Progression Of White Matter Hyperintensities Research Articles

Topological relationships between perivascular spaces and progression of white matter hyperintensities: A pilot study in a sample of the Lothian Birth Cohort 1936.

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves−1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves−1–2: 73%; 2–3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear.

Patterns of progression of cerebral small vessel disease markers in older adults of Amerindian ancestry: a population-based, longitudinal prospective cohort study.

BackgroundProgression of cerebral small vessel disease (cSVD) markers has been studied in different races/ethnic groups. However, information from individuals of Amerindian ancestry is lacking. We sought to evaluate progression patterns of cSVD markers in community-dwelling older adults of Amerindian ancestry.MethodsFollowing a longitudinal prospective study design, participants of the Atahualpa Project Cohort aged ≥ 60 years received a baseline brain MRI and clinical interviews. Those who also received a brain MRI at the end of the study were included. Poisson regression models were fitted to assess cSVD markers progression according to their baseline load after a median follow-up of 6.5 ± 1.4 years. Logistic regression models were fitted to assess interrelations in the progression of the different cSVD markers at the end of the study.ResultsThe study included 263 individuals (mean age: 65.7 ± 6.2 years). Progression of white matter hyperintensities (WMH) was noticed in 103 (39%) subjects, cerebral microbleeds in 25 (12%), lacunes in 12 (5%), and enlarged basal ganglia-perivascular spaces (BG-PVS) in 56 (21%). Bivariate Poisson regression models showed significant associations between WMH severity at baseline and progression of WMH and enlarged BG-PVS. These associations became non-significant in multivariate models adjusted for clinical covariates. Logistic regression models showed interrelated progressions of WMH, cerebral microbleeds and enlarged BG-PVS. The progression of lacunes was independent.ConclusionsPatterns of cSVD marker progression in this population of Amerindians are different than those reported in other races/ethnic groups. The independent progression of lacunes suggests different pathogenic mechanisms with other cSVD markers.

Arterial stiffness and progression of white matter hyperintensities of presumed vascular origin in community-dwelling older adults of Amerindian ancestry: The Atahualpa Project Cohort

ObjectiveArterial stiffness – as measured by the aortic pulse wave velocity (aPWV) – has been associated with biomarkers of cerebral small vessel disease (cSVD), in particular with white matter hyperintensities (WMH) of presumed vascular origin. Most studies have been conducted in White and Asian populations, and information on this relationship in other ethnic groups is limited. We designed a longitudinal prospective study to assess the impact of aPWV on WMH progression in individuals of Amerindian ancestry. Patients and methodsParticipants of the Atahualpa Project Cohort were assessed at baseline with aPWV determinations, clinical interviews and brain MRIs. At the end of the study, brain MRIs were repeated in order to ascertain WMH progression. Poisson regression models adjusted for demographics and cardiovascular risk factors were fitted to assess WMH progression incidence rate by baseline levels of aPWV. ResultsThe study included 260 individuals aged ≥60 years (mean age: 65.6 ± 6.1 years; 57 % women). The mean aPWV was 9.9 ± 1.5 m/s. Follow-up MRIs revealed WMH progression in 102 (39 %) individuals after a mean follow-up of 6.5 ± 1.4 years. Unadjusted analysis showed a higher baseline aPWV among subjects that developed WMH progression compared with those who did not (p < 0.001). Multivariate Poisson regression models showed an increased WMH progression rate among individuals in the second (IRR: 2.06; 95 % C.I.: 1.09–3.88) and third (IRR: 2.75; 95 % C.I.: 1.29–5.87) tertiles of aPWV compared with those in the first tertile. ConclusionsaPWV is associated with WMH progression, suggesting a link between atherosclerosis and cSVD in the study population.

Associations between cerebral blood flow and progression of white matter hyperintensity in community-dwelling adults: a longitudinal cohort study.

