Higher White Matter Hyperintensities Burden 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.

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 WP186: The Burden of White Matter Hyperintensities on Function Outcomes in Patients Treated for Acute Ischemic Stroke: A Post-Hoc Analysis of the IMS-III Trial

Objective: This study is a post-hoc analysis of the Interventional Management of Stroke (IMS) III trial investigating the burden of white matter hyperintensities (WMH), using the van Swieten Scale (VSS), on functional outcomes for acute ischemic stroke (AIS) patients treated with either intravenous thrombolysis (IVT) or IVT with mechanical thrombectomy (MT). Background: WMH are a well-established marker for underlying cerebral microvascular disease. VSS quantifies the disease burden from zero to four with higher numbers signifying more advanced disease. A higher burden of WMH is associated with poor functional outcomes after IVT. However, early studies regarding WMH and outcomes after MT have been conflicting. Methods: We included IMS-III trial patients in either treatment arm whose VSS was graded on initial brain CT and 90-day function outcomes were not missing. The primary study outcome was a 90-days modified Rankin Scale of 0-2, termed good outcome. Results: There was a total of 656 patients enrolled in the trial and 618 patients were included in this analysis. The VSS grades of WMH range from 0-4 and included 476 (77.02%), 56 (9.06%), 38 (6.15%), 24 (3.88%), and 24 (3.88%) patients, respectively. Overall, higher VSS grade was associated with a lower probability of achieving a good functional outcome, even after adjustments (Figure 1). Of the 142 patients with any degree of WMH, only 22.5% had a good functional outcome compared to 46.6% of 476 patients without WMH (Table 1). Conclusions: Patients enrolled in the IMS-III trial with any burden of WMH on brain CT had a statistically significant lower odds of a good functional outcome compared to patients without WMH.

Serum Placental Growth Factor as a Marker of Cerebrovascular Disease Burden in Alzheimer's Disease.

Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer's disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF's clinical utility.

Associations Between Cardiac Function and Brain Health in Diverse Middle-Aged Adults: The Dallas Heart Study-2

BackgroundPrevious studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations. ObjectivesThe objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults. MethodsA cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV Ecc) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity. ResultsLV ejection fraction was associated with total Montreal Cognitive Assessment score (β = 0.06 [95% CI: 0.003-0.12], P = 0.042) and LV Ecc was associated with WMH volume (β = 0.08 [95% CI: 0.01-0.14], P = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (β = 0.13 [95% CI: 0.03-0.23], P = 0.008 and 0.10 [95% CI: 0.03-0.17], P = 0.005). These associations were more predominant in Black than White participants (β = 0.17 [95% CI: 0.04-0.30] vs β = −0.009 [95% CI: −0.16 to 0.14], P = 0.036 and β = 0.22 [95% CI: 0.13-0.32] vs β = −0.11 [95% CI: −0.21 to −0.01], P < 0.0001, for LV mass and concentricity, respectively). ConclusionsSubclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals.

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.

Effects of cerebrovascular disease on tau progression and cognitive decline in Alzheimer’s disease

