Citations

AbstractAimWe investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology.Materials and MethodsN = 1306 participants (Visit 5 mean age = 76.5 [standard deviation = 5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N = 248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β‐amyloid positivity were regressed on periodontal status in logistic regressions.ResultsPeriodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β‐amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all‐type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants.ConclusionsWithin the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β‐amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Abstract Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5′ UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer’s disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

AbstractIntroductionMotoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood.MethodsThe Atherosclerosis Risk in Communities (ARIC) community‐based cohort study classified participants using standardized criteria as MCR+/– and mild cognitive impairment (MCI)+/– at study baseline (2011–2013). We examined the 5‐year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status.ResultsOf 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities.DiscussionMCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross‐sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03–1.83) after adjusting for demographic and cardiovascular risk factors. In race‐stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15–3.50), compared with White participants (OR, 1.29; 95% CI, 0.89–1.89). However, the race interaction was not statistically significant ( P interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.

Background: Midlife obesity is associated with dementia in later life, but how the metabolic syndrome (MetS) relates to cognitive change is less understood. We hypothesized that MetS would be more predictive of 6-year cognitive decline than its individual components in a large biethnic cohort (the ARIC study) and that combinations of risk factors would further increase likelihood of change. Methods: The MetS was defined in 1987-89 on 10,687 participants with two cognitive assessments at two time points. In subjects aged 44 to 66, obesity measures included body mass index (BMI) and waist-to-hip ratio (WTHR). The main outcome measure was change in 1990-92 to 96-99 of three cognitive tests: Delayed Word Recall (DWR), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). Linear and logistic regressions were all adjusted for age, combined race-center, sex, education, smoking, drinking, coronary artery disease and prior stroke. Change was measured as the difference divided by the number of years between visits. Results: At baseline, the prevalence of MetS was 22% (mean age 54 years, 27% black, 55% female, and 28% BMI>30 kg/m2). Subjects with MetS performed in the lowest test quintile (adjusted ORs: DWR 1.3 95% CI 1.1-1.4) in 1996-99, and much of this effect size was explained by an elevated WTHR (DWR OR 1.3 CI 1.1-1.5) and diabetes (DWR OR 1.4 CI 1.2-1.7). MetS was not associated with annual cognitive change, and diabetes was the only significant component associated with change (adjusted beta: DWR 0.03 p=.01, DSST 0.2 p<.001, WFT 0.09 p=.01). Conclusion: MetS at ages 44 to 66 was associated with worse cognitive function at follow-up, but not with annual cognitive decline over several years. Elevated WTHR and diabetes explained most of the association of MetS with cognitive function measures, and diabetes with cognitive decline. Until we have a definition of the MetS more based on pathophysiology, the components of the MetS should be the focus of analysis in future studies.

Introduction: Recent reports have linked visit-to-visit blood pressure (BP) variability to risk of mortality and stroke, independent of the effect of mean BP level. We sought to confirm these findings in the Cardiovascular Health Study (CHS), a cohort study of cardiovascular risk factors. Hypothesis: Variability in visit-to-visit SBP, defined as intraindividual SBP SD, is directly associated with risk of mortality, myocardial infarction (MI), and stroke, independent of intraindividual SBP mean and trend over time. Methods: Participants from CHS were eligible if they attended their first five annual clinic visits and did not have stroke, MI, or death by the 5th visit (N=3513). Follow-up started at the 5th visit and extended through June 2008. Analyses were further restricted to subjects who used no antihypertensive medications during the entire 5-year baseline period (non-users, n=1570) and subjects who used the same antihypertensive regimen during that time (users, n=978). Intraindividual SBP variables were defined using each subject’s 5-visit BPs. Cox proportional hazards models estimated adjusted hazard ratios (HR) per standard deviation (SD) increase in intraindividual SD (iSD) SBP or intraindividual mean (iMean) SBP. Results were stratified on medication use or non-use. Results: Participants’ mean age was 71 years, 42% were men, and 95% were white. Mean(SD) of iSD SBP was 9.8(4.6) mmHg for anti-hypertensive medications non-users and 12.0(6.0) mmHg for users. iMean SBP was significantly associated with all 3 outcomes among non-users and with stroke among users (table). iSD SBP was significantly associated with mortality in all participants and with MI among non-users; associations for stroke were not significant. Conclusion: Long-term visit-to-visit SBP variability may be an important determinant of MI and mortality risk in the elderly. Results for stroke are not consistent with other, previous reports. More research is needed to determine the clinical implications.