BackgroundWhite matter hyperintensity (WMH) is prevalent in elderly populations. Ischemia is characterized by a decline in cerebral blood flow (CBF) and may play a key role in the pathogenesis of WMH. However, the association between CBF reduction and WMH progression remains controversial. This study aimed to investigate the association between CBF and the progression of WMH at a 2-year follow-up of community-based, asymptomatic adults in a longitudinal cohort study across the lifespan.MethodsAsymptomatic adults who participated in a community-based study were recruited and underwent brain structural and perfusion magnetic resonance imaging (MRI) at baseline and at a 2-year follow-up visit. The CBF was measured on pseudo-continuous arterial spin-labeling (pCASL) MRI. The WMH was evaluated on T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images. Tissue segmentation was conducted on T1-weighted (T1W) images to derive binary masks of gray matter and normal-appearing white matter. Linear mixed effect models were conducted to analyze the cross-sectional and longitudinal associations between CBF and WMH.ResultsA total of 229 adults (mean age 57.3±12.6 years; 94 males) were enrolled at baseline, among whom 84 participants (mean age 54.1±11.9 years; 41 males) completed a follow-up visit with a mean time interval of 2.77±0.44 years. At baseline, there was a decreasing trend in gray matter (GM) CBF with an increase of WMH burden (P=0.063), but this association was attenuated after adjusting for age (P=0.362). In the longitudinal analysis, baseline WMH volume was significantly associated with the reduction of perfusion in GM [coefficient =−1.96, 95% confidence interval (CI): −3.25 to −0.67; P=0.004] and normal appearing white matter (coefficient =−0.99, 95% CI: −1.66 to −0.31; P=0.005) during follow-up. On the contrary, neither baseline CBF in GM (P=0.888) nor normal appearing white matter (P=0.850) was associated with WMH progression. In addition, CBF changes within WMH were significantly associated with both baseline (coefficient =−0.014, 95% CI: −0.025 to −0.003; P=0.017) and progression (coefficient =−1.01, 95% CI: −1.81 to −0.20; P=0.015) of WMH volume.ConclusionsA WMH burden was not found to be directly associated with cortex perfusion at baseline due to the effects of age on both CBF and WMH. However, baseline WMH volume could predict the reduction of perfusion.

August 2022 Stroke Highlights

August 2022 Stroke Highlights

Age related increase in internal jugular vein size parallels temporal development of periventricular white matter hyperintensities.

Age-related white matter hyperintensities are associated with cognitive impairment and dementia. Venous insufficiency has recently been proposed as a potential mechanism for the development of periventricular white matter hyperintensities based on the neuroanatomic distribution. The current study assesses age related changes of the internal jugular veins and its association with white matter hyperintensities. A retrospective study was performed assessing patients with computed tomography angiography (CTA) and magnetic resonance imaging (MRI) within a 4-week window. The size of the internal jugular veins, straight sinus, vein of Galen and internal cerebral veins were measured on the CT angiography. A normalized neck venous ratio was developed. Burden of white matter hyperintensities were quantified on MRI using periventricular/deep Fazekas scores. Association was assessed using correlation analysis and multrivariate linear modeling, and differences between groups were assessed using t test, ANOVA or Kruskal-Wallis test, using p < 0.05 for significance. One hundred eighty-two patients were included with a mean age of 65.2 ± 16.8 (51.6% females). Age was correlated with the normalized neck venous ratio (rs =0.25, p < 0.001), and, with both, the periventricular Fazekas (rs =0.63, p < 0.001) and the deep Fazekas (rs =0.57, p < 0.001) grades. The periventricular Fazekas score was positively correlated with the normalized neck venous ratio (rs =0.21, p=0.003), but not significant on multivariate analysis accounting for age. The internal jugular veins demonstrate age related increase in size, paralleling the progression of periventricular white matter hyperintensities. Age remains the strongest predictor of white matter hyperintensities. Further work is needed to evaluate any causal role of venous changes on white matter hyperintensities.

Excessive Visit-to-Visit Small and Dense Low-Density Lipoproteins Elevate Cerebral Small Vessel Disease Progression Risk in the Elderly.

