Higher White Matter Hyperintensities Research Articles

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer’s disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = −.02, 95% CI (-.04, −.008), p =.003] and in APOE4 carriers [B = −.03, 95% CI (-.06, −.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Abstract P335: Predictors of Cognitive Resilience in Those With and Without High White Matter Hyperintensity Burden: A Post-Hoc Analysis of Systolic Blood Pressure Intervention Trial Memory & Cognition in Decreased Hypertension (SPRINT MIND)

Introduction: Little is known if predictors of cognitive resilience (CR) differ between adults with or without large white matter hyperintensity burdens. In the current analysis of cross-sectional baseline SPRINT MIND data, we a) determined bivariate associations of sociodemographic, vascular-metabolic, and neurodegenerative biomarkers with CR and b) delineated variables that maximized predictive fit of CR among participants with the highest and lowest white matter hyperintensity volumes (WMHv). Methods: We included SPRINT MIND participants with baseline available plasma biomarker concentrations & Montreal Cognitive Assessment (MoCA) scores. We then created two analytic samples: those with the highest tertile of WMHv (N = 186) and those with the lowest tertile (N=134). We defined CR two ways: as a MoCA score a) >25 or b) >22. We determined the association between sociodemographic, vascular-metabolic, and serum neurodegenerative variables, as well as WMHv with CR using logistic regressions to generate unadjusted odds ratios (OR) & 95% confidence intervals (CI). Multivariate lasso regressions were then used to determine which variables optimized predictive fit of CR, and R 2 values were calculated. Results: In participants with the lowest tertile of WMHv , the median age was 66 years, 45.5% were female and 63% were Non-Hispanic white. In participants with the highest tertile of WMHv, the median age was 73 years, 45.7% were female and 66% were Non-Hispanic white. . CR defined as MoCA scores > 25 & >22 was present in 37.3% and 64.9% in those with the lowest tertile of WMHv and 28.5% & 56.5% in those with the highest tertile, respectively. Higher education and self-reported race generally had the strongest ORs in all analyses (Table 1 excerpt). Only age and education level were included in all four predictive models after lasso shrinkage. The R 2 values for all lasso regressions were <0.25. Conclusion: Education level may be associated with CR irrespective of WMHv. However, a large variation of CR remains unaccounted for.

Associations between vascular health, brain stiffness and global cognitive function.

Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values < 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

Depression, Vascular Burden, and Dementia Prevalence in Late Middle-Aged and Older Black Adults.

Late-life depression and white matter hyperintensities (WMH) have been linked to increased dementia risk. However, there is a dearth of literature examining these relationships in Black adults. We investigated whether depression or WMH volume are associated with a higher likelihood of dementia diagnosis in a sample of late middle-aged to older Black adults, and whether dementia prevalence is highest in individuals with both depression and higher WMH volume. Secondary data analysis involved 443 Black participants aged 55+ with brain imaging within 1 year of baseline visit in the National Alzheimer's Coordinating Center Uniform Data Set. Chi-square analyses and logistic regression models controlling for demographic variables examined whether active depression in the past 2 years, WMH volume, or their combination were associated with higher odds of all-cause dementia. Depression and higher WMH volume were associated with a higher prevalence of dementia. These associations remained after controlling for demographic factors, as well as vascular disease burden. Dementia risk was highest in the depression/high WMH volume group compared to the depression-only group, high WMH volume-only group, and the no depression/low WMH volume group. Post hoc analyses comparing the Black sample to a demographically matched non-Hispanic White sample showed associations of depression and the combination of depression and higher WMH burden with dementia were greater in Black compared to non-Hispanic White individuals. Results suggest late-life depression and WMH have independent and joint relationships with dementia and that Black individuals may be particularly at risk due to these factors.

