Greater White Matter Hyperintensity Volume Research Articles

White matter hyperintensity volume (WMHV) association with APOE e4 carriers and non-carriers (P11-5.005)

<h3>Objective:</h3> Determine whether white matter hyper-intensity volume (WMHV) differs with APOE4 carriage. <h3>Background:</h3> Apolipoprotein E4 (APOE4) allele is associated with an increased risk for both Alzheimer’s Disease (AD) and cardiovascular disease (CVD). APOE4 association with WMHV (a measure of small vessel vasculopathy) is ambiguous. While APOE4 carriage is associated with greater AD pathology, it remains unclear whether cerebrovascular damage is also associated with APOE4 carriage. The aim of this meta-analysis is to determine whether WMHV is associated with APOE carrier status. <h3>Design/Methods:</h3> 12 studies from Pubmed and EMBASE were found where data for sample size, age, WMHV, study setting, and WMHV quantification method were extracted from each article. Random effect models were used to estimate raw and standardized mean differences for WMHV in APOE4 carriers and non-carriers in addition to subgroup analyses (clinic and community). Analyses were carried out using the ‘metacont’ function in the ‘meta’ package in R 4.0.3. <h3>Results:</h3> The 12 studies yielded a total sample size of 16,738 (e4 carrier n=4,721; e4 non-carrier n=12,017) with an average age of 69.72 years. The primary analysis found no significant difference in WMHV between e4 carriers and non-carriers (95% CI (−0.01, 0.15), p = 0.09) with a moderate level between-study heterogeneity (I2 = 64%, 95% CI (33%, 81%). Subgroup analyses showed a small effect size indicating that APOE4 carriers had a greater WMHV (n = 8, 95% CI (0.02, 0.16), p = 0.008) with moderate heterogeneity (I2 = 55%, 95% CI (1%, 80%). No significant difference in WMHV by APOE4 status was noted among clinic-based studies (n = 3, 95% CI (−0.60, 0.41), p = 0.70). <h3>Conclusions:</h3> Our findings show an insignificant difference in WMHV between APOE4 carriers and non-carriers. However, utilized community-based samples showed that WMHV was greater in e4 carriers. This suggests that non-APOE factors have a greater influence on WMHV. <b>Disclosure:</b> Mr. Stipho has nothing to disclose. Mr. Stipho has nothing to disclose. Michael Ahmadi has nothing to disclose.

Carotid intima media thickness and white matter hyperintensity volume among midlife women.

Carotid atherosclerosis may be associated with brain white matter hyperintensities (WMH). Few studies consider women at midlife, a critical time for women's cardiovascular and brain health. We tested the hypothesis that higher carotid intima media thickness (IMT) would be associated with greater WMH volume (WMHV) among midlife women. We explored interactions by apolipoprotein E (APOE) ε4 status. Two hundred thirty-nine women aged 45 to 67 underwent carotid artery ultrasound, phlebotomy, and magnetic resonance imaging (MRI). One hundred seventy participants had undergone an ultrasound 5 years earlier. Higher IMT was associated with greater whole brain (B[standard error (SE)]=0.77 [.31], P=0.01; multivariable) and periventricular (B[SE]=0.80 [.30], P=0.008; multivariable) WMHV. Associations were observed for IMT assessed contemporaneously with the MRI and 5 years prior to the MRI. Associations were strongest for APOE ε4-positive women. Among midlife women, higher IMT was associated with greater WMHV. Vascular risk is critical to midlife brain health, particularly for APOE ε4-positive women.

Premature Cardiovascular Disease and Brain Health in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