AbstractBackgroundRecent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathobiological and/or clinical AD progression is rare. Thus, we assessed in‐vivo, whether i) higher cerebrovascular burden is associated with accelerated progression of primary AD pathology and ii) whether cerebrovascular burden synergistically accelerates AD‐related cognitive decline.MethodWe included n = 256 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) across the AD spectrum with longitudinal 18F‐flortaucipir tau‐PET (follow‐up∼2.30±1.32 years), 18F‐florbetapir or 18F‐florbetaben Aß‐PET transformed to centiloid (A7: n = 85 Cognitively normal (CN); Aß+: n = 83 CN, n = 57 Mild Cognitive Impairment, n = 31 Dementia). We focused on global white matter hyperintensity (WMH) volume adjusted to intracranial volume and microhemorrhage (MCH) count as well‐established cerebrovascular disease markers. Cognition was probed through the AD Assessment Scale Cognition 13‐item scale (ADAS‐13). Subject‐specific annual changes in tau‐PET and cognition were calculated via linear mixed models, including random slope and intercept. To enhance reproducibility of our findings, statistical analyses were pre‐specified at AsPredicted.org. All statistical models were controlled for age, sex and APOE.ResultUsing linear regression, we found no main effect of cerebrovascular disease markers on baseline amyloid‐PET or tau‐PET (ps&gt;0.05). Further, higher cerebrovascular burden was not associated with faster Aß‐related tau‐PET SUVR increase (Fig. 1A+B). In contrast, higher cerebrovascular burden was associated with accelerated cognitive decline. Specifically, interaction models revealed that a higher MCH count was associated with faster cognitive decline at higher tau levels (Fig. 1C), while higher white matter hyperintensity burden was associated with faster cognitive decline at lower tau levels (Fig. 1D).ConclusionWe found no effect of cerebrovascular disease on primary AD pathology. In contrast, cerebrovascular disease was linked to accelerated tau‐associated cognitive decline. This suggests that cerebrovascular disease may not modulate pathobiological AD trajectories but rather add synergistically to AD symptom severity. This has important therapeutic implications, as treating cerebrovascular disease in addition to primary AD pathology (e.g. amyloid) may yield largest clinical efficacy.

Accelerated brain ageing in participants with higher cerebrovascular lesion load across aging, cognitive impairment, and mixed presentation

AbstractBackgroundWe aimed to investigate the association between cortical brain age and white matter hyperintensities (WMH) in diverse forms of clinically‐defined vascular conditions. Our hypothesis was that a higher WMH burden would be associated with higher cortical brain age in all clinical subtypes.MethodWe used standardized MRI data obtained from participants in the COMPASS‐ND cohort of the CCNA. We used a standard linear support vector regression algorithm to estimate brain age, matching chronological age to cortical anatomical measurements obtained with the FreeSurfer toolbox on T1‐weighted MRI, sex, and intracranial volume. We calculated brain‐PAD (i.e., predicted brain age minus real age) and applied bias adjustment to remove age‐dependency in the estimates. A validated automated technique utilizing T2‐weighted and fluid attenuated inversion recovery MRIs was used to compute WMH loads.ResultParticipants included 107 CIE, 240 mild cognitive impairment (MCI), 115 vascular‐MCI (V‐MCI), 81 probable Alzheimer’s disease (AD), and 50 V‐AD. There was a significant difference in brain‐PAD [ F (4,599) = 56, P &lt; 0.001, ANCOVA test] among groups, whilst adjusting for sex and chronological age. All four categories of patients exhibited a significantly higher mean brain‐PAD than CIE (P &lt; 0.001), with the AD cohort having the highest brain‐PAD. There was a significant difference in WMH loads [ F (4,586) = 48, P &lt; 0.001, ANCOVA test] between groups, whilst adjusting for sex and age. All cohorts showed a positive correlation between brain‐PAD and WMH, indicating accelerated ageing in people with higher WMHs. We observed moderate and significant correlations between brain‐PAD and WMH loads for V‐MCI (r = 0.34, P &lt; 0.001) and V‐AD (r = 0.36, P = 0.001) but weaker, while significant correlations in CIE (r = 0.20, P = 0.035) and AD cohorts (r = 0.24, P = 0.025).ConclusionWe observed a positive and significant link between brain‐PAD and WMH in all categories. This finding indicates on the importance of treatment and prevention strategies for vascular risk factors, which might be able to slow down the progression of cerebrovascular lesions and delay the effect on cortical thickness.

