Windham, B. Gwen

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.

Dementia affects approximately 5 million people in the United States and cost $183 billion in 2011, with African Americans (AA) experiencing a disproportionate burden of dementia compared to European Americans (EA). Inflammation is considered by many to be a potential mediator in the development of cognitive dysfunction. High sensitivity C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α), increasingly measured by the soluble TNF receptors 1 & 2 (sTNFRI1, sTNFR2), are among the most frequently cited inflammatory markers associated with dementia and are also elevated in vascular disease. Few studies have compared associations of inflammatory markers with cognitive function in EA and AA. We examined the association of CRP, sTNFR1 and sTNFR2 with cognitive function using detailed neuropsychological assessments in the Genetic Epidemiology Network of Arteriopathy (GENOA)-Genetics of Microangiopathic Brain Injury (GMBI) participants, a cohort considered at high risk of vascular disease due to family history (> 2 individuals in sibships with hypertension at age <60 years) and high prevalence rates of hypertension (74%), diabetes (27%), and obesity (51%). Cognitive function was measured across 5 cognitive domains: global cognitive function, processing speed, language, memory, and executive function. In AA, higher sTNFR2 was associated with poorer performance across all five domains. Higher sTNFR1 and CRP were associated with slower processing speed. In EA, higher sTNFR1 was associated with slower processing speed. CRP and sTNFR2 were not associated with cognitive function in EA. Inflammatory markers in this cohort were associated differentially across cognitive domains in AA and EA, and may reflect racial differences in vascular responses to inflammation.

Background: Brain infarcts, white matter hyperintensities (WMH), and brain atrophy appear to contribute to the development of mild cognitive impairment (MCI) and dementia in selected populations, but few prospective studies are available in general populations. Methods: The study included 732 black and white participants, sampled from the original ARIC cohort, who had 3T brain Magnetic Resonance Imaging (MRI) scans, were free of MCI and dementia during 2011-13 (Visit 5), and were evaluated for cognitive impairment during 2016-17 (Visit 6, about 90% complete). We assessed the associations of brain infarcts, WMH, and brain volumes measured on MRI from 2011-2013 with incident MCI and dementia (combined), diagnosed using a computer algorithm based on specified criteria and comprehensive assessment at Visit 6. We used logistic regression, incorporating sampling weights, to evaluate the risk for incident MCI/dementia with adjustment for demographic covariates, major dementia risk factors, and history of cardiovascular diseases. Results: Participants had a median age of 75 (IQR: 71, 79) at Visit 5 (baseline); 62% (453) were female and 33% (242) were African American. There were 156 newly identified cases of MCI or dementia during a median follow-up time of 4.9 (IQR: 3.4, 5.2) years. The presence of any brain infarct was associated with a nonsignificantly higher risk of MCI/dementia (OR: 1.50; 95%CI: 0.87 to 2.58), but the only significant individual association was with cortical infarcts (OR: 1.99; 95%CI: 1.03 to 3.85). WMH volume above the median value was nonsignificantly associated with conversion to MCI/dementia. Smaller Alzheimer’s disease (AD) signature region was an independent predictor for greater risk of MCI/dementia (OR: 1.49; 95%CI: 1.00 to 2.22). A similar but nonsignificant association was observed for total brain volume. Conclusions: Brain infarcts (cortical infarcts) and lower brain volume (AD signature region), measured in community-based older residents, are risk factors for MCI and dementia incidence.

