Hyperintensity Burden Research Articles

White Noise—Is Anxiety in Late-Life Associated With White Matter Hyperintensity Burden?

We investigated the relationship between anxiety phenotypes (global anxiety, worry, and rumination) and white matter hyperintensities (WMH), with special consideration for the roles of age and executive function (EF). Our hypotheses were 1) anxiety phenotypes would be associated with WMH and 2) EF would moderate this relationship. Cross-sectional. Participants were recruited from the local community (Pittsburgh, PA). We recruited 110 older adults (age ≥ 50) with varying worry severity and clinical comorbidity. Not applicable. Demographics (age, sex, race, education), clinical measures (cumulative illness burden, global anxiety, worry, and rumination), EF, and WMH quantified with magnetic resonance imaging. Lower global anxiety and worry severity were significantly correlated with higher WMH volume, though the global anxiety relationship was not significant after controlling for age. Rumination as not associated with WMH burden. EF was not correlated with either global anxiety, worry, rumination, or WMH. However, in those with advanced age and/or greater WMH burden, there was an association between worry and EF as well as EF and WMH. Longitudinal studies are needed in order to clarify the complex interactions between anxiety phenotypes, WMH, and EF.

Vascular mechanisms leading to progression of mild cognitive impairment to dementia after COVID-19: Protocol and methodology of a prospective longitudinal observational study.

Mild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population worldwide. Patients with MCI have an annual conversion rate to dementia of 15-20%. Thus, conditions that increase the conversion from MCI to dementia are of the utmost public health concern. The COVID-19 pandemic poses a significant impact on our aging population with cognitive decline as one of the leading complications following recovery from acute infection. Recent findings suggest that COVID-19 increases the conversion rate from MCI to dementia in older adults. Hence, we aim to uncover a mechanism for COVID-19 induced cognitive impairment and progression to dementia to pave the way for future therapeutic targets that may mitigate COVID-19 induced cognitive decline. A prospective longitudinal study is conducted at the University of Oklahoma Health Sciences Center. Patients are screened in the Department of Neurology and must have a formal diagnosis of MCI, and MRI imaging prior to study enrollment. Patients who meet the inclusion criteria are enrolled and followed-up at 18-months after their first visit. Visit one and 18-month follow-up will include an integrated and cohesive battery of vascular and cognitive measurements, including peripheral endothelial function (flow-mediated dilation, laser speckle contrast imaging), retinal and cerebrovascular hemodynamics (dynamic vessel retinal analysis, functional near-infrared spectroscopy), and fluid and crystalized intelligence (NIH-Toolbox, n-back). Multiple logistic regression will be used for primary longitudinal data analysis to determine whether COVID-19 related impairment in neurovascular coupling and increases in white matter hyperintensity burden contribute to progression to dementia.

Blood-Brain Barrier Breakdown is a Sensitive Biomarker of Cognitive and Language Impairment in Patients with White Matter Hyperintensities.

Similar white matter hyperintensities (WMH) burden may have varied cognitive outcomes in patients with cerebral small vessel disease (CSVD). This study aimed to evaluate whether blood-brain barrier (BBB) permeability is associated with cognitive impairment (CI) heterogeneity in patients with WMH. We recruited 51 participants with WMH. We evaluated WMH burden using the Fazekas scale and WMH volume on structural magnetic resonance imaging (MRI), and assessed BBB permeability using dynamic contrast-enhanced (DCE)-MRI. We used permeability-surface area product (PS) from the Patlak model to represent BBB permeability. All patients underwent Mini-Mental State Examination (MMSE), Boston Naming Test (BNT) and animal verbal fluency test (VFT) for cognitive assessment. We divided patients into CI and non-CI groups based on their MMSE scores (< 27 or ≥ 27) and used multiple linear regression models to investigate the associations between MRI parameters and cognitive function. Patients in the two groups did not differ in Fazekas scores and WMH volume. However, patients in the CI group showed significantly higher PS in the WMH regions than those in non-CI group (1.89 × 10-3 versus 1.00 × 10-3, p = 0.032 in periventricular WMH [PVWMH]; 1.27 × 10-3 versus 0.74 × 10-3, p = 0.043 in deep WMH [DWMH]), indicating the breakdown of BBB in the CI group. In all patients with WMH, increased BBB permeability in PVWMH and DWMH was significantly associated with lower cognitive and language function after adjustment for age, education level (EL) and intracranial volume (ICV). In the CI group, this correlation remained significant. WMH volume was not associated with cognitive performance in either all patients or those with CI. BBB impairment might be a more sensitive indicator for cognitive and language dysfunction than WMH volume in patients with WMH and possibly explains the heterogeneity of cognitive performance in patients with similar WMH burden.

