Subclinical Cerebrovascular Disease Research Articles

Abstract 12: Blood Pressure Phenotypes, Subclinical Cerebrovascular Diseases and Coronary Artery Calcification in Japanese Men

Introduction: Hypertension, with its various phenotypes including white-coat hypertension (WCHT), masked hypertension (MHT), and sustained hypertension (SHT), is a known risk factor for cardiovascular diseases (CVDs). Yet, it remains unclear whether the association between subclinical CVD and hypertension varies based on its phenotype, and if this relationship differs depending on the location of atherosclerosis. Hypothesis: We hypothesized that MHT, WCHT, and SHT are associated with greater subclinical cerebrovascular diseases and coronary artery calcification (CAC) compared to normotension. Methods: In this community-based observational study of Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA), a total of 740 male participants underwent brain magnetic resonance imaging (MRI) to assess the presence of lacunar infarction, white-matter hyperintensities (WMHs), microbleed, and intracranial artery stenosis (ICAS) between 2012 and 2015. They also underwent office blood pressure (BP) measurements, home BP monitoring for at least 5 consecutive days, and CAC assessments between 2010-2014. The final analysis included 686 participants without a history of CVDs. Results: Of the 686 participants, the mean age was 68.0 years (SD±8.3) and 39.3% were receiving antihypertensive medicine. Using a multivariable logistic regression analysis, WCHT, MHT, and SHT each were significantly associated with higher risk for microbleeds compared to the normotensive group (see Table). However, the association of WCHT with microbleeds was evident in participants on antihypertensive medication (Odds ratios 7.98, 95% confidence interval 2.10-30.24), but was absent in those not taking such medication (Odds ratios 1.23, 95% confidence interval 0.31-4.83). SHT was associated with lacunar infarction, ICAS and CAC compared to the normotensive group (see Table). Conclusions: In Japanese men, WCHT, MHT, and SHT were associated with subclinical cerebrovascular diseases, whereas only SHT was associated to CAC.

Impact of Sleep Disorders and Disturbed Sleep on Brain Health: A Scientific Statement From the American Heart Association.

Accumulating evidence supports a link between sleep disorders, disturbed sleep, and adverse brain health, ranging from stroke to subclinical cerebrovascular disease to cognitive outcomes, including the development of Alzheimer disease and Alzheimer disease-related dementias. Sleep disorders such as sleep-disordered breathing (eg, obstructive sleep apnea), and other sleep disturbances, as well, some of which are also considered sleep disorders (eg, insomnia, sleep fragmentation, circadian rhythm disorders, and extreme sleep duration), have been associated with adverse brain health. Understanding the causal role of sleep disorders and disturbances in the development of adverse brain health is complicated by the common development of sleep disorders among individuals with neurodegenerative disease. In addition to the role of sleep disorders in stroke and cerebrovascular injury, mechanistic hypotheses linking sleep with brain health and biomarker data (blood-based, cerebrospinal fluid-based, and imaging) suggest direct links to Alzheimer disease-specific pathology. These potential mechanisms and the increasing understanding of the "glymphatic system," and the recognition of the importance of sleep in poststroke recovery, as well, support a biological basis for the indirect (through the worsening of vascular disease) and direct (through specific effects on neuropathology) connections between sleep disorders and brain health. Given promising evidence for the benefits of treatment and prevention, sleep disorders and disturbances represent potential targets for early treatment that may improve brain health more broadly. In this scientific statement, we discuss the evidence supporting an association between sleep disorders and disturbances and poor brain health ranging from stroke to dementia and opportunities for prevention and early treatment.

