Windham, B. Gwen

Objectives To quantify associations between inflammatory biomarkers and hippocampal volume ( HV ) and to examine effect modification according to sex, race, and age. Design Cross‐sectional analyses using generalized estimating equations to account for familial clustering; standardized β ‐coefficients adjusted for age, sex, race, and education. Setting Community cohorts in Jackson, Mississippi and Rochester, Minnesota. Participants The Genetic Epidemiology Network of Arteriopathy study. Measurements C‐reactive protein ( CRP ), interleukin‐6 ( IL ‐6), and soluble tumor necrosis factor receptors 1 ( sTNFR ‐1) and 2 ( sTNFR ‐2) from peripheral blood were measured in a sample of 773 non‐Hispanic whites (61% women, aged 60.2 ± 9.8) and 514 African Americans (70% women, aged 63.9 ± 8.1) who also underwent brain magnetic resonance imaging. Biomarkers were standardized and compared according to sex, race and age with HV. Results In the full sample, higher sTNFR ‐1 and sTNFR ‐2 were associated with smaller HV . Each standard deviation ( SD ) increase in sTNFR ‐1 was associated with 59.1 mm 3 (95% confidence interval ( CI ) = −101.4 to −16.7 mm 3 ) smaller HV and each SD increase in sTNFR ‐2 associated with 48.8 mm 3 (95% CI = −92.2 to −5.3 mm 3 ) smaller HV . Relationships were stronger for sTNFR ‐2 in men ( HV = −116.6 mm 3 for each SD increase, 95% CI = −201.0 to −32.1) than women ( HV = −26.0 per SD increase, 95% CI = −72.4–20.5) and sTNFR ‐1 in non‐Hispanic whites ( HV = −84.7 mm 3 per SD increase, 95% CI = −142.2 to −27.1) than African Americans ( HV = −14.1 mm 3 per SD increase, 95% CI = −78.3–50.1). Associations between IL ‐6 or CRP and HV were not supported. Conclusion Higher levels of sTNFR s were associated cross‐sectionally with smaller hippocampi. Longitudinal data are needed to determine whether these biomarkers may help to identify risk of late‐life cognitive impairment.

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— Hypertensive pregnancy disorders have been associated with subjective cognitive complaints or brain white-matter lesions 5 to 10 years after the hypertensive pregnancy. The long-term effects of hypertensive pregnancies on brain structure and cognitive function remain unknown. Methods and Results— This study included 1279 women who participated in the Family Blood Pressure Project Genetic Epidemiology Network of Arteriopathy (GENOA) study. As part of the ancillary Genetics of Microangiopathic Brain Injury (GMBI) study, a neurocognitive battery was administered; 1075 also had a brain magnetic resonance imaging. A history of a hypertensive pregnancy disorder was obtained by a self-report using a validated questionnaire. Linear models fit with generalized estimating equations were used to assess the association between hypertensive pregnancy disorders and cognition, adjusting for age, race, education, body mass index, smoking, current hypertension, hypertension duration, and family history of hypertension. Regression models for the brain magnetic resonance imaging outcomes also were adjusted for total intracranial volume. Women with histories of hypertensive pregnancy disorders performed worse on all measures of processing speed (Digital Symbol Substitution Test [mean score, 41.2 versus 43.4; P =0.005], Trail Making Test Part A [mean seconds, 45.1 versus 42.2; P =0.035], and Stroop [mean score, 173.9 versus 181.0; P =0.002]) and had smaller brain volumes compared with women with histories of normotensive pregnancies (286 versus 297; P =0.023). Conclusions— Hypertensive pregnancy disorders are associated with worse performance on tests of processing speed and smaller brain volumes decades later. Population-based studies are needed to provide critical insight as to the contribution of hypertensive pregnancies to risk of cognitive decline and dementia.

AbstractIntroductionWe examined prevalence of mild cognitive impairment (MCI) and dementia in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive study.MethodsBeginning in June, 2011, we invited all surviving ARIC participants to undergo cognitive, neurologic, and brain imaging assessments to diagnose MCI or dementia and assign an etiology for the cognitive disorder.ResultsOf 10,713 surviving ARIC participants (age range, 69–88 years), we ascertained cognitive diagnoses in 6471 in person, 1966 by telephone interviews (participant or informant), and the remainder by medical record review. The prevalence of dementia was 9.0% and MCI 21%. Alzheimer's disease (AD) was the primary or secondary etiology in 76% of dementia and 75% of MCI participants. Cerebrovascular disease was the primary or secondary etiology in 46% of dementia and 32% of MCI participants.DiscussionMCI and dementia were common among survivors from the original ARIC cohort. Nearly 30% of the ARIC cohort received diagnoses of either dementia or MCI, and for the majority of these individuals, the etiologic basis was attributed to AD.

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.