Greater White Matter Hyperintensities Research Articles

Association of past and current sleep duration with structural brain differences: A large population-based study from the UK Biobank

ObjectiveThis study aimed to examine the association between past/current sleep duration and macro-/micro-structural brain outcomes and explore whether hypertension or social activity plays a role in such association. MethodsWithin the UK Biobank, 40 436 dementia-free participants (age 40–70 years) underwent a baseline assessment followed by a brain magnetic resonance imaging (MRI) scan 9 years later. Past (baseline) and current (MRI scans) sleep duration (hours/day) were recorded and classified as short (≤5), intermediate (6–8), and long (≥9). Brain structural volumes and diffusion markers were assessed by MRI scans. ResultsCompared with past intermediate sleep, past short sleep was related to smaller cortex volumes (standardized β [95 % CI]: −0.04 [-0.07, −0.02]) and lower regional fractional anisotropy (FA) (−0.08 [-0.13, −0.03]), while past long sleep was related to smaller regional subcortical volumes (standardized β: −0.04 to −0.07 for thalamus, accumbens, and hippocampus). Compared to current intermediate sleep, current short sleep was associated with smaller cortex volumes (−0.03 [-0.05, −0.01]), greater white matter hyperintensities (WMH) volumes (0.04 [0.01, 0.08]), and lower regional FA (−0.07 [-0.11, −0.02]). However, current long sleep was related to smaller total brain (−0.03 [-0.05, −0.02]), grey matter (−0.05 [-0.07, −0.03]), cortex (−0.05 [-0.07, −0.03]), regional subcortical volumes [standardized β: −0.05 to −0.09 for putamen, thalamus, hippocampus, and accumbens]), greater WMH volumes (0.06 [0.03, 0.09]), as well as lower regional FA (−0.05 [-0.09, −0.02]). The association between current long sleep duration and poor brain health was stronger among people with hypertension or low frequency of social activity (all Pinteraction <0.05). ConclusionsBoth past and current short/long sleep are associated with smaller brain volume and poorer white matter health in the brain, especially in individuals with hypertension and low frequency of social activity. Our findings highlight the need to maintain 6–8 h’ sleep duration for healthy brain aging.

Association of white matter hyperintensities with BMD, incident fractures, and falls in the UK Biobank cohort.

Osteoporosis is the most common metabolic bone disease globally, which increases the healthcare service burden. Recent studies have linked higher white matter hyperintensities (WMH) to reduced BMD, increasing the risk of fractures and falls in older adults. However, limited evidence exists regarding the dose-response relationship between WMH and bone health in a larger and younger population. Our study aimed to examine the association of WMH volume with BMD, incident fractures and falls, focusing on dose-response relationship with varying levels of WMH volume. We included 26 410 participants from the UK Biobank. The association between WMH volume and BMD was analyzed using multiple linear regression. Cox regression models were used to estimate the hazard ratios of incident fractures and falls. Restricted cubic spline (RCS) fitted for linear and Cox regression models were employed to explore potential non-linearity. Over a mean follow-up time of 3.8yr, we documented 59 hip fractures, 392 all fractures, and 375 fall incidents. When applying RCS, L-shaped relationships were identified between WMH volume and BMD across all 4 sites. Compared with those in the lowest fifth of WMH volume, individuals in the second to the highest fifths were associated with a reduction of 0.0102-0.0305g/cm2 in femur neck BMD, 0.0075-0.0273g/cm2 in femur troch BMD, 0.0173-0.0345g/cm2 in LS BMD, and 0.0141-0.0339g/cm2 in total body BMD. The association was more pronounced among women and younger participants under age 65 (Pinteraction < .05). Per 1 SD increment of WMH volume was associated with 36.9%, 20.1%, and 14.3% higher risks of incident hip fractures, all fractures, and falls. Genetically determined WMH or apolipoprotein E genotypes did not modify these associations. We demonstrated that a greater WMH was associated with BMD in an L-shaped dose-response manner, especially in women and those under 65yr.