AbstractBackgroundCardiovascular disease (CVD) is associated with cognitive impairment and dementia risk in late life, yet little is known about the role of premature (defined younger than 60 years) CVD events with cognition and brain health earlier in the life course, including in midlife. As part of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, we investigated the association of premature CVD events in young and middle adulthood with cognition and white‐matter health in midlife.MethodsWe studied 3,146 Black and White participants (57% women, 48% Black) aged 18‐30 years at baseline (1985‐86) who were followed up to Year 30 (mean age 55.1±3.6 years) when 5 cognitive tests measuring different domains were administered. A subset (656 participants) had brain MRI with measures of white matter hyperintensity (WMH) burden and white matter integrity. Premature CVD events were adjudicated based on participants' history and medical records of coronary heart disease, stroke/TIA, cardiac revascularization, congestive heart failure, carotid artery disease, and peripheral artery disease. We conducted linear regression to determine the association of premature CVD with cognitive and structural brain measures.ResultsFive percent (n = 147) of participants had premature CVD events over the 30 years. Having premature CVD events was associated with lower cognitive function in all domains. After adjustment for demographics, education, depressive symptoms, physical activity, diet, APOE ε4, and cardiovascular risk factors (CVRFs), premature CVD was associated with lower cognition (z‐standardized) except for verbal fluency: global cognition (‐0.19, 95% CI ‐0.35 to ‐0.03), verbal memory (‐0.24, 95% CI ‐0.41 to ‐0.07), processing speed (‐0.46, 95% CI ‐0.63 to ‐0.30), and executive function (‐0.38, 95% CI ‐0.56 to ‐0.20). Premature CVD was also associated with greater WMH volumes (total, frontal, temporal, and parietal lobes) and alternations of white matter integrity (higher total and temporal lobe mean diffusivity and lower parietal lobe fractional anisotropy) after adjusting for demographics, total intracranial volume, and CVRFs.ConclusionPremature CVD is associated with worse midlife cognition and white‐matter health independent of CVRFs. Young and middle adulthood is a critical time for CVD prevention, the efforts of which may delay the onset of cognitive decline and dementia later in life.

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.

Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study

Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR. Cross-sectional study nested in a cohort study. 1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study. Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or β2-microglobulin (B2M). Brain volume reduction, infarcts, microhemorrhages, white matter lesions. Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value. Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient:-0.07 [95% CI,-0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient:-0.08 [95% CI,-0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex. No inference about longitudinal effects due to cross-sectional design. We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

Anosmia, mild cognitive impairment, and biomarkers of brain aging in older adults.

Olfactory impairment is a potential marker for prodromal dementia, but the underlying mechanisms are poorly understood. This population-based study included 4214 dementia-free participants (age ≥65 years). Olfaction was assessed using the 16-item Sniffin' Sticks identification test. In the subsamples, we measured plasma amyloid beta (Aβ)40, Aβ42, total tau, and neurofilament light chain (NfL; n = 1054); and quantified hippocampal, entorhinal cortex, and white matter hyperintensity (WMH) volumes, and Alzheimer's disease (AD)-signature cortical thickness (n = 917). Data were analyzed with logistic and linear regression models. In the total sample, mild cognitive impairment (MCI) was diagnosed in 1102 persons (26.2%; amnestic MCI, n = 931; non-amnestic MCI, n = 171). Olfactory impairment was significantly associated with increased likelihoods of MCI, amnestic MCI, and non-amnestic MCI. In the subsamples, anosmia was significantly associated with higher plasma total tau and NfL concentrations, smaller hippocampal and entorhinal cortex volumes, and greater WMH volume, and marginally with lower AD-signature cortical thickness. These results suggest that cerebral neurodegenerative and microvascular lesions are common neuropathologies linking anosmia with MCI in older adults.

Associations Between Handgrip Strength and Dementia Risk, Cognition, and Neuroimaging Outcomes in the UK Biobank Cohort Study