Investigating associations of multiple common infections with brain structure and white matter lesions: findings from prospective neuroimaging studies

AbstractBackgroundEvidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common pathogens – selected based on their relevance to public health – and brain volume, hippocampal volume, and white matter lesions in two population‐based cohorts in the UK.MethodSerology and imaging data were available for 1371 participants across two studies: the UK Biobank (N = 935, mean age(SD)[years] = 55.3(7.7) at serology; 63.8(7.7) at imaging) and the Medical Research Council National Survey of Health and Development [N = 436, mean age(SD) [years] = 63.3(1.1) years at serology; 70.7(0.7) years at imaging). Serology measures included a) serostatuses of 17 pathogens, b) total proportion of 17 pathogens exposed to, and c) total proportion of 11 neurotropic pathogens exposed to (Table 1). Associations between serology measures and outcomes (brain volume, hippocampal volume, and white matter lesion volume) were tested using linear regression. Regression models included adjustments for total intracranial volume and clinic information (basic models), and age, sex, ethnicity, education, socioeconomic position and lifestyle factors (Figure 1). Findings across cohorts were meta‐analysed using random‐effects models. The present study will be expanded to include an additional cohort (Southall and Brent Revisited,N≤1200) to add more precision for identifying associations.ResultSeropositivity to seven pathogens associated with an outcome in basic models, and four in fully‐adjusted models: seropositivity to JC virus was associated with smaller brain volumes, Epstein‐Barr virus with larger brain volumes, Merkel cell virus with larger hippocampal volumes and fewer white matter lesions, and C.trachomatis with fewer white matter lesions (Figure 2). Neurotropic pathogen burden scores associated with smaller hippocampal volumes in basic models, but no associations were seen for either pathogen burden score in fully‐adjusted models.ConclusionWe found some evidence of both positive and negative associations between common infections and imaging markers of subclinical cerebrovascular disease and neurodegeneration, with no evidence of relationships with pathogen burden. This work highlights key relationships for further investigation, which may reveal novel pathways associated with brain structure and cerebrovascular pathology.

Predicting progression of white matter hyperintensity using coronary artery calcium score based on coronary CT angiography-feasibility and accuracy.

Coronary artery disease (CAD) usually coexists with subclinical cerebrovascular diseases given the systematic nature of atherosclerosis. In this study, our objective was to predict the progression of white matter hyperintensity (WMH) and find its risk factors in CAD patients using the coronary artery calcium (CAC) score. We also investigated the relationship between the CAC score and the WMH volume in different brain regions. We evaluated 137 CAD patients with WMH who underwent coronary computed tomography angiography (CCTA) and two magnetic resonance imaging (MRI) scans from March 2018 to February 2023. Patients were categorized into progressive (n = 66) and nonprogressive groups (n = 71) by the change in WMH volume from the first to the second MRI. We collected demographic, clinical, and imaging data for analysis. Independent risk factors for WMH progression were identified using logistic regression. Three models predicting WMH progression were developed and assessed. Finally, patients were divided into groups based on their total CAC score (0 to <100, 100 to 400, and > 400) to compare their WMH changes in nine brain regions. Alcohol abuse, maximum pericoronary fat attenuation index (pFAI), CT-fractional flow reserve (CT-FFR), and CAC risk grade independently predicted WMH progression (p < 0.05). The logistic regression model with all four variables performed best (training: AUC = 0.878, 95% CI: 0.790, 0.938; validation: AUC = 0.845, 95% CI: 0.734, 0.953). An increased CAC risk grade came with significantly higher WMH volume in the total brain, corpus callosum, and frontal, parietal and occipital lobes (p < 0.05). This study demonstrated the application of the CCTA-derived CAC score to predict WMH progression in elderly people (≥60 years) with CAD.

Abstract 13302: Associations of Allostatic Load With Brain Macro-Morphology, Subclinical Cerebrovascular Disease, and Microstructural Integrity of White Matter Pathways: The Boston Puerto Rican Health Study