Background: Vascular risk factors have been associated with risk of cognitive decline, with increasing evidence that midlife exposure to these risk factors may be most important in conferring late-life risk of cognitive impairment. We explored associations between vascular risk factors measured in midlife and the development of dementia over 25 years in the biracial Atherosclerosis Risk in Communities (ARIC) cohort. Methods: Participants in the ARIC study were recruited from four U.S. communities in 1987-1989, at ages 45-64, with four additional in-person visits, surveillance for hospitalizations, annual phone calls, and repeated cognitive evaluations over a 25-year period. In 2011-2013, ARIC participants were seen for the ARIC Neurocognitive Study (ARIC-NCS), and underwent a detailed neurocognitive battery and informant interviews. Through adjudicated review, dementia cases were defined. Additional dementia cases were identified through the telephone interview for cognitive status (TICS) or informant interview for those participants not attending ARIC-NCS; or by a prior dementia ICD-9 code during a hospitalization. Results: Of 15,744 participants in the cohort, 1516 cases of dementia were identified, of whom over one third were among black participants. Risk of dementia was highest in individuals of black race, with less than a high school education, older age, APOE ε4 carriage, and who, at ARIC baseline, had hypertension, diabetes, or were current smokers (table). APOE ε4 and smoking were each stronger risk factors for dementia in whites than in blacks. Discussion: Vascular risk factors measured in midlife are associated with increased risk of dementia in this biracial cohort, in black and white participants. The risk associated with diabetes nears the increased risk associated with having an APOE ε4 allele. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Introduction: Cerebral microbleed (CMB) location may predict underlying pathology. Deep CMBs are more associated with hypertensive vascular disease, while lobar CMBs are more associated with cerebral amyloid angiopathy (CAA). The objective of this study was to determine the neuroimaging pathology associated with CMBs. Methods: We analyzed 1,831 nondemented ARIC participants (mean age=76.3 ±5.3 years, 40% male, 27% black) with 3T MRI scans at the fifth exam (2011-13). We fit multinomial logistic regression models to assess the effect of brain volumes (AD signature region atrophy, total gray matter, frontal, and log 2 -transformed white matter hyperintensities (WMH) volume), infarct frequencies (lacunar, non-lacunar, and total), and APOE (number of ε4 alleles) on CMB location (no, any deep, or lobar only CMBs). Models were weighted for the sample selection scheme and adjusted for age, male, education, hypertension, ever smoking status, diabetes, race-site membership, and estimated intracranial volume (brain volume models only). Results: The frequency of CMBs was 24.1%. A larger WMH volume, greater total infarct frequency, and smaller total grey volume increased the relative risks (RR) of both deep and lobar CMBs compared to no CMBs; increasing the WMH volume also increased the RR of deep to lobar CMBs. Additional lacunar infarcts increased the RR of deep compared to no CMBs, whereas AD signature region atrophy and APOE ε4 homozygosity increased the RR of lobar CMBs. Conclusion: CMBs are a common vascular pathology in the elderly. Deep CMB presence is associated with MRI features of hypertensive small vessel disease, while lobar CMB presence is associated with MRI features of CAA and Alzheimer’s disease.

Abstract Few studies examined race-regional influences on mild cognitive impairment (MCI) and dementia risk factors. We examined 14 risk factors in 5 race-regions, e.g. cross-sectional age- and sex-adjusted relative prevalence ratios (RPR) from multinomial regression comparing associations of low education (&lt;12yrs) with MCI and dementia (versus normal cognition) across 3 race-region groups, average age 76yrs: whites in the Mayo Clinic Study of Aging[MCSA, Olmsted County, MN—MCSA-MN-Whites); Atherosclerosis Risk in Communities(ARIC) whites in suburban Minneapolis, MN—ARIC-MN-Whites); ARIC-African Americans in Jackson, MS—ARIC-MS-AA. Among 3,787 MCSA-Whites, low education exerted a 2-fold risk for MCI, RPR=2.09(95%CI: 1.57,2.78). Conversely, low education was not a supported MCI risk factor for ARIC-MN-Whites (n=1,901—RPR=0.63(0.31,1.28) or ARIC-MS-AA, (n=1,416—RPR=.0.81 (0.60,1.10)), with substantially differential race-region effects. Low education RPRs for dementia also differed by race-region: RPR=4.43(2.68,7.31-MCSA-MN-W), RPR=0.70 (0.16,2.99-ARIC-MN-Whites), and RPR=2.54 (1.74,3.72-ARIC-MS-AA). Understanding why risk factors differ by race and region likely requires diverse samples and harmonized methods using culturally-appropriate assessments.

Abstract Plasma-based biomarkers of amyloid beta (Aβ), a neuropathological hallmark of Alzheimer’s disease, show promise in predicting cognitive impairment and mapping onto cerebral amyloidosis, but little is known about how midlife plasma Aβ associates with late-life cognitive outcomes. Midlife plasma variants Aβ42 and Aβ40 were measured using a fluorimetric bead-based immunoassay in a subsample of visit 3 ARIC participants (1993-95; n=2585, mean age=59.4±5.2, 57% female, 23% African American). We investigated the relationship between midlife plasma Aβ and late-life mild cognitive impairment (MCI; n=923) and dementia (n=628) diagnosed from 2011-19. Multinomial logistic regressions estimated relative risk ratios (RRR) of MCI, dementia, and death vs normal cognitive status as a function of:(1) Aβ42:Aβ40 ratio, (2) Aβ42 and Aβ40 included as separate terms, and (3) Protected Aβ group (participants with Aβ42≥46 pg/ml and Aβ40 &lt;233 pg/ml). Adjusters included age, sex, education, site-race, and APOE4. Every doubling of midlife plasma Aβ42:Aβ40 up to a threshold of 0.20 was associated with 41% lower risk of developing MCI/dementia in comparison to cognitively normal (RRR=0.59 [95% CI:0.42, 0.82]), with no association for ratio values ≥0.20. Every standard deviation increase in plasma Aβ42 was associated with 17% lower risk of dementia (RRR=0.83 [0.70, 0.99]), whereas every standard deviation increase in plasma Aβ40 was associated with 16% higher risk of MCI (RRR=1.16 [1.02, 1.31]). The protected midlife plasma Aβ group had 86% lower risk of late-life dementia vs all others (RRR=0.14 [0.04, 0.47]). Early measurement of plasma Aβ may prove an accessible and effective population screener for future cognitive impairment.

