White Matter Hyperintensities Accumulation Research Articles

Investigating the relationship between sleep disturbances and white matter hyperintensities in older adults on the Alzheimer's disease spectrum.

While studies report that sleep disturbance can have negative effects on brain vasculature, its impact on cerebrovascular diseases such as white matter hyperintensities (WMHs) in beta-amyloid-positive older adults remains unexplored. Sleep disturbance, WMH burden, and cognition in normal controls (NCs), and individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD), were examined at baseline and longitudinally. A total of 912 amyloid-positive participants were included (198 NC, 504 MCI, and 210 AD). Individuals with AD reported more sleep disturbances than NC and MCI participants. Those with sleep disturbances had more WMHs than those without sleep disturbances in the AD group. Mediation analysis revealed an effect of regional WMH burden on the relationship between sleep disturbance and future cognition. These results suggest that WMH burden and sleep disturbance increase from aging to AD. Sleep disturbance decreases cognition through increases in WMH burden. Improved sleep could mitigate the impact of WMH accumulation and cognitive decline.

Differences in pathology, brain atrophy, and WMHs across APOE subtypes

AbstractBackgroundThe apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer’s disease (AD), while the e2 allele is thought to be protective. As few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype, we do so here.MethodsWe analyzed Alzheimer’s Disease Neuro Imaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load (obtained using Dadar 2018); ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV‐45), and phosphorylated tau (pTau), all downloaded from LONI. Participants were divided into one of four APOE allele profiles (E4 = e4e4 or e3e4; E2 = e2e2 or e2e3; E3 = e3e3; or E24 = e2e4, Fig.1). Linear mixed effects models examined the relationship between APOE profiles and each pathology while controlling for age, sex, education, and diagnostic status.ResultsAt baseline (Fig.2), E4 exhibited increased pTau (p<.001) compared to E2 and E3 and smaller HC and EC volumes than all other APOE profiles (p<.01). The E24 group exhibited smaller ventricles than E3 and E4 (p<.05). The E2 group exhibited less amyloid than all other APOE profiles (p<.001), while E4 and E24 had more amyloid compared to E3 (p<.001).Longitudinally (Fig.3), ventricular enlargement and HC atrophy significantly differed between all profiles (p<.001). Furthermore, E2 was observed to have slower WMH accumulation compared to all other profiles (p<.001), while E4 exhibited faster accumulation compared to E3 (p<.001). The E4 group exhibited increased EC atrophy compared to E3 and E2 (p<.001), and E24 exhibited more atrophy than E2 (p = .015). Amyloid increased faster in the E4 group compared to E3 and E2 (p<.001), while E2 amyloid progressed slower than E3 (p = .005).ConclusionsAPOE E4 positivity is associated with increased baseline and greater accumulation of pathologies and rates of neurodegeneration. APOE E2 positivity is associated with reduced pathology burden (i.e., WMH and amyloid) and less neurodegeneration as measured by ventricle size and hippocampal and entorhinal cortex volume over time. APOE E2E4 is similar to E4 (i.e., increased neurodegeneration and pathology burden) but with a slightly slower rate of change.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease

Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Association of white matter hyperintensity accumulation with domain-specific cognitive decline: a population-based cohort study

We investigated the association of load and accumulation of white matter hyperintensities (WMHs) with rate of cognitive decline. This population-based study included 510 dementia-free people (age ≥60 years) who had repeated measures of global and regional (lobar, deep, periventricular) WMHs up to 6 years (from 2001–2003 to 2007–2010) and repeated measures of cognitive function (episodic memory, semantic memory, category fluency, letter fluency, executive function, perceptual speed) up to 15 years (from 2001–2004 to 2016–2019). We found that greater baseline loads of global and regional WMHs were associated with faster decline in letter fluency, perceptual speed, and global cognition. Furthermore, faster accumulation of global, deep, and periventricular WMHs was related to accelerated cognitive decline, primarily in perceptual speed. These data show that WMHs are associated with decline in perceptual speed rather than episodic or semantic memory and that cognitive change is more vulnerable to WMH accumulations in deep and periventricular regions.

Cognitive disturbances during perimenopause: are they linked to dementia?