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.

White Matter Hyperintensity Trajectories in Patients With Progressive and Stable Mild Cognitive Impairment.

White matter hyperintensities (WMH) are pathologic brain changes that are associated with increased age and cognitive decline. However, the association of WMH burden with amyloid positivity and conversion to dementia in people with mild cognitive impairment (MCI) is unclear. The aim of this study was to expand on this research by examining whether change in WMH burden over time differs in amyloid-negative (Aβ-) and amyloid-positive (Aβ+) people with MCI who either remain stable or convert to dementia. To examine this question, we compared regional WMH burden in 4 groups: Aβ+ progressor, Aβ- progressor, Aβ+ stable, and Aβ- stable. Participants with MCI from the Alzheimer Disease Neuroimaging Initiative were included if they had APOE ɛ4 status and if amyloid measures were available to determine amyloid status (i.e., Aβ+, or Aβ-). Participants with a baseline diagnosis of MCI and who had APOE ɛ4 information and amyloid measures were included. An average of 5.7 follow-up time points per participant were included, with a total of 5,054 follow-up time points with a maximum follow-up duration of 13 years. Differences in total and regional WMH burden were examined using linear mixed-effects models. A total of 820 participants (55-90 years of age) were included in the study (Aβ+ progressor, n = 239; Aβ- progressor, n = 22; Aβ+ stable, n = 343; Aβ- stable, n = 216). People who were Aβ- stable exhibited reduced baseline WMH compared with Aβ+ progressors and people who were Aβ+ stable at all regions of interest (β belongs to 0.20-0.33, CI belongs to 0.03-0.49, p < 0.02), except deep WMH. When examining longitudinal results, compared with people who were Aβ- stable, all groups had steeper accumulation in WMH burden with Aβ+ progressors (β belongs to -0.03 to 0.06, CI belongs to -0.05 to 0.09, p < 0.01) having the largest increase (i.e., largest increase in WMH accumulation over time). These results indicate that WMH accumulation contributes to conversion to dementia in older adults with MCI who are Aβ+ and Aβ-.

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases

BackgroundNeuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases.MethodsFive hundred thirteen participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss.ResultsAlthough NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson’s disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities.ConclusionsIn participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Association of Dual-Task Gait Cost and White Matter Hyperintensity Burden Poststroke: Results From the ONDRI

Background Acute change in gait speed while performing a mental task [dual-task gait cost (DTC)], and hyperintensity magnetic resonance imaging signals in white matter are both important disability predictors in older individuals with history of stroke (poststroke). It is still unclear, however, whether DTC is associated with overall hyperintensity volume from specific major brain regions in poststroke. Methods This is a cohort study with a total of 123 older (69 ± 7 years of age) participants with history of stroke were included from the Ontario Neurodegenerative Disease Research Initiative. Participants were clinically assessed and had gait performance assessed under single- and dual-task conditions. Structural neuroimaging data were analyzed to measure both, white matter hyperintensity (WMH) and normal appearing volumes. Percentage of WMH volume in frontal, parietal, occipital, and temporal lobes as well as subcortical hyperintensities in basal ganglia + thalamus were the main outcomes. Multivariate models investigated associations between DTC and hyperintensity volumes, adjusted for age, sex, years of education, global cognition, vascular risk factors, APOE4 genotype, residual sensorimotor symptoms from previous stroke and brain volume. Results There was a significant positive global linear association between DTC and hyperintensity burden (adjusted Wilks’ λ = .87, P = .01). Amongst all WMH volumes, hyperintensity burden from basal ganglia + thalamus provided the most significant contribution to the global association (adjusted β = .008, η2 = .03; P = .04), independently of brain atrophy. Conclusions In poststroke, increased DTC may be an indicator of larger white matter damages, specifically in subcortical regions, which can potentially affect the overall cognitive processing and decrease gait automaticity by increasing the cortical control over patients’ locomotion.

