Brain White Matter Hyperintensity Volume Research Articles

Regional covariance of white matter hyperintensity volume patterns associated with hippocampal volume in healthy aging.

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.

Abstract 18846: A Noninvasive Smartphone Assessment of Aortic Arch Pulse Wave Velocity and Total Arterial Compliance

Introduction: Several clinical studies including a large multiethnic population (Dallas Heart Study) have shown that total arterial compliance (TAC) and aortic arch pulse wave velocity (PWV aa ) are predictors of cardiovascular disease (CVD) events. Dallas Heart Study also showed that PWV aa predicts brain white matter hyperintensity volume independent of cardiovascular risk factors. Recently, Intrinsic Frequency (IF) analysis of carotid pressure waveform from the Framingham Heart Study was used to predict heart failure (HF) events and CVD (Hypertension, 2021 PMID: 33390053). Aim: Our goal was to show the IF method can determine PWV aa and TAC when applied on carotid pulse waveforms obtained from a standard iPhone camera. Methods: The clinical cohort consisted of 120 individuals (40% women) with ages from 20-92 yrs (mean 53 ± 18), including 54 healthy and 66 patients with CVD (22 HF). Phase-contrast magnetic resonance imaging (PC-MRI) and carotid pressure tonometry data were used to compute TAC. PWV aa values were obtained using PC-MRI flow in ascending and descending aorta (not achieved in 1 patients). A custom Apple iPhone 5S application was used to obtain carotid pulse waves by holding the camera against the neck. IF parameters of iPhone waveforms (calibrated by cuff brachial pressures) were used in machine learning algorithms (IF-iPhone). The models of TAC and PWV aa were developed using 100 participants (99 for PWV aa ) and blindly tested on an additional 20 individuals. Results: In blind tests, iPhone-IF models showed Pearson correlations of r=0.89 and r=0.84 with the measured values of TAC and PWV aa , respectively (Fig.1). Conclusions: Assessment of PWV aa and TAC can be accurately achieved using an unmodified smartphone (iPhone). PWV aa evaluation with an iPhone can be used to identify, predict, and quantify risk of vascular brain damage. A Noninvasive iPhone-based method can be used in a clinical or home setting to routinely assess TAC in the general population or in HF.

Posttraumatic Stress Disorder Symptoms and Cardiovascular and Brain Health in Women

Posttraumatic stress disorder (PTSD), cardiovascular disease (CVD), and Alzheimer disease are major public health issues, particularly for women. The implications of PTSD for cardiovascular and brain health for women is poorly understood. To assess whether PTSD symptoms among midlife women are associated with carotid intima media thickness (IMT), an indicator of carotid atherosclerosis; brain white matter hyperintensity volume (WMHV), an indicator of brain small vessel disease; and cognitive performance and to test a modifying role of the APOEε4 genotype. In this cross-sectional study, participants were enrolled between 2016 to 2021 and completed questionnaires (PTSD Checklist-Civilian Version), physical measures, phlebotomy, neuropsychological testing, a carotid ultrasonographic examination, and 3-Tesla brain magnetic resonance imaging. Participants included community-based women ages 45 to 67 years without a history of CVD, stroke, or dementia. Data were analyzed from July 2022 to September 2023. PTSD symptoms. Outcomes of interest were associations of PTSD symptoms with carotid IMT, brain WMHV, and cognition, assessed in linear regression models. Interactions by APOEε4 were tested. Covariates included age, race and ethnicity, education, and CVD risk factors. Among 274 participants (mean [SD] age, 59.03 [4.34] years; 6 Asian participants [2.2%]; 48 Black participants [17.5%]; 215 White participants [78.5%]; 5 multiracial participants [1.8%]), 64 participants (24.71%) were APOEε4 genotype carriers. Higher PTSD symptoms were associated with greater carotid IMT (multivariable β = 0.07 [95% CI, 0.01 to 0.13]; P = .03). Associations of PTSD symptoms with neurocognitive outcomes significantly varied by APOEε4 status. Among women with APOEε4, PTSD symptoms were associated with greater whole-brain WMHV (β = 0.96 [95% CI, 0.30 to 1.63]; P = .009), periventricular WMHV (β = 0.90 [95% CI, 0.24 to 1.56]; P = .02), deep WMHV (β = 1.21 [95% CI, 0.23 to 2.20]; P = .01), and frontal WMHV (β = 1.25 [95% CI, 0.05 to 2.45]; P = .04), as well as with poorer cognition, specifically attention and working memory (β = -3.37 [95% CI, -6.12 to -0.62]; P = .02), semantic fluency (β = -6.01 [95% CI, -10.70 to -1.31]; P = .01), perceptual speed (β = -12.73 [95% CI, -20.71 to -4.75]; P = .002), and processing speed (β = -11.05 [95% CI, -17.80 to -4.30]; P = .002) in multivariable models. In this cross-sectional study of midlife women, greater PTSD symptoms were associated with higher carotid atherosclerosis and, among women who were APOEε4 carriers, greater brain small vessel disease and poorer cognitive performance. These findings point to the adverse implications of PTSD symptoms for cardiovascular and neurocognitive health among women in midlife, particularly for women who are APOEε4 carriers.

