Mosley, Thomas H.

Abstract We hypothesized that poorer cerebral perfusion could impair mobility, particularly at lower systolic blood pressure (SBP). Cerebral perfusion was measured via arterial spin-labelled (ASL)-MRI in community-dwelling adults of the Mayo Clinic Study of Aging. Usual-pace gait speed was assessed over 5.6 meters on an electronic mat. Linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP, adjusting for sex and body mass index. Results report differences in gait speed (meter/second) per standard deviation (SD) lower ASL or SBP (mean=139.1 mmHg, SD=19.7 mmHg). Among 479 participants (aged 31-94 years; mean age 67.6 years; 44% women; mean gait speed 1.17m/s), relationships of ASL with gait speed varied by age and SBP (ASL-x-age interaction: p<.007; ASL-x-SBP interaction: p<.007). At age 65, 75 or 85 years and a SBP of 120mmHg, each SD lower ASL was associated with a 0.04 m/s (0.01,0.07), 0.07 m/s (0.04,0.10), and 0.09 m/s (0.05,0.13) slower gait speed at respective ages. At age 65, 75 or 85 years with low ASL (1 SD below the mean), each SD lower SBP was associated with 0.06 (0.02,0.09) m/s, 0.03 (0.01,0.06) m/s or .01 (-0.02,0.04) m/s slower gait speed, respectively. With high ASL (mean ASL+1SD), lower SBP trended towards faster gait at older age, e.g. estimated gait speed was 0.04 m/s (0.00,0.09) faster for each SD lower SBP at age 85years. Poorer cerebral perfusion may contribute to slower gait, particularly with lower SBP. The interrelations of cerebral perfusion, SBP, and age with mobility merit further study.

Abstract Hearing loss is a risk factor for dementia; whether this association differs by race is unknown. Although hearing loss is less prevalent in Blacks than Whites, we hypothesized the hearing loss-dementia relationship is stronger in Blacks. All-cause dementia and mild cognitive impairment (MCI) were adjudicated using longitudinal cognitive data. Hearing was measured using pure tone better-ear thresholds (0.5-4 kHz). Cox proportional hazards models adjusted for demographic and clinical covariates and included an interaction term between hearing and race. In 3,605 participants from a population-based cohort (68-89 years, 23% Black, 59% female), estimates for 7-year dementia risk per 10 decibels increase in hearing loss were stronger in Blacks (hazard ratio [HR]:1.24, 95% Confidence Interval (CI):1.07,1.43) than Whites (HR:1.07; 95%CI:0.96,1.19). Hearing loss is a risk factor for dementia in Black Americans. These findings emphasize the need to address existing racial disparities in hearing healthcare.

At visit 3 (1993–1995) of the ARIC Study, 1.5T brain MRI was completed in 1,881 stroke-free participants (Mean age = 62.9±4.9, 50% Black). Cox regression examined associations between infarct group [infarct-free (referent; n = 1,611), smaller only (<3 mm; n = 50), larger only (≥3 mm but <20 mm; n = 185), both (n = 35)] and up to 25-year incident dementia (n = 539). Participants with both infarcts were over 2.5 times more likely to develop dementia [HR = 2.61; 95% CI = 1.44, 4.72]. Smaller only (HR = 1.22; 95% CI = 0.70, 2.13) and larger only (HR = 1.27; 95% CI = 0.92, 1.74) groups showed associations with wide confidence intervals, unsupported statistically. A late midlife infarct profile including smaller and larger infarcts may represent particular vulnerability to dementia risk.

AbstractIntroductionWe evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk.MethodsTwo longitudinal population‐based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)‐Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0–12/0–14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0–4/0–5), intermediate (5–7/6–9), or high (8–12/10–14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations.ResultsMidlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES‐Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one‐point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk.DiscussionBetter cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk.Highlights Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

Background: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. Objective: To study the cross-sectional associations of pulmonary function with structural brain variables. Methods: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. Results: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. Conclusion: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