Increased white matter hyperintensity burden on MRI in autosomal dominant familial compared to young onset sporadic Alzheimer’s disease.

AbstractBackgroundWhite matter hyperintensities (WMH) on MRI may be observed in familial and sporadic AD. However, studies comparing WMH burden between these two groups are lacking. We conducted this study to evaluate the load and distribution of WMH in individuals with autosomal dominant familial Alzheimer’s disease (FAD) and young onset sporadic AD (SAD), their relationship to grey matter volumes and to neuropsychological test scores (NPT).MethodIn this cross‐sectional study, we evaluated global and local differences in WMH severity on MRI in 19 individuals with symptomatic FAD due to Presenilin 1 mutations, 20 individuals with young onset SAD and 19 healthy control subjects, controlling for age, cerebrovascular risk (CVR) and APOEε4 carrier status. Relationships between WMH, grey matter (GM) volumes and NPT were also investigated.ResultThe FAD group had higher WMH load in all the areas considered apart from juxta‐cortical and periventricular layers when compared to the SAD group. The two groups were well matched for disease duration and severity of cognitive impairment as assessed by the MMSE. APOEε4 genotype and cardiovascular risk factors acted as negative confounders in the identified differences in WMH volumes. There was no association between WMH and GM volumes or NPT in either AD group.ConclusionDespite their young age and minimal CVR, the FAD group in this study had a higher load of WMH compared to the SAD group, suggesting that WMH may reflect aspects of AD pathology that are particularly prominent in FAD. Our analysis suggests that APOEε4 genotype and cardiovascular risk factors may have a greater influence on WMH burden in SAD than in FAD. Furthermore, we did not identify a correlation between WMH load and GM volumes in either group, suggesting that WMH are not merely correlates of GM pathology in AD but may represent independent features of the disease.

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.

Association of Blood Lipid Profile Components with White Matter Hyperintensity Burden in Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) refers to a common cerebrovascular disease and white matter hyperintensities (WMHs) constitute a typical feature of CSVD. However, there has not been a large number of studies investigating the relationship between lipid profile components and WMHs. Altogether, 1019 patients with CSVD were enrolled at the First Affiliated Hospital of Zhengzhou University between April 2016 to December 2021. Baseline data were collected for all patients, including demographic characteristics and clinical data. WMH volumes were evaluated by two experienced neurologists using the MRIcro software. Multivariate regression analysis was used to investigate the relationship among the severity of WMHs, blood lipids and common risk factors. Altogether, 1019 patients with CSVD were enrolled, including 255 in the severe WMH group and 764 in the mild WMH group. After including age, sex and blood lipids to construct a multivariate logistic regression equation, we observed that the severity of WMHs was independently predicted by low-density lipoprotein (LDL), homocysteine level and history of cerebral infarction. We used WMH volume, a highly accurate measure, to assess its relationship with lipid profiles. The WMH volume increased with a decrease in LDL. This relationship was more significant, especially among the subgroups of patients aged <70 years and men. Patients with cerebral infarction and higher homocysteine levels were more likely to have higher WMH volumes. Our study has provided a reference for clinical diagnosis and therapy, especially for discussing the role of blood lipid profiles in the pathophysiology of CSVD.

White matter hyperintensities burden in the frontal regions is positively correlated to the freezing of gait in Parkinson's disease.

Previous studies have reported that white matter hyperintensities (WMHs) are associated with freezing of gait (FOG), but it is not clear whether their distribution areas have correlations with FOG in Parkinson's disease (PD) and the potential influencing factors about WMHs. Two hundred and forty-six patients with PD who underwent brain MRI were included. Participants were divided into PD with FOG (n = 111) and PD without FOG (n = 135) groups. Scheltens score was used to assess the WMHs burden in the areas of deep white matter hyperintensities (DWMHs), periventricular hyperintensities (PVHs), basal ganglia hyperintensities (BGHs), and infratentorial foci of hyperintensities (ITF). Whole brain WMHs volume was evaluated by automatic segmentation. Binary logistic regression was used to evaluate relationships between WMHs and FOG. The common cerebrovascular risk factors that may affect WMHs were evaluated by mediation analysis. There were no statistical differences between PD with and without FOG groups in whole brain WMHs volume, total Scheltens score, BGHs, and ITF. Binary logistic regression showed that the total scores of DWMHs (OR = 1.094; 95% CI, 1.001, 1.195; p = 0.047), sum scores of PVHs and DWMHs (OR = 1.080; 95% CI, 1.003, 1.164; p = 0.042), especially the DWMHs in frontal (OR = 1.263; 95% CI, 1.060, 1.505 p = 0.009), and PVHs in frontal caps (OR = 2.699; 95% CI, 1.337, 5.450; p = 0.006) were associated with FOG. Age, hypertension, and serum alkaline phosphatase (ALP) are positively correlated with scores of DWMHs in frontal and PVHs in frontal caps. These results indicate that WMHs distribution areas especially in the frontal of DWMHs and PVHs play a role in PD patients with FOG.