Introduction: Allostatic load (AL), a measure of overall body wear and tear, has been associated with structural and functional alterations of the brain, but the evidence remains scarce. We aimed to evaluate the prospective associations of AL with brain MRI measures in the Boston Puerto Rican Health Study (BPRHS). Research Questions: Whether AL is associated with 1) brain macro-morphology: brain age and volumes, 2) subclinical cerebrovascular disease: white matter hyperintensity (WMH) and brain infarcts, and 3) microstructural integrity of white matter (WM) pathways in Puerto Rican adults. Methods: Adults from the BPRHS cohort who provided blood and urine samples at baseline, 2-y, and 6-y visits and underwent MRI scans at 13-y visit were included in analyses (n=226). AL was evaluated as a composite score (0-11) of 11 physiological parameters in five body systems. An overall AL score was calculated by averaging the scores of the baseline, 2-y, and 6-y visits, with higher scores indicating greater dysregulation. We evaluated brain age and volumes using T1-weighted MRI, WMH and brain infarcts using T2-weighted MRI, and microstructural integrity of WM pathways using diffusion tensor imaging. Multivariable logistic regression models were used to examine the associations between AL and brain infarcts, and linear regression models were used for other MRI outcomes. Results: Mean age at baseline was 54.6 ± 6.6 y, with 79.2% female. Higher AL was associated with higher brain age z scores (β = 0.129, P = 0.031) and lower volumes of total WM, cerebral WM (especially parietal and temporal lobes), cerebellum, and brain stem. Higher AL was also associated with higher grades of WMH (β = 0.207, P = 0.024) and higher odds of small vessel infarcts [OR (95% CI) = 3.50 (1.56-7.87), P = 0.002], but not large vessel infarcts [OR (95% CI) = 1.33 (0.73-2.40), P = 0.348]. Diffusion tensor imaging parameters showed that participants with higher AL had more microstructural deterioration patterns in major WM pathways. Conclusions: Higher AL score was associated with brain macro- and microstructural disruptions and a higher risk of subclinical cerebrovascular disease, suggesting that AL may be a potential indicator of the need for early intervention in preventing neuronal damage in older adults.

Association between Obstructive Sleep Apnea and Intracranial Artery Calcification Stratified by Gender and Body Mass Index: A Hospital-Based Observational Study

Background and Objectives: Obstructive sleep apnea (OSA) is an independent risk factor for stroke. Furthermore, intracranial arterial calcification (IAC) has been validated as a marker for subclinical cerebrovascular disease. However, the relationship between OSA with IAC was less studied compared with its established association with coronary artery calcification. In this study, we aimed to investigate the association between the severity of OSA and the degree of IAC in hospitalized patients without preexisting cardiovascular disease. Methods: This hospital-based observational study was conducted from June 1, 2017, to May 1, 2019. In total, 901 consecutive patients who underwent head computed tomography scans and portable sleep monitoring were included. On the basis of the apnea-hypopnea index (AHI), patients were divided into four OSA severity groups (normal: AHI <5/h; mild: 5≤ AHI <15/h; moderate: 15≤ AHI <30/h; severe: AHI ≥30/h). Associations of OSA with IAC scores were assessed by using multivariate logistic regression analysis. Results: Of the 901 patients, 484 (53.7%) were men; the mean (SD) age was 66.1 (10.0) years. The non-OSA group included 207 (23.0%) patients; mild OSA, 209 (23.2%); moderate OSA, 235 (26.1%); and severe OSA, 169 (18.8%). Mean IAC scores were higher in the severe OSA group compared with non-, mild, and moderate OSA groups (4.79 vs. 2.58; 4.79 vs. 2.94; 4.79 vs. 3.39; p < 0.001). Multivariate analysis adjusted for confounding factors revealed that only severe OSA was associated with a higher IAC score (odds ratio [OR]: 1.65; 95% confidence interval [CI]: 1.43–1.91; p < 0.001). In stratified analyses by BMI, among participants with a BMI <25 kg/m², the positive association between AHI values and IAC scores was found in the moderate OSA group (OR: 1.23; 95% CI: 1.05, 1.43; p = 0.01) and the severe OSA group (OR: 1.96; 95% CI: 1.55, 2.48; p < 0.001). When stratified by gender, in women, the positive association was found in the moderate OSA group (adjusted OR: 1.21; 95% CI: 1.02–1.51; p = 0.016) and the severe OSA group (adjusted OR: 1.76; 95% CI: 1.36–2.25; p < 0.001). For the men group, a positive association between IAC scores and AHI was only observed in the severe OSA group. Discussion: These findings suggest that OSA, in particular severe OSA (AHI ≥30), is independently associated with higher IAC scores. Women and no-obesity individuals appeared more susceptible to adverse OSA-related subclinical cerebrovascular disease as measured by IAC scores.