NEIGHBORHOOD DISADVANTAGE, IMAGING BIOMARKERS OF ALZHEIMER’S DISEASE, AND COGNITION IN DIVERSE OLDER ADULTS

Abstract Neuroimaging biomarkers of Alzheimer’s disease (AD) are well-validated in White populations. However, it remains unclear how these biomarkers are associated with cognition in non-White populations disproportionately affected by systemic socioeconomic discrimination. We investigated whether neighborhood disadvantage modifies associations of neuroimaging biomarkers with cognition in a diverse cohort of 198 adults ≥50 years, 50% of whom are Black. Outcomes included cognitive impairment and neuropsychological test scores. Predictors were indices of neurodegeneration, vascular damage, and brain amyloid burden, quantified using MR-based measures of cortical thickness and white matter hyperintensities (WMH) and [11C]PiB PET, respectively. We measured neighborhood disadvantage using area deprivation index (ADI), a composite measurement of socioeconomic conditions in a census tract. In linear models, higher ADI, neurodegeneration, and WMH were separately associated with worse cognition. We found an ADI*neurodegeneration interaction on delayed recall memory (p=0.08). Neurodegeneration-positive participants had worse story delayed recall compared to neurodegeneration-negative regardless of ADI (β=-1.57, p=0.01). In neurodegeneration-negative participants, higher ADI is associated with worse delayed recall (β=-0.04, p=0.004): those with a high ADI exhibited low delayed recall, comparable to neurodegeneration-positive participants. ADI was not associated with cognition in neurodegeneration-positive participants. WMH and ADI interacted in models of impairment, visual memory, and visual copy (interaction p’s&amp;lt; 0.10). In those with high ADI, greater WMH was associated with worse cognition (β=-0.30, p=0.02) while participants with low ADI scored well regardless of WMH volume. Taken together, the relationship between neuroimaging biomarkers and cognition differs by neighborhood socioeconomic conditions, highlighting the need for clinical strategies that acknowledge structural disadvantage.

Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with greater WMH more than a decade later in the KEEPS Continuation

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p = 0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p&lt;0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with greater WMH more than a decade later in the KEEPS Continuation

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p&lt;0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

Serum Arachidonic Acid Oxylipins Indicate Small Vessel Injury And the Related Executive Function Decline In Stroke Patients

AbstractBackgroundCerebral small vessel disease (SVD) frequently co‐occurs with other neurodegenerative pathologies and collectively lead to cognitive deficits. Previously, we found that the ratios of soluble epoxide hydrolase (sEH)‐ derived diols to the parent epoxides (generated by CYP2J/2Cs) linoleic acids were associated with greater white matter hyperintensities (WMH) and poorer executive function in patients with transient ischemic attack. However, the associations with the diol and epoxide species derived from arachidonic acid (AA) have not been explored.MethodsThe study cohort is comprised of 159 stroke patients (mean age = 69.2, 32.1% female) from the Ontario Neurodegenerative Degenerative Research Initiative. EpETrEs (AA epoxides) and DiHETrEs (AA diols) were quantified by a targeted ultrahigh pressure liquid chromatography mass spectrometry (UPLC‐MS/MS). Executive function was assessed using a composite score that included Digit Symbol Substitution Test (DSST), Trial‐Making Test Part B, Stroop Color‐Word Interference Test, and FAS Verbal Fluency Test. WMHs were quantified from T2‐Fluid‐Attenuated‐Inversion‐Recovery MRI through Lesion Explorer (https://imaging.brainlab.ca/lesion‐explorer.html).In linear models controlling for age, sex, education or age, sex, glucose, cholesterol, and waist circumferences were used for cognitive and imaging out comes, respectively.Results11(12)‐EpETrE was found to be associated with less WHM (ρ = ‐0.175, p = 0.040) and better executive function (ρ = 0.166, p = 0.039). In a sub‐cohort of patients with small vessel stroke (n = 50), the relationship between WMH and 11(12)‐EpETrE became stronger (ρ = ‐0.390, p = 0.014). 14(15)‐EpETrE was also associated with less WMH (ρ = ‐0.416, p = 0.009). Similar relationships were not seen with the diols or diol to epoxide ratios.ConclusionsOxylipins derived from sEH activity may be potential biomarkers of vascular cognitive impairment and small vessel disease in stroke patients.

Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values&gt;0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082

Subjective cognitive complaints in White and African American older adults: associations with demographic, mood, cognitive, and neuroimaging features

ABSTRACT Subjective cognitive complaints (SCC) in cognitively intact older adults have been investigated as a clinically important symptom that may portend the onset of a neurodegenerative disorder such as Alzheimer’s disease. Few studies have concurrently incorporated demographic features, depressive symptoms, neuropsychological status, and neuroimaging correlates of SCC and evaluated whether these differ in White and African American older adults. In the current study, 131 (77 White, 54 African American) healthy participants ≥50 years old completed the Cognitive Function Instrument (CFI) to assess SCC, and they underwent objective cognitive testing, assessment of mood, and brain magnetic resonance imaging. Pearson Product Moment correlations were performed to evaluate associations of the CFI self-ratings with the above measures for the combined group and separately for White and African American participants. SCC were associated with greater depressive symptoms in both White and African American participants in adjusted models controlling for overall cognitive status, education, and hypertension. Greater white matter hyperintensities, lower cortical thickness, older age, and slower set shifting speed were associated with increased SCC in White participants. Although the correlations were not significant for African Americans, the strength of the associations were comparable to White participants. Hippocampal volume was not associated with either total SCC or items specific to memory functioning in the entire group. Longitudinal studies are needed to further evaluate the clinical significance of these associations with risk of conversion to mild cognitive impairment and dementia.

Premature Cardiovascular Disease and Brain Health in Midlife: The CARDIA Study.

To understand the role of premature (defined as ≤ 60 years) cardiovascular disease (CVD) in brain health earlier in life, we examined the associations of premature CVD with midlife cognition and white matter health. We studied a prospective cohort in the Coronary Artery Risk Development in Young Adults study, who were 18-30 years at baseline (1985-1986) and followed up to 30 years when 5 cognitive tests measuring different domains were administered. A subset (656 participants) had brain MRI measures of white matter hyperintensity (WMH) and white matter integrity. A premature CVD event was adjudicated based on medical records of coronary heart disease, stroke/TIA, congestive heart failure, carotid artery disease, and peripheral artery disease. We conducted linear regression to determine the associations of nonfatal premature CVD with cognitive performance (z-standardized), cognitive decline, and MRI measures. Among 3,146 participants, the mean age (57% women and 48% Black) was 55.1 ± 3.6 years, with 5% (n = 147) having premature CVD. Adjusting for demographics, education, literacy, income, depressive symptoms, physical activity, diet, and APOE, premature CVD was associated with lower cognition in 4 of 5 domains: global cognition (-0.22, 95% CI -0.37 to -0.08), verbal memory (-0.28, 95% CI -0.44 to -0.12), processing speed (-0.46, 95% CI -0.62 to -0.31), and executive function (-0.38, 95% CI -0.55 to -0.22). Premature CVD was associated with greater WMH (total, temporal, and parietal lobes) and higher white matter mean diffusivity (total and temporal lobes) after adjustment for covariates. These associations remained significant after adjusting for cardiovascular risk factors (CVRFs) and excluding those with stroke/TIA. Premature CVD was also associated with accelerated cognitive decline over 5 years (adjusted OR 3.07, 95% CI 1.65-5.71). Premature CVD is associated with worse midlife cognition and white matter health, which is not entirely driven by stroke/TIA and even independent of CVRFs. Preventing CVD in early adulthood may delay the onset of cognitive decline and promote brain health over the life course.

Evaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8, and Their Binding Proteins Follistatin and Follistatin-Like Protein-3 With Dementia and Cognition.

Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models. We assessed growth differentiation factors (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in the Cardiovascular Health Study (CHS; N = 1 506) and the Health, Aging and Body Composition (Health ABC) Study (N = 1 237). CLL-11 and beta-2 microglobulin (β2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only), and incident dementia using correlations, linear regression, and Cox proportional hazards models. In CHS, levels of GDF-11, GDF-8, and follistatin were not correlated cross-sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy, or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities, and atrophy on MRI, as well as with incident dementia with an adjusted hazard ratio (HR) of 1.72 (95% CI = 1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95% CI = 1.07, 2.10) per doubling of GDF-8. Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicate TGFβ superfamily inhibition in the pathogenesis of dementia.

Amyloid, tau, cerebrovascular disease, neurodegeneration, and cognition in middle‐aged adults from a racially and ethnically diverse, community‐based study

AbstractBackgroundAlzheimer’s disease (AD) pathophysiology (i.e., amyloid‐induced tau) and cerebrovascular disease drive neurodegeneration and cognitive impairment. Our objective was to investigate moderation and mediation pathways among amyloid PET, tau PET, vascular MRI, and structural MRI in a middle‐aged, racially and ethnically diverse sample.MethodsIn an ongoing study, participants (n=63; 61±6 years old, 68% women, 13±4 years of education, 12% Non‐Latinx White/25% Non‐Latinx Black/63% Latinx) underwent amyloid PET (weighted average Florbetaben SUVR in Thaal phase regions), tau PET (average MK‐6240 SUVR in Braak stage I), vascular MRI (white matter hyperintensity (WMH) volume), and structural MRI (AD‐signature cortical thickness) in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease. Serial parallel mediation was used to assess two pathways from age to neurodegeneration (i.e., age to amyloid to tau to neurodegeneration; age to WMH to tau to neurodegeneration).ResultsOlder age was associated with greater amyloid (7E‐3 [3E‐3, 0.01], p=0.001), which was in turn trend level associated with greater tau (0.55 [‐0.1, 1.2], p=0.09); tau was not associated with cortical thickness (‐6E‐3 [‐0.09, 0.08], p=0.88). The total indirect effect of this amyloid pathway was not significant (‐2E‐5 [‐3E‐4, 3E‐4], p=0.88). Older age was associated with greater WMH (0.01 [2E‐4, 0.02], p=0.048), but WMH was not associated with tau (0.01 [‐0.20, 0.22], p=0.91) or cortical thickness (‐8E‐3 [‐0.08, 0.06], p=0.82). The total indirect effect of this vascular pathway was not significant (‐9E‐7 [‐2E‐5, 2E‐5], p=0.93). The direct effect from age to neurodegeneration, given both indirect pathways, was significant (‐5E‐3 [‐9E‐3, ‐1E‐3], p=0.005).ConclusionsIn midlife, there is evidence of age‐related increases in cerebrovascular disease and amyloid‐induced tau, but the two pathways do not have an effect on neurodegeneration in this age group. Older age is the strongest predictor of neurodegeneration, but AD and cerebrovascular pathology may become stronger predictors later in the AD continuum.

Testing the Association Between Neighborhood Disadvantage and White Matter Hyperintensities