Analysis of clinical and imaging characteristics of patients with freezing of gait in cerebral small vessel disease (P11-5.004)

<h3>Objective:</h3> This study aims to study the clinical and imaging characteristics of patients with freeing of gait (FOG) in Cerebral small vessel disease (CSVD). <h3>Background:</h3> FOG is prevalent in Parkinson’s disease in those with severe gait disorders. However, little is known about vascular FOG in patients with CSVD. <h3>Design/Methods:</h3> The current study is a case-control study. Symptomatic CSVD patients were recruited. Patients with FOG (CSVD-FOG) and without FOG (CSVD-no-FOG) were categorized into two groups. The differences of clinical and imaging characteristics in these two groups were studied. <h3>Results:</h3> In 444 symptomatic CSVD patients with gait testing records, 24 were CSVD-FOG. 72 CSVD-no-FOG patients were matched according to age and sex. Prevalence of vascular risk factors including hypertension, diabetes mellitus, and hyperlipidemia were not significantly different between two groups. In CSVD-FOG groups, 83.3% were claimed about gait disorder, and had a higher percentage of urinary disorders and impaired cognitive functions compared with CSVD-no-FOG. Patients with apathy were not different between two groups. In assessing quantitative gait parameters, CSVD-FOG patients had slower gait speed, shorter gait stride and gait length, lower gait height and wider gait width. For CSVD imaging burdens, the CSVD-FOG had similar white matter hyperintensity burden with CSVD-no-FOT. However, CSVD-FOG had higher prevalence of silent brain infarction (SBI) and cerebral microbleeds (CMBs) in location of whiter matter and brain stem. <h3>Conclusions:</h3> CSVD-FOG patients had severe clinical symptoms of gait disorder, cognitive impairment and urinary problems, as well as higher imaging burdens of SBI and CMBs in whiter matter and brain stem. <b>Disclosure:</b> Dr. Su has nothing to disclose. Miss Mao has nothing to disclose. Jiangxia Zhang has nothing to disclose. Mr. Zhu has nothing to disclose. Fei Han has nothing to disclose. Ming Yao has nothing to disclose. Lixin Zhou has nothing to disclose. Jun Ni has nothing to disclose. Dr. Fan has nothing to disclose. Feng Tian has nothing to disclose. Yi-Cheng Zhu has nothing to disclose.

Higher Lifetime Exposure to Gonadal Hormones is Associated With Lower White Matter Hyperintensities Burden: A UK Biobank Study in Post-Menopausal Women (P6-5.006)