AbstractBackgroundAlthough both age‐related and highly prevalent, little is known regarding the prevalence of hearing loss among persons with dementia (PwD). Current understanding is based on convenience samples primarily from specialized memory clinics. The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS) is a large, prospective study of a population‐based cohort from 4 U.S. community sites with audiometric and neurocognitive testing and bi‐racial representation. We examined the prevalence of hearing loss and hearing aid use among older adults with cognitive impairment and whether cognitive status influences hearing aid use.MethodWe analyzed audiometric and hearing care data from ARIC‐NCS Visit 6 (2016‐2018). Participants underwent a full neurocognitive battery and audiometric evaluation at Visit 6. Participants with complete audiometric data and an adjudicated diagnosis of cognitively normal, mild cognitive impairment (MCI), or dementia were included in the analytical cohort (N=3,385). Differences in participant characteristics by cognitive status were descriptively compared using Chi‐square tests or one‐way ANOVAs. We performed a series of logistic regression models to estimate the odds of hearing aid non‐use by cognitive status.ResultPrevalence of hearing loss was greater with increasing cognitive impairment (cognitively normal:64.7%; MCI:71.3%; dementia:83.3%). Prevalence of hearing aid use among those with hearing loss and cognitive impairment varied by race (African Americans 7.2%; whites 32.8%). In a multivariable‐adjusted model, cognitive impairment was independently associated with higher odds of non‐use of hearing aids (MCI odds ratio (OR):1.4 (95%CI:1.0‐1.8); dementia OR:1.8 (95%CI:1.2‐2.9) versus cognitively normal). The strongest risk factor for non‐use of hearing aids was race, where African Americans have almost a 5 times higher odds of not using hearing aids compared to whites (95% CI:2.9‐7.4).ConclusionHearing loss is highly prevalent but vastly untreated among older adults with cognitive impairment, particularly African Americans, and cognitive impairment is independently associated with hearing aid use. These estimates are some of the first population‐based estimates of audiometric hearing loss among diverse older adults with adjudicated diagnoses of MCI or dementia. With increased calls to address ethnic/racial disparities, we must include hearing loss, as one of the most common co‐morbidities, in order to optimize health and well‐being among all PwD.

Background The impact of the new 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline on dementia risk at the population level has not been evaluated. Methods and Results We studied dementia‐free participants in the ARIC (Atherosclerosis Risk in Communities) Study cohort in 1987 to 1989. Hypertension was defined by 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and 2017 ACC/AHA guidelines using blood pressure measured at baseline. Dementia was defined using adjudicated consensus diagnoses, informant telephone interviews, and discharge codes from hospitalizations and death certificates. Cox regression estimated hazard ratios (HRs) for dementia and 95% CIs by hypertension categories, adjusting for confounders. Population attributable fraction of dementia was calculated by hypertension categories. Among 13 971 participants followed up for a median of 23 years, 1381 dementia cases were identified. Prevalence of hypertension was 34% and 48%, according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and ACC/AHA criteria, respectively. HRs (95% CIs) compared with normal blood pressure, according to ACC/AHA categories, were 1.35 (1.12–1.61) for elevated blood pressure, 1.28 (1.07–1.52) for hypertension stage 1, and 1.36 (1.18–1.57) for hypertension stage 2. Population attributable fractions (95% CIs) of dementia from blood pressure categories were 3% (1%–5%), 3% (1%–5%), and 9% (4%–14%), respectively. Population attributable fractions (95% CIs) using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure categories were 6% (3%–9%) for prehypertension, 0% (−2% to 2%) for hypertension stage 1, and 9% (5%–13%) for hypertension stage 2. Conclusions Risk of dementia increased across hypertension categories defined by ACC/AHA guidelines. The population impact on dementia incidence using ACC/AHA categories was similar to the impact of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.