AbstractBackgroundSocial determinants of health—the conditions in the places where people live, learn, work, and play—have been shown to affect a broad range of health outcomes, including risk for Alzheimer’s disease and related dementias (ADRD). However, the biological mechanisms by which socio‐contextual factors increase risk for ADRD are poorly known. Higher levels of neighborhood disadvantage have been linked with increased cardiovascular disease (CVD) risk. CVD risk has been associated with white matter lesions known as white matter hyperintensities (WMH) because they produce increased signal on fluid‐attenuated inversion recovery (FLAIR) MRI scans. WMH have been associated with increased risk for stroke, cognitive decline, and dementia. We investigated whether greater neighborhood‐level disadvantage was associated with greater WMH volume.MethodParticipants (n = 804) were enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center Clinical Core. MRI was performed at 3 T to acquire T2‐weighted FLAIR images which were then processed using the lesion prediction algorithm from the Lesion Segmentation Toolbox to measure WMH volume. Area Deprivation Index (ADI) distributions from the state of Wisconsin were used to create a dichotomous variable that compared the highest state‐ranked quintile (most disadvantaged neighborhoods) to the lowest 4 state‐ranked quintiles (least disadvantaged neighborhoods). Multiple linear regression tested ADI as a predictor of natural log‐transformed WMH volume. Age, sex, education, intracranial volume, MRI head coil, and study cohort were controlled.ResultFour percent (n = 33) of participants were identified as living in the most disadvantaged neighborhoods (see Table 1). The association between neighborhood‐level disadvantage and log‐transformed WMH volume was not statistically significant (see Table 2 and Figure 1).ConclusionNeighborhood disadvantage was not related to WMH volume in this study. This finding contrasts with previous studies demonstrating associations between increased neighborhood disadvantage and reduced cerebral and hippocampal volume (Hunt et al., 2020) and increased odds for AD neuropathology (Powell et al., 2020). Statistical power to assess the primary effect was likely limited by the small number of participants from the most disadvantaged neighborhoods. This illustrates the need for additional research and increased population‐representative recruitment from disadvantaged contexts for ADRD research studies.

Cardiorespiratory fitness attenuates the deleterious effects of sleep apnea on cerebral structure, perfusion, and risk of Alzheimer’s disease in the Wisconsin Sleep Cohort study

AbstractBackgroundEmerging evidence suggests that age‐related changes in cerebral structure and perfusion—hallmark features of preclinical Alzheimer’s disease (AD)—may be sensitive to vascular risk modifiers such as physical exercise and sleep quality. Here, we examine whether cardiorespiratory fitness modifies the effects of obstructive sleep apnea (OSA) on cerebral structure, perfusion, and AD risk.MethodUsing data from a sample of participants (n=134 for analyses of imaging outcomes and n=1,182 for analyses examining AD outcomes) in the Wisconsin Sleep Cohort (WSC) study, we examined cross‐sectional associations between OSA severity, estimated cardiorespiratory fitness (eCRF), and their interaction with MRI‐assessed total and regional gray (GM) and white matter (WM) volumes, WM hyperintensities (WMHs), total lesion volume, and arterial spin labeling cerebral blood flow (CBF), using multiple linear regression models adjusted for age, sex, BMI, hypertension, and education level. We further assessed whether eCRF modifies the associations between OSA and risk of AD using Cox proportional hazard models.ResultOSA severity was associated with greater total lesion volume, reduced total GM volume, and greater WMHs among less‐fit, but not among more‐fit, subjects. Perfusion models likewise revealed significant regional differences in CBF between fitness groups. OSA severity was likewise associated with greater risk of AD among less‐fit individuals, but there was no significant association among the more‐fit.ConclusionThis work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging and AD.

Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging

Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50–89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.

Blunted Cerebrovascular Resistance In Response To Isometric Handgrip Exercise Is Associated With Greater White Matter Hyperintensities In Middle-aged And Older Adults

Blunted Cerebrovascular Resistance In Response To Isometric Handgrip Exercise Is Associated With Greater White Matter Hyperintensities In Middle-aged And Older Adults

White matter hyperintensities in former American football players.

The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. In older former football players, WMH may have unique presentations, risk factors, and etiologies. Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

Regional white matter hyperintensities in posterior cortical atrophy and logopenic progressive aphasia

White matter hyperintensities (WMH) are markers of cerebral small vessel disease and are associated with higher risk of typical amnestic Alzheimer's disease (tAD). Little is known about the frequency and distribution of WMH in atypical variants of AD, including logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). We investigated WMHs in 75 LPA, 39 PCA, and 50 tAD patients and associations with age, beta-amyloid PET burden, and cognition. PCA had greater subcortical WMHs in right occipital, parietal, and temporal lobes compared to LPA, and greater parieto-occipital subcortical and occipital periventricular WMHs than tAD. LPA had greater subcortical WMHs in left parietal lobe and deep white matter WMHs than PCA, and greater fronto-occipital subcortical and occipital periventricular WMHs than tAD. Total WMH increased with increasing age but was not related to beta-amyloid burden. Greater WMH was associated with visuoperceptual performance in LPA and PCA after correcting for atrophy. WMH topography differs across AD variants. Further work is needed to determine whether they reflect cerebrovascular disease or regionally specific neurodegenerative changes.