Association between proprotein convertase subtilisin/kexin type 9 and subclinical cerebrovascular disease in the community.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new target for reducing low-density lipoprotein cholesterol and incident cardiovascular disease, including stroke. However, the clinical relevance of circulating PCSK9 levels has been poorly elucidated in the general population, particularly in association with subclinical cerebrovascular disease including cerebral small vessel disease (CSVD) and intracranial artery stenosis (ICAS). In community-dwelling Japanese men (n=526) aged 46-82 years without a history of cardiovascular disease, the associations of serum PCSK9 levels with the prevalence of CSVD and ICAS were assessed using magnetic resonance imaging. CSVD included lacunar infarction, deep and subcortical white matter hyperintensity, periventricular hyperintensity and cerebral microbleeds. The median (interquartile range) age at baseline and serum PCSK9 levels were 69 (63-74) years and 240 (205-291) ng/ml, respectively. After adjusting for traditional cardiovascular risk factors including low-density lipoprotein cholesterol, multivariable Poisson regression with robust error variance revealed a significant association between PCSK9 levels (per 1 SD) and ICAS (relative risks 1.18, 95% confidence interval 1.02-1.37). Multivariable ordinal logistic regression for ICAS, with stenosis graded as mild (<50%) or moderate-severe (≥50%), revealed a similar association (common odds ratio 1.31, 95% confidence interval 1.04-1.64). However, no significant association was observed between serum PCSK9 levels and CSVD. Higher circulating PCSK9 levels were independently associated with an ICAS prevalence but not with CSVD prevalence. The quantification of circulating PCSK9 levels may help to identify individuals at high risk for cerebrovascular disease in the general population.

Association of Left Atrial Strain With Ischemic Stroke Risk in Older Adults

The risk of ischemic stroke is higher among patients with left atrial (LA) enlargement. Left atrial strain (LAε) and LA strain rate (LASR) may indicate LA dysfunction when LA volumes are still normal. The association of LAε with incident ischemic stroke in the general population is not well established. To investigate whether LAε and LASR are associated with new-onset ischemic stroke among older adults. The Cardiovascular Abnormalities and Brain Lesions study was conducted from September 29, 2005, to July 6, 2010, to investigate cardiovascular factors associated with subclinical cerebrovascular disease. A total of 806 participants in the Northern Manhattan Study who were aged 55 years or older without history of prior stroke or atrial fibrillation (AF) were included, and annual follow-up telephone interviews were completed May 22, 2022. Statistical analysis was performed from June through November 2022. Left atrial strain and LASR were assessed by speckle-tracking echocardiography. Global peak positive longitudinal LAε and positive longitudinal LASR during ventricular systole, global peak negative longitudinal LASR during early ventricular diastole, and global peak negative longitudinal LASR during LA contraction were measured. Brain magnetic resonance imaging was used to detect silent brain infarcts and white matter hyperintensities at baseline. Risk analysis with cause-specific Cox proportional hazards regression modeling was used to assess the association of positive longitudinal LAε and positive longitudinal LASR with incident ischemic stroke, adjusting for other stroke risk factors, including incident AF. The study included 806 participants (501 women [62.2%]) with a mean (SD) age of 71.0 (9.2) years; 119 participants (14.8%) were Black, 567 (70.3%) were Hispanic, and 105 (13.0%) were White. During a mean (SD) follow-up of 10.9 (3.7) years, new-onset ischemic stroke occurred in 53 participants (6.6%); incident AF was observed in 103 participants (12.8%). Compared with individuals who did not develop ischemic stroke, participants with ischemic stroke had lower positive longitudinal LAε and negative longitudinal LASR at baseline. In multivariable analysis, the lowest (ie, closest to zero) vs all other quintiles of positive longitudinal LAε (adjusted hazard ratio [HR], 3.12; 95% CI, 1.56-6.24) and negative longitudinal LASR during LA contraction (HR, 2.89; 95% CI, 1.44-5.80) were associated with incident ischemic stroke, independent of left ventricular global longitudinal strain and incident AF. Among participants with a normal LA size, the lowest vs all other quintiles of positive longitudinal LAε (HR, 4.64; 95% CI, 1.55-13.89) and negative longitudinal LASR during LA contraction (HR, 11.02; 95% CI 3.51-34.62) remained independently associated with incident ischemic stroke. This cohort study suggests that reduced positive longitudinal LAε and negative longitudinal LASR are independently associated with ischemic stroke in older adults. Assessment of LAε and LASR by speckle-tracking echocardiography may improve stroke risk stratification in elderly individuals.