Effects of cerebrovascular disease on tau progression and cognitive decline in Alzheimer’s disease

AbstractBackgroundRecent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathobiological and/or clinical AD progression is rare. Thus, we assessed in‐vivo, whether i) higher cerebrovascular burden is associated with accelerated progression of primary AD pathology and ii) whether cerebrovascular burden synergistically accelerates AD‐related cognitive decline.MethodWe included n = 256 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) across the AD spectrum with longitudinal 18F‐flortaucipir tau‐PET (follow‐up∼2.30±1.32 years), 18F‐florbetapir or 18F‐florbetaben Aβ‐PET transformed to centiloid (Aβ–: n = 85 Cognitively normal (CN); Aβ+: n = 83 CN, n = 57 Mild Cognitive Impairment, n = 31 Dementia). We focused on global white matter hyperintensity (WMH) volume adjusted to intracranial volume and microhemorrhage (MCH) count as well‐established cerebrovascular disease markers. Cognition was probed through the AD Assessment Scale Cognition 13‐item scale (ADAS‐13). Subject‐specific annual changes in tau‐PET and cognition were calculated via linear mixed models, including random slope and intercept. To enhance reproducibility of our findings, statistical analyses were pre‐specified at AsPredicted.org. All statistical models were controlled for age, sex and APOE.ResultUsing linear regression, we found no main effect of cerebrovascular disease markers on baseline amyloid‐PET or tau‐PET (ps&gt;0.05). Further, higher cerebrovascular burden was not associated with faster Aβ‐related tau‐PET SUVR increase (Fig. 1A+B). In contrast, higher cerebrovascular burden was associated with accelerated cognitive decline. Specifically, interaction models revealed that a higher MCH count was associated with faster cognitive decline at higher tau levels (Fig. 1C), while higher white matter hyperintensity burden was associated with faster cognitive decline at lower tau levels (Fig. 1D).ConclusionWe found no effect of cerebrovascular disease on primary AD pathology. In contrast, cerebrovascular disease was linked to accelerated tau‐associated cognitive decline. This suggests that cerebrovascular disease may not modulate pathobiological AD trajectories but rather add synergistically to AD symptom severity. This has important therapeutic implications, as treating cerebrovascular disease in addition to primary AD pathology (e.g. amyloid) may yield largest clinical efficacy.

Cognitively healthy Indians with higher Framingham Cardiovascular Risk Scores have higher WMH burden with lesser grey matter, white matter and hippocampal volumes

AbstractBackgroundIncreasing evidence indicates the important role of cardiovascular risk factors in dementia risk, particularly in Indians. It is known that cardiovascular risk factors tend to cluster together, and a widely used multivariable risk scoring is the Framingham Cardiovascular Risk Score (FRS). However, very little is known about the association between FRS and structural brain MRI parameters in cognitively healthy Indians.MethodBaseline clinical and brain MRI data of 487 cognitively healthy Indians (Clinical Dementia Rating score of ‘0’), who are part of two ongoing, large, aging cohort studies in India – Srinivaspura Aging, Neuro Senescence and COGnition study (SANSCOG) study (n = 200) and Tata Longitudinal Study of Aging (TLSA, n = 289) were utilized. FRS was calculated using clinical and blood biochemistry data, whereas brain MRI scans were performed on 3T MRI scanners. White matter hyperintensity (WMH) lesion segmentation was performed using Lesion Segmentation Toolbox (LST) and brain volumes (total grey matter, total white matter, 3rd ventricle, right and left hippocampus) were derived using FreeSurfer software and normalized according to total intracranial volumes of the respective subjects. Linear regression analysis was performed with FRS as independent variable and various structural MRI parameters as dependent variables. A p value of &lt;0.05 was considered significant.ResultUrban subjects with higher FRS had significantly higher WMH volume (β = 0.00011, p&lt;0.001, R2 = 0.130), lower grey matter (β = ‐0.00285, p&lt;0.001, R2 = 0.206), white matter (β = ‐0.00180, p&lt;0.001, R2 = 0.106), right hippocampal (β = ‐0.00004, p&lt;0.001, R2 = 0.180), left hippocampal (β = ‐0.00003, p&lt;0.001, R2 = 0.156) volumes and higher 3rd ventricle volumes (β = 0.00003, p&lt;0.001, R2 = 0.150). Rural subjects higher FRS had lower grey matter (β = ‐0.00166, p&lt;0.001, R2 = 0.118, white matter (β = ‐0.0011, p&lt;0.001, R2 = 0.060), right hippocampal (β = ‐0.00002, p&lt;0.001, R2 = 0.087), left hippocampal (β = ‐0.00002, p&lt;0.001, R2 = 0.084) volumes and higher 3rd ventricle volumes (β = 0.00004, p&lt;0.001, R2 = 0.264) but no significant association was seen with WMH volume.ConclusionThese findings indicate that cardiovascular risk is associated with structural brain changes in cognitively healthy Indians. Since cardiovascular risk can be reduced through cost‐effective community level strategies, such as lifestyle‐based interventions, promptly addressing this risk in Indians could be an important part of dementia prevention strategies.