Introduction: Among older adults with diabetes, cognitive dysfunction is of particular concern as it has implications for treatment adherence and diabetes self-management. The prevalence of cognitive dysfunction has not been well characterized in this population. Methods: We conducted a cross-sectional analysis of 5509 participants (1815 with diabetes) from visit 5 (2011-2013) of the ARIC Study. Diabetes was defined based on self-reported physician diagnosis, diabetes medication use, or HbA1c ≥ 6.5%. Cognitive function was measured using 8 neuropsychological tests, which were grouped into three cognitive domains representing memory, executive function, and language. Participants were categorized as having cognitive dysfunction if test scores were more than 1.5 standard deviations below age-, race-, and education-adjusted scores derived from a cognitively healthy population. We calculated crude prevalence estimates and used Poisson regression to estimate adjusted prevalence ratios (PRs), comparing cognitive dysfunction in persons with and without diabetes. We adjusted for demographic and clinical characteristics. Results: The mean age of participants was 75 years, 59% were female, 79% were white, and 33% had diabetes. In each domain, the prevalence of cognitive dysfunction among persons with diabetes ranged from 14% to 27%. Persons with diabetes were more likely than persons without diabetes to have dysfunction in multiple domains (PR = 1.29, 95% CI: 1.12, 1.49). Prevalence of cognitive dysfunction was significantly higher in persons with versus without diabetes for memory (PR=1.13, 95% CI: 1.02, 1.25), language (PR=1.24, 95% CI: 1.09, 1.45), and executive function (PR=1.10, 95% CI: 1.00, 1.22)(Figure). PRs were similar in crude models. Conclusions: The prevalence of cognitive dysfunction among older adults with diabetes is high. These results have implications for how physicians educate patients in appropriate self-management practices and for the prevention of diabetes-related complications.

Introduction: Understanding the role of risk factors associated with accelerated cognitive decline has important public health relevance for the aging US population. To test hypotheses that mid-life cardiovascular (CV) risk factors increase risk of dementia in old age, the Atherosclerosis Risk in Communities (ARIC) cohort was evaluated for dementia in 2011-2013. Anticipating challenges of complete dementia ascertainment in an elderly population, supplementary data sources were collected to aid analysis accounting for potentially informative attrition. Methods: ARIC enrolled 15,792 participants 45-64 years old at baseline (1987-1989) from four US communities and collected baseline CV exposure data. A complete neurocognitive battery including informant interview was completed 2011-2013, yielding an algorithmic diagnosis of dementia, mild cognitive impairment (MCI) or normal cognition. Cognitively impaired and a random sample of cognitively normal were selected for further clinical evaluation. Syndromic diagnoses (dementia/MCI/normal) and etiologic diagnoses were made by a panel of experts using standardized criteria. Standardized protocols, timely reports of reviewer reliability, ongoing training of reviewers and a web-based data management system were developed to ensure reliability, consistency and efficiency of data collection and review. Living participants not attending the visit were asked to complete the Telephone Interview for Cognitive Status (TICS). Based on dementia discharge codes and death codes identified during cohort surveillance, interviewer impression of hearing loss or cognitive impairment or need for a proxy during semi-annual calls, or random sampling, participants refusing the TICS are eligible for proxy dementia interview. Medicare claims are being examined to identify missed dementia discharge codes. Results: Of 11,017 participants alive as of 2011, 6495 (59%) completed the neurocognitive battery; 2937 of these (45%) were selected for, and completed, additional clinical assessments and classification by committee (algorithmic or reviewer diagnosis: dementia 5%, MCI 21%). Of the 4522 participants who did not undergo the neurocognitive battery, 1463 (32%) completed the TICS (dementia 7%), while 1627 of the remaining participants were eligible for proxy calls (903 completed to date, dementia 58%). Conclusions: Participants who were not examined were more likely to be cognitively impaired, highlighting the importance of collecting supplementary data to support analyses of midlife CV risk factors accounting for informative attrition. Collection of exam data in an elderly cohort is difficult and requires a multi-pronged approach, especially for an outcome highly correlated with attrition. The strategy described here could be applied in other settings.

Introduction: Recent studies, mainly performed in elderly whites, suggest that vitamin D, measured by 25-hydroxyvitamin D [25(OH)D], is important for cognition. Less is known about the association of 25(OH)D measured in mid-life with cognition and dementia risk in whites and blacks. Hypothesis: We hypothesized that lower concentrations of 25(OH)D would be associated cross-sectionally with lower cognitive test scores and prospectively with greater decline in cognitive test scores and with increased risk of dementia. Methods: We conducted cross-sectional (1993-1995), change (1993-1995 to 2004-2006), and prospective (follow-up through 2010) analyses of 1,652 participants in the ARIC Brain Ancillary Study with measured 25(OH)D (1993-1995). 25(OH)D was analyzed in race-specific tertiles and continuously. Cognition was measured by 3 tests: Delayed Word Recall (DWR), Digit Symbol Substitution (DSS), and Word Fluency (WF). Dementia was defined by hospitalization ICD-9 codes. Adjusted race-stratified linear regression and Cox proportional hazards models were used. Results: Mean age of participants was 62 years, 60% were female, and 48% were black. Mean 25(OH)D was higher in whites than blacks (25.5 versus 17.3 ng/ml, p<0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. In prospective analyses, lower levels of 25(OH)D trended towards an association with increased dementia risk in whites and in blacks, but these results were not statistically significant (lowest versus highest tertile: whites, HR: 1.32 [95% CI: 0.69, 2.55]; blacks, HR: 1.53 [95% CI: 0.84, 2.79]) (Figure). Conclusion: In contrast to prior studies performed in elderly populations, our study did not find significant associations between lower levels of 25(OH)D in mid-life with lower cognitive test scores at baseline, change in score over time, or increased dementia risk.