Abstract TP29: Neurodegenerative Plasma Biomarker Associations With Cognitive Resilience in Adults With High White Matter Hyperintensity Volume: A Post-Hoc Analysis of Systolic Blood Pressure Intervention Trial Memory &amp; Cognition in Decreased Hypertension (SPRINT MIND)

Introduction: Although high cerebral white matter hyperintensity volume (WMHv) is associated with cognitive decline, many adults with high WMHv show no cognitive deficits. Neurodegenerative plasma biomarkers may be associated with cognitive decline via vascular processes causing higher WMHv such as cerebral amyloid angiopathy &amp; inflammatory small vessel disease. We determined associations of plasma amyloid β 42 (AB42), amyloid β 40 (AB40), AB42/AB40, total tau, &amp; neurofilament light chain (NfL) with cognitive resilience (CR) in adults with high WMHv using baseline MRIs &amp; measurements from SPRINT MIND. Methods: This study included baseline data from 186 SPRINT MIND participants who were in the highest WMHv tertile &amp; had available plasma biomarker concentrations &amp; Montreal Cognitive Assessment (MoCA) scores. We defined CR two ways: A) MoCA score &gt;25 or B) MoCA score &gt;22. We determined univariate &amp; adjusted odds ratios (OR) &amp; 90% confidence intervals (CI) for each aforementioned plasma biomarker with CR. Confounders in adjusted models were: age, sex, race-ethnicity (Non-Hispanic white, Non-Hispanic Black, Hispanic, or other) education (no college education, college education, or post-graduate education), smoking history (never smoker, prior smoker, or current smoker) physical activity (0, 1-4, or ≥ 5 days of vigorous physical activity), diabetes, having insurance, &amp; average systolic blood pressure. Residual confounding and effect modification by WMHv were tested in sensitivity analyses. Results: In our sample, the mean age was 72.6 years, 45.7% were female &amp; 66% were Non-Hispanic white. The median WMHv was 10.0 cm 3 (25%-75% range: 6.3 - 16.9 cm 3 ). . CR defined as MoCA scores &gt; 25 &amp; &gt;22 was present in 28.5% &amp; 56.5% of participants respectively. Lower plasma AB40 was marginally associated with CR using a MoCa cutoff of &gt;25 (OR 1.003, 90% CI: 1.001-1.006) in univariate analyses. There were no other significant (P&gt;0.1) univariate or adjusted associations between plasma biomarkers with CR using either MoCa cutoff, nor significant confounding or effect modification by WMHv (P&gt; 0.1). Conclusion: There were no significant adjusted associations between any plasma biomarker with CR. Future work should identify factors associated with CR in adults with high WMHv.

Feelings of tense and risk of incident dementia: A prospective study of 482,360 individuals

BackgroundThe relationship between feelings of tense, as a significant emotional distress, and dementia remains unclear. This study aimed to evaluate the association between feelings of tense and dementia. MethodsIn UK Biobank, feelings of tense were measured with a standard item. The primary outcome was all cause of dementia (ACD) and its subtypes (Alzheimer's disease (AD), vascular dementia (VD), and other dementia). Cox regression models analyzed the association between feelings of tense and dementia risk, while linear regression examined the correlation with neuroimaging outcomes. The potential association and joint effects of AD and tenseness were evaluated based on the established genetic risk score (GRS). ResultsDuring a median follow-up of 12.7 years among 482,360 participants, 7331 dementia cases were identified. Individuals with feelings of tense had a significantly increased risk of ACD (HR, 1.194; 95 % CI: 1.115–1.278), VD (HR, 1.164; 95 % CI: 1.007–1.346), and other dementia (HR, 1.181; 95 % CI: 1.081–1.289), but not AD in multi-adjusted models. This association persisted across various sensitivity analyses and exhibited some heterogeneity in subgroup analyses. Furthermore, feelings of tense are associated with total brain volume shrinkage, higher white matter hyperintensities, and decreased partial subcortical volume, particularly in the hippocampus. No interaction between tenseness and AD genetic susceptibility was observed (P for interaction =0.346). LimitationsOur study only considered feelings of tense measured at a one-time point. ConclusionsOur findings demonstrate a significant association between feeling of tense and elevated dementia risk, indicating that tenseness could serve as a modifiable psychological determinant for dementia.