Association of Carotid Intima-Media Thickness with Brain MRI Markers in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

ObjectiveElevated carotid intima-media thickness (cIMT) and carotid plaque are markers of arterial injury and may be linked to structural brain injury. We hypothesized cIMT or presence of carotid plaque at midlife are associated with presence of infarcts and cerebral microbleeds, greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late-life. MethodsWe included 1,795 Atherosclerosis Risk in Communities (ARIC) Study participants (aged 57±6 years, 57% female, 23% Black) with carotid ultrasounds in 1990-1992 and brain MRI scans in 2011-2013. Weighted linear regression was used for brain volume outcomes, while logistic regression was used for infarcts and cerebral microbleeds. ResultsAfter multivariable adjustments, the highest cIMT quintile was associated with smaller deep gray matter (β [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (β [95% CI]: -0.10 [-0.20, -0.01]) in late-life. Similarly, those with carotid plaque had smaller regional brain volumes than those without (βs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep gray matter and temporal-parietal meta ROI). No significant relations were observed with WMH volume, infarcts, or cerebral microbleeds. ConclusionOver a median follow-up of 21 years, greater midlife cIMT and presence of carotid plaque were associated with smaller deep gray matter volume and cortical volume in a meta ROI involving temporal and parietal lobe regions typically involved in neurodegeneration, including Alzheimer's disease, in later life. Contrary to our hypothesis, associations between measures of arterial injury and markers of vascular brain injury were null.

Vascular risk profile and white matter hyperintensity volume among Mexican Americans and non-Hispanic Whites: The HABLE study.

IntroductionAmong vascular risk factors we hypothesized that an increased prevalence of diabetes in Hispanics would be associated with greater white matter hyperintensity (WMH) volume, which may contribute to cognitive decline.MethodsA total of 1318 participants (60% female; 49% Hispanic, 51% non‐Hispanic White; age 66.2 ± 8.9 years) underwent clinical evaluation and brain magnetic resonance imaging (MRI). WMH volume associations were assessed with age, sex, and ethnicity and then with vascular risk factors in a selective regression model.ResultsWMH volume was greater with older age (P < .0001), Hispanic ethnicity (P = .02), and female sex (P = .049). WMH volume was best predicted by age, diastolic blood pressure, hypertension history, hemoglobin A1c (HbA1c), white blood cell count, and hematocrit (P < .01 for all). Elevated HbA1c was associated with greater WMH volume among Hispanics (parameter estimate 0.08 ± 0.02, P < .0001) but not non‐Hispanic Whites (parameter estimate 0.02 ± 0.04, P = .5).DiscussionWMH volume was greater in Hispanics, which may be partly explained by increased WMH volume related to elevated HbA1c among Hispanics but not non‐Hispanic Whites.

A link between frontal white matter integrity and dizziness in cerebral small vessel disease

One in three older people (>60 years) complain of dizziness which often remains unexplained despite specialist assessment. We investigated if dizziness was associated with vascular injury to white matter tracts relevant to balance or vestibular self-motion perception in sporadic cerebral small vessel disease (age-related microangiopathy). We prospectively recruited 38 vestibular clinic patients with idiopathic (unexplained) dizziness and 36 age-matched asymptomatic controls who underwent clinical, cognitive, balance, gait and vestibular assessments, and structural and diffusion brain MRI. Patients had more vascular risk factors, worse balance, worse executive cognitive function, and worse ankle vibration thresholds in association with greater white matter hyperintensity in frontal deep white matter, and lower fractional anisotropy in the genu of the corpus callosum and the right inferior longitudinal fasciculus. A large bihemispheric white matter network had less structural connectivity in patients. Reflex and perceptual vestibular function was similar in patients and controls. Our results suggest cerebral small vessel disease is involved in the genesis of dizziness through its effect on balance.