The associations between muscle strength and cognitive outcomes have sparked interest in interventions that increase muscle strength for prevention of dementia, but the associations between muscle strength and cognitive aging are unclear, particularly among middle-aged adults. To evaluate the association between handgrip strength (HGS) and dementia, reduced cognition, and poorer neuroimaging outcomes in a UK population of middle-aged adults. This cohort study evaluated UK Biobank participants aged 39 to 73 years enrolled from 2006 to 2010 with measured HGS and prospectively followed up for dementia diagnosis. Data were analyzed from October 2021 to April 2022. HGS assessed in both hands via dynamometer. Outcomes included cognitive test scores (fluid intelligence and prospective memory), brain magnetic resonance imaging measures (total brain volume, white matter hyperintensity, and hippocampal volume), and incident dementia (all-cause, vascular, and Alzheimer disease [AD] from primary care, hospital, or death records) over a median (IQR) of 11.7 (11.0-12.4) years of follow-up. Mixed-effects linear and logistic regressions and Cox proportional-hazard models were used to estimate associations, stratified by gender and adjusted for covariates. Estimates are presented per 5-kg decrement in HGS. To evaluate reverse causation, we assessed whether a polygenic risk score for AD is associated with HGS. A subsample of 190 406 adult participants in the UK Biobank (mean [SD] age, 56.5 [8.1] years; 102 735 women [54%]) were evaluated. A 5-kg decrement in HGS was associated with lower fluid intelligence scores in men (β, -0.007; 95% CI, -0.010 to -0.003) and women (β, -0.04; 95% CI, -0.05 to -0.04. A 5-kg decrement in HGS was associated with worse odds of correctly responding to a prospective memory task for men (odds ratio, 0.91; 95% CI, 0.90 to 0.92) and women (odds ratio, 0.88; 95% CI, 0.87 to 0.90). A 5-kg decrement in HGS was associated with greater white matter hyperintensity volume in men (β, 92.22; 95% CI, 31.09 to 153.35) and women (β, 83.56; 95% CI, 13.54 to 153.58). A 5-kg decrement in HGS was associated with incident dementia for men (hazard ratio, 1.20; 95% CI, 1.12 to 1.28) and women (hazard ratio, 1.12; 95% CI, 1.00 to 1.26). The AD genetic risk score was not significantly associated with HGS. These findings suggest that HGS is associated with measures of neurocognitive brain health among men and women and they add to a growing body of research indicating that interventions designed to increase muscle strength, particularly among middle-aged adults, may hold promise for the maintenance of neurocognitive brain health.

Physical Frailty and Brain White Matter Abnormalities: The Atherosclerosis Risk in Communities Study.

Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline. In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

Relations of Metabolic Health and Obesity to Brain Aging in Young to Middle-Aged Adults.

BackgroundWe aimed to evaluate the association between metabolic health and obesity and brain health measured via magnetic resonance imaging and neurocognitive testing in community dwelling adults.Methods and ResultsFramingham Heart Study Third Generation Cohort members (n=2170, 46±9 years of age, 54% women) without prevalent diabetes, stroke, dementia, or other neurologic conditions were grouped by metabolic unhealthiness (≥2 criteria for metabolic syndrome) and obesity (body mass index ≥30 kg/m2): metabolically healthy (MH) nonobese, MH obese, metabolically unhealthy (MU) nonobese, and MU obese. We evaluated the relationships of these groups with brain structure (magnetic resonance imaging) and function (neurocognitive tests). In multivariable‐adjusted analyses, metabolically unhealthy individuals (MU nonobese and MU obese) had lower total cerebral brain volume compared with the MH nonobese referent group (both P<0.05). Additionally, the MU obese group had greater white matter hyperintensity volume (P=0.004), whereas no association was noted between white matter hyperintensity volume and either groups of metabolic health or obesity alone. Obese individuals had less favorable cognitive scores: MH obese had lower scores on global cognition, Logical Memory‐Delayed Recall and Similarities tests, and MU obese had lower scores on Similarities and Visual Reproductions‐Delayed tests (all P≤0.04). MU and obese groups had higher free water content and lower fractional anisotropy in several brain regions, consistent with loss of white matter integrity.ConclusionsIn this cross‐sectional cohort study of younger to middle‐aged adults, poor metabolic health and obesity were associated with structural and functional evidence of brain aging. Improvement in metabolic health and obesity may present opportunities to improve long‐term brain health.

Diastolic Blood Pressure Variability in Later Life May Be a Key Risk Marker for Cognitive Decline.

There is an increasing awareness of the need to understand the interaction between long-term blood pressure patterns and their impact on the brain and cognition. Our aim was to investigate the relationship between repeated blood pressure measures and change in cognitive performance over 12 years and imaging data at 12 years using a longitudinal population study. The data consisted of 2 cohorts, one midlife and one later life. Using linear regression, we examined the relationship between blood pressure (systolic, diastolic, change in blood pressure between visits, and visit-to-visit variability), change in cognitive performance and imaging at 12 years. Data on cognitive change were available in 1054 at midlife, baseline age 42.7 (SD 1.5) and 1233 in later life, 62.5 (1.5) years. Imaging data were available in 168 and 233, respectively. After adjustment for multiple comparisons greater diastolic blood pressure variability in later life was associated with a -1.95 point decline (95% CI, -2.89 to -1.01) on an attention-based task and a -0.42 point (95% CI, -0.68 to -0.15) decline in performance on a psychomotor task. A higher SD in diastolic pressure across follow-up was associated with greater white matter hyperintensity volume (%increase per 10 mm Hg increase in the SD [1.50 (95% CI, 1.16-1.94]). In a largely normotensive/mildly hypertensive population, our analyses reported no relationships between blood pressure and cognition in midlife but a potential role for diastolic blood pressure variability in later life as a risk marker for cognitive decline. This may indicate an at-risk period or a means to identify an at-risk population at the age where diastolic pressure is starting to decline.

