AD can be made in community-based studies without the use of informant interviews, neuroimaging, blood work or routine case conferencing. This approach holds promise for reducing the operational costs of epidemiologic studies of aging and AD.

Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline

Background: Dementia can be caused by severe niacin insufficiency, but it is unknown whether variation in intake of niacin in the usual diet is linked to neurodegenerative decline. We examined whether dietary intake of niacin was associated with incident Alzheimer’s disease (AD) and cognitive decline in a large, prospective study. Methods: This study was conducted in 1993–2002 in a geographically defined Chicago community of 6158 residents aged 65 years and older. Nutrient intake was determined by food frequency questionnaire. Four cognitive tests were administered to all study participants at 3 year intervals in a 6 year follow up. A total of 3718 participants had dietary data and at least two cognitive assessments for analyses of cognitive change over a median 5.5 years. Clinical evaluations were performed on a stratified random sample of 815 participants initially unaffected by AD, and 131 participants were diagnosed with 4 year incident AD by standardised criteria. Results: Energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks (95% confidence intervals) for incident AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3 (0.1 to 0.6), 0.3 (0.1 to 0.7), 0.6 (0.3 to 1.3), and 0.3 (0.1 to 0.7) adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p for linear trend = 0.002 in the adjusted model). In an adjusted random effects model, higher food intake of niacin was associated with a slower annual rate of cognitive decline, by 0.019 standardised units (SU) per natural log increase in intake (mg) (p = 0.05). Stronger associations were observed in analyses that excluded participants with a history of cardiovascular disease (β = 0.028 SU/year; p = 0.008), those with low baseline cognitive scores (β = 0.023 SU/year; p = 0.02), or those with fewer than 12 years’ education (β = 0.035 SU/year; p = 0.002) Conclusion: Dietary niacin may protect against AD and age related cognitive decline.

Education and the course of cognitive decline in Alzheimer disease

Objective: To test the hypothesis that higher level of education is related to more rapid cognitive decline in Alzheimer disease (AD). Methods: Participants are older persons with clinically diagnosed AD recruited from health care facilities in the Chicago area. At 6-month intervals for up to 4 years, they underwent uniform structured clinical evaluations that included administration of nine cognitive performance tests from which a composite measure of global cognition was derived. Analyses are based on 494 persons with follow-up data (89.3% of those eligible). In mixed models that allowed for linear and nonlinear decline, the authors first accounted for the effects of age on cognition and then tested the relation of education to rate of cognitive decline. Results: Global cognitive decline had linear and nonlinear components, resulting in a gradually accelerating course of decline. Age was related to linear but not nonlinear decline, with more rapid decline observed in younger compared with older persons. Higher educational level was related to more rapid global cognitive decline, as hypothesized, with education related to the nonlinear but not the linear component of decline. Conclusion: Higher educational attainment is associated with a slightly accelerated rate of cognitive decline in Alzheimer disease.

MIND diet associated with reduced incidence of Alzheimer's disease

In a previous study, higher concordance to the MIND diet, a hybrid Mediterranean‐Dietary Approaches to Stop Hypertension diet, was associated with slower cognitive decline. In this study we related these three dietary patterns to incident Alzheimers disease (AD).

Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease.

CONTEXT It is currently not known whether dietary intakes of folate and vitamins B12 and B6, co-factors in the methylation of homocysteine, protect against Alzheimers disease. OBJECTIVE To examine the association between risk of incident Alzheimers disease and dietary intakes of folate, vitamin B-12, and vitamin B-6. DESIGN Prospective cohort study. SETTING Geographically defined biracial Chicago community. PARTICIPANTS 1,041 residents, aged 65 years and older, initially free of Alzheimers disease and followed a median 3.9 years for the development of incident disease. MAIN OUTCOME MEASURE Probable Alzheimers disease identified through structured clinical neurological evaluation using standardized criteria. RESULTS A total of 162 persons developed incident Alzheimers disease during follow-up. In logistic regression models adjusted for age, sex, race, education, cognitive activities, APOE-epsilon4, and dietary intakes of vitamin E in food and total niacin, there was no association between risk of developing Alzheimers disease and quintiles of folate intake or of vitamin B-12 intake. The adjusted odds ratio was 1.6 (95% confidence interval: 0.5, 5.2) for persons in the highest quintile of total folate intake (median of 752.7 microg/d) compared with persons in the lowest quintile of intake (median, 202.8 microg/d). Compared with persons in the first quintile of total vitamin B-12 intake (median, 3.1 microg/d) the odds ratio was 0.6 (95% confidence interval: 0.2, 1.6) for persons in the fifth quintile of intake (median, 20.6 microg/d). Intake of vitamin B-6 was not associated with incident Alzheimers disease after control for dietary intakes of vitamin E and total niacin. CONCLUSION Dietary intakes of folate, vitamin B-12, or vitamin B-6 do not appear to be associated with the development of Alzheimers disease.