ObjectiveSmall and dense low-density lipoprotein (sdLDL) elevation may be among the most sensitive early biomarkers for nascent cardiovascular disease. This study, therefore, investigated the association between visit-to-visit changes in sdLDL and cerebral small vessel disease (CSVD) progression in older individuals, and the influence of Apolipoprotein E (APOE) genotype on this association.MethodsBetween April 2007 and July 2009, 1,143 participants ≥60 years old were recruited from the Shandong region of China, and sdLDL was measured at baseline and at each follow-up visit. White matter hyperintensities (WMHs), lacunes, microbleeds, and enlarged perivascular spaces (EPVSs) were assessed by magnetic resonance imaging. The APOE genotype was determined and participants were stratified as ε4-positive or ε4-negative.ResultsDuring an average follow-up of 86.0 months, 225 participants (19.7%) developed WMH progression, 193 (16.9%) lacune progression, 170 (14.9%) microbleed progression, and 185 (16.2%) EPVS progression. Compared with patients in the first (lowest) tertile of visit-to-visit mean sdLDL, those in the second and third tertiles demonstrated significantly greater risks of WMH progression (53.5 and 105.3% higher), lacune progression (53.3 and 60.8%), microbleed progression (47.2 and 127.6%), and EPVS progression (54.0 and 135.0%) after adjustment for confounders (all adjusted P values for trends <0.001). Compared with patients in the first tertile of visit-to-visit sdLDL SD, those in the second and third tertiles also demonstrated significantly greater risks of WMH progression (49.9% and 143.6%), lacune progression (75.3 and 178.0%), microbleed progression (12.7 and 64.7%), and EPVS progression (41.7 and 114.6%) after adjustment (all P < 0.001). There were significant and positive visit-to-visit mean sdLDL × visit-to-visit sdLDL SD, visit-to-visit mean sdLD×ε4-positive, visit-to-visit sdLDL SD×ε4-positive, and visit-to-visit mean sdLDL×visit-to-visit sdLDL SD×ε4-positive interactions influencing CSVD progression after confounder adjustment (all P < 0.05).ConclusionLarge and variable visit-to-visit changes in sdLDL are independent predictors of aggressive CSVD progression, and this association is strongly influenced by APOE ε4 allele genotype.

Association of Arterial Spin Labeling Parameters With Cognitive Decline, Vascular Events, and Mortality in a Memory-Clinic Sample

BackgroundCognitive decline in older adults has been attributed to reduced cerebral blood flow (CBF). Recently, the spatial coefficient of variation (sCoV) of ASL has been proposed as a proxy marker of cerebrovascular insufficiency. We investigated the association between baseline ASL parameters with cognitive decline, incident cerebrovascular disease, and risk of vascular events and mortality. Design, Setting, and ParticipantsAbout 368 memory-clinic patients underwent three-annual neuropsychological assessments and brain MRI scans at baseline and follow-up. MRIs were graded for white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), cortical infarcts, and intracranial stenosis. Baseline gray (GM) and white matter (WM) CBF and GM-sCoV were obtained with ExploreASL from 2D-EPI pseudo-continuous ASL images. Cognitive assessment was done using a validated neuropsychological battery. Data on incident vascular events (heart disease, stroke, transient ischemic attack) and mortality were obtained. ResultsHigher baseline GM-sCoV was associated with decline in the memory domain over 3 years of follow-up. Furthermore, higher GM-sCoV was associated with a decline in the memory domain only in participants without dementia. Higher baseline GM-sCoV was associated with progression of WMH and incident CMBs. During a mean follow-up of 3 years, 29 (7.8%) participants developed vascular events and 18 (4.8%) died. Participants with higher baseline mean GM-sCoV were at increased risk of vascular events. ConclusionsHigher baseline GM-sCoV of ASL was associated with a decline in memory and risk of cerebrovascular disease and vascular events, suggesting that cerebrovascular insufficiency may contribute to accelerated cognitive decline and worse clinical outcomes in memory clinic participants.

Dietary oily fish intake and progression of diffuse subcortical damage of vascular origin: A longitudinal prospective study in community-dwelling older adults.

Oily fish intake may reduce the progression of white matter hyperintensities (WMH) of presumed vascular origin due to their high content of omega-3 polyunsaturated fatty acids and other nutrients. However, information on this relationship is limited. We aimed to assess the association between oily fish intake and WMH progression in older adults living in rural coastal Ecuador. Participants of the Atahualpa Project Cohort received baseline clinical interviews and brain MRIs. Oily fish intake was calculated at every annual door-to-door survey from enrollment to the end of the study. Individuals who also received a follow-up brain MRI were included. Poisson regression models were fitted to assess the incidence rate ratio (IRR) of WMH progression according to the amount of oily fish intake, after adjusting for demographics, level of education and traditional vascular risk factors. The study included 263 individuals of Amerindian ancestry aged ⩾60 years (mean age: 65.7 ± 6.2 years; 57% women). The mean oily fish intake was 8.3 ± 4 servings per week. Follow-up MRIs demonstrated WMH progression in 103 (39%) individuals after a median follow-up of 6.5 years. A multivariate Poisson regression model showed an inverse relationship between oily fish intake and WMH progression (IRR: 0.89; 95% CI: 0.84-0.95; p < 0.001). A similar model also revealed an inverse relationship between tertiles of oily fish intake and probabilities of WMH progression, which became significant when individuals allocated to the third tertile were compared to those in the first and second tertiles. Study results show an inverse relationship between the amount of oily fish intake and WMH progression in frequent fish consumers of Amerindian ancestry.