Post‐mortem MRI white matter hyperintensities are associated with cortical astrocytopathy and water channel expression in the oldest‐old

AbstractBackgroundCerebrovascular small vessel disease, a common cause of cognitive impairment in older individuals, is characterized by the presence of MRI white matter hyperintensities (WMH). Our previous MRI‐targeted histopathological studies have found WMHs and the surrounding NAWM penumbra to be associated with glial markers. This study aims to assess the relationship between cortical markers of glial dysfunction and post‐mortem (PM) MRI WMH.MethodLeft brain hemispheres were obtained from 45 Oregon Alzheimer’s Disease Research Center subjects &gt;/ = 80 years of age without significant AD pathology. Intact and sliced hemispheres were scanned at 7T MRI. MRI scans were used to target histological sampling. Slides were stained for glial fibrillary acid protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), aquaporin‐1 (AQP1), aquaporin‐4 (AQP4), vimentin and amyloid‐beta (ABETA). Slides were co‐registered to MRI. Tissue masks were hand‐drawn to delineate white matter and cortex. Cortical ROIs were quantified for mean pixel value (AQP1, AQP4, GFAP, and Vimentin) or area coverage (IBA1, ABETA). Cassettes with no local WMH were compared with those in the top third of slide WMH coverage (187 cassettes). Global WMH burden was dichotomized at the mean. Linear mixed‐effects models regressed stain quantification on local WMH (in slide) and global WMH burden, with a random effect for staining batch (levels = 4). The final model controlled for age at death and ABETA expression within a slide. Interactions between local and global WMH were included where appropriate.ResultHigh local WMH burden was associated with greater cortical vimentin (p = 0.036), GFAP (p = 0.066), and AQP4 (p = 0.004), while high global WMH burden was associated with greater IBA1 (p = 0.034) and AQP1 (p = 0.071). An interaction was identified between local and global WMH burden for AQP1 (p&lt;0.10), such that in subjects with high global WMH burden, high local WMH burden was associated with higher AQP1. Greater local cortical ABETA was associated with cortical AQP1 (p = 0.004) expression.ConclusionIn oldest‐old individuals without significant AD pathology, high local and global PM‐MRI WMH burden is associated with cortical astrocytopathy, including increased water channel expression and inflammation. Findings implicate WMH as a state marker of widespread cortical pathology that may confer increased vulnerability to cognitive decline with advanced age.

Biological sex and vessel specific relationships between cerebral pulsatility and white matter hyperintensities: a 4D flow MRI study

AbstractBackgroundBrain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex‐specific.Method407 cognitively healthy middle‐aged and older adults (45‐87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid‐attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume.ResultPI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P≤0.01, all male P≥0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P≤0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P≤0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (β = 0.39±0.09 a.u., R2 = 0.13) compared with females (β = 0.18±0.05 a.u., R2 = 0.05).ConclusionThese data suggest that, among cognitively healthy middle‐aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex‐ and vessel‐specific which may contribute to sex‐specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.

Biological sex and vessel specific relationships between cerebral pulsatility and white matter hyperintensities: a 4D flow MRI study

AbstractBackgroundBrain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex‐specific.Method407 cognitively healthy middle‐aged and older adults (45‐87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid‐attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume.ResultPI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P = 0.01, all male P = 0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P = 0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P = 0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (ß = 0.39±0.09 a.u., R2 = 0.13) compared with females (ß = 0.18±0.05 a.u., R2 = 0.05).ConclusionThese data suggest that, among cognitively healthy middle‐aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex‐ and vessel‐specific which may contribute to sex‐specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.

