Gottesman, Rebecca F.

Background: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six plasma metabolites (two plasma phosphatidylcholines [PCs]: PC aa C36:5 and PC aa 36:6 and four sphingomyelins [SMs]: SM C26:0, SM [OH] C22:1, SM [OH] C22:2, SM [OH] C24:1) with magnetic resonance imaging (MRI) features of cerebral SVD and neurodegeneration in older adults. Methods: This study included 238 older adults in the Atherosclerosis Risk in Communities study at the fifth exam. Multiple linear regression was used to assess the association of each metabolite (log-transformed) in separate models with MRI measures except lacunar infarcts, for which binary logistic regression was used. Results: Higher concentrations of plasma PC aa C36:5 had adverse associations with MRI features of cerebral SVD (odds ratio of 1.69 [95% confidence interval: 1.01, 2.83] with lacunar infarct, and beta of 0.16 log [cm3] [0.02, 0.30] with log [White Matter Hyperintensities (WMH) volume]) while higher concentrations of 3 plasma SM (OH)s were associated with higher total brain volume (beta of 12.0 cm3 [5.5, 18.6], 11.8 cm3 [5.0, 18.6], and 7.3 cm3 [1.2, 13.5] for SM [OH] C22:1, SM [OH] C22:2, and SM [OH] C24:1, respectively). Conclusions: This study identified associations between certain plasma metabolites and brain MRI measures of SVD and neurodegeneration in older adults, particularly higher SM (OH) concentrations with higher total brain volume.

Abstract White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Background and Purpose— Evidence suggests that atrial fibrillation (AF) is associated with increased risk of cognitive decline and dementia, even in the absence of stroke. White matter disease (WMD) is a potential mechanism linking AF to cognitive impairment. In this study, we explored the association between prevalent AF and WMD. Methods— We performed a cross-sectional analysis of participants attending the ARIC-NCS (Atherosclerosis Risk in Communities–Neurocognitive Study) in 2011 to 2013 who underwent brain magnetic resonance imaging. AF was ascertained from study visit electrocardiograms or prior hospitalization codes. Extent of WMD was defined by measures of white matter (WM) microstructural integrity and WM hyperintensity volume. Multivariable linear regression models were used to assess the association between AF and WMD. Results— Among 1899 participants (mean age, 76 years; 28% black; 60% women), 133 (7%) had prevalent AF. After multivariable adjustment, differences between participants with and without AF were −0.001 (95% CI, −0.006 to 0.004) for global WM fractional anisotropy, 0.031×10 −4 mm 2 /s (95% CI, −0.075 to 0.137) for global WM mean diffusivity, and 0.08 mm 3 (95% CI, −0.14 to 0.30) for WM hyperintensity volume. Conclusions— The results suggest that there is no association between prevalent AF and WMD.