Diabetes Mellitus-Related Neurobehavioral Deficits in Mice Are Associated With Oligodendrocyte Precursor Cell Dysfunction.

Recent clinical studies demonstrated an increase of the incidence of neurobehavioral disorders in patients with diabetes mellitus. Studies also found an association between severity of diabetes mellitus and the progression of white matter hyperintensity on magnetic resonance imaging, which conferred risk for developing cognitive impairment. Since oligodendrocyte precursor cells participated in the white matter repair and remodeling after ischemic brain injury, we explored whether hyperglycemia induced neurobehavioral deficits were associated with dysfunction of oligodendrocyte precursor cells. Adult male C57BL/6 mice (n = 40) were randomly divided into 4-week diabetes, 8-week diabetes, and control groups. Experimental diabetic mice were induced by streptozotocin injection. Learning and cognitive function, exploratory, anxiety and depression behaviors were assessed by Morris water maze, open field test, elevated plus maze, and tail suspension test, respectively. Immunofluorescence staining of neuron-glial antigen 2 and myelin basic protein were performed. Oligodendrocyte precursor cells were cultured in different glucose level to explore possible mechanism in vitro. The learning and cognitive function of 4-week and 8-week diabetic mice were attenuated compared to the control group (p < 0.05). The diabetic mice had less exploratory behavior compared to the control (p < 0.05). However, the diabetic mice were more likely to show anxiety (p < 0.05) and depression (p < 0.01) compared to the control. Further study demonstrated the number of oligodendrocyte precursor cells and the level of myelin basic protein expression were decreased in diabetic mice and the migration and survival ability were suppressed in the hyperglycemic environment in vitro (p < 0.05). Our results demonstrated that diabetes mellitus induced neurological deficits were associated with the decreased number and dysfunction of oligodendrocyte precursor cells.

High Social Risk Influence Progression of White Matter Hyperintensities of Presumed Vascular Origin: A Prospective Study in Community-Dwelling Older Adults.

Information on cerebrovascular consequences of high social risk, as determined by the social determinants of health, is limited. We sought to evaluate the impact of high social risk on the progression of white matter hyperintensities (WMHs) of presumed vascular origin. Following a longitudinal prospective study design, participants of the Atahualpa Project Cohort received baseline social risk determinations by means of social determinants of health components included in the Gijon's Social-Familial Evaluation Scale together with clinical interviews and brain magnetic resonance imagings. Those who also received follow-up brain magnetic resonance imaging at the end of the study were included. We used Poisson regression models adjusted for demographics, education levels and traditional cardiovascular risk factors to assess the incidence rate ratio of WMH progression according to the Gijon's Social-Familial Evaluation Scale score. The study included 263 individuals aged ≥60 years (mean age, 65.7±6.2 years; 57% women). The Gijon's Social-Familial Evaluation Scale mean score was 8.9±2.2 points. Follow-up magnetic resonance imagings revealed WMH progression in 103 (39%) individuals after a mean follow-up of 6.5 years (SD±1.4 years). Poisson regression models showed increased WMH progression rate among individuals in the third tertile of the Gijon's Social-Familial Evaluation Scale score compared with those in the first tertile (incidence rate ratio, 1.65 [95% CI, 1.05-2.61]; P=0.032). Separate Poisson regression models using individual social determinants of health components showed that poor social relationships (incidence rate ratio, 1.39 [95% CI, 1.10-1.77]; P=0.006) and deficient support networks (incidence rate ratio, 1.79 [95% CI, 1.19-2.69]; P=0.005) were independently associated with WMH progression, whereas family situation, economic status, and housing did not. Poor social relationships and deficient support networks were significantly associated with WMH progression in community-dwelling older adults living in a rural setting. Our findings may help planning cost-effective preventive policies to reduce progression of cerebral small vessel disease among vulnerable populations.