The influence of vascular pathology on the generalizability of machine learning models for cognitive performance estimation

AbstractBackgroundImage‐based machine learning models are promising to aid diagnosis in dementia, e.g. by diagnostic classification or estimating cognitive performance. However, the contribution of vascular pathology is often ignored, although many patients have mixed pathologies. This may hamper model generalizability from research setting to clinical practice, as the models are generally developed on populations with lower vascular burden than is encountered clinically. This study aims to evaluate whether model generalizability is influenced by differences in vascular pathology load between training and test groups, represented by white matter hyperintensities (WMHs).MethodWe developed a convolutional neural network to estimate cognitive performance through ADAS13. We included 4791 timepoints from 1632 ADNI subjects. To mimic differences in vascular burden between research and clinical populations, we split the data into a low, middle and high WMH load group using WMH ratio tertiles (WMH volume corrected for intracranial volume). The model was applied to maps derived from T1‐weighted and FLAIR brain MRI using voxel‐based morphometry: model 1 (gray matter density map (GMDM), age, sex), model 2 (GMDM, WMH density map (WMHDM), age, sex) and model 3 (GMDM, log(WMH ratio), age, sex) (Fig. 1). First, we trained all models on the low WMH load group, meaning to test on the high WMH load group to assess generalizability. Second, we trained models 1 and 2 on all data. Mean Absolute Error (MAE) served as the performance metric.ResultThe models trained on the low WMH load group (MAE = 5.08 – 5.41) performed similar to constant value prediction (MAE = 5.63) (Fig. 2, circles). Using all data, models did train successfully (model 1: MAE = 5.64, model 2: MAE = 6.31, constant value: MAE = 7.39) (Fig. 2, crosses). Because of the suboptimal model training in the low WMH load group, especially for individuals with higher ADAS13 scores which were underrepresented in the data (Fig. 3), we could not evaluate generalizability to the high WMH load group.ConclusionThis study was unable to provide new insight into the influence of vascular pathology on the generalizability of machine learning models in dementia. More clinically representative data is needed, covering the full cognitive performance spectrum and higher vascular pathology loads.

Association of self‐reported and objective sleep parameters with hippocampus and white matter hyperintensities volumes in a community‐dwelling older adults

AbstractBackgroundNumerous studies report that sleep disturbances are associated with brain alterations; yet, results still remain controversial. Our aim was thus to examine the associations between self‐reported and objective sleep parameters, and volumes of hippocampus and white matter hyperintensities (WMH).MethodThis cross‐sectional analysis used data from the French ESPRIT study. At baseline, 718 participants aged 65‐80 underwent a brain magnetic resonance imaging examination. Among them, 675 had hippocampus volume data and 712 had WMH volume data. They also completed a sleep questionnaire at baseline and 167 participants underwent an ambulatory polysomnography to assess their objective sleep. Logistic regression models were performed and minimally adjusted for age, sex, educational level, and APOE ε4 status to assess the associations between sleep parameters and volumes of hippocampus and WMH.ResultThe participants’ mean age at baseline was 71.4 years (±4.0) and 51.3% were women. We found that a short (≤6 hours) but also a long (≥9 hours) 24‐hour sleep duration, a late (&gt;8 am) get‐up time and a low score at the Epworth Severity Scale were associated with a low hippocampal volume. However, these associations did not remain significant after false discovery rate (FDR) correction. We also observed, even after FDR correction, that an early get‐up time (≤6 am) and having difficulty in initiating sleep were associated with a high WMH volume whereas a late bedtime (≥11 pm) was associated with a low WMH volume. Regarding objective data, longer rapid eye movement sleep and slow wave sleep durations were associated with a low WMH volume, and a higher number of periodic leg movements during sleep was associated with a high WMH volume; but these associations were not significant after FDR correction. All the results remained similar after taking into account intracranial volume.ConclusionIn this population‐based study in older adults, the most robust findings concerned higher WMH volume for participants with early get‐up time, difficulties in initiating sleep or late bedtime. Overall, these results are consistent with the general view that there may be specific types of sleep parameters that can play a role in brain alterations.