Automatic segmentation of white matter hyperintensities and correlation analysis for cerebral small vessel disease.

Cerebral white matter hyperintensity can lead to cerebral small vessel disease, MRI images in the brain are used to assess the degree of pathological changes in white matter regions. In this paper, we propose a framework for automatic 3D segmentation of brain white matter hyperintensity based on MRI images to address the problems of low accuracy and segmentation inhomogeneity in 3D segmentation. We explored correlation analyses of cognitive assessment parameters and multiple comparison analyses to investigate differences in brain white matter hyperintensity volume among three cognitive states, Dementia, MCI and NCI. The study explored the correlation between cognitive assessment coefficients and brain white matter hyperintensity volume. This paper proposes an automatic 3D segmentation framework for white matter hyperintensity using a deep multi-mapping encoder-decoder structure. The method introduces a 3D residual mapping structure for the encoder and decoder. Multi-layer Cross-connected Residual Mapping Module (MCRCM) is proposed in the encoding stage to enhance the expressiveness of model and perception of detailed features. Spatial Attention Weighted Enhanced Supervision Module (SAWESM) is proposed in the decoding stage to adjust the supervision strategy through a spatial attention weighting mechanism. This helps guide the decoder to perform feature reconstruction and detail recovery more effectively. Experimental data was obtained from a privately owned independent brain white matter dataset. The results of the automatic 3D segmentation framework showed a higher segmentation accuracy compared to nnunet and nnunet-resnet, with a p-value of <0.001 for the two cognitive assessment parameters MMSE and MoCA. This indicates that larger brain white matter are associated with lower scores of MMSE and MoCA, which in turn indicates poorer cognitive function. The order of volume size of white matter hyperintensity in the three groups of cognitive states is dementia, MCI and NCI, respectively. The paper proposes an automatic 3D segmentation framework for brain white matter that achieves high-precision segmentation. The experimental results show that larger volumes of segmented regions have a negative correlation with lower scoring coefficients of MMSE and MoCA. This correlation analysis provides promising treatment prospects for the treatment of cerebral small vessel diseases in the brain through 3D segmentation analysis of brain white matter. The differences in the volume of white matter hyperintensity regions in subjects with three different cognitive states can help to better understand the mechanism of cognitive decline in clinical research.

White matter hyperintensities burden in the frontal regions is positively correlated to the freezing of gait in Parkinson's disease.