Effect of Antihypertensives by Class on Cerebral Small Vessel Disease: A Post Hoc Analysis of SPRINT-MIND.

Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining. Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years; P<0.001) and systolic blood pressure (128.3±11.0 versus 126.2±9.4 mm Hg; P=0.039). Seventy-two (48.3%) of the top tertile cohort and 177 (59.2%) of the remaining cohort were in the intensive blood pressure arm. Those within the top tertile of progression had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL (P<0.001). Use of angiotensin-converting enzyme inhibitors (odds ratio, 0.36 [95% CI, 0.16-0.79]; P=0.011) and dihydropyridine calcium channel blockers (odds ratio, 0.39 [95% CI, 0.19-0.80]; P=0.011) was associated with less WMH progression, although dihydropyridine calcium channel blockers lost significance when WMH was treated as a continuous variable. Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

Poststroke White Matter Hyperintensities and Physical Activity: A CANVAS Study Exploratory Analysis.

White matter hyperintensities (WMHs) are associated with poststroke cognitive decline and mortality. Physical activity (PA) may decrease WMH risk by reducing vascular risk factors and promoting cerebral perfusion. However, the association between poststroke PA and WMH progression remains unclear. We examined the association between PA and WMH volume 12 months after stroke, and between PA and change in WMH volume between 3 and 12 months after stroke. We included ischemic stroke survivors from the Cognition And Neocortical Volume After Stroke cohort with available brain magnetic resonance imaging and objective PA data. Total, periventricular, and deep WMH volumes (in milliliters) were estimated with manually edited, automated segmentations (Wisconsin White Matter Hyperintensities Segmentation toolbox). Moderate-to-vigorous intensity PA (MVPA) was estimated using the SenseWear® Armband. Participants with MVPA ≥30 min·d -1 were classified as "meeting PA guidelines." We used quantile regression to estimate the associations between PA (MVPA and meeting PA guidelines) with WMH volume at 12 months and change in WMH volume between 3 and 12 months after stroke. A total of 100 participants were included (median National Institutes of Health Stroke Scale 2; interquartile range, 1-4). MVPA was not associated with WMH volume. In univariable analysis, meeting PA guidelines was associated with lower total, periventricular, and deep WMH volumes by 3.0 mL (95% confidence interval (CI), 0.5-9.7 mL), 2.8 mL (95% CI, 0.5-7.1 mL), and 0.9 mL (95% CI, 0.1-3.0 mL), respectively. However, in multivariable analysis, meeting PA guidelines was not associated with WMH volume, and older age was associated with greater WMH volume at 12 months. PA was not associated with change in WMH volume. Meeting PA guidelines was associated with lower WMH volume at 12 months in univariable analysis, but not in multivariable analysis. Age consistently predicted greater WMH volume.

Decreased Nighttime Heart Rate Variability and Progression of White Matter Hyperintensities of Presumed Vascular Origin. A Prospective Study in Community-Dwelling Older Adults

ObjectivesEvidence on the role of autonomic dysfunction on white matter hyperintensities (WMH) progression is limited. This study aims to assess the impact of a low nighttime heart rate variability (HRV) on WMH progression in community-dwelling older adults. Materials and methodsFollowing a prospective longitudinal study design, all individuals aged ≥60 years enrolled in the Atahualpa Project Cohort from 2012 to 2019 were invited to receive baseline HRV determinations through 24-h Holter monitoring, together with clinical interviews and brain MRIs. These individuals were periodically followed by means of annual door-to-door surveys, and those who also received brain MRIs at the end of the study (May 2021) were included in the analysis. Poisson regression models, adjusted for relevant confounders, were fitted to assess the incidence rate ratio (IRR) of WMH progression according to nighttime standard deviation of normal-to-normal R-R intervals (SDNN). ResultsThis study included 254 individuals aged ≥60 years (mean age: 65.4 ± 5.9 years; 55% women). The mean nighttime SDNN was 116.8 ± 36.3 ms. Follow-up MRIs showed WMH progression in 103 (41%) individuals after a median follow-up of 6.5 years. In unadjusted analyses, nighttime SDNN was lower among participants who developed WMH progression than in those who did not (p < 0.001). A Poisson regression model, adjusted for relevant covariates, disclosed a significantly inverse association between nighttime SDNN and WMH progression (IRR: 0.99; 95% C.I.: 0.98–0.99; p = 0.014). ConclusionsStudy results show an inverse association between nighttime SDNN and WMH progression, and provide support for the role of sympathetic overactivity in this relationship.