Association of white matter hyperintensity burden and cognitive performance in young‐aged, middle‐aged and old‐aged participants: Results of the population‐based 1000BRAINS study

AbstractBackgroundSome individuals seem less susceptible to the effect of high white matter hyperintensity (WMH) load on cognition reflecting differences in individual cognitive reserve (CR). Little is known about young‐ or middle‐aged participants. The aim of the present study was to examine (1) the effect of WMH on global cognition in three different age groups and (2) if education (as proxy for CR) moderates this association.MethodWe included 707 healthy participants (18‐85 years) without evidence of cardiovascular/neurological disease (young‐aged: 18‐44 years (Ø33.5±6.7): n = 108; middle‐aged: 45‐65 years (Ø57.9±5.5): n = 341; old‐aged: &gt;65 years (Ø72.0±4.1): n = 258) from the population‐based 1000BRAINS study. An extensive cognitive assessment was conducted. The sum of all cognitive domain z‐scores defined the global score. Education was classified according to the International Standard Classification of Education as total years of formal education, combining school and vocational training. Magnetic resonance imaging (MRI) was carried out on a 3‐Tesla‐MR‐scanner (Tim‐TRIO, Siemens Medical Systems, Erlangen, Germany). WMH volume was determined using the Brain‐Intensity‐Abnormality‐Classification‐Algorithm. The associations of global cognition as outcome with WMH volume (in cm3) as predictor were analyzed using linear models (PROCESS v4.1 macro for SPPS) stratified by age group resulting in regression coefficient b with 95% confidence intervals (CI; adjusted for age, sex, depression, diabetes mellitus). To examine moderation effects of education, all models contained an interaction term (WMH x education).ResultHigher WMH volume was associated with lower global cognition in middle‐aged participants (b:‐0.27 (‐0.52 to ‐0.03, all reported results are fully adjusted). This effect was moderated by education (interaction term: b:‐0.07 (‐0.014 to ‐0.01)). In the young‐aged group, the association between WMH load and cognition was ‐1.27 (‐3.30 to 0.77). No association was found in the old‐aged group (b: ‐0.03 (‐0.20 to 0.14)).ConclusionHigher WMH load was associated with lower cognitive performance only in middle‐aged participants and was moderated to a small degree by education. Overall, the influence of WMH on global cognition in our cohort of healthy participants seems limited. Future analyses will focus on specific cognitive domains that might be more vulnerable to higher WMH load and will examine participants with certain cardiovascular risk profile.

Association of Cerebrovascular Imaging Biomarkers, Depression, and Anxiety, with Mild Cognitive Impairment.

The study included 1,738 Mayo Clinic Study of Aging participants (≥50 years old; 1,460 cognitively unimpaired and 278 with mild cognitive impairment (MCI)) and examined the cross-sectional association between cerebrovascular (CVD) imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) and Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) scores, as well as their association with MCI. High (abnormal) WMH burden was significantly associated with having BDI-II>13 and BAI > 7 scores, and both (CVD imaging biomarkers and depression/anxiety) were significantly associated with MCI when included simultaneously in the model, suggesting that both were independently associated with the odds of MCI.