Women have a greater risk of developing Alzheimer's disease (AD) compared to men. This biological sex difference is primarily due to the greater longevity of women compared to men, but other factors also contribute to this difference, including a greater risk of AD among those with the apolipoprotein epsilon 4 (APOE4) genetic risk factor. Sex steroid hormones have myriad effects on the central nervous system, and other bodily systems that play an important role in brain health, including immune, metabolic and cardiovascular systems. Knowledge of the brain changes that occur in menopause is limited by the lack of large-scale longitudinal neuroimaging studies of women transitioning through the menopause, though such studies are currently underway. Initial evidence from cross-sectional studies and small longitudinal studies suggest that both brain structure and function may undergo changes, and that AD biomarkers may accumulate more rapidly during the menopause. Clearly the menopause is not a universal trigger for the development of AD, as all women who live into late life transition through the menopause and only a minority of women with develop AD. One of the factors that may make certain women more vulnerable to AD is vasomotor symptoms (VMS). Although a causal role of VMS is not established, correlational studies link objectively measured VMS with memory deficits, disruptions in brain function and the accumulation of white matter hyperintensities, small ischemic lesions that increase the risk of both vascular dementia and AD. Mood symptoms and sleep disruption also contribute to cognitive changes and alterations in brain health. Some evidence indicates that hormone therapy (HT) may be associated with lower levels of AD biomarkers, but more clinical trial data is needed, particularly in women with VMS. Medical societies reliably conclude based on the evidence to date that HT should not be used for the treatment of cognitive issues or the prevention of dementia. The use of HT for the treatment of VMS, however, is indicated and may help women to maintain more optimal brain health as they age.

Mediterranean diet and longitudinal change of white matter hyperintensity in cognitively intact young and older adults

AbstractBackgroundA healthy dietary pattern, Mediterranean diet (MeDi), has been reported to be associated with better brain and cognition. White matter hyperintensities (WMHs), seen in brain magnetic resonance imaging, are considered to be due to cerebral small vessel diseases and have been shown to predict faster cognitive decline in older adults. However, current evidence on the association between MeDi and WMH is inconsistent and longitudinal data are scarce. This study aims to examine whether better adherence to MeDi is associated with less accumulation of WMH over time.MethodThis longitudinal study was conducted among 183 cognitively intact adults aged 20‐80 years. MeDi was calculated from dietary data assessed by a self‐reported food frequency questionnaire, ranging from 0‐55, with a higher score indicating better adherence. WMH was assessed by 3T MRI, and log‐transformed prior to analyses. A one‐sample T‐test was used to examine if WMH burden increased from baseline to follow‐up over an average of five years. Multivariable linear regression was used to estimate the effect of MeDi on the change in WMH. Covariates included age, gender, race/ethnicity, education, IQ, follow‐up interval, caloric intake, baseline WMH, baseline total gray matter volume, and baseline mean cortical thickness. Moderation effects by age (young: &lt;43, middle‐aged: 43‐65, and older: ≥65 years), sex, and race/ethnicity (non‐Hispanic White and other, non‐Hispanic Black, and Hispanic) were examined, followed by stratification analyses.ResultAmong all participants, WMH increased from baseline to follow‐up (mean difference [follow‐up‐baseline][standard error(SE)] = 0.31[0.04], p&lt;0.001). A higher MeDi was associated with less increase of WMH (β[SE] = ‐0.014[0.006], p = 0.034), adjusting by all covariates. The association between MeDi and WMH change was moderated by age group (young group as the reference, p‐interaction[middle‐aged*MeDi] = 0.024, p‐interaction[older*MeDi] = 0.017), adjusting by follow‐up interval: the association was observed among the young group (β[SE] = ‐0.038[0.010], p&lt;0.001), but not among the middle‐aged ((β[SE] = ‐0.002[0.013, p = 0.872]) or the older group ((β[SE] = ‐0.002[0.009], p = 0.836). No significant moderation effects by sex or race/ethnicity were found, adjusting by age and follow‐up interval.ConclusionBetter adherence to MeDi was associated with reduced increase of WMH over time. Following a healthy diet, especially at an early age, may help maintain a healthy brain.