Previous studies have reported that white matter hyperintensities (WMHs) are associated with freezing of gait (FOG), but it is not clear whether their distribution areas have correlations with FOG in Parkinson's disease (PD) and the potential influencing factors about WMHs. Two hundred and forty-six patients with PD who underwent brain MRI were included. Participants were divided into PD with FOG (n = 111) and PD without FOG (n = 135) groups. Scheltens score was used to assess the WMHs burden in the areas of deep white matter hyperintensities (DWMHs), periventricular hyperintensities (PVHs), basal ganglia hyperintensities (BGHs), and infratentorial foci of hyperintensities (ITF). Whole brain WMHs volume was evaluated by automatic segmentation. Binary logistic regression was used to evaluate relationships between WMHs and FOG. The common cerebrovascular risk factors that may affect WMHs were evaluated by mediation analysis. There were no statistical differences between PD with and without FOG groups in whole brain WMHs volume, total Scheltens score, BGHs, and ITF. Binary logistic regression showed that the total scores of DWMHs (OR = 1.094; 95% CI, 1.001, 1.195; p = 0.047), sum scores of PVHs and DWMHs (OR = 1.080; 95% CI, 1.003, 1.164; p = 0.042), especially the DWMHs in frontal (OR = 1.263; 95% CI, 1.060, 1.505 p = 0.009), and PVHs in frontal caps (OR = 2.699; 95% CI, 1.337, 5.450; p = 0.006) were associated with FOG. Age, hypertension, and serum alkaline phosphatase (ALP) are positively correlated with scores of DWMHs in frontal and PVHs in frontal caps. These results indicate that WMHs distribution areas especially in the frontal of DWMHs and PVHs play a role in PD patients with FOG.

Menopausal Vasomotor Symptoms and White Matter Hyperintensities in Midlife Women.

The menopause transition is increasingly recognized as a time of importance for women's brain health. A growing body of work indicates that the classic menopausal symptom, vasomotor symptom (VMS), may be associated with poorer cardiovascular health. Other work links VMS to poorer cognition. We investigate whether VMS, when rigorously assessed using physiologic measures, are associated with greater white matter hyperintensity volume (WMHV) among midlife women. We consider a range of potential explanatory factors in these associations and explore whether VMS are associated with the spatial distribution of WMHV. Women aged 45-67 years and free of hormone therapy underwent 24 hours of physiologic VMS monitoring (sternal skin conductance), actigraphy assessment of sleep, physical measures, phlebotomy, and 3 Tesla neuroimaging. Associations between VMS (24-hour, wake, and sleep VMS, with wake and sleep intervals defined by actigraphy) and whole brain WMHV were considered in linear regression models adjusted for age, race, education, smoking, body mass index, blood pressure, insulin resistance, and lipids. Secondary models considered WMHV in specific brain regions (deep, periventricular, frontal, temporal, parietal, and occipital) and additional covariates including sleep. The study sample included 226 women. Physiologically assessed VMS were associated with greater whole brain WMHV in multivariable models, with the strongest associations observed for sleep VMS (24-hour VMS, B[SE] = 0.095 [0.045], p = 0.032; Wake VMS, B[SE] = 0.078 [0.046], p = 0.089, Sleep VMS, B[SE] = 0.173 [0.060], p = 0.004). Associations were not accounted for by additional covariates including actigraphy-assessed sleep (wake after sleep onset). When considering the spatial distribution of WMHV, sleep VMS were associated with both deep WMHV, periventricular WMHV, and frontal lobe WMHV. VMS, particularly VMS occurring during sleep, were associated with greater WMHV. Identification of female-specific midlife markers of poor brain health later in life is critical to identify women who warrant early intervention and prevention. VMS have the potential to serve as female-specific midlife markers of brain health in women.

Small vessel disease disrupts EEG postural brain networks in ‘unexplained dizziness in the elderly’

Abstract Objective To examine the hypothesis that small vessel disease disrupts postural networks in older adults with unexplained dizziness in the elderly (UDE). Methods Simultaneous electroencephalography and postural sway measurements were undertaken in upright, eyes closed standing, and sitting postures (as baseline) in 19 younger adults, 33 older controls and 36 older patients with UDE. Older adults underwent magnetic resonance imaging to determine whole brain white matter hyperintensity volumes, a measure of small vessel disease. Linear regression was used to estimate the effect of instability on electroencephalographic power and connectivity. Results Ageing increased theta and alpha desynchronisation on standing. In older controls, delta and gamma power increased, and theta and alpha power reduced with instability. Dizzy older patients had higher white matter hyperintensity volumes and more theta desynchronisation during periods of instability. White matter hyperintensity volume and delta power during periods of instability were correlated, positively in controls but negatively in dizzy older patients. Delta power correlated with subjective dizziness and instability. Conclusions Neural resource demands of postural control increase with age, particularly in patients with UDE, driven by small vessel disease. Significance EEG correlates of postural control saturate in older adults with UDE, offering a neuro-physiological basis to this common syndrome.

