The role of diabetes, glycemia, and glucose peaks in cognitive impairment and dementia among community-dwelling adults

This dissertation explores the association between diabetes, measures of glycemia (average glycemia and glycemic peaks), and cognitive decline and dementia. We also examine the association between diabetes, glycemia, and cognitive impairment in older adults. Additionally, we address two methodological issues: handling missing cognitive data in longitudinal analyses of change in cognitive function, and characterizing the factor structure of the neurocognitive battery used in some of these analyses. We have used data from the Atherosclerosis Risk in Communities (ARIC). We document that diabetes, higher average glycemic levels (measured by hemoglobin A1c), and more glycemic peaks (measured by 1,5-anhydroglucitol) are associated with accelerated cognitive decline over 20 years. Among persons with diabetes, those with HbA1c ≥7% (poorly controlled diabetes) had greater decline over 20 years than persons with diabetes and HbA1c <7%. Among persons with diabetes, glycemic peaks were associated with incident dementia, independent of HbA1c and other risk factors. To address attrition, we used multiple imputation by chained equations (MICE) to impute cognitive performance scores. MICE produced unbiased imputations of cognitive function, and simulations showed a substantial reduction in the bias of the 20-year association between diabetes and cognitive decline comparing MICE to analyses without imputed values. Finally, estimated associations between diabetes and 20-year cognitive decline were stronger with MICE than in the analyses without imputed values. We found that the cognitive battery of 11 tests given at the 2011-2013 ARIC exam represented 3 underlying constructs of memory, language, and sustained attention and processing speed. These constructs were not different by age, race, sex, education, diabetes, and hypertension, providing compelling evidence for the robustness of the cognitive domains measured by the test battery across demographic and vascular factors. Lastly, we characterized the level of cognitive impairment by diabetes status and glycemia among older adults. Persons with diabetes, longer duration of diabetes, and with glucose peaks had higher estimated prevalence of cognitive impairment. In conclusion, we have documented the association of diabetes, mean glycemia (HbA1c), and glucose peaks (1,5-AG) with cognitive decline and dementia. This research adds to the literature that diabetes, HbA1c, and glucose peaks are risk factors for cognitive decline and dementia. This has important implications for the prevention of diabetes as a means to prevent or delay cognitive decline. Additionally, the careful management of glycemia among middle-aged adults with diabetes may be an important avenue for prevention of cognitive decline and dementia

Diabetes in Midlife and Cognitive Change Over 20 Years: A Cohort Study

Type 2 diabetes mellitus is associated with dementia risk, however evidence is limited for possible associations of diabetes and pre-diabetes with cognitive decline

Midlife Hypertension and 20-Year Cognitive Change: The Atherosclerosis Risk in Communities Neurocognitive Study

Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age

Impact of Differential Attrition on the Association of Education With Cognitive Change Over 20 Years of Follow-up: The ARIC Neurocognitive Study

Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48–67 years (1990–1992) through ages 70–89 years (2011–2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors

DOI: 10.1161/CIRCULATIONAHA.115.015415 1 Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death Running title: Selvin et al.; Glycemic markers and CVD

2 Background—HbA1c is the standard measure to monitor glucose control in diabetes and is a marker of future cardiovascular risk. Fructosamine and glycated albumin are markers of short-term glycemic control but their associations with cardiovascular outcomes are uncharacterized. Methods and Results—We measured glycated albumin and fructosamine in 11,104 participants with and without diabetes in the community-based Atherosclerosis Risk in Communities (ARIC) Study in 1990-1992 (baseline). We evaluated associations of fructosamine and glycated albumin with risk of coronary heart disease, ischemic stroke, heart failure and mortality. We compared associations to those observed for HbA1c. During two decades of follow-up there were 1096 new cases of coronary heart disease, 605 of ischemic stroke, 1432 of heart failure, and 2860 deaths. Elevated baseline concentrations of fructosamine and glycated albumin were significantly associated with each of the outcomes even after adjustment for traditional cardiovascular risk factors, with especially strong associations in persons with diabetes

Herpes zoster diagnosis in relation to hazard of dementia, overall and by age group and sex.

Herpes zoster diagnosis in relation to hazard of dementia, overall and by age group and sex.</p

Herpes zoster diagnosis in relation to hazard of dementia, overall and by age group and sex applying minimum 5-year lag between exposure and outcome.

Herpes zoster diagnosis in relation to hazard of dementia, overall and by age group and sex applying minimum 5-year lag between exposure and outcome.</p

Anti-herpetic medication use^b'*' in relation to hazard of dementia among subjects with herpes zoster diagnoses, overall and by age group and sex.

Anti-herpetic medication useb'*' in relation to hazard of dementia among subjects with herpes zoster diagnoses, overall and by age group and sex.</p

Demographic and clinical characteristics of HZ cases and matched unexposed subjects.

Demographic and clinical characteristics of HZ cases and matched unexposed subjects.</p

ICD-9-CM and ICD-10-CM codes for dementia.

BackgroundEvidence suggests that some infectious diseases, such as herpes zoster (HZ), are associated with elevated risk of subsequent dementia, while certain anti-viral medications are associated with lower risk. We sought to evaluate associations between HZ diagnosis and treatment with incident dementia in a large, retrospective matched cohort.MethodsUsing ICD-9 and ICD-10 diagnosis codes in electronic medical records, we identified members of Kaiser Permanente Northwest age 50 and older from 2000–2019 with a HZ diagnosis during this period. A comparison group without HZ diagnosis was individually matched 3:1 on age at HZ diagnosis date (index date), sex, and membership length prior to index date. We excluded subjects with dementia diagnosed before the index date. Antiherpetic medication was identified using pharmacy fills 1 month before to 12 months after the index date. We employed survival analysis to examine the associations between dementia and HZ diagnosis and antiherpetic medication, adjusting multivariable models for demographic and clinical factors. We stratified on age and sex and conducted a sensitivity analysis with a 5-year lag period.ResultThe study included 101,328 persons, 25,332 with HZ. Over a median follow-up of 4.8 years, 6,000 developed dementia. HZ diagnosis was not associated with higher hazard of dementia (hazard ratio (HR) = 0.99, 95% CI 0.93–1.05) in the primary analysis. Among persons with HZ diagnoses, the HR for receipt of any antiherpetic medication was 0.79 (95% CI 0.70–0.90) in univariate analysis and 0.88 (95% CI 0.77–1.00) after adjustment for demographic and clinical factors. Dementia was not associated with trends in duration of medication use or cumulative dose.ConclusionsWe found little evidence for an association between HZ diagnosis and dementia overall. Antiherpetic medication prescribed around the time of HZ diagnosis was statistically associated with lower risk of subsequent dementia in some but not all analyses and subgroups.</div