<h3>Objective:</h3> The aim of this study was to examine the relationship between lifetime exposure to endogenous and exogenous gonadal hormones on white matter hyperintensities (WMH) in post-menopausal women. <h3>Background:</h3> The onset of menopause accelerates the development of brain biomarkers of small vessel disease, such as WMH, supporting the cerebrovascular-protective effects of hormones. However, whether this effect is influenced by lifetime exposure to hormones is unclear. <h3>Design/Methods:</h3> Two measures of lifetime endogenous hormone exposure (ENHE) were explored: 1) cumulative number of years with a natural menstrual cycle and 2) cumulative number of live childbirths in women having never received hormone replacement therapy (HRT, n=6039). For exogenous hormone exposure (EXHE): 1) the use of oral HRT and 2) topical HRT (n=246). WMH volume was obtained from preprocessed T2-FLAIR images. <h3>Results:</h3> In a linear model adjusted for intracranial volume, age, oral contraceptive use, socio-demographics, and cardiovascular risk factors, both ENHEcycle and EMNHEparity were negatively associated with WMH (R2 = 0.30, F = 241, DF = 6027, p&lt;0.0001; βparity = −0.025, p = 0.006; βcycle = −0.003 p = 0.017). For EXHE, women who received topical HRT had significantly lower WMH volume than oral HRT (t=1.99, p= 0.048) after correcting for intracranial volume, age, socio-demographics, cardiovascular risk factors, ENHEcycle and ENHEparity. <h3>Conclusions:</h3> Our results provide further evidence that lifetime exposure to endogenous hormones appears to have an independent protective effect on WMH burden, and extending this with exogenous topical HRT may confer additional protection. The stronger effect of parity may be due to prolonged exposure to elevated estrogen resulting in long-lasting structural or functional changes in the small cerebral vessels. <b>Disclosure:</b> Dr. Perron has nothing to disclose. Miss Cote has nothing to disclose. Prof. Lepage has nothing to disclose. Dr. Bocti has nothing to disclose. Kevin Whittingstall has nothing to disclose.

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.

Associations of deep medullary veins with vascular risk factors, laboratory indicators, and cerebral small vessel disease: A population-based study.

Deep medullary veins (DMVs) were not considered a typical marker of cerebral small vessel disease (CSVD) due to limited understanding of their involvement in pathology of CSVD. This study aimsto investigate potential vascular risk factors for DMVs and their associations with CSVD. In total, 1909 community-dwelling participants were included in this analysis. Demographic, clinical, laboratory, and imaging data were collected. DMV scores (0-18) werecalculated as the sum of bilateral frontal, parietal, and occipital regional scores using a semiquantitative visual scale (0-3). The presence, total burden, and imaging markers of CSVD were assessed. Linear regression analyses were conducted to explore potential vascular factors for DMV scores. Binary and ordinal logistic regression analyses were performed to investigate the associations of DMV scores with CSVD and its markers. Mean age was 61.8(SD 6.5)years, and 1027 (53.8%) of participants were men. The median DMV scores were14 (IQR 12-16). DMV scores wererelated to age, male sex, body mass index, diastolic blood pressure, hypercholesterolaemia, atrial fibrillation, current drinking, total cholesterol, triglycerides, low-density lipoprotein, hemoglobin A1c, leukocytes, lymphocytes, hemoglobin, and platelets (p<.05). DMV scores wereassociated with the presence and total burden of CSVD (Rothwell's scale), modified white matter hyperintensity burden, and enlarged perivascular spaces in centrum semiovale (p<.05). However, these associations between DMV scoresand CSVD disappeared after adjusting for potential confounders. Several conventional vascular factors were associated with DMVs. The relationship between DMVs and CSVD was vulnerable, suggesting decreased visible and discontinuous DMVs may differ mechanistically from traditional markers of CSVD.

Low neighborhood deprivation buffers against hippocampal neurodegeneration, white matter hyperintensities, and poorercognition.

There is increasing recognition that socioeconomic inequalities contribute to disparities in brain and cognitive health in older adults. However, whether neighborhood socioeconomic status (SES) buffers individuals with low individual SES against neurodegeneration, cerebrovascular disease, and poorercognitive function is not well understood. Here, we evaluated whether neighborhood deprivation (Townsend deprivation index) interacted with individual SES (composite household income and education levels) on hippocampus volume, regional cortical thickness, white matter hyperintensities, and cognition in 19,638 individuals (mean age = 54.8) from the UK Biobank. We found that individuals with low individual SES had the smallest hippocampal volumes, greatest white matter hyperintensity burden, and poorest cognition if they were living in high deprivation neighborhoods but that these deleterious effects on brain and cognitive function were attenuated if they were living in low deprivation neighborhoods (p for interactions < .05). While neighborhood deprivation did not interact with individual SES to influence regional cortical thickness, higher neighborhood deprivation was independently associated with lower cortical thickness in 16 regions (false discovery rate q < .05). Across multiple brain indices and cognitive function analyses, we found converging evidence suggesting that low neighborhood deprivation may have a neuroprotective effect against neurodegeneration, cerebrovascular pathology, and cognitive impairment, particularly in vulnerable individuals with low household income and education levels.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. White matter hyperintensity burden at baseline predicted cognitive butnotmotordecline inearly to mid-stage PD. The motor decline observed after 2 years in these olderadultswithPDis probably related to the primary neurodegenerative process than comorbid white matter pathology.