Sexual assault and white matter hyperintensities among midlife women.

Traumatic experiences have been linked to poor mental and physical health. However, there has been little examination of their relationship to neuroimaging markers of cerebrovascular risk. White matter hyperintensities (WMHs) are markers of brain small vessel disease. WMHs can be detected decades before the onset of dementia and other disorders and can serve as early markers for these brain disorders. We tested whether traumatic experiences were associated with brain WMH volume among midlife women. In the MsBrain study, 145 women (mean age = 59years) without cardiovascular disease, stroke, or dementia were recruited. Women completed questionnaires [trauma checklist, depression, post-traumatic stress measures]; physical measures [body mass index (BMI), blood pressure (BP)]; phlebotomy; actigraphy sleep measurement, and 3 Tesla magnetic resonance brain imaging for WMHs. Cross-sectional associations between traumatic experiences and WMH volume were assessed in linear regression models. Covariates were age, race/ethnicity, education, BMI, BP, lipids, preeclampsia, sleep, and additionally depressive and post-traumatic stress disorder symptoms. 68% of women endorsed at least one of the traumas assessed. The most common trauma was sexual assault (23% of women). Women with trauma exposure had greater WMH volume than women without trauma [B(SE) = .24 (.09), p = .01, multivariable]. The single trauma most associated with WMH was sexual assault [B(SE) = .25 (.11), p = .02, multivariable]. Results persisted adjusting for depressive or post-traumatic stress symptoms. A trauma history, particularly sexual assault, was associated with greater WMH volume controlling for covariates, including depressive and post-traumatic symptoms. Sexual assault may place women at risk for poor brain health.

Small vessel disease disrupts EEG postural brain networks in ‘unexplained dizziness in the elderly’

ObjectiveTo examine the hypothesis that small vessel disease disrupts postural networks in older adults with unexplained dizziness in the elderly (UDE). MethodsSimultaneous electroencephalography and postural sway measurements were undertaken in upright, eyes closed standing, and sitting postures (as baseline) in 19 younger adults, 33 older controls and 36 older patients with UDE. Older adults underwent magnetic resonance imaging to determine whole brain white matter hyperintensity volumes, a measure of small vessel disease. Linear regression was used to estimate the effect of instability on electroencephalographic power and connectivity. ResultsAgeing increased theta and alpha desynchronisation on standing. In older controls, delta and gamma power increased, and theta and alpha power reduced with instability. Dizzy older patients had higher white matter hyperintensity volumes and more theta desynchronisation during periods of instability. White matter hyperintensity volume and delta power during periods of instability were correlated, positively in controls but negatively in dizzy older patients. Delta power correlated with subjective dizziness and instability. ConclusionsNeural resource demands of postural control increase with age, particularly in patients with UDE, driven by small vessel disease. SignificanceEEG correlates of postural control saturate in older adults with UDE, offering a neuro-physiological basis to this common syndrome.

Do Gendered Psychosocial Factors Explain Sex Differences in White Matter Hyperintensities?

Women have a greater burden than men of white matter hyperintensities (WMH), a marker of cerebral small vessel disease (cSVD). Psychosocial factors including education, household income, neighborhood socioeconomic status (nSES), happiness, and depression may differ by gender and could explain women’s higher burden of WMH. In a cohort of older adults (N=250, median age=82, 58% women, 39% Black), we found that women had lower education, household income, nSES and were less happy and more depressed. Race stratified Spearman correlations showed women had greater whole brain WMH volume in white participants only (white: rho=0.23, p=0.004; Black: rho=-0.05, p=0.64). In partial Spearman correlations, education, happiness, and depression attenuated but did not fully explain the relationship when added individually or all together to the model for whites (fully adjusted rho=0.19, p=0.03). Gendered psychosocial factors may partially explain sex differences in WMH; interventions targeting these factors may reduce cSVD burden, particularly in white women.