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.

White matter hyperintensities and regional tau‐PET signal independently contribute to cognitive deficits in symptomatic patients on the Alzheimer’s disease continuum

AbstractBackgroundWe examined the associations of white matter hyperintensities (WMH), amyloid‐PET, and tau‐PET with multi‐domain cognitive performance in symptomatic patients on the Alzheimer’s disease (AD) continuum.Method119 amyloid‐PET‐positive patients diagnosed with MCI or AD dementia underwent 3‐Tesla structural MRI, 18F‐flortaucipir (tau)‐PET,11C‐PIB (amyloid)‐PET, and neuropsychological assessment. Standardized uptake value ratio (SUVR) flortaucipir‐ and PIB‐PET images were created using tracer‐specific reference regions and warped to template space. Patients were split based on availability of FLAIR‐MRI (Figure 1). The exploratory sample (n=50; no FLAIR) was used to run voxelwise models to identify regions where flortaucipir‐ and PIB‐PET were associated with episodic memory, executive, language, semantic memory, and visuospatial composite scores. In the validation sample (n=69), WMH were segmented from FLAIR and T1‐MRIs using a two‐step supervised algorithm. Linear regression models assessed the independent contributions of global WMH volume (corrected for intracranial volume and log‐transformed) and cognitive domain‐specific regional PET‐SUVR (derived in the exploratory sample) to each cognitive domain.ResultThe two samples had comparable demographics and clinical characteristics, with relatively young age (mean ∼65.5) and moderate impairment (mean MMSE ∼ 22, Table 1). In the exploratory sample, cognitive scores were associated with regional flortaucipir‐SUVR patterns (Figure 2); PIB‐SUVR was not robustly associated with cognition. In the validation sample, global WMH volume was inversely correlated with global PIB‐SUVR (r=‐.25, p=.04) but not global cortical flortaucipir‐SUVR (r=‐.18, p=.15). Older age predicted lower cortical flortaucipir‐SUVR (r=‐.70, p&lt;.001) and greater WMH volume (r=.46, p&lt;.001). Female sex was specifically associated with greater cortical flortaucipir‐SUVR (d=0.64, p=.01; psdsps ConclusionIn patients at the early clinical stages of AD, tau‐PET and global WMH volume were not associated with each other, but independently contributed to cognitive impairment. These findings emphasize the clinical relevance of cerebrovascular injury in the context of AD pathology, even in younger patients.

Comparison of white matter hyperintensity abnormalities and cognitive performance in individuals with low and high cardiovascular risk: Data from the Diabetes and Dementia (D2) study

AbstractBackgroundType 2 diabetes Mellitus (T2DM) is recognised as a major contributor to cognitive decline. People with T2DM demonstrate increased white matter hyperintensity (WMH) abnormalities on MRI compared to control individuals. We investigated associations between a validated vascular risk score: The Framingham Risk Score (FRS), WMH volumes and cognitive function in the Diabetes‐and‐Dementia (D2) study, a longitudinal cohort study of community dwelling people with T2DM.MethodOne hundred and twenty‐three non‐demented participants with T2DM (age 66.7±6.8 years, range 50‐80, 68M/55F) completed neuropsychological assessments, health questionnaires to allow FRS calculation, 24‐hour ambulatory blood pressure monitoring, and a 3T‐MRI scan. WMH were calculated using the functionality "run‐samseg" in FreeSurfer 7. Quality control on the traced lesions was performed using an in‐house semi‐automated MATLAB tool. Periventricular and deep WMH volumes were estimated based on the edited lesion traces. We divided participants into low (n=61) and high (n=62) FRS groups based on the median score (x=48.7). Differences in WMH volumes were compared between the FRS groups after correcting for sex and age. We compared cognitive performance between low/high FRS individuals across five composite cognitive domains: memory, language, visuospatial skills, executive function, and attention‐and‐processing‐speed. The composite score for each domain was the normalised z‐scores average for the respective tests.ResultParticipants with high FRS (implicating greater vascular risk) were significantly older (age F(1, 122)=14.97; p&lt;0.001), were less likely to be female (sex χ2=16.73, p&lt;0.001), and tend to have less than 12 years of education (χ2= 3.69, p = 0.041). Relative to individuals with low FRS, those with high FRS showed significantly higher WMH volumes (F(1, 121)=6.11; p=0.015). Significant differences were also identified for periventricular (F(1, 121)=6.16; p=0.014) and deep (F(1, 121)=4.25; p=0.042) WMH volumes. When the cognitive data were analysed, the low FRS group performed signifcantly better than the high FRS group only on the attention‐and‐processing‐speed factor (F(1,115)=5.17; p=0.025).ConclusionHigh cardiovascular risk, defined as a high FRS, in participants with T2DM was associated with greater WMH volume, a marker of white matter dysfunction, and with deficits in processing speed and attention. Subclinical cognitive deficits were common in our community dwelling cohort without known or preceding cognitive dysfunction.