Progression of cerebral white matter hyperintensities is related to leucocyte gene expression.

Cerebral white matter hyperintensities are an important contributor to ageing brain pathology. Progression in white matter hyperintensity volume is associated with cognitive decline and gait impairment. Understanding the factors associated with white matter hyperintensity progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression, and thus evaluated the relationship of blood leucocyte gene expression to progression of cerebral white matter hyperintensities. A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (interquartile range 3.5-8.2 years). White matter hyperintensity volumes were measured by semi-automated segmentation and percentage change in white matter hyperintensity per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in white matter hyperintensity volumes over time and baseline leucocyte gene expression was analysed. The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median white matter hyperintensity volume was 13.4 ml (SD 17.4 ml). The mean change in white matter hyperintensity volume was 12% per year. Patients were divided in quartiles by percentage change in white matter hyperintensity volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3 and 33.6% per year in quartile 4. There were 148 genes associated with changing white matter hyperintensity volumes over time (P < 0.05 r > |0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, focal adhesion kinase and SIGLEC1 were among the identified genes. The progression of white matter hyperintensity volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of white matter hyperintensity progression and the contribution to cognitive decline.

Abnormal Cerebrovascular Reactivity and Functional Connectivity Caused by White Matter Hyperintensity Contribute to Cognitive Decline

AimsThis study aimed to investigate the relationships of impaired cerebrovascular reactivity (CVR) and abnormal functional connectivity (FC) with white matter hyperintensity (WMH)-related cognitive decline.MethodsA total of 233 WMH subjects were recruited and categorized into WMH-I (n = 106), WMH-II (n = 72), and WMH-III (n = 55) groups according to Fazekas visual rating scale. All participants underwent neuropsychological tests and multimodal MRI scans, including 3D-T1, and resting-state functional magnetic resonance imaging (rs-fMRI). The alterations of CVR maps and FC were further explored.ResultsSubjects with a higher WMH burden displayed a lower CVR in the left medial occipital gyrus (MOG). The FC analysis using MOG as a seed revealed that the FC of the left insula, left inferior parietal lobule, and thalamus changed abnormally as WMH aggravated. After adjusting for age, gender, and education years, the serial mediation analysis revealed that periventricular white matter hyperintensity contributes indirectly to poorer Mini-Mental State Examination (MMSE) scores (indirect effect: β = −0.1248, 95% CI: −0.4689, −0188), poorer Montreal Cognitive Assessment (MoCA) (indirect effect: β = −0.1436, 95% CI: −0.4584, −0.0292) scores, and longer trail making tests A (TMT-A) (indirect effect: β = 0.1837, 95% CI: 0.0069, 0.8273) times, specifically due to the lower CVR of the left MOG and the higher FC of the left insula-MOG.ConclusionThe CVR decline of the left MOG and the abnormal FC of the left insula-MOG attributed to WMH progression were responsible for the poor general cognition (MMSE and MoCA) and information processing speed (TMT-A). The left MOG may act as a connection, which is involved in the processing of cognitive biases by connecting with the left insula-cortical regions in WMH individuals.

Longitudinal Changes in Global Cerebral Blood Flow in Cognitively Normal Older Adults: A Phase-Contrast MRI Study.