Background The contribution of atrial cardiopathy to dementia risk is uncharacterized. We aimed to evaluate the association of atrial cardiopathy with incident dementia and potential mediation by atrial fibrillation (AF) and stroke. Methods and Results We conducted a prospective cohort analysis of participants in the ARIC (Atherosclerosis Risk in Communities) study attending visit 5 (2011–2013). We used Cox regression to determine the association between atrial cardiopathy and risk of dementia. Structural equation modeling methods were used to determine potential mediation by AF and/or stroke. Atrial cardiopathy was defined if ≥1 of the following at visit 5: P‐wave terminal force >5000 mV·ms in ECG lead V1, NT‐proBNP (N‐terminal pro–brain natriuretic peptide) >250 pg/mL or left atrial volume index ≥34 mL/m 2 by transthoracic echocardiography. We repeated our analysis necessitating ≥2 markers to define atrial cardiopathy. The prevalence of atrial cardiopathy was 34% in the 5078 participants (mean age 75 years, 59% female, 21% Black adults), with 763 participants developing dementia. Atrial cardiopathy was significantly associated with dementia (adjusted HR, 1.35 [95% CI, 1.16–1.58]), with strengthening of the effect estimate when necessitating ≥2 biomarkers (adjusted HR, 1.54 [95% CI, 1.25–1.89]). There was an increased risk of dementia among those with atrial cardiopathy when excluding those with AF (adjusted HR, 1.31 [95% CI, 1.12–1.55]) or stroke (adjusted HR, 1.28 [95% CI, 1.09–1.52]). The proportion of the effect mediated by AF was 4% ( P =0.005), and 9% was mediated by stroke ( P =0.048). Conclusions Atrial cardiopathy was significantly associated with an increased risk of dementia, with only a small percent mediation of the effect by AF or stroke.

Abstract Background Whether diabetes and adipokine‐driven inflammation explain the association of obesity to cognitive impairment is unknown. Methods Structural equation models estimated the total effects of waist circumference on cognitive outcomes among African American participants cross‐sectionally (index exam) and longitudinally. Total effects were deconstructed into direct pathways of waist circumference to cognitive impairment and indirect mediation pathways through leptin, soluble tumor necrosis factor receptor 2 (sTNFR2), and diabetes. Waist circumference, leptin, and sTNFR2 were standardized. Cognitive impairment was defined as MMSE <21 or a z‐score < −1.5 standard deviation (SD). Incident cognitive impairment was defined among those without cognitive impairment at the index exam as follow‐up MMSE<21, z‐ score < −1.5, MMSE decline >1 point/year, or z‐score decline of >0.1 SD/year. Results Among 1008 participants (70% women, mean age 62.9 years, 14.5% with obesity, 26% with diabetes), 132 (13%) had baseline cognitive impairment. Each SD higher waist circumference was associated with higher odds of cognitive impairment, odds ratio (OR) = 1.63; (95% confidence interval: 1.17, 2.24), with mediating pathways explaining 65% of the total effect (58% from diabetes; 7% from inflammation). At follow‐up (mean 6.8 years), 106 of 535 (19.8%) had developed cognitive impairment. Each SD higher waist circumference was associated with higher odds of developing cognitive impairment (OR = 1.87; 95%CI: 1.18, 2.74); the direct effect of waist circumference explained 37% of the total effect and mediating pathways explained 63% (61% from diabetes; 2% from inflammation), although individual pathways were not statistically supported in the smaller sample. Conclusion Diabetes, and to a lesser degree, adiposity‐driven inflammation, appear to explain a substantial proportion of abdominal adiposity relationships with cognitive impairment. The impact of preventing and treating obesity on cognitive outcomes merits study.

Background: Olfactory identification (OI) impairment appears early in the course of Alzheimer’s disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. Objective: We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin’ Sticks odor identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. Results: In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume ( p < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. Conclusion: The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD.

Objective Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease‐associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Methods Participants in the Atherosclerosis Risk in Communities–Positron Emission Tomography study were followed from 1987–1989 (45–64 years old) through 2016–2017 (74–94 years old), with repeat cognitive assessment and dementia adjudication. In 2011–2013, dementia‐free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. Results In 298 individuals, 36 developed dementia (median follow‐up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16–5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72–3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18–5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03–2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83–3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18–4.01). Interpretation Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607–619