Social isolation and subclinical vascular pathways to cerebrovascular disease

ABSTRACT Social isolation and lack of social support are risk factors for cardiovascular and cerebrovascular disease (CVD). This study explored the relationship between measures of social support and subclinical measures of CVD risk. 58 healthy adults ages 18 to 85 years participated in this study. The Berkman-Syme Social Network Inventory (SNI) was used to assess social isolation, with higher scores signifying less isolation. Social support was defined using the 12-Item Interpersonal Support Evaluation List (ISEL-12) with a higher score signifying higher social support. Subclinical CVD measures included carotid-femoral pulse wave velocity (cfPWV), carotid beta-stiffness index, and middle cerebral artery (MCA) pulsatility index. Path analysis models for both the SNI and ISEL appraisal domain predicting cfPWV and cerebrovascular pulsatility fit the data well. Path analyses showed significant direct paths from the SNI (β = −.363, t = −2.91) and ISEL appraisal domain (β = −.264, t = −2.05) to cfPWV. From cfPWV, both models revealed significant direct paths to carotid stiffness (β = .488, t = 4.18) to carotid pulse pressure (β = .311, t = 2.45) to MCA pulsatility (β = .527, t = 4.64). Social isolation and appraisal of social support are related to unfavorably higher aortic stiffness, with subsequent detrimental effects on cerebrovascular hemodynamic pulsatility.

PS-BPP01-3: DIFFERENTIAL ASSOCIATION OF CIRCULATING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 WITH THE SUBCLINICAL CEREBRAL SMALL VESSEL DISEASE AND INTRACRANIAL ARTERY STENOSIS

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new target for reducing low density lipoprotein cholesterol (LDL C) and incident cardiovascular disease, including stroke. However, how PCSK9 work on developing stroke is not fully elucidated. In this study we assessed the association of circulating PCSK9 levels with subclinical cerebrovascular disease, including cerebral small vessel diseases (CSVD) and intracranial artery stenosis (ICAS), in a general population. Methods: In community dwelling Japanese men (n = 526) aged 46–82 years, without a history of lipid lowering medications or cardiovascular disease, we assessed the associations of serum PCSK9 levels with CSVD and ICAS using magnetic resonance imaging. CSVD included lacunar infarction, deep and subcortical white matter hyperintensity, periventricular hyperintensity, cerebral microbleeds. Multivariable Poisson regression with robust error variance was performed to estimate the relative risk (RR) and 95% confidence interval (CI) of the serum PCSK9 levels for the presence of CSVD and ICAS. Additionally, ordinal logistic regression was performed to estimate odds ratio (OR) and 95% CI for ICAS, with graded detectable stenosis, mild (1%-50%) and severe (&gt; 50%). Results: The average (standard deviation: SD) age at baseline and median (interquartile range) PCSK9 were 68 (9) years and 240 (205 - 291) ng/mL, respectively. After multivariable adjustment including traditional cardiovascular risk factors (e.g., LDL C), a 1- SD increase of PCSK9 levels was associated with ICAS (adjusted RR 1.18, 95% CI 1.02 - 1.37), and the ordinal logistic regression model also showed a similar association (adjusted OR 1.31, 95% CI 1.04 - 1.64). However, there was no significant association between serum PCSK9 levels and CSVD. Conclusions: Higher circulating PCSK9 level was associated with the higher prevalence of ICAS but not with CSVD, and the association was independent of traditional cardiovascular risk factors including LDL-C. The results of this study imply the direct and independent association of PCSK9 with cerebral atherosclerotic plaque formation.

Associations Between Vascular Risk Factors and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia.

Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (&lt;10), 2 (11-20), 3 (21-40), and 4 (&gt;40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (β= 0.03/year, p &lt; 0.0001), Hispanic ethnicity (β= 0.29, p = 0.01), education (β= 0.04/year, p = 0.04), and coronary bypass surgery (β= 0.93, p = 0.02). CSO PVS only associated with age (β= 0.03/year, p &lt; 0.01). APOE4 and amyloid-β were not associated with PVS. BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

Subclinical left ventricular systolic dysfunction and incident stroke in the elderly: long-term findings from Cardiovascular Abnormalities and Brain Lesions.