Increased tortuosity of bilateral distal internal carotid artery is associated with white matter hyperintensities.

Although the pathophysiology of white matter hyperintensities remains unclear, we can recently explore the possible relationship with white matter hyperintensities by using quantitative parameter. To demonstrate the relationship between bilateral distal internal carotid arterial tortuosity and total brain white matter hyperintensities volume in elderly individuals. A total of 345 patients (age > 65 years) with brain magnetic resonance (MR) examinations were retrospectively included (44.1% men; mean age = 72.1 ± 6.25 years; 55.9% ≥ 70 years). We measured the Tortuosity Index (TI) of the bilateral distal internal carotid artery and basilar artery on MR angiography imaging, and white matter hyperintensities volume on fluid-attenuated inversion recovery MR sequence. Multiple linear regression was used to assess the association of the TI with quantitatively derived brain white matter hyperintensity volume, after adjusting for demographics (age, sex), vascular risk factors (hypertension, diabetes, heart disease), and vessel diameters, total intracranial volume (TIV). Increased tortuosity of bilateral distal internal carotid artery was associated with greater burden of white matter hyperintensity volume (right: β = 11.223, P = 0.016; left: β = 20.701, P < 0.001). This relationship was independent of age and hypertension, both of which have been considered the strongest risk factors for white matter hyperintensities. Our results suggest that tortuosity of the bilateral distal internal carotid artery is associated with white matter hyperintensities, independent of age and hypertension.

Cerebral white matter disease and functional decline in older adults from the Northern Manhattan Study: A longitudinal cohort study.

BackgroundCerebral white matter hyperintensities (WMHs) on MRI are common and associated with vascular and functional outcomes. However, the relationship between WMHs and longitudinal trajectories of functional status is not well characterized. We hypothesized that whole brain WMHs are associated with functional decline independently of intervening clinical vascular events and other vascular risk factors.Methods and findingsIn the Northern Manhattan Study (NOMAS), a population-based racially/ethnically diverse prospective cohort study, 1,290 stroke-free individuals underwent brain MRI and were followed afterwards for a mean 7.3 years with annual functional assessments using the Barthel index (BI) (range 0–100) and vascular event surveillance. Whole brain white matter hyperintensity volume (WMHV) (as percentage of total cranial volume [TCV]) was standardized and treated continuously. Generalized estimating equation (GEE) models tested associations between whole brain WMHV and baseline BI and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors, as well as stroke and myocardial infarction (MI) occurring during follow-up. Mean age was 70.6 (standard deviation [SD] 9.0) years, 40% of participants were male, 66% Hispanic; mean whole brain WMHV was 0.68% (SD 0.84). In fully adjusted models, annual functional change was −1.04 BI points (−1.20, −0.88), with −0.74 additional points annually per SD whole brain WMHV increase from the mean (−0.99, −0.49). Whole brain WMHV was not associated with baseline BI, and results were similar for mobility and non-mobility BI domains and among those with baseline BI 95–100. A limitation of the study is the possibility of a healthy survivor bias, which would likely have underestimated the associations we found.ConclusionsIn this large population-based study, greater whole brain WMHV was associated with steeper annual decline in functional status over the long term, independently of risk factors, vascular events, and baseline functional status. Subclinical brain ischemic changes may be an independent marker of long-term functional decline.

Periventricular White Matter Hyperintensities and Functional Decline.