Background: Although associations between hypertension in mid-life and the development of dementia and cognitive decline have been established, the impact of the new 2017 ACC/AHA guidelines on dementia risk at the population level has not been evaluated. Objectives: To assess the association of hypertension categories with the risk of incident dementia and to calculate the population attributable fraction (PAF) for dementia from hypertension categories according to the 2017 ACC/AHA guidelines, and compare these associations with hypertension defined according to JNC7. Methods: We studied dementia-free participants recruited to the Atherosclerosis Risk in Communities (ARIC) cohort in 1987-89. Hypertension was defined by 2003 JNC7 and 2017 ACC/AHA guidelines using blood pressure measured at baseline; participants using antihypertensive medication were included in hypertension stage 2 for both sets of guidelines. Dementia was defined using adjudicated consensus diagnoses at visit 5 (2011-13), informant telephone interviews, and ICD-9 codes from hospitalizations and death certificates through 2013. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) by hypertension categories, adjusting for potential confounders, including sociodemographic, lifestyle and clinical variables. PAF of dementia by hypertension category was calculated using rate ratios from Poisson regression and the prevalence of the risk factor in the population. Results: Among 13,971 participants followed for a median of 23.0 years, 1381 cases of dementia were identified. Prevalence of elevated BP (systolic BP [SBP] 120-129 and diastolic BP [DBP] <80), hypertension stage 1 (SBP 130-139 or DBP 80-89) and hypertension stage 2 (SBP ≥140 or DPB ≥90) according to 2017 ACC/AHA categories was 13%, 15% and 44%, respectively. Corresponding HR (95%CI) compared to normal BP were 1.35 (95%CI 1.12, 1.61), 1.28 (1.07, 1.52) and 1.36 (1.18, 1.57), respectively. PAF (95%CI) of dementia from hypertension categories were 3% (1%, 5%), 3% (1%, 5%) and 9% (4%, 14%). PAF using JNC7 categories were similar to 2017 ACC/AHA: 6% (3%, 9%) for prehypertension (SBP 120-129 or DBP 80-89), 0% (-2%, 2%) for hypertension stage 1 (SBP 140-159 or DBP 90-99), and 9% (5%, 13%) for hypertension stage 2 (SBP ≥160 or DBP ≥100). Conclusions: Risk of dementia was increased across categories defined by the new ACC/AHA hypertension guidelines. However, the population impact on dementia incidence using 2017 ACC/AHA was similar to the impact of JNC7. These results suggest that the new criteria for diagnosis of hypertension will not increase the number of persons in whom hypertension could be reasonably labeled as a risk for dementia.

Background: Dementia is increasingly appreciated to have important vascular disease contributions. Albuminuria and decreased estimated glomerular filtration rate (eGFR) define chronic kidney disease (CKD) and are related to the risk of its consequences as well as microvascular disease and endothelial damage across multiple vascular beds. We extend previous studies by examining albuminuria and eGFR measured at both mid-life and older age as risk factors for dementia. Methods: We studied 10,876 adult participants in the Atherosclerosis Risk in Communities (ARIC) Study excluding participants with end-stage renal disease, stroke and incident dementia at baseline. We analyzed the adjusted relative hazard of incident dementia as a function of eGFR (linear spine with a knot at 60 ml/min per 1.73m 2 ) and log urinary albumin-creatinine-ratio (UACR) adjusting for age, sex, race, education level, Apolipoprotein E4 level, smoking, alcohol consumption, body mass index, diabetes and hypertension. We used two different baseline visits: (1) Starting in 1996-1999 (Visit 4, age 54-74 years); (2) Starting 2011-2013 (Visit 5, age 70-90 years) with follow-up to 2017. Results: We observed 2,001 dementia cases over 16 years of follow-up (446 after Visit 5). Risk of dementia increased with higher levels of albuminuria with a stronger magnitude at older-age than in midlife ( see table ). Estimated GFR was more weakly associated with dementia (p>0.05 at both baselines). The albuminuria association was consistent across sex and race (p-interaction>0.05). Conclusion: Albuminuria, a marker of kidney disease and endothelial damage, is strongly related to dementia incidence. Albuminuria’s association with dementia is stronger in late-life unlike other vascular risk factors, where the association is weaker at older age.

Introduction: Cerebral small-vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate if chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods: Consecutive patients with MCA±ICA occlusion presenting within 6 hours after stroke symptoms onset from 2012- 2016 were included. Primary outcome was collateral flow, which was assessed on baseline CT-angiogram (poor ≤50% filling, good >50% filling). Markers of chronic SVD on brain MRI were rated for the presence of WMH (Fazekas scale 2-3), enlarged perivascular spaces (EPVS), chronic lacunae, and any cerebral microbleeds (CMB) using the STRIVE criteria. Severity of SVD was quantified by adding the presence of each SVD feature to a maximum score of 4. Multivariable logistic regression models were performed to evaluate the relationships between SVD and poor collaterals. Results: Of the 100 patients, the mean age was 65±16, median NIHSS was 15, and 68% had SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals (aOR 1.9; 95%CI 1.1-3.2) than patients without SVD. Of the SVD types, poor collaterals were associated with WMH (aOR 2.9 per Fazekas increment; 95%CI 1.6-5.3) but not EPVS (aOR 1.3; 0.4-4.0), lacunae (aOR 2.1; 0.6-7.1), or CMB (aOR 2.1; 0.6-7.8). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend p<.001; adjusted p=.056). There was a dose-dependent relationship between WMH burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1-3 (trends P=.015, Table). No patient with SVD score of 4 had good collaterals. Conclusions: Chronic cerebral small-vessel disease is associated with poor recruitment of collaterals in large-vessel occlusive stroke. A prospective study to elucidate the mechanism of how SVD may impair the recruitment of collaterals is ongoing.