Heart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort. Two-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>-14.7%: 95% percentile of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47-4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51-8.43; P = 0.004) but not other subtypes. LV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain-heart interaction and may help improve stroke primary prevention strategies.

Effects of white matter hyperintensities distribution and clustering on late-life cognitive impairment

White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels (‘bullseye’ parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and tested the relation between these latent components and cognitive function. We observed that different, well-defined cognitive constructs mapped to specific WMH distributions. Speed of processing was correlated with WMH in the frontal lobe, while in the case of episodic memory, the relationship was more ubiquitous, involving most of the parcellations. A principal components analysis revealed that the 36 bullseye regions factored onto 3 latent components representing the natural aggrupation of WMH: fronto-parietal periventricular (WMH principally in the frontal and parietal lobes and basal ganglia, especially in the periventricular region); occipital; and temporal and juxtacortical WMH (involving WMH in the temporal lobe, and at the juxtacortical region from frontal and parietal lobes). We found that fronto-parietal periventricular and temporal & juxtacortical WMH were independently associated with speed of processing and episodic memory, respectively. These results indicate that different cognitive impairment phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations.

Associations of Serum Magnesium with Brain Morphology and Subclinical Cerebrovascular Disease: The Atherosclerosis Risk in Communities-Neurocognitive Study.

Circulating magnesium has been associated with a lower risk of dementia, but the physiologic effects by which magnesium may prevent neurological insults remain unclear. We studied 1466 individuals (mean age 76.2 ± 5.3, 28.8% black, 60.1% female) free of prevalent stroke, with measured serum magnesium and with available MRI scans obtained in 2011–2013, participating in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Cross-sectional differences in frontal, temporal, parietal, and occipital lobe volume, along with deep grey matter, total brain, and white matter hyperintensity volume across serum magnesium (categorized into quintiles and per standard deviation increases) were assessed using multiple linear regression. We also examined associations of magnesium with the prevalence of cortical, subcortical, and lacunar infarcts using multiple logistic regression. After adjusting for demographics, biomarkers, medications, and cardiometabolic risk factors, higher circulating magnesium was associated with greater total brain volume and frontal, temporal, and parietal lobe volumes (volumes 0.14 to 0.19 standard deviations higher comparing Q5 to Q1). Elevated magnesium was also associated with lower odds of subcortical infarcts (OR (95%CI): 0.44 (0.25, 0.77) comparing Q5 to Q1) and lacunar infarcts (OR (95%CI): 0.40 (0.22, 0.71) comparing Q5 to Q1). Elevated serum magnesium was cross-sectionally associated with greater brain volumes and lower odds of subclinical cerebrovascular disease, suggesting beneficial effects on pathways related to neurodegeneration and cerebrovascular damage. Further exploration through prospective analyses is needed to assess increasing circulating magnesium as a potential neuroprotective intervention.

Fatty liver and cerebrovascular disease: plausible association and possible mechanisms.

Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity and has wide ranging extrahepatic manifestations, including through cardiometabolic pathways. As such, there is growing interest in the impact of NAFLD on cerebrovascular disease and brain health more broadly. In this review, we assess recent research into understanding the association between NAFLD and brain health while highlighting potential clinical implications. Mechanistically, NAFLD is characterized by both a proinflammatory and proatherogenic state, which results in vascular inflammation and neurodegeneration, potentially leading to clinical and subclinical cerebrovascular disease. Mounting epidemiological evidence suggests an association between NAFLD and an increased risk and severity of stroke, independent of other vascular risk factors. Studies also implicate NAFLD in subclinical cerebrovascular disease, such as carotid atherosclerosis and microvascular disease. In contrast, there does not appear to be an independent association between NAFLD and cognitive impairment. The current literature supports the formulation of NAFLD as a multisystem disease that may also have implications for cerebrovascular disease and brain health. Further prospective studies are needed to better assess a temporal relationship between the two diseases, confirm these early findings, and decipher mechanistic links.