We previously showed that global brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. The objective of the current study was to determine whether WMHV in particular brain regions is more predictive of functional decline. Prospective population-based study. Northern Manhattan magnetic resonance imaging (MRI) study. Individuals free of stroke at baseline (N = 1,195; mean age 71 ± 9; n = 460 (39%) male). Participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences. Volumetric WMHV distribution across 14 brain regions (brainstem; cerebellum; bilateral frontal, occipital, temporal, and parietal lobes; and bilateral anterior and posterior periventricular white matter (PVWM)) was determined using a combination of bimodal image intensity distribution and atlas-based methods. Participants had annual functional assessments using the Barthel Index (BI) (range 0-100) over a mean of 7.3 years and were followed for stroke, myocardial infarction (MI), and mortality. Because there were multiple collinear variables, least absolute shrinkage and selection operator (LASSO) regression-selected regional WMHV variables most associated with outcomes and adjusted generalized estimating equations models were used to estimate associations with baseline BI and change over time. Using LASSO regularization, only right anterior PVWM was found to meet criteria for selection, and each standard deviation greater WMHV was associated with accelerated functional decline of 0.95 additional BI points per year (95% confidence interval (CI) = -1.20 to -0.70) in an unadjusted model, -0.92 points per year (95% CI = -1.18 to -0.67) with baseline covariate adjustment, and -0.87 points per year (95% CI = -1.12 to -0.62) after adjusting for incident stroke and MI. In this large population-based study with long-term repeated measures of function, periventricular WMHV was particularly associated with accelerated functional decline.

Cognitive abilities, brain white matter hyperintensity volume, and structural network connectivity in older age.

ObjectiveTo assess brain structural connectivity in relation to cognitive abilities in healthy ageing, and the mediating effects of white matter hyper‐intensity (WMH) volume.MethodsMRI data were analysed in 558 members of the Lothian Birth Cohort 1936. Brains were segmented into 85 regions and combined with tractography to generate structural connectomes. WMH volume was quantified. Relationships between whole‐brain connectivity, assessed using graph theory metrics, and four major domains of cognitive ability (visuospatial reasoning, verbal memory, information processing speed and crystallized ability) were investigated, as was the mediating effects of WMH volume on these relationships.ResultsVisuospatial reasoning was associated with network strength, mean shortest path length, and global efficiency. Memory was not associated with any network connectivity metric. Information processing speed and crystallized ability were associated with all network measures. Some relationships were lost when adjusted for mean network FA. WMH volume mediated 11%–15% of the relationships between most network measures and information processing speed, even after adjusting for mean network FA.ConclusionBrain structural connectivity relates to visuospatial reasoning, information processing speed and crystallized ability, but not memory, in this relatively healthy age‐homogeneous cohort of 73 year olds. When adjusted for mean FA across the network, most relationships are lost, except with information processing speed suggesting that the underlying topological network structure is related to this cognitive domain. Moreover, the connectome‐processing speed relationship is partly mediated by WMH volume in this cohort. Hum Brain Mapp 39:622–632, 2018. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Abstract WP192: Periventricular White Matter Hyperintensities Are Associated With Functional Decline: The Northern Manhattan Study

Background: We previously showed that overall brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. However, it was unclear whether WMHV in particular brain regions was more predictive of decline. We hypothesized that WMHV in particular brain regions would be more predictive of functional decline. Methods: In the Northern Manhattan MRI study, participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences, with baseline interview and examination. Volumetric WMHV distribution across 14 brain regions (brainstem, cerebellum, and bilateral frontal, occipital, temporal, and parietal lobes, and bilateral anterior and posterior periventricular white matter [PVWM]) was determined separately by combining bimodal image intensity distribution and atlas based methods. Participants had annual functional assessments with the Barthel index (BI, range 0-100) over a mean of 7.3 years and were followed for stroke and myocardial infarction (MI). Due to multiple collinear variables, lasso regression was used to select regional WMHV variables, and adjusted generalized estimating equations models estimated associations with baseline BI and change over time. Results: Among 1195 participants, mean age was 71 (SD 9) years, 460 (39%) were male, 802 (67%) had hypertension and 224 (19%) diabetes. Using lasso regularization, only right anterior PVWM was selected, and each SD increase was associated with accelerated functional decline, of -0.95 additional BI points per year (95% CI -1.20, -0.70) in an unadjusted model, -0.92 points per year (95% CI -1.18, -0.67) with baseline covariate adjustment, and -0.87 points per year (95% CI -1.12, -0.62) after adjusting for stroke and MI. This decline was in addition to a mean decline of -1.13 (95% CI -1.29, -0.97), -1.19 (95% CI -1.36, -1.01), and -1.04 (95% CI -1.21, -0.88) BI points per year, respectively. Conclusions: In this large population-based study with long-term repeated measures of function, periventricular WMHV was particularly associated with accelerated functional decline. Periventricular WMHV may have a greater effect on mobility due to dysfunction in descending leg motor tracts.