Retinal ganglion cell-inner plexiform layer, white matter hyperintensities, and their interaction with cognition in older adults.

We explored the interaction of optical coherence tomography (OCT) parameters and white matter hyperintensities with cognitive measures in our older adult cohort. This observational study enrolled participants who underwent a comprehensive neuropsychological battery, structural 3-T brain magnetic resonance imaging (MRI), visual acuity examination, and OCT imaging. Cerebral small vessel disease (CSVD) markers were read on MR images; lacune, cerebral microbleeds (CMB), white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS), were defined according to the STRIVE standards. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses (μm) were measured on the OCT tool. Older adults with cognitive impairment (CI) showed lower RNFL (p = 0.001), GCIPL (p = 0.009) thicknesses, and lower hippocampal volume (p = 0.004) when compared to non-cognitively impaired (NCI). RNFL (p = 0.006) and GCIPL thicknesses (p = 0.032) correlated with MoCA scores. GCIPL thickness (p = 0.037), total WMH (p = 0.003), PWMH (p = 0.041), and DWMH (p = 0.001) correlated with hippocampal volume in our older adults after adjusting for covariates. With hippocampal volume as the outcome, a significant interaction (p < 0.05) between GCIPL and PWMH and total WMH was observed in our older adults. Both GCIPL thinning and higher WMH burden (especially PWMH) are associated with hippocampal volume and older adults with both pathologies are more susceptible to subclinical cognitive decline.

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.

Orthostatic hypotension and its association with cerebral small vessel disease in a memory clinic population.

Orthostatic hypotension (OH), an impaired blood pressure (BP) response to postural change, has been associated with cognitive decline and dementia, possibly through cerebral small vessel disease (CSVD). We hypothesized that longer duration of BP drop and a larger BP drop is associated with increased risk of CSVD. This cross-sectional study included 3971 memory clinic patients (mean age 68 years, 45% female, 42% subjective cognitive complaints, 17% mild cognitive impairment, 41% dementia) from the Amsterdam Ageing Cohort and Amsterdam Dementia Cohort. Early OH (EOH) was defined as a drop in BP of ±20 mmHg systolic and/or 10 mmHg diastolic only at 1 min after standing, and delayed/prolonged OH (DPOH) at 1 and/or 3 min after standing. Presence of CSVD [white matter hyperintensities (WMH), lacunes, microbleeds] was assessed with MRI ( n  = 3584) or CT brain (n = 389). The prevalence of early OH was 9% and of delayed/prolonged OH 18%. Age- and sex-adjusted logistic regression analyses showed that delayed/prolonged OH, but not early OH, was significantly associated with a higher burden of WMH (OR, 95%CI: 1.21, 1.00-1.46) and lacunes (OR, 95%CI 1.34, 1.06-1.69), but not microbleeds (OR, 95%CI 1.22, 0.89-1.67). When adjusting for supine SBP, these associations attenuated (ORs, 95%CI for WMH 1.04, 0.85-1.27; for lacunes 1.21, 0.91-1.62; for microbleeds 0.95, 0.68-1.31). A larger drop in SBP was associated with increased risk of WMH and microbleeds, however, when adjusted for supine SBP, this effect diminished. Among memory clinic patients, DPOH is more common than EOH. While longer duration and larger magnitude of BP drop coincided with a higher burden of CSVD, these associations were largely explained by high supine BP.