Vascular risk factors as predictors of epilepsy in older age: The Framingham Heart Study.

Stroke is the most common cause of epilepsy in older age. Subclinical cerebrovascular disease is believed to underlie some of the 30%-50% of late-onset epilepsy without a known cause (Li et al. Epilepsia. 1997;38:1216; Cleary et al. Lancet. 2004;363:1184). We studied the role of modifiable vascular risk factors in predicting subsequent epilepsy among participants ages 45 or older in the Framingham Heart Study (FHS), a longitudinal, community-based study. Participants of the Offspring Cohort who attended FHS exam 5 (1991-1995) were included who were at least 45-years-old at that time, had available vascular risk factor data, and epilepsy follow-up (n=2986, mean age 58, 48% male). Adjudication of epilepsy cases included review of medical charts to exclude seizure mimics and acute symptomatic seizures. The vascular risk factors studied included hypertension, diabetes mellitus, smoking, and hyperlipidemia. The role of the Framingham Stroke Risk Profile score was also investigated. Cox proportional hazards regression models were used for the analyses. Fifty-five incident epilepsy cases were identified during a mean of 19years of follow-up. Hypertension was associated with a near 2-fold risk (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.10-3.37, p=.022) of developing epilepsy, even after adjustment for prevalent and interim stroke. In secondary analysis, excluding patients with normal blood pressure who were receiving anti-HTN (anti-hypertensive) treatment (n=2613, 50 incident epilepsy cases) the association was (HR: 2.44, 95% CI: 1.36-4.35, p=.003). Our results offer further evidence that hypertension, a potentially modifiable and highly prevalent vascular risk factor in the general population, increases 2- to 2.5-fold the risk of developing late-onset epilepsy.

Fish Intake and MRI Burden of Cerebrovascular Disease in Older Adults.

Fish intake may prevent cerebrovascular disease (CVD), yet the mechanisms are unclear, especially regarding its impact on subclinical damage. Assuming that fish may have pleiotropic effect on cerebrovascular health, we investigated the association of fish intake with global CVD burden based on brain MRI markers. This cross-sectional analysis included participants from the Three-City Dijon population-based cohort (age ≥65 years) without dementia, stroke, or history of hospitalized cardiovascular disease who underwent brain MRI with automated assessment of white matter hyperintensities, visual detection of covert infarcts, and grading of dilated perivascular spaces. Fish intake was assessed through a frequency questionnaire, and the primary outcome measure was defined as the first component of a factor analysis of mixed data applied to MRI markers. The association of fish intake with the CVD burden indicator was studied with linear regressions. In total, 1,623 participants (mean age 72.3 years, 63% women) were included. The first component of factor analysis (32.4% of explained variance) was associated with higher levels of all 3 MRI markers. Higher fish intake was associated with lower CVD burden. In a model adjusted for total intracranial volume, compared to participants consuming fish <1 time per week, those consuming fish 2 to 3 and ≥4 times per week had a β = -0.19 (95% confidence interval -0.37 to -0.01) and β = -0.30 (-0.57 to -0.03) lower indicator of CVD burden, respectively (p trend < 0.001). We found evidence of effect modification by age such that the association of fish to CVD was stronger in younger participants (65-69 years) and not significant in participants ≥75 years of age. For comparison, in the younger age group, consuming fish 2 to 3 times a week was roughly equivalent (in the opposite direction) to the effect of hypertension. In this large population-based study, higher frequency of fish intake was associated with lower CVD burden, especially among participants <75 years of age, suggesting a beneficial effect on brain vascular health before manifestation of overt brain disease. This study provides Class II evidence that in individuals without stroke or dementia, higher fish intake is associated with lower subclinical CVD on MRI.

Relationship of Four Blood Pressure Indexes to Subclinical Cerebrovascular Diseases Assessed by Brain MRI in General Japanese Men.