Brain aerobic glycolysis and resilience in Alzheimer disease

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.

Abstract WP179: Menopause Is Related To Accelerated Accumulation Of White Matter Hyperintensity Burden In Small Artery Occlusion Strokes

Introduction: Sex differences in white matter hyperintensity (WMH) burden exist and are affected by menopausal status. Here, we investigate the difference in age-related WMH burden with respect to stroke subtype (TOAST) and menopausal status. Methods: We reviewed 4443 patients across 18 sites with information on age, TOAST, prior stroke, hypertensive (HTN) and diabetic (DM2) status, smoking history, and WMH and brain volume. WMH load was defined as the ratio between WMH and brain volume and Box Cox transformed. All variables underwent z-score standardization. Pre- (PRM), peri- (PEM), and post-menopausal (POM) categories were defined using age (PEM: 45-59 years). WMH load was modeled using age, prior stroke, HTN, DM2, smoking status, and interaction terms between age, TOAST, and sex/menopausal status. A second model included TOAST as an independent variable. Models accounted for acquisition site and were compared using Bayes Information Criteria (BIC). Significance was set to p&lt;0.05. Results: Of all patients (median age: 64), 42% were female (6%, 10%, and 26% PRM, PEM, and POM, respectively). The model without TOAST as an independent variable was selected (BIC 9237 compared to 9779). Our results (Figure 1) show (beta [95% confidence interval]) prior stroke (0.22 [0.15-0.29]), smoking (0.09 [0.04-0.14]), HTN (0.19 [0.14-0.25]), DM2 (0.08 [0.01-0.15]), and age (0.54 [0.43-0.65]) as independent factors. TOAST did not affect age-related WMH load in men and PRE. Effects of age were modified for small artery occlusion strokes in POM (0.40 [0.03-0.76]), increasing the age-related disease burden. Conclusions: Menopausal status affects age-related WMH burden for different TOAST.

Abstract WMP99: Effect Of Intensive Glycemic Control And Microvascular Complications On White Matter Hyperintensity Progression

Background: Individuals with diabetes mellitus are prone to neurologic complications from prolonged hyperglycemia. While the effects of hyperglycemia are well documented, aggressive correction of systemic glucose levels may have deleterious effects. We aimed to identify whether diabetic treatment goals influenced the progression of white matter hyperintensities (WMH) burden in a meaningful way in a cohort of known diabetics. We hypothesized that more aggressive treatment would yield less WMH progression. Methods: We included individuals enrolled in the ACCORD-MIND trial who had a baseline and 40-month follow-up MRI with volumetric quantification of WMH in mL. The primary outcome was WMH progression, defined as the baseline adjusted difference in WMH between the two scans. The exposure was the interaction between a microvascular outcome (ACCORD composite of photocoagulation or vitrectomy for retinopathy, acute renal failure, ESRD/dialysis, or serum creatinine ≥3.3 mg/dL) and glucose treatment arm (standard therapy with target A1c 7-7.9 or intensive therapy with target A1c 6-6.9). We fit a linear regression model adjusted for baseline age, sex, race/ethnicity, history of cardiovascular disease including stroke, Hgb A1c, and mean systolic blood pressure between the MRIs. Results: We included 502 individuals (mean age 62.7±5.7 years, 46.2% female, 67.9% White), of which 29 had a microvascular outcome and 229 were randomized to the intensive glucose arm. The interaction between microvascular outcome*glucose arm was highly significant (p=0.009). In individuals without a microvascular outcome, WMH progression was not significantly different in the intensive vs. standard glucose arm (difference of 0.3 mL, 95% CI -0.2, 0.7; p=0.299), but in those with a microvascular outcome there was 2.6 mL more WMH progression in the intensive than standard glucose arm (95% CI 0.9-4.4; p=0.003). Conclusion: Although hypothesis-generating, these results suggest that in diabetic individuals with microvascular disease, intensive glucose lowering may have a harmful effect on WMH progression. Our data is similar to other findings amongst the ACCORD trial suggesting intensive glucose control may not be benign in all diabetics.