1 Quantifying the Role of Social Determinants of Health in Racial Disparities

Objective:In the United States, Black individuals have suffered from 300 years of racism, bias, segregation and have been systematically and intentionally denied opportunities to accrue wealth. These disadvantages have resulted in disparities in health outcomes. Over the last decade there has been a growing interest in examining social determinants of health as upstream factors that lead to downstream health disparities. It is of vital importance to quantify the contribution of SDH factors to racial disparities in order to inform policy and social justice initiatives. This demonstration project uses years of education and white matter hyperintensities (WMH) to illustrate two methods of quantifying the role of a SDH in producing health disparities.Participants and Methods:The current study is a secondary data analysis of baseline data from a subset of the National Alzheimer's Coordinating Center database with neuroimaging data collected from 2002-2019. Participants were 997 cognitively diverse, Black and White (10.4% Black) individuals, aged 60-94 (mean=73.86, 56.5% female), mean education of 15.18 years (range= 0-23, SD=3.55). First, mediation, was conducted in the SEM framework using the R package lavaan. Black/White race was the independent variable, education was the mediator, WMH volume was the dependent variable, and age/sex were the covariates. Bootstrapped standard errors were calculated using 1000 iterations. The indirect effect was then divided by the total effect to determine the proportion of the total effect attributable to education. Second, a population attributable fraction (PAF) or the expected reduction in WMH if we eliminated low education and structural racism for which Black serves as a proxy was calculated. Two logistic regressions with dichotomous (median split) WMH as the dependent variable, first with low (less than high school) versus high education, and second with Black/White race added as predictors. Age/sex were covariates. PAF of education, and then of Black/White race controlling for education were obtained. Subsequently, a combined PAF was calculated.Results:In the lavaan model, the total effect of Black/White race on WMH was not significant (B=.040, se=.113, p=.246); however, Black/White race significantly predicted education (B= -.108, se=.390, p=.001) and education significantly predicted WMH burden (B=-.084, se=.008, p=.002). This resulted in a significant indirect effect (effect=.009, se=.014, p=.032). 22.6 % of the relationship between Black/White race and WMH was mediated by education. In the logistic models, the PAF of education was 5.3% and the additional PAF of Black/White race was 2.7%. The combined PAF of Black race and low education was 7.8%.Conclusions:From our mediation we can conclude that 22.6% of the relationship between Black/White race and WMH volume is explained by education. Our PAF analysis suggests that we could reduce 7.8% of the cases with high WMH burden if we eliminated low education and the structural racism for which Black serves as a proxy. This is an under estimation of the role that education and structural racism play in WMH burden due to our positively selected sample and crude measure of education. However, these methods can help researchers quantify the contribution of SDH to disparities in older adulthood and provide targets for policy change.

Ambient Air Pollution Exposure and Cerebral White Matter Hyperintensities in Older Adults: A Cross-Sectional Analysis in the Three-City Montpellier Study.

Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive health, and this could be related to the effect of air pollution on vascular health. We aim to evaluate the association between air pollution exposure and a magnetic resonance imaging (MRI) marker of cerebral vascular burden, white matter hyperintensities (WMH). This cross-sectional analysis used data from the French Three-City Montpellier study. Randomly selected participants 65-80 years of age underwent an MRI examination to estimate their total and regional cerebral WMH volumes. Exposure to fine particulate matter (), nitrogen dioxide (), and black carbon (BC) at the participants' residential address during the 5 years before the MRI examination was estimated with land use regression models. Multinomial and binomial logistic regression assessed the associations between exposure to each of the three pollutants and categories of total and lobar WMH volumes. Participants' () median age at MRI was 70.7 years [interquartile range (IQR): 6.1], and 52% () were women. Median exposure to air pollution over the 5 years before MRI acquisition was 24.3 (IQR: 1.7) for , 48.9 (14.6) for , and 2.66 (0.60) for BC. We found no significant association between exposure to the three air pollutants and total WMH volume. We found that exposure was significantly associated with higher risk of temporal lobe WMH burden [odds ratio (OR) for an (95% confidence interval: 1.41, 2.36) for the second volume tercile, 2.04 (1.59, 2.61) for the third volume tercile, reference: first volume tercile]. Associations for other regional WMH volumes were inconsistent. In this population-based study in older adults, exposure was associated with increased risk of high WMH volume in the temporal lobe, strengthening the evidence on adverse effect on the brain. Further studies looking at different markers of cerebrovascular damage are still needed to document the potential vascular effects of air pollution. https://doi.org/10.1289/EHP12231.

