Lirette, Seth

Objectives To examine associations between inflammation and physical function and potential mediation by white matter hyperintensities ( WMH s) in African Americans ( AA s) and European Americans ( EA s). Design Cross‐sectional analysis using linear and logistic models with generalized estimating equations to account for family clustering, reporting results as regression coefficients (β) and odds ratios ( OR s) adjusted for education, alcohol, exercise, body mass index, hypertension, diabetes mellitus, heart disease, cognition, ankle–brachial index, race (site), and supported interactions. Setting Genetic Epidemiology Network of Arteriopathy‐Genetics of Microangiopathic Brain Injury Study cohort. Participants AA and EA sibships with two or more siblings with hypertension before age 60 (N = 1,960; 65% female, 51% AA , aged 26–91, 50% obese, 72% hypertensive). Measurements Inflammation (C‐reactive protein ( CRP ), interleukin‐6 ( IL 6), soluble tumor necrosis factor receptors ( sTNFR s) 1 and 2, WMH volume (cm 3 ) according to magnetic resonance imaging), walking speed (cm/s) over 25 feet, and mobility difficulty (any self‐reported difficulty walking half a mile). Results In separate models, inflammatory markers were associated with walking speed ( sTNFR 1: β = −2.74, P < .001; sTNFR 2: β = −1.23, P = .03; CRP : β = −1.95, P = .001; IL 6: β = −1.24, P = .03) and mobility difficulty ( sTNFR 1: OR = 1.36, P = .001; sTNFR 2: OR = 1.25, P = .005; CRP : OR = 1.22, P = .005; IL 6: OR = 1.18, P = .02); the association between WMH volume and sTNFR 1 in AA (β = 0.07, P = .06) did not reach typical statistical thresholds. WMH volume was associated with walking speed in AA (β = −3.17, P = .02) but not with mobility difficulty ( OR = 1.10, P = .54). Adjusting for WMH did not change associations. Conclusion In young, middle‐aged, and older adults with prevalent cardiovascular risk factors, multiple inflammatory biomarkers were associated with slower walking speed independent of microvascular disease in the brain. There was little evidence of mediation by brain WMH volume. Inflammation may contribute to physical function impairments through pathways other than brain microvascular disease, particularly in AA s.

Background and Purpose— The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Methods— Total of 1906 nondemented participants (59% women; 25% African–American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. Results— In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Conclusions— Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.

Objectives To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors. Design Cross‐sectional analysis using generalized estimating equations to account for familial clustering; standardized β‐coefficients, adjusted for age, sex, and education are reported. Setting Community cohort study in Jackson, Mississippi, and Rochester, Minnesota. Participants Genetic Epidemiology Network of Arteriopathy (GENOA)–Genetics of Microangiopathic Brain Injury (GMBI) Study participants. Measurements Associations between inflammation (high‐sensitivity C‐reactive protein (CRP), interleukin (IL)‐6, soluble tumor necrosis factor (TNF) receptor 1 and 2 (sTNFR1, sTNFR2)) and cognitive function (global, processing speed, language, memory, and executive function) were examined in AAs and EAs (N = 1,965; aged 26–95, 64% women, 52% AA, 75% with hypertension). Results In AAs, higher sTNFR2 was associated with poorer cognition in all domains (global: −0.11, P = .009; processing speed: −0.11, P < .001; language: −0.08, P = .002; memory: −0.09, P = .008; executive function: −0.07, P = .03); sTNFR1 was associated with slower processing speed (−0.08, P < .001) and poorer executive function (−0.08, P = .008); higher CRP was associated with slower processing speed (−0.04, P = .024), and higher IL6 was associated with poorer executive function (−0.07, P = .02). In EA, only higher sTNFR1 was associated with slower processing speed (−0.05, P = .007). Associations were not found between cognition and sTNFR2, CRP, or IL6 in EA. Conclusion In a population with high vascular risk, adverse associations between inflammation and cognitive function were especially apparent in AAs, primarily involving markers of TNFα activity.