Independent effects of amyloid and vascular markers on long-term functional outcomes: An 8-year longitudinal study of subcortical vascular cognitive impairment.

Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long-term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta-amyloid (Aβ) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. During a 8.6-year follow-up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aβ positivity (subdistribution hazard ratio [SHR]=2.73), greater white matter hyperintensity (WMH) volume (SHR=3.11) and ≥3microbleeds (SHR=2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio =2.07) was an independent predictor of mortality. Our findings suggest that diverse imaging markers may predict long-term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long-term outcomes of SVCI.

Associations among vascular risk factors, neuroimaging biomarkers, and cognition: Preliminary analyses from the Multi-Ethnic Study of Atherosclerosis (MESA).

Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health. We examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N=159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core. African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline. Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.

Cardiac Hypertrophy Is Associated With Advanced Brain Aging in the General Population.

BackgroundHypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities (WMHs). Whether greater LV size or mass is also related to WMH burden in middle‐aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date.Methods and ResultsData from 1602 participants of the population‐based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21–82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat‐free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness.ConclusionsLV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.

Brain White Matter Structure and Amyloid Deposition in Black and White Older Adults: The ARIC-PET Study.

BackgroundWhite matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross‐sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race.Methods and ResultsParticipants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03–1.83) after adjusting for demographic and cardiovascular risk factors. In race‐stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15–3.50), compared with White participants (OR, 1.29; 95% CI, 0.89–1.89). However, the race interaction was not statistically significant (P interaction=0.09). We found no association between white matter microstructure and elevated amyloid.ConclusionsThe results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.

Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes

Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed. To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.

Relationship Between Central Artery Stiffness, Brain Arterial Dilation, and White Matter Hyperintensities in Older Adults: The ARIC Study-Brief Report.

[Figure: see text].

Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer's disease.

We investigated whether subtle visuomotor deficits were detectable in familial and sporadic preclinical Alzheimer’s disease. A circle-tracing task—with direct and indirect visual feedback, and dual-task subtraction—was completed by 31 individuals at 50% risk of familial Alzheimer’s disease (19 presymptomatic mutation carriers; 12 non-carriers) and 390 cognitively normal older adults (members of the British 1946 Birth Cohort, all born during the same week; age range at assessment = 69–71 years), who also underwent β-amyloid-PET/MRI to derive amyloid status (positive/negative), whole-brain volume and white matter hyperintensity volume. We compared preclinical Alzheimer’s groups against controls cross-sectionally (mutation carriers versus non-carriers; amyloid-positive versus amyloid-negative) on speed and accuracy of circle-tracing and subtraction. Mutation carriers (mean 7 years before expected onset) and amyloid-positive older adults traced disproportionately less accurately than controls when visual feedback was indirect, and were slower at dual-task subtraction. In the older adults, the same pattern of associations was found when considering amyloid burden as a continuous variable (Standardized Uptake Value Ratio). The effect of amyloid was independent of white matter hyperintensity and brain volumes, which themselves were associated with different aspects of performance: greater white matter hyperintensity volume was also associated with disproportionately poorer tracing accuracy when visual feedback was indirect, whereas larger brain volume was associated with faster tracing and faster subtraction. Mutation carriers also showed evidence of poorer tracing accuracy when visual feedback was direct. This study provides the first evidence of visuomotor integration deficits common to familial and sporadic preclinical Alzheimer’s disease, which may precede the onset of clinical symptoms by several years.