Characterization of blood supply changes in older individuals is important in understanding brain aging and diseases. However, prior studies largely focused on cross-sectional design, thus change in cerebral blood flow (CBF) could not be assessed on an individual level. To evaluate longitudinal short-term changes in global CBF in cognitively normal older adults. Prospective, longitudinal, and cohort. One-hundred twenty-seven cognitive-normal participants (mean age 69 ± 7 years, 47 males) underwent serial MRI with an average follow-up time of 2.1 years. 3 T phase-contrast (PC), three-dimensional magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) and fluid-attenuated inversion recovery (FLAIR) MRI. Total CBF was measured with PC MRI allowing assessment of quantitative flow in four major feeding arteries by a trained radiologist with >3 years' experience (O.K.). Brain volume was obtained from MPRAGE MRI and measured by T1-MultiAtlas MRICloud tool. The ratio between total CBF and brain volume yielded global CBF in mL/100 g/min. White matter hyperintensity (WMH) was measured automatically using a Bayesian probability approach on FLAIR. Linear mixed effect model was used to simultaneously assess cross-sectional age-differences and longitudinal age-changes in CBF. Spearman rank correlation was used to evaluate the relationship between CBF change and WMH progression. A P-value of <0.05 (two-tailed) was considered significant. Global CBF decreased with age at a longitudinal rate of -0.56 mL/100 g/min/year (95% confidence interval [CI]: -1.09, -0.03), compared to a cross-sectional rate of -0.26 mL/100 g/min/year (95% CI: -0.41, -0.11). Changes in CBF were significantly associated with progression of WMH (Spearman rank correlation r=-0.25), as those participants who had a more rapid CBF reduction had greater increases in WMH volumes and the relationship remained significant when adjusting for baseline vascular risk scores. Additionally, age-related changes in whole-brain volume were found to be -0.151%/year (95% CI: -0.186, -0.116). These findings suggest that brain aging in older adults is accompanied by a rapid longitudinal reduction in CBF, the rate of which is associated with white matter damage. 1 TECHNICAL EFFICACY STAGE: 2.

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study

BackgroundMarkers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We...

Abstract WP181: Statin Usage Increases White Matter Hyperintensities: A Post-hoc Analysis Of SPRINT-MIND

Introduction: White matter hyperintensity (WMH), a radiographic marker of cerebral small vessel disease, is typically treated by modification of conventional cerebrovascular risk factors. However, the influence of dyslipidemia and the impact of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) on WMH is less certain. The goal of this study was to evaluate the influence of statins on progression of WMH over a four-year interval. Methods: We performed a post-hoc analysis of the SPRINT-MIND database for participants who had completed a baseline and a 4-year follow-up brain MRI with volumetric WMH calculations. Follow-up visits within this time window included data on medications, including statins. We defined statin usage as no therapy (0% of visits), partial therapy (1 - 99% of visits) or full therapy (100% of visits) based on this self-reported data. WMH progression was calculated as the difference in WMH volume between the two scans and then segmented into tertiles. ANOVA and chi-squared tests were used for continuous and categorical variables with adjustments made for variables known to influence WMH development. Results: 425 individuals were included in this study: 53% (226/425) without statins use, 27% (115/425) with partial use and 20% (84/425) and full use. Demographic characteristics and baseline WMH volumes were similar amongst the cohort. With increasing statin use, a significant reduction in LDL was identified. Those with full statin use were significantly more likely to be in the top tertile of worse WMH progression (adjusted OR 2.30, 95% CI 1.11 - 4.77, p = 0.025). Conclusion: SPRINT-MIND participants prescribed a statin were nearly 2.5 times more likely to be within the top tertile of WMH progression over four years, despite adjustment for synergistic risk factors and improvement in LDL.

Abstract 102: Effect Of Antihypertensives By Class On Cerebral Small Vessel Disease: A Post-hoc Analysis Of SPRINT-MIND

Introduction: Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, though it is unclear whether this reduction occurs due to blood pressure control or antihypertensive class-specific pleotropic effects. The goal of this study was to investigate the influence of antihypertensive medication class on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. Methods: Using the SPRINT-MIND dataset, we completed a post-hoc analysis of participants who completed a baseline and 4-year follow-up brain MRI with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the MRIs. A percentage of follow-up time participants were prescribed each of the eleven classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between two scans and, to address skew, dichotomized into a top tertile (greatest) accumulation and combined middle and bottom tertiles (slowest) accumulation. Results: Among 448 individuals included in this study, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 years versus 65.7±7.3 years, p&lt;0.001) and systolic blood pressure (128.3±11.0 mmHg versus 126.2±9.4 mmHg, p=0.039). The high had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL for the slowest progressors (p&lt;0.001). Only angiotensin converting enzyme inhibitors (ACE-I) (OR 0.34, 95% CI 0.15-0.75, p=0.008) and dihydropyridine calcium channel blockers (d-CCB) (OR 0.39, 95% CI 0.19-0.81, p=0.012) were independently associated with lower odds of being in the greatest progression grouping. Conclusions: Amongst hypertensive participants in the SPRINT-MIND trial, ACE-I and d-CCB antihypertensive medications were associated with significantly lower odds of being in the highest tertile of WMH progression compared with other antihypertensive classes, independent of blood pressure control.