Abstract TMP56: Differential Effect of Left versus Right White Matter Hyperintensity Burden on Functional Decline: The Northern Manhattan Study

Background: We previously showed that overall brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. Asymmetry of brain dysfunction may disrupt brain network efficiency. We hypothesized that greater left-right WMHV asymmetry was associated with functional trajectories. Methods: In the Northern Manhattan MRI study, participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences, with baseline interview and examination. Volumetric WMHV distribution across 14 brain regions (brainstem, cerebellum, and bilateral frontal, occipital, temporal, and parietal lobes, and bilateral anterior and posterior periventricular white matter) was determined separately by combining bimodal image intensity distribution and atlas based methods.. Participants had annual functional assessments with the Barthel index (BI, range 0-100) over a mean of 7.3 years. Generalized estimating equations models estimated associations of regional WMHV and regional left-right asymmetry with baseline BI and change over time, adjusted for baseline medical risk factors, sociodemographics, and cognition, and stroke and myocardial infarction during follow-up. Results: Among 1195 participants, mean age was 71 (SD 9) years, 39% were male, 67% had hypertension and 19% diabetes. Greater WMHV asymmetry in the frontal lobes (-3.53 BI points per unit greater WMHV on the right compared to left, 95% CI -0.18, -6.88) and whole brain (-7.23 BI points, 95% CI 0.07, -14.54) was associated with lower overall function. Greater WMHV asymmetry in the frontal lobes (-0.74 additional BI points per year per unit greater WMHV on the right compared to left, 95% CI 0.05, -1.54) and parietal lobes (1.11 additional BI points per year, 95% CI 0.30, 1.93) was independently associated with accelerated functional decline. Periventricular WMHV asymmetry was not associated with function. Conclusions: In this large population-based study with long-term repeated measures of function, greater regional WMHV asymmetry was associated with lower function and functional decline, especially with greater WMHV on the right. In addition to global WMHV, WHMV asymmetry may be an important predictor of long-term functional decline.

Associations Between Inflammation and Physical Function in African Americans and European Americans with Prevalent Cardiovascular Risk Factors.

To examine associations between inflammation and physical function and potential mediation by white matter hyperintensities (WMHs) in African Americans (AAs) and European Americans (EAs). 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 (ORs) adjusted for education, alcohol, exercise, body mass index, hypertension, diabetes mellitus, heart disease, cognition, ankle-brachial index, race (site), and supported interactions. Genetic Epidemiology Network of Arteriopathy-Genetics of Microangiopathic Brain Injury Study cohort. 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). Inflammation (C-reactive protein (CRP), interleukin-6 (IL6), soluble tumor necrosis factor receptors (sTNFRs) 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). In separate models, inflammatory markers were associated with walking speed (sTNFR1: β = -2.74, P < .001; sTNFR2: β = -1.23, P = .03; CRP: β = -1.95, P = .001; IL6: β = -1.24, P = .03) and mobility difficulty (sTNFR1: OR = 1.36, P = .001; sTNFR2: OR = 1.25, P = .005; CRP: OR = 1.22, P = .005; IL6: OR = 1.18, P = .02); the association between WMH volume and sTNFR1 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. 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 AAs.