Aim: The relationship of blood pressure (BP) indexes (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], mean arterial pressure [MAP]) to subclinical cerebrovascular diseases (SCVDs) remains unclear. This study aimed to elucidate the relationship of four BP indexes measured at two visits on SCVDs assessed by magnetic resonance imaging (MRI) in general Japanese men. Methods: In general Japanese men aged 40–79 years ( N =616), office BP indexes were measured at two visits (Visits 1 [2006–2008] and 2 [2010–2014]). MRI images obtained on the third visit (2012–2015) were examined for prevalent SCVDs: lacunar infarction, periventricular hyperintensity (PVH), deep subcortical white matter hyperintensity (DSWMH), microbleeds, and intracranial artery stenosis (ICAS). Using a multivariable logistic regression analysis, we computed and estimated the odds ratio of each prevalent SCVD for one standard deviation higher BP indexes. The same analyses were performed using home BP. Results: All four office BP indexes at both visits associated with lacunar infarction. Visit 1 and 2 DBP and Visit 1 MAP associated with PVH and DSWMH, and Visit 1 SBP associated with DSWMH. All Visit 2 BP indexes appear to show stronger association with microbleeds than Visit 1 indexes, and Visit 1 and 2 SBP, PP, and MAP showed similar associations with ICAS. Additional analyses using home BP indexes revealed similar relationships; however, the significance of some relationships decreased. Conclusion: In general Japanese men, BP indexes were associated with most of SCVDs, and BP indexes measured at different periods associated with different SCVDs assessed by MRI.

Cerebrovascular Disease and Cognition in Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) affects both brain structure and function. Patients with CKD have a higher risk of both ischemic and hemorrhagic strokes. Age, prior disease history, hypertension, diabetes, atrial fibrillation, smoking, diet, obesity, and sedimentary lifestyle are most common risk factors. Renal-specific pathophysiologic derangements, such as oxidative stress, chronic inflammation, endothelial dysfunction, vascular calcification, anemia, gut dysbiosis, and uremic toxins are important mediators. Dialysis initiation constitutes the highest stroke risk period. CKD significantly worsens stroke outcomes. It is essential to understand the risks and benefits of established stroke therapeutics in patients with CKD, especially in those on dialysis. Subclinical cerebrovascular disease, such as of silent brain infarction, white matter lesions, cerebral microbleeds, and cerebral atrophy are more prevalent with declining renal function. This may lead to functional brain damage manifesting as cognitive impairment. Cognitive dysfunction has been linked to poor compliance with medications, and is associated with greater morbidity and mortality. Thus, understanding the interaction between renal impairment and brain is important in to minimize the risk of neurologic injury in patients with CKD. This article reviews the link between chronic kidney disease and brain abnormalities associated with CKD in detail.

Abstract P172: Relationship of Four Blood Pressure Indexes to Subclinical Cerebrovascular Diseases Assessed by Brain MRI in General Japanese Men

Background: Blood pressure (BP) indexes (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], mean arterial pressure [MAP]) shows association with subclinical cerebrovascular diseases (SCVDs). Although various studies reported this association, there are still controversy in the effect size of long period versus short period of these indexes to SCVDs. Aim: Identifying the effect size of four BP indexes measured at two visits on SCVDs assessed by magnetic resonance imaging (MRI) in general Japanese men. Methods: Four office BP indexes were measured at two visits 4.5 years apart in general Japanese men aged 40-79 years. Participants without myocardial infarction or stroke history were analyzed (N=629). MRI obtained at 3 rd visit were investigated for prevalent of five SCVDs diagnosed as follows; lacunar infarction (LI)= any presence, periventricular hyperintensity (PVH)= Fazekas grade ≥2, deep subcortical white matter hyperintensity (DSWMH)= Fazekas grade ≥3, microbleeds= any presence, and intracranial arterial stenosis (ICAS)= ≥1% stenosis. Using multivariable logistic regression, we computed and compared odds ratio OR (95% CI) of each prevalent SCVD for 1 standard deviation higher of each of 4 BP indexes after adjusting for SCVDs’ conventional risk factors. Results: Participants’ mean age at Visit 1 was 63.9 years. Our results show all office BP indexes, except PP, similar association with MRI outcomes at both Visit 1 and Visit 2. SBP, DBP and MAP were associated with LI, PVH, DSWMH, microbleed and ICAS, while PP was associated with LI and ICAS only. Conclusion: In general Japanese men, BP indexes SBP, DBP and MAP measured at two distinct visits show similar association to all future MRI assessed SCVD, while PP shows association to LI and ICAS only.