The association between white matter hyperintensities and amyloid and tau deposition

White matter hyperintensities (WMHs) frequently occur in Alzheimer’s Disease (AD) and have a contribution from ischemia, though their relationship with β-amyloid and cardiovascular risk factors (CVRFs) is not completely understood. We used AT classification to categorize individuals based on their β-amyloid and tau pathologies, then assessed the effects of β-amyloid and tau on WMH volume and number. We then determined regions in which β-amyloid and WMH accumulation were related. Last, we analyzed the effects of various CVRFs on WMHs. As secondary analyses, we observed effects of age and sex differences, atrophy, cognitive scores, and APOE genotype. PET, MRI, FLAIR, demographic, and cardiovascular health data was collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-3) (N = 287, 48 % male). Participants were categorized as A + and T + if their Florbetapir SUVR and Flortaucipir SUVR were above 0.79 and 1.25, respectively. WMHs were mapped on MRI using a deep convolutional neural network (Sepehrband et al., 2020). CVRF scores were based on history of hypertension, systolic and diastolic blood pressure, pulse rate, respiration rate, BMI, and a cumulative score with 6 being the maximum score. Regression models and Pearson correlations were used to test associations and correlations between variables, respectively, with age, sex, years of education, and scanner manufacturer as covariates of no interest. WMH volume percent was significantly associated with global β-amyloid (r = 0.28, p < 0.001), but not tau (r = 0.05, p = 0.25). WMH volume percent was higher in individuals with either A + or T + pathology compared to controls, particularly within in the A+/T + group (p = 0.007, Cohen’s d = 0.4, t = -2.5). Individual CVRFs nor cumulative CVRF scores were associated with increased WMH volume. Finally, the regions where β-amyloid and WMH count were most positively associated were the middle temporal region in the right hemisphere (r = 0.18, p = 0.002) and the fusiform region in the left hemisphere (r = 0.017, p = 0.005). β-amyloid and WMH have a clear association, though the mechanism facilitating this association is still not fully understood. The associations found between β-amyloid and WMH burden emphasizes the relationship between β-amyloid and vascular lesion formation while factors like CVRFs, age, and sex affect AD development through various mechanisms. These findings highlight potential causes and mechanisms of AD as targets for future preventions and treatments. Going forward, a larger emphasis may be placed on β-amyloid’s vascular effects and the implications of impaired brain clearance in AD.

Racial differences in white matter hyperintensity burden in older adults

White matter hyperintensities (WMHs) may be one of the earliest pathological changes in aging. Race differences in WMH burden has been conflicting. This study examined if race influences WMHs and whether these differences are influenced by vascular risk factors. Alzheimer's Disease Neuroimaging Initiative participants were included if they had a baseline MRI, diagnosis, and WMH measurements. Ninety-one Blacks and 1937 Whites were included. Using bootstrap re-sampling, 91 Whites were randomly sampled and matched to Blacks based on age, sex, education, and diagnosis 1000 times. Linear models examined the influence of race on baseline WMHs, and change of WMHs over time, with and without vascular factors. Vascular risk factors had higher prevalence in Blacks than Whites. When not including vascular factors, Blacks had greater frontal, parietal, deep, and total WMH burden compared to Whites. There were no race differences in longitudinal progression of WMH accumulation. After controlling for vascular factors, only overall longitudinal parietal WMH group differences remained significant, suggesting that vascular factors contribute to racial group differences observed in WMHs.

White matter hyperintensity load varies depending on subjective cognitive decline criteria.

Increased age and cognitive impairment is associated with an increase in cerebrovascular pathology often measured as white matter hyperintensities (WMHs) on MRI. Whether WMH burden differs between cognitively unimpaired older adults with subjective cognitive decline (SCD +) and without subjective cognitive decline (SCD -) remains conflicting, and could be related to the methods used to identify SCD. Our goal was to examine if four common SCD classification methods are associated with different WMH accumulation patterns between SCD + and SCD - . A total of 535 cognitively unimpaired older adults with 1353 time points from the Alzheimer's Disease Neuroimaging Initiative were included in this study. SCD was operationalized using four different methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry. Linear mixed-effects models were used to investigate the associations between SCD and overall and regional WMH burden. Overall temporal WMH burden differences were only observed with the Worry questionnaire. Higher WMH burden change over time was observed in SCD + compared to SCD - in the temporal and parietal regions using the CCI (temporal, p = .01; parietal p = .02) and ECog (temporal, p = .02; parietal p = .01). For both the ECog + Worry and Worry questionnaire, change in WMH burden over time was increased in SCD + compared to SCD - for overall, frontal, temporal, and parietal WMH burden (p < .05). These results show that WMH burden differs between SCD + and SCD - depending on the questionnaire and the approach (regional/global) used to measure WMHs. The various methods used to define SCD may reflect different types of underlying pathologies.

