Mosley, Thomas H.

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.

Objectives: Determine relationships between calcification and cognitive function. Background: Dementia affects over 5.4 million Americans; prevalence will quadruple in the next 50 years. Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, may affect cognitive function through microvascular brain effects. Abdominal aortoiliac calcification (AAC) generally precedes CAC and may provide earlier risk determination. Effects of calcification on cognition have not been studied in African Americans (AA). Methods: The 2008-2011 GENOA CAC cohort consists of AA sibships (n=657, mean age 69 [range 40-98], 74% women, 82% hypertensive) enriched with hypertension from Jackson, MS with computed tomography (CT) Agatston calcification measures. Cognition was assessed in 4 domains: global cognitive function (Mini-Mental State Examination); processing speed (Digit Symbol Substitution and Trail Making A); memory (RAVLT and WAIS-III Incidental Learning); and executive function (Trail Making B). Relationships of cognition (standardized) and calcification (log base 2 scale accounting for skewness) were examined using linear regressions with GEE to account for sibship clustering, adjusting parsimoniously for age, sex, and education. Results: Doublings of CAC were significantly associated with poorer processing speed (ß=-0.049 [-0.072, -0.025] p=0.000) and executive function (ß=-0.037 [-0.070, -0.003] p=0.031) in younger subjects and with poorer global function (ß=-0.0648 [-0.096, -0.020] p=0.000), memory (ß=-0.034 [-0.060, -0.007] p=0.013), and processing speed (ß=-0.051 [-0.076, -0.025] p=0.000) in older subjects. Doublings of AAC were significantly associated with poorer processing speed (ß=-0.0381 [-0.056, -0.020] p=0.000) and executive function (ß=-0.045 [-0.070, -0.020] p=0.000) in younger subjects and poorer processing speed (ß=-0.050 [-0.075, -0.025] p=0.000) in older subjects. Conclusions: Calcification is associated with processing speed in young and old AA with prevalent cardiovascular risk factors and may be differentially associated with other cognitive domains by age. Processing speed in particular may be a domain affected early in the calcification process, warranting further study. This supports existing literature addressing the relationship between calcification and cognitive function in ethnically diverse cohorts. Further studies can focus on the temporal and causal relationships between calcification and cognition across age in AA samples enriched for hypertension to identify predictive factors associated with future cognitive decline.

Background: Compared to those with natural nocturnal blood pressure (BP) decreases, those lacking nocturnal BP decreases (“non-dippers”) are at greater risk of cardiovascular disease (CVD). Substantial evidence also supports a role of chronic systemic inflammation in the pathogenesis of CVD. The purpose of this study was to examine associations of markers of inflammation with two common definitions of BP dipping status using 24-hour ambulatory blood pressure (AMBP) readings. Methods: AMBP monitoring and assays of C-reactive protein (CRP), interleukin-6 (IL-6), e-selectin, tissue inhibitor of metalloproteinase-2 (TIMP-2), and a selection of thirteen other inflammatory-pathway biomarkers were performed in 722 participants (mean age 64 [range 42-83] years, 36% men, 39% black, 83% hypertensive) in the Genetic Epidemiology Network of Arteriopathy (GENOA) Study (2001-2004). Non-dippers were classified using two common definitions: (1) nocturnal systolic and diastolic BP both decreased by <10% compared to daytime values [“dual non-dippers”, n=161 (22%)], and (2) nocturnal SBP decreased by <10% [“systolic non-dippers”, n=380 (53%)]. Logistic regressions, fit with generalized estimating equations to account for sibship clustering, yielded odds ratios (OR) of dipping status for log-transformed inflammatory biomarkers, adjusted for age, race, and sex. Results: IL-6 (range 0-37 pg/ml) was associated with dual non-dipping status (OR=1.55 [95%CI: 1.03, 2.32] p=0.035), translating into a 55% increase in the likelihood of being a dual non-dipper for every approximate doubling of IL-6. IL-6 (OR=1.63 [1.13, 2.35] p=0.009) and CRP (OR=1.35 [1.08,1.68] p=0.008) overall, as well as e-selectin (OR=0.49 [0.28, 0.87] p=0.014) and TIMP-2 (OR=0.54 [0.30,0.98] p=0.041) in hypertensive subjects were associated with systolic non-dipping status. Conclusions: These results suggest that non-dipping classification should be approached with prudence, as the two different criteria may influence conclusions about predictive marker associations. In addition, markers involved in direct versus inhibitory inflammation pathways may operate differentially across patient subgroups. Our findings support the link between inflammation and non-dipping circadian BP patterns and provide novel information on markers and definitions which may be useful for early detection and subsequent prevention of CVD.