Cocaine use is associated with cerebral white matter hyperintensities in HIV disease.

White matter hyperintensities (WMH), a marker of cerebral small vessel disease and predictor of cognitive decline, are observed at higher rates in persons with HIV (PWH). The use of cocaine, a potent central nervous system stimulant, is disproportionately common in PWH and may contribute to WMH. The sample included of 110 PWH on antiretroviral therapy. Fluid-attenuated inversion recovery (FLAIR) and T1-weighted anatomical MRI scans were collected, along with neuropsychological testing. FLAIR images were processed using the Lesion Segmentation Toolbox. A hierarchical regression model was run to investigate predictors of WMH burden [block 1: demographics; block 2: cerebrovascular disease (CVD) risk; block 3: lesion burden]. The sample was 20% female and 79% African American with a mean age of 45.37. All participants had persistent HIV viral suppression, and the median CD4+ T-cell count was 750. Nearly a third (29%) currently used cocaine regularly, with an average of 23.75 (SD = 20.95) days in the past 90. In the hierarchical linear regression model, cocaine use was a significant predictor of WMH burden (β = .28). WMH burden was significantly correlated with poorer cognitive function (r = -0.27). Finally, higher WMH burden was significantly associated with increased serum concentrations of interferon-γ-inducible protein 10 (IP-10) but lower concentrations of myeloperoxidase (MPO); however, these markers did not differ by COC status. WMH burden is associated with poorer cognitive performance in PWH. Cocaine use and CVD risk independently contribute to WMH, and addressing these conditions as part of HIV care may mitigate brain injury underlying neurocognitive impairment.

Neuroimaging biomarkers of the Amyloid, Tau, Neurodegeneration and Vascular framework in association with sleep duration changes over time

AbstractBackgroundBoth short and long sleep duration were previously associated with incident dementia, but underlying mechanisms of this association remains unknown. This project aims to evaluate how self‐reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration and (V)ascular neuroimaging markers of Alzheimer’s disease (AD).MethodWithin the Framingham Heart Study, two samples were studied: 271 participants (age:53.6±8.0 years; 51%M) who underwent 11C‐PiB amyloid (global, precuneus) and 18F‐Flortaucipir tau (several medial cortical limbic structures) PET imaging; and 2165 participants (age:61.3±11.1 years; 45%M) who underwent an MRI. To estimate neurodegeneration, total brain volume was extracted from MRI. Vascular MRI metrics included white matter hyperintensities (continuous, and dichotomous indicator for extensive for age), covert brain infarcts, and average free‐water. Self‐reported sleep duration was assessed both at the time of neuroimaging testing and around 15 years before, and split by categories (≤6h, 7‐8h, ≥9h). Sleep duration change over time was assessed by change between categories and by continuous delta change (split by negative and positive values for decreased or increased respectively). Logistic and linear regression models were tested between self‐reported sleep duration and neuroimaging metrics, adjusted for age and age2, sex, PET camera, APOE4 carrier status, depression, diabetes, hypertension, and prevalent cardiovascular diseases.ResultsNo association was observed between cross‐sectional self‐reported sleep duration and neuroimaging metrics. Transitioning to longer sleep over time (≤6h to ≥9h and 7‐8h to ≥9h as compared to consistently sleeping 7‐8h) was associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:3.50[0.95‐12.92], p = 0.040;ß[SE]:0.25[0.10], p = 0.015) and higher free‐water (ß[SE]:0.021[0.007], p = 0.003;ß[SE]:0.009[0.002], p = 0.0002). When looking at continuous sleep duration change, increasing sleep duration over time was also associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:1.26[1.02‐1.55], p = 0.032;ß[SE]:0.10[0.04], p = 0.007) and higher free‐water (ß[SE]:0.002[0.001], p = 0.031). Self‐reported sleep duration change was not associated with PET amyloid or tau outcomes.ConclusionVascular pathology in the brain as evidenced by higher white matter hyperintensities burden and free‐water is associated with sleep duration that is getting longer over time, thus potentially explaining its association with dementia risk. In fact, elongation of sleep duration may be an early change in the AD trajectory.