Abstract 18689: Lower Carotid Artery Compliance and Greater Carotid β-stiffness Index are Associated With Slower Processing Speed and Reduced Working Memory Performance in Older Healthy Adults

Introduction: Higher central elastic artery stiffness is associated with greater brain white matter hyperintensity volume and lower cognitive performance in older adults. However, it is unknown if higher central artery stiffness is related to regional decreases in brain white matter integrity (WMI) and reductions in working memory or processing speed. We hypothesized that greater large elastic artery stiffness would be associated with lower working memory and slower processing speed as well as lower regional WMI in older adults. Methods: In young (n=19; 23.8 ± 0.7 yrs) and older (n=22; 64.4 ± 4.2 yrs; range 60-71 yrs) healthy adults, aortic stiffness (carotid-femoral pulse wave velocity, cfPWV, via tonometry) and carotid artery compliance and β-stiffness index (carotid artery ultrasound and tonometry) were determined non-invasively. WMI was assessed by fractional anisotrophy (FA) (3T MRI) from diffusion tensor images. An N-Back task and letter and pattern comparison tests were performed as measures of working memory and processing speed, respectively. d’Prime, a measure of signal detection, was calculated on the N-Back task as a ratio of positive ‘hits’ to ‘false alarm’ responses. Results: cfPWV (8.4 ± 0.5 vs. 5.2 ± 0.2 m/sec, P&lt;0.01) and carotid β-stiffness (11.3 ± 0.9 vs. 6.1 ± 0.7 U, P&lt;0.01) were greater and carotid compliance (0.16 ± 0.02 vs. 0.07 ± 0.01 mm/mmHg, P&lt;0.01) was lower in older vs. young adults. Carotid β, but not aortic, stiffness was associated with slower processing speed on letter (10.7 ± 0.5 vs. 13.5 ± 0.6 units/ 30 sec, p&lt;0.01) and pattern (16.6 ± 0.6 vs. 22.0 ± 0.7 units/30 sec, p&lt;0.01) comparison tasks and reduced working memory (1.8 ± 0.2 vs. 3.1± 0.2, P&lt;0.01) in older vs. young adults. Lower carotid compliance was associated with slower performance on the letter (r=0.55, P&lt;0.01) and pattern (r=0.54, P&lt;0.01) tests and lower d’Prime (r=0.48, P&lt;0.05). Greater β-stiffness was related to pattern comparison scores only (r=-0.54, P&lt;0.01). Aortic stiffness, carotid compliance and β-stiffness were not related to WMI in any brain region. Conclusions: Our results suggest that lower carotid artery compliance and greater β-stiffness are associated with reduced working memory performance and slower processing speed but not regional WMI in older adults.

An inverse relationship between serum macrophage inhibitory cytokine-1 levels and brain white matter integrity in community-dwelling older individuals

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a marker of inflammation that has been associated with atherosclerosis. We have previously demonstrated its relationships with cognitive decline and cerebral gray matter volumes, suggesting its role as a biomarker of cognitive impairment. Considering that it is widely distributed in the brain, and both inflammation and vascular pathology impact on white matter (WM) integrity, we examined the relationship between MIC-1/GDF15 and measures of WM integrity, including WM volumes, mean fractional anisotropy (FA) values and WM hyperintensity (WMH) volumes in a community-dwelling non-demented sample of older individuals (n=327, 70–90 years old). We found that the mean FA values were negatively associated with MIC-1/GDF15 serum levels, after Bonferroni correction. The voxel-wise analysis showed negative relationships between MIC-1/GDF15 serum levels and FA values in corticospinal tract, corpus callosum (including genu, body and splenium parts), superior longitudinal fasciculus, cingulum, as well as anterior and posterior thalamic radiation. Whole brain WMH volumes, especially deep WMH volumes, showed a non-significant trend for a positive association with MIC-1/GDF15 serum levels. The associations between MIC-1/GDF15 serum levels and WM integrity showed a non-significant trend of being stronger for the individuals classified as mild cognitive impairment, compared to the normal ageing participants. The findings suggest that high serum MIC-1/GDF15 levels indicate reduced WM integrity and possibly greater WM pathology.

Brain white-matter hyperintensity volume is related to lower cognitive function in older community-dwelling individuals without cognitive impairment

Brain white-matter hyperintensity volume is related to lower cognitive function in older community-dwelling individuals without cognitive impairment