Brain Changes and Fast Cognitive and Motor Decline in Older Adults.

To identify brain magnetic resonance imaging (MRI) signatures characterizing people with different patterns of decline in cognition and motor function. In the Swedish National Study on Aging and Care in Kungsholmen, Stockholm, 385 participants had available repeated brain MRI examinations, where markers of brain volumes and white matter integrity were assessed. The speed of cognitive and motor decline was estimated as the rate of a Mini-Mental State Examination and gait speed decline over 12 years (linear mixed models), and further dichotomized into the upper (25% fastest rate of decline) versus the lower quartiles. Participants were grouped in slow/no decliners (reference), isolated motor decliners, isolated cognitive decliners, and cognitive and motor decliners. We estimated the associations between changes in brain markers (linear mixed models) and baseline diffusion tensor imaging measures (linear regression model) and the 4 decline patterns. Individuals with concurrent cognitive and motor decline (n = 51) experienced the greatest loss in the total brain (β: -12.3; 95% confidence interval [CI]: -18.2; -6.38) and hippocampal (β: -0.25; 95% CI: -0.34; -0.16) volumes, the steepest accumulation of white matter hyperintensities (β: 1.61; 95% CI: 0.54; 2.68), and the greatest ventricular enlargement (β: 2.07; 95% CI: 0.67; 3.47). Compared to the reference, those only experiencing cognitive decline presented with steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed a greater white matter hyperintensities burden. Lower microstructural white matter integrity was associated with concurrent cognitive and motor decline. Concurrent cognitive and motor decline is accompanied by rapidly evolving and complex brain pathology involving both gray and white matter. Isolated cognitive and motor declines seem to exhibit brain damage with different qualitative features.

Effect of Antihypertensives by Class on Cerebral Small Vessel Disease: A Post Hoc Analysis of SPRINT-MIND.

Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining. Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years; P<0.001) and systolic blood pressure (128.3±11.0 versus 126.2±9.4 mm Hg; P=0.039). Seventy-two (48.3%) of the top tertile cohort and 177 (59.2%) of the remaining cohort were in the intensive blood pressure arm. Those within the top tertile of progression had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL (P<0.001). Use of angiotensin-converting enzyme inhibitors (odds ratio, 0.36 [95% CI, 0.16-0.79]; P=0.011) and dihydropyridine calcium channel blockers (odds ratio, 0.39 [95% CI, 0.19-0.80]; P=0.011) was associated with less WMH progression, although dihydropyridine calcium channel blockers lost significance when WMH was treated as a continuous variable. Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

Abstract 102: Effect Of Antihypertensives By Class On Cerebral Small Vessel Disease: A Post-hoc Analysis Of SPRINT-MIND

Introduction: Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, though it is unclear whether this reduction occurs due to blood pressure control or antihypertensive class-specific pleotropic effects. The goal of this study was to investigate the influence of antihypertensive medication class on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. Methods: Using the SPRINT-MIND dataset, we completed a post-hoc analysis of participants who completed a baseline and 4-year follow-up brain MRI with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the MRIs. A percentage of follow-up time participants were prescribed each of the eleven classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between two scans and, to address skew, dichotomized into a top tertile (greatest) accumulation and combined middle and bottom tertiles (slowest) accumulation. Results: Among 448 individuals included in this study, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 years versus 65.7±7.3 years, p&lt;0.001) and systolic blood pressure (128.3±11.0 mmHg versus 126.2±9.4 mmHg, p=0.039). The high had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL for the slowest progressors (p&lt;0.001). Only angiotensin converting enzyme inhibitors (ACE-I) (OR 0.34, 95% CI 0.15-0.75, p=0.008) and dihydropyridine calcium channel blockers (d-CCB) (OR 0.39, 95% CI 0.19-0.81, p=0.012) were independently associated with lower odds of being in the greatest progression grouping. Conclusions: Amongst hypertensive participants in the SPRINT-MIND trial, ACE-I and d-CCB antihypertensive medications were associated with significantly lower odds of being in the highest tertile of WMH progression compared with other antihypertensive classes, independent of blood pressure control.