Introduction: Robust leptomeningeal collaterals protect brain from ischemia, yet the determinants of poor collaterals remains unclear. We aimed to identify predictors of poor collaterals in patients with large-vessel occlusive stroke. Methods: We analyzed 112 consecutive patients with middle cerebral artery ± internal carotid artery occlusion from 2012-2016 who presented within 6 hours after stroke symptoms onset. Collaterals on baseline CT-angiogram (poor collaterals ≤50% filling, good collaterals >50% filling) were reviewed blinded to clinical data. Pre-specified predictors of poor collaterals were analyzed with adjusted logistic regression models: including known predictors (age, vascular risk factors and metabolic derangements) and hypothesized predictors (low cardiac output, elevated inflammatory markers, and imaging evidence for chronic cerebral small-vessel disease and chronic steno-occlusive arterial disease). Results: The mean age was 67± 16 years, there were 48% women, 57% white, and median NIHSS was 15 (IQR 11-20). Poor collaterals at baseline were detected in 48%. Multivariable modeling identified that age (aOR 1.8 per 10 years; 95% CI 1.3-2.6; p<0.001), black race (aOR 2.1; 95% CI 1.0-4.5; p=0.043), high blood glucose level (aOR 2.4 per 100 mg/dl; 95% CI 1.1-5.1; p=0.029), and high WMH burden (aOR 6.1; 95%CI 1.8-20.4; p=0.003) were independent predictors of poor collaterals. Associations between low cardiac output, elevated inflammatory markers, intracranial atherosclerosis and poor collaterals did not reach statistical significance (Table). Conclusions: We have identified that advanced age, black race, hyperglycemia, and white matter hyperintensities are predictors of poor collaterals. Independent replication study at another institution is ongoing to further explore the hypothesized predictors.

Background: High blood pressure (BP), particularly in mid-life, increases the risk for late-life cognitive impairment and dementia (CID). The extent to which Blacks’ and Hispanics’ worse BP control starting in young adulthood contributes to their greater risk of CID compared to Whites is uncertain. Objective: To describe a pooled, multi-ethnic cohort created to determine the associations between BP levels over the life course and CID risk in Blacks, Hispanics, and Whites. Methods: We pooled individual-level data from 35,473 adults (22.6% Blacks, 8.1% Hispanics, 67.3% Whites, 2% Other) with baseline age ≥18 and cognitive assessments across 6 longitudinal cohorts in the United States from 1971 to 2016: Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), Cardiovascular Health Study (CHS), Framingham Offspring Study (FOS), Multi-Ethnic Study of Atherosclerosis (MESA), and Northern Manhattan Study (NOMAS). We harmonized cognitive tests across studies into 3 factors representing global cognitive performance, executive function, and memory using statistically appropriate confirmatory factor analysis. Mean (SD) follow up was 17.1 (10.9) years. Results: The mean (SD) baseline age was 54.3 (16.4) years and 19554 (55.1%) participants were female (Table). There were 3193 (9.0%) first incident strokes (2651 ischemic, 348 hemorrhagic, and 117 other or undetermined type) and 15147 (42.7%) deaths. The Table presents mean BPs at the first and last visits by cohort and the pooled sample. From the initial to the last assessment, mean global cognition decreased over time (p<0.001), as did mean executive function (p<0.001) and mean memory scores (p<0.001) in the pooled sample. Conclusion: This will be the first comprehensive, large investigation of the association of BP levels from young adulthood to late-life and CID risk in Blacks, Hispanics, and Whites.