The Relationship of MRI-Derived Alzheimer's and Cerebrovascular-Related Signatures With Level of and Change in Health and Financial Literacy

The cortical thickness "signature" of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden have each been associated with cognitive aging and incident AD and related dementias. Less is known about how these structural neuroimaging markers associate with other critical behaviors. We investigated associations of AD-CT and WMH volumes with a composite index of health and financial literacy given that the ability to access, understand, and utilize health and financial information significantly influences older adults' health outcomes. Participants were 303 adults without dementia (age∼80 years; 74% women) from the Rush Memory and Aging Project. Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess AD-CT and WMH volumes, respectively. Literacy was measured using questions designed to assess comprehension of health and financial information and concepts, yielding a total literacy score. Multivariable linear mixed effects regression models determined the relationship of each neuroimaging marker, first separately and then combined, with the level of and change in literacy. Reduced AD-CT and higher WMH at baseline were each associated with lower levels of literacy; only AD-CT was associated with the rate of decline in literacy over time. The association of AD-CT with change in literacy persisted when both neuroimaging markers were included in the same model. The cortical thickness signature of AD predicts changes in health and financial literacy in nondemented older adults suggesting that the multidimensional construct of health and financial literacy relies on specific brain networks implicated in AD.

Elecsys Cerebrospinal Fluid Immunoassays Accurately Detect Alzheimer's Disease Regardless of Concomitant Small Vessel Disease.

Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer's disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. Frozen CSF samples (n = 84) were measured using Elecsys β-Amyloid(1-42) (Aβ42), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® e 411 analyzer (Roche Diagnostics International Ltd), and a robust prototype β-Amyloid(1-40) (Aβ40) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman's correlation, sensitivity/specificity, and logistic/linear regression analyses. The extent of WMH showed significant correlation with Aβ42/Aβ40 ratio (Rho=-0.250; p = 0.040), tTau (Rho = 0.292; p = 0.016), tTau/Aβ42 ratio (Rho = 0.247; p = 0.042), age (Rho = 0.373; p = 0.002), and MMSE (Rho=-0.410; p = 0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology.

Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea.

Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter (WM) integrity in older adults with obstructive sleep apnea (OSA). From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least 1 brain MRI and PSG. We quantified 2 CVD biomarkers: WM hyperintensities (WMHs) from fluid-attenuated inversion recovery (FLAIR)-MRI, and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (NREM stage 1 percentage, NREM stage 3 percentage [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOE ε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG. We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± SD age was 72.7 ± 9.6 years at MRI with nearly 60% being men. The absolute median (interquartile range [IQR]) interval between MRI and PSG was 1.74 (0.9-3.2) years. 90.7% were cognitively unimpaired (CU) during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006-0.111, p = 0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p = 0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005-0.015] vs 0.006 [0.003-0.009], p = 0.042) and lower genu FA (median [IQR] 0.57 [0.55-0.63] vs 0.63 [0.58-0.65], p = 0.007), when compared with those with mild/moderate OSA. We found that reduced slow-wave sleep and severe OSA were associated with higher burden of WM abnormalities in predominantly CU older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation.

Comparing three neuropsychological subgrouping approaches in subjective and mild cognitive impairment from a naturalistic multicenter study

Subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are two clinical groups with an increased risk to develop dementia, but they are highly heterogeneous. This study compared three different approaches to subgroup SCI and MCI patients and investigated their capacity to disentangle cognitive and biomarker heterogeneity. We included 792 patients from the MemClin-cohort (142 SCI and 650 MCI). Biomarkers included cerebrospinal fluid measures of beta-amyloid-42 and phosphorylated tau, as well as visual ratings of medial temporal lobe atrophy and white matter hyperintensities on magnetic resonance imaging. We found that a more inclusive approach identified individuals with a positive beta-amyloid-42 biomarker; a less inclusive approach captured individuals with higher medial temporal lobe atrophy; and a data-driven approach captured individuals with high white matter hyperintensities burden. The three approaches also captured some neuropsychological differences. We conclude that choice of approach may differ depending on the purpose. This study helps to advance our current understanding of the clinical and biological heterogeneity within SCI and MCI, particularly in the unselected memory clinic setting.