White matter lesion load is associated with lower within- and greater between- network connectivity across older age

White matter hyperintensities (WMH) are among the most prominent structural changes observed in older adulthood. These changes coincide with functional changes to the intrinsic network organization of the aging brain. Yet little is known about how WMH are associated with changes to the whole-brain functional connectome in normal aging. We used a lesion prediction algorithm to quantify WMH as well as resting-state multiecho functional magnetic resonance imaging to characterize resting-state functional connectivity in a cross-sectional sample of healthy older adults (N = 105, 60–83 years of age). In a multivariate analysis, we found that higher lesion load was associated with a global pattern of network dedifferentiation, marked by lower within- and greater between- network connectivity. Network specific changes included greater visual network integration and greater posterior-anterior connectivity. The relationship between WMH and resting-state functional connectivity was negatively associated with fluid IQ as well as Blood Oxygen Level Dependent signal dimensionality. Reduced functional network segregation is a widely observed pattern of age-related change. Our findings show that these functional changes are associated with the accumulation of WMH in older adulthood.

The Impact of Common Epidemiological Factors on Gray and White Matter Volumes in Magnetic Resonance Imaging-Is Prevention of Brain Degeneration Possible?

Introduction: The aim of the study was to evaluate the impact of multiple risk factors (age, diabetes, hypertension, hyperlipidemia, BMI, smoking, alcohol) on the gray and white matter volumes as well as on the burden of white matter hyperintensities (WMH).Material and Methods: The study group consisted of 554 subjects (age range: 50–69 yrs, F/M: 367/187) recruited from the larger cohort of the Polish fraction of the Prospective Urban Rural Epidemiological (PURE) study. The participants answered questionnaires about their lifestyle, underwent physical and psychological examination (MoCA test), laboratory blood tests followed by brain MRI. Volumetric measurements of the total gray matter (GMvol), total white matter (WMvol) and WHM (WMHvol) normalized to the total intracranial volume were performed using the Computational Anatomy Toolbox 12 (CAT12) and Statistical Parametric Maps 12 (SPM12) based on 3D T1-weighted sequence. The influence of risk factors was assessed using multiple regression analysis before and after correction for multiple comparisons.Results: Older age was associated with lower GMvol and WMvol, and higher WMHvol (p < 0.001). Smaller GMvol volume was associated with higher WMHvol (p < 0.001). Higher WMHvol was associated with hypertension (p = 0.01) and less significantly with hyperlipidemia (only before correction p = 0.03). Diabetes, abnormal BMI, smoking and alcohol intake did not have any significant impact on GMvol, WMvol or WMHvol (p > 0.05). MoCA score was not influenced by any of the factors.Conclusions: Gray matter loss is strongly associated with the accumulation of WMH which seems to be potentially preventable by maintaining normal blood pressure and cholesterol levels.

An anatomical knowledge-based MRI deep learning pipeline for white matter hyperintensity quantification associated with cognitive impairment.

Recent studies have confirmed that white matter hyperintensities (WMHs) accumulated in strategic brain regions can predict cognitive impairments associated with Alzheimer's disease (AD). The knowledge of white matter anatomy facilitates lesion-symptom mapping associated with cognition, and provides important spatial information for lesion segmentation algorithms. However, deep learning-based methods in the white matter hyperintensity (WMH) segmentation realm do not take full advantage of anatomical knowledge in decision-making and lesion localization processes. In this paper, we proposed an anatomical knowledge-based MRI deep learning pipeline (AU-Net), handcrafted anatomical-based spatial features developed from brain atlas were integrated with a well-designed U-Net configuration to simultaneously segment and locate WMHs. Manually annotated data from WMH segmentation challenge were used for the evaluation. We then applied this pipeline to investigate the association between WMH burden and cognition within another publicly available database. The results showed that AU-Net significantly improved segmentation performance compared with methods that did not incorporate anatomical knowledge (p < 0.05), and achieved a 14-17% increase based on area under the curve (AUC) in the cohort with mild WMH burden. Different configurations for incorporating anatomical knowledge were evaluated, the proposed stage-wise AU-Net-two-step method achieved the best performance (Dice: 0.86, modified Hausdorff distance: 3.06 mm), which was comparable with the state-of-the-art method (Dice: 0.87, modified Hausdorff distance: 3.62 mm). We observed different WMH accumulation patterns associated with normal aging and cognitive impairments. Furthermore, the characteristics of individual WMH lesions located in strategic regions (frontal and parietal subcortical white matter, as well as corpus callosum) were significantly correlated with cognition after adjusting for total lesion volumes. Our findings suggest that AU-Net is a reliable method to segment and quantify brain WMHs in elderly cohorts, and is valuable in individual cognition evaluation.