Introduction: Impairment in the sense of smell is associated with plaques and tangles in the olfactory region of the brain, which connects to the hippocampus where neuropathologic changes related to mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease are first sited. Olfactory impairments may thus be a marker for poor cognitive function and MCI. We assessed olfaction and cognitive function in 6055 White and Black men and women aged 60-99 years. Methods: Sense of smell was measured in ARIC-NCS participants (2011-2013) by the 12-item Sniffin’ Sticks screening test (score range: 0-12, median: 10). A clinically validated threshold (smell score <6) defined olfactory impairment (OI). A multidimensional neuropsychological assessment (10 tests) ascertained performance in domains of memory, language, executive function/processing speed, and global cognition. For relative comparisons across the tests, raw cognitive test scores were standardized to z scores and averaged to yield domain scores. Following review of neuropsychological assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, MCI was classified by a neurologist and neuropsychologist, and adjudicated by a third reviewer. Multivariable linear regression estimated the mean difference in domain-specific z scores among participants with and without OI. Logistic regression was used to quantify the prevalence odds of MCI in participants with vs. those without OI. Models were adjusted for age, sex, race, education, ARIC study center, hypertension, diabetes, smoking, and ApoE4. Race and sex were explored as effect modifiers. Results: The participants’ mean age was 76 years; 41% were male and 23% Black. The prevalence of olfactory impairment was 14%. Compared to participants with no OI, those with OI had a statistically significantly lower mean z score across all cognitive domains [memory: Beta= -0.37 (95% confidence interval [CI]: -0.45, -0.30); language: Beta= -0.39 (95% CI: -0.46, -0.33); executive function/processing speed: Beta= -0.24 (95% CI: -0.32, -0.17); global cognition: Beta= -0.34 (95% CI: -0.41, -0.26). Effect modification by race was observed in the domain of language. Blacks with OI had a greater mean difference in language z score compared to Blacks without OI (Beta= -0.57 (95% CI: -0.70, -0.44)). OI was associated with MCI in Whites, but not Blacks: white participants with OI had greater odds of MCI (Odds Ratio [OR] =1.76, 95% CI: 1.40, 2.21). Sex did not modify these associations. Conclusions: Compared to average cognitive aging (annual rate of decline of 0.04-0.05 standard deviation units/year) relatively large differences in standardized cognitive domain scores are observed between those with and without olfactory impairment among older adults. An impaired sense of smell may serve as a readily accessible early marker of neurodegeneration.

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: Small vessel disease is associated with decreased cognitive function, possibly differential by race. Age-related central arterial stiffening increases pulsatility resulting in hypoperfusion, microvascular damage and remodeling in the brain, potentially impairing cognition. We examined if arterial stiffness and pressure amplification are associated with lacunar infarcts and greater volumes of white matter hyperintensities (WMH) in a sample of Caucasian and African American (AA) older adults. Methods: We analyzed a cross-sectional sample of ARIC participants aged 67-90 years (n=1486) from visit 5 (2011-2013), with brain magnetic resonance imaging (MRI). The Omron VP-1000 Plus was used to measure aortic stiffness (carotid-femoral pulse wave velocity [cfPWV]) and pressure amplification measures (pulse pressure amplification [PPA], central pulse pressure [cPP], and estimated central systolic blood pressure [cSBP]). Aortic stiffness and pressure amplification were dichotomized at race-specific 25th percentile cut points. Brain MRI using 3D-1.5T equipment quantified the presence of lacunar infarcts and volumes of WMH following a standardized protocol. Logistic regression, adjusted for age, sex, education, ApoE4, heart rate, smoking and body mass index, was used to quantify the odds of lacunar infarcts in participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Linear regression models, additionally adjusted for intracranial volume, estimated the difference in log-transformed volumes of WMH among participants with high vs. low cfPWV, cPP, cSBP, and low vs. high PPA. Probability sampling weights for an MRI were included to allow for generalizability to the full visit 5 cohort. Results: Among the 1486 participants with a brain MRI (mean age: 76, 41% male, 26% AA), measures of aortic stiffness and pressure amplification were associated with lacunar infarcts in Caucasians, but not in AAs. Caucasian participants with a high cfPWV had greater odds of lacunar infarcts (Odds Ratio [OR] =2.02, 95% confidence interval [CI]: 1.23, 2.20). Caucasians with high cSBP had higher odds of lacunar infarcts (OR=1.72, 95% CI: 1.10, 2.69). In Caucasians, high cfPWV was associated with a 21% (95% CI: 6, 38) greater volume of WMH as compared to a low cfPWV; high cSBP was associated with a 28% (95% CI: 14, 45) greater volume of WMH compared to a low cSBP. In AAs, high cfPWV was associated with a 32% (95% CI: 7, 62) greater volume of WMH as compared to low cfPWV. Cerebral microvascular imaging markers did not differ quantitatively with measures of PPA and cPP. Conclusions: Central arterial stiffening and pressure amplification are plausible microvascular contributors to cognitive aging, providing new information on modifiable pathways for previously observed associations between cardiovascular disease risk factors and the rates of cognitive decline and dementia among older adults.

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.