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.

Vascular risk factors, cerebral collateral efficiency and burden of small vessel disease in anterior circulation large vessel occlusion stroke (P11-5.025)

<h3>Objective:</h3> To determine the association between cerebral collateral circulation status and cerebral small vessel disease (CSVD) burden. <h3>Background:</h3> Subclinical ischemia is thought to play a central role in CSVD pathogenesis. In patients with large vessel occlusion, good collaterals on initial presentation are associated with improved outcomes. The relationship between an increased burden of CSVD and collateral network has not been explored in the setting of thrombectomy. <h3>Design/Methods:</h3> This was a retrospective single-center cohort of consecutive patients with anterior circulation large vessel occlusions with available brain MRI and CT-Angiogram. We identified the burden of individual CSVD markers[white matter hyperintensities (WMH), cerebral microbleeds(CMB), lacunes, and enlarged perivascular spaces (EPVS)] and computed the global CSVD burden on MRI obtained in the acute stroke. We used the Tan Collateral score (CS) in CT-Angiogram to grade collaterals (0–3; 0=absent supply, 3=100% collateral supply). We performed univariable and multivariable adjusted analyses to explore the association between collaterals and CSVD. <h3>Results:</h3> 237 patients (66.1±16.8 years), 123(52%) female were included. Mean CS was 2(IQR 1–3). WMH (89%), basal ganglia EPVS (77%) and centrum semiovale EPVS (77%) were the most prevalent markers. Older age(beta=0.15, p&lt;0.0001) had the most potent association with individual CSVD markers and higher global CSVD burden. Older age(beta=−0.01, p=0.002) was associated with lower CS. Although a trend was detected between lower CS score and higher WMH burden, it did not reach statistical significance after adjusting for confounders (beta=−0.21, p=0.15). <h3>Conclusions:</h3> In this cohort of large vessel occlusion patients, we found that older age is associated with higher individual CSVD marker and global CSVD burden and poor collateral status. We did not find an overt association between CS and WMH or global CSVD burden. <b>Disclosure:</b> Dr. McMillan has nothing to disclose. Ms. Carvalho has nothing to disclose. Sarah Marchina has nothing to disclose. Dr. Cole has nothing to disclose. Dr. Selim has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MedRhythms Inc.. Dr. Lioutas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Qmetis. Dr. Lioutas has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association.

Association between White Matter Hyperintensities Burden and Cognitive Function in Adult Asymptomatic Moyamoya Disease.

Background and Purpose: White matter hyperintensities (WMH) caused by chronic cerebral hypoperfusion are common in Moyamoya disease (MMD) patients, but WMH burden with comprehensive cognition in adult asymptomatic MMD remains unknown. This study tried to investigate the association between the WMH burden and cognitive function in adult asymptomatic MMD. Methods: Sixty-four adult asymptomatic MMD patients without surgical revascularization were enrolled in this study and underwent a 3T MRI scan and complete cognitive tests from 2021 to 2022. WMH volume was extracted with brain anatomical analysis using the diffeomorphic deformation (BAAD) toolbox, which works on SPM 12 software. Multivariable linear regression analysis was performed to assess the association between WMH burden and cognitive function in asymptomatic MMD. Results: Firstly, our data showed that lower education levels and higher WMH burden were strongly related to global cognitive impairment after adjusting for other variables. Secondly, WMH severity was significantly associated with several domains of neurocognitive function, including memory, semantic memory, and executive function. Finally, when stratified by sex, the female participants with WMH severity had lower cognitive performance in all areas than male participants. Conclusions: These results suggest that WMH burden was highly correlated with global cognition, memory, semantic memory, and executive function in asymptomatic MMD. Especially in female participants, the relationship became more evident.