Effects of omega‐3 fatty acids on cerebral white matter hyperintensities and medial temporal lobe atrophy in older non‐demented adults: A 3‐year randomized‐controlled phase 2 trial

AbstractBackgroundThe n‐3 PUFA may modulate risk for age‐related cognitive impairment through vascular mechanisms. MRI derived cerebral white matter hyperintensities (WMH) presumptively reflect small vessel disease and their accumulation increases risk for age‐related cognitive decline and dementia. Blood n‐3 PUFA are consistently associated with reduced WMH and stroke. The primary aim here was to evaluate n‐3 PUFA supplementation on WMH accumulation over 3 years in an older population with evidence of WMH and absence of n‐3 PUFA supplementation.MethodsThe study was a double‐blind, placebo‐controlled trial, with participants randomized to a daily dose of fish oil (1650 mg combined eicosapentaenoic acid‐EPA and docosahexaenoic acid‐DHA) or placebo oil (soybean) for a 3‐year intervention. Main inclusion criteria were: non‐demented (MMSE &gt; 24), age &gt; 74 years, WMH volume &gt; 5.0 cc, and plasma n‐3 PUFA (EPA+DHA) &lt; 110 umol/L (or &lt; 5.5 percent of total fatty acids). The primary endpoint was 3‐year change in total WMH volume. Secondary endpoints include changes in regional brain volumes and white matter integrity. Exploratory endpoints include measures of cerebral blood flow, domain‐specific and global cognitive measures with subgroup analyses by APOE4 genotype. A linear mixed‐effects model was used to assess the outcomes.Results102 subjects were enrolled (mean age 81±4.4, MMSE 27.8±1.7; 60% female, 27.5% APOE4 positive) and a total of 78 participants completed the trial. Supplementation had no beneficial effect on rate of WMH progression, which increased by a mean of 1.07 cc per year in the n‐3 PUFA group vs 1.12 cc per year in the placebo group (p = 0.30 for time*trial arm interaction). Three‐year changes in executive cognitive function z‐scores were not different between treatment groups (p = 0.24). No differences in adverse events between groups were observed .ConclusionN‐3 PUFA compared with placebo, failed to slow 3‐year WMH accumulation and executive function decline in older non‐demented adults presenting with evidence of WMH. N‐3 PUFA at the 1.65‐gram dose appears safe in older adults over 3‐years. Additional MRI and cognitive outcomes with detailed safety profiles are planned for presentation.

EFFECTS OF FUNCTIONAL BRAIN NETWORKS AND WHITE MATTER DISEASE ON MOBILITY OF OLDER ADULTS IN AN EXERCISE INTERVENTION

Declining mobility is associated with increased accumulation of white matter hyperintensities (WMH). However, a high WMH burden is not always accompanied by impaired mobility. Our previous work demonstrates that some variance in mobility may be explained by brain network connectivity. Here, we extended this work by measuring WMHs and brain networks in older adults participating in a lifestyle intervention. The Short Physical Performance Battery (SPPB) and resting state functional magnetic resonance imaging (fMRI) were collected before and after a 5-month caloric restriction plus aerobic exercise intervention in 57 obese, sedentary adults aged 65-78. Participants were categorized based on median splits of baseline SPPB scores and WMH burden: Expected Healthy (EH: low WMH, SPPB≥11, n=16), Expected Impaired (EI: high WMH, SPPB≤10, n=17), Unexpected Healthy (UH: high WMH, SPPB≥11, n=12), and Unexpected Impaired (UI: low WMH, SPPB≤10, n=12). Graph theory-based methods were used to characterize brain networks and compare the four groups. At baseline, the somatomotor cortex community structure (SMC-CS) was less consistent in EI (p=0.05) and UI (p=0.23) compared to EH. The EI (mean=1.25, p=0.003) and UI (mean=1.57, p=0.001) significantly improved their SPPB scores following the intervention. Although both groups had equivalent SPPB scores, SMC-CS was less consistent in the UH than EH (p=0.16). However, UH displayed a significant (p=0.004) increase in second-order connections to the precuneus compared to EH. These data suggest that studying brain networks could improve the understanding of the development of mobility disability and the CNS contributions to mobility independent of white matter disease.

344 The Relationship between Late Life Depressive Symptoms and Cerebral White Matter Disease is Modified by Systemic and Orthostatic Blood Pressure

Abstract Background Cerebral white matter hyperintensity (WMH) burden is a key biological risk factor underpinning late life depression (LLD) and cerebral hypoperfusion has been identified as an important cause of WMH. The aim of this study therefore is to clarify if orthostatic hypotension (OH) and lower systemic blood pressure (BP), both of which cause reduced cerebral blood flow, modify the relationship between depression and cerebral white matter disease in a cohort of community-dwelling older people aged ≥70 years. Methods This study uses data from wave 3 of TILDA. Participants were included if they were aged ≥70 years and had undergone assessment for depressive symptoms, brain MRI and cardiovascular measures. Depressive symptoms were measured using the 8-item Centre for Epidemiological Studies Depression Scale. Scheltens Score was used by a trained radiologist to calculate overall WMH burden. Orthostatic BP was measured by active stand. OH was defined as a drop in Systolic BP≥20 mmHg or drop in diastolic BP≥10 mmHg at 30, 60 or 90 seconds post standing. Results Participants with depressive symptoms (8%, 16/202) had a significantly higher burden of WMH measured by Scheltens Score (14.6 (95% CI:11.0–18.2) vs. 11.0 (95% CI:10.1–11.8); p=0.0211). Two-way interaction models demonstrated that the association between depressive symptoms and WMH burden is significant only in those with co-existing OH. Similarly, the two-way interaction between depressive symptoms and systolic BP shows that this association remains statistically significant only in those with both depressive symptoms and lower BP, i.e. &lt;130 mm Hg. Conclusion This study demonstrates that depressive symptoms are associated with cerebral WMH in a cohort of community-dwelling people aged ≥70 years but this relationship is modified by co-existing OH or lower BP. Identifying the processes that lead to WMH accumulation and progression in depression is crucial in order to inform strategies aimed at preventing and ameliorating LLD.

Randomized Trial of Marine n-3 Polyunsaturated Fatty Acids for the Prevention of Cerebral Small Vessel Disease and Inflammation in Aging (PUFA Trial): Rationale, Design and Baseline Results.

Vascular risk factors for age-related cognitive decline are significant, and their management may ultimately prove the most successful strategy for reducing risk and sustaining cognitive health. This randomized, double-blinded, placebo-controlled trial with parallel group allocation to either marine n-3 polyunsaturated fatty acids (n-3 PUFA) or soybean oil placebo assesses the effects on the total volume of accumulation in cerebral white matter hyperintensities (WMH), a potentially modifiable neurovascular component of age-related cognitive decline. Total WMH accumulation over 3 years is the primary endpoint. The safety and efficacy of n-3 PUFA is evaluated in older adults with significant WMH and suboptimum plasma n-3 PUFA as inclusion criteria. One hundred and two non-demented older adults were enrolled with a mean age of 81.1 (±4.4) years, WMH of 19.4 (±16.1) cm3, and a plasma n-3 PUFA of 86.64 (±29.21) µg/mL. 61% were female, 28% were apolipoprotein E epsilon 4 carriers, and the mean mini-mental state exam (MMSE) was 27.9 (±1.7). This trial provides an initial evaluation of n-3 PUFA effects on WMH, a reproducible and valid risk biomarker for cognitive decline, as well as on inflammatory biomarkers thought to play a role in WMH accumulation. We present the baseline results and operational experience of enriching a study population on advanced age, blood n-3 PUFA, and magnetic resonance imaging (MRI) derived WMH with biomarker outcomes (WMH, inflammation markers) in a dementia prevention paradigm.

Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort

BackgroundAge is the cardinal risk factor for Alzheimer’s disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD.MethodsOne hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF.ResultsAs expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH.ConclusionsHigher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.