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Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults ( N  = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort ( N  = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets. Genomic analyses of large population-based cohorts uncover the genetic determinants of perivascular space burden, an MRI marker of cerebral small vessel disease, across the lifespan, and reveal potential pathways implicated in the etiology of stroke and dementia.

Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy. RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627. Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05). Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision. British Heart Foundation.

Abstract Study Objectives Obstructive sleep apnea (OSA) may increase the risk of dementia. A potential pathway for this risk is through cerebral small vessel disease (CSVD). In the context of an existing randomized trial of aspirin for primary prevention, we aimed to investigate OSA’s impact on CSVD imaging measures and explore whether aspirin effects these measures over 3 years that differ in the presence or absence of OSA. Methods A substudy of the aspirin in reducing events in the elderly (ASPREE) randomized placebo-controlled trial of low-dose aspirin. Community-dwelling participants aged 70 years and above, without cognitive impairment, cardiovascular disease, or known OSA completed an unattended limited-channel sleep study that calculated the oxygen desaturation index and apnea–hypopnea index. At baseline and 3 years later, volumes of white matter hyperintensities (WMH) and silent brain infarctions (SBI) were measured on 1.5 Tesla brain magnetic resonance imaging, and retinal vessel calibers were calculated from retinal vascular imaging. Results Mild and moderate/severe OSA was detected in 48.9% and 29.9%, respectively, of the 311 participants, who had a mean age of 73.7 years (SD 3.4 years), 38.6% female. OSA of any severity was not associated with WMH volumes, SBI, nor retinal vessel calibers at baseline, nor with change in these measures in the 277 participants with repeated measures acquired after 3 years. OSA of any severity did not interact with aspirin on change in these measures over 3 years. Conclusions In healthy older adults undiagnosed OSA was not associated with retinal vascular calibers and neuroimaging measures of CSVD. Clinical Trial Information ASPREE trial has registration with the International Standard Randomized Controlled Trial Number (ISRCTN) www.isrctn.com, ISRCTN83772183 and with www.clinicaltrials.gov, NCT01038583. SNORE-ASA has registration with the Australian New Zealand Clinical Trials Registry (ANZCTR) at www.anzctr.org.au, ACTRN12612000891820. Graphical Abstract Graphical Abstract

Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD. MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI). Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected. C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear. ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Background and purposeTo investigate the association of different status of cerebral small vessel disease (CSVD) and infarction number with recurrence after acute minor stroke and transient ischaemic attack (TIA).MethodsThis study was a post hoc analysis of the Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, and includes 886 patients with acute minor stroke and TIA. The status of CSVD and infarction number was recorded for each individual. Infarction number were classified as multiple acute infarctions (MAIs≥2), single acute infarction (SAI =1), and non-acute infarction (NAI =0). The CSVD burden were grouped into non-CSVD (0 score) and CSVD (1–4 score). The primary outcome was a recurrent stroke at the 1-year follow-up. The secondary outcomes were recurrent ischaemic stroke, composite vascular event (CVE), and TIA. We analyzed the relationships between different status of CSVD burden and infarction pattern with the risk of outcomes using multivariable Cox regression models.ResultsAmong all 886 patients included in present analysis, recurrent stroke was occurred in 93 (10.5%) patients during 1-year follow-up. After adjusted for all potential covariates, compared with patients with non-CSVD and NAI, patients with CSVD and MAIs were associated with approximately 9.5-fold increased risk of recurrent stroke at 1 year (HR 9.560, 95% CI 1.273–71.787, p=0.028). Similar results observed in ischaemic stroke and CVE.ConclusionThe status of CSVD and infarction number predicted recurrent stroke in patients with acute minor stroke and TIA, especially for those with coexistent CSVD and MAIs.

Background Statins have been recommended by several guidelines as the primary prevention medication for cardiovascular diseases. However, the benefits of statin therapy for cerebral small vessel disease (CSVD), particularly in adults ≥75 years of age, have not been fully evaluated. Methods We analyzed the data from a prospective population-based cohort study and a randomized, double-blind, placebo-controlled clinical trial to determine whether statin therapy might aid in slowing the progression of CSVD in adults ≥75 years of age. For the cohort study, 827 participants were considered eligible and were included in the baseline analysis. Subsequently, 781 participants were included in follow-up analysis. For the clinical trial, 227 participants were considered eligible and were used in the baseline and follow-up analyses. Results The white matter hyperintensities (WMH) volume, the WMH-to-intracranial volume (ICV) ratio, the prevalence of a Fazekas scale score ≥ 2, lacunes, enlarged perivascular spaces (EPVS), and microbleeds were significantly lower in the statin group than the non-statin group at baseline in the cohort study (all P  < 0.05). During the follow-up period, in both the cohort and clinical trial studies, the WMH volume and WMH-to-ICV ratio were significantly lower in the statin/rosuvastatin group than the non-statin/placebo group (all P  < 0.001). Statin therapy was associated with lower risk of WMH, lacunes, and EPVS progression than the non-statin therapy group after adjustment for confounders (all P  < 0.05). There was no statistically significant difference in the risk of microbleeds between the statin and non-statin therapy groups (all, P  > 0.05). Conclusions Our findings indicated that statin therapy alleviated the progression of WMH, lacunes, and EPVS without elevating the risk of microbleeds. On the basis of the observed results, we concluded that statin therapy is an efficient and safe intervention for CSVD in adults ≥75 years of age. Trial registration Chictr.org.cn: ChiCTR-IOR-17013557 , date of trial retrospective registration November 27, 2017 and ChiCTR-EOC-017013598 , date of trial retrospective registration November 29, 2017.

INTRODUCTION Neighborhood deprivation increases dementia risk, although mechanisms remain unclear. We tested a framework in which modifiable risk factors and cerebral small vessel disease (SVD) mediate the link between neighborhood deprivation and cognition. METHODS In 585 cognitively healthy midlife adults (ages 40–59), neighborhood deprivation was derived from postcodes, cognition was assessed using the COGNITO, lifestyle risk factors were measured using clinical assessments, and SVD (white matter hyperintensities, lacunes, microbleeds, perivascular spaces) was assessed on 3T magnetic resonance imaging. Multivariate analyses examined association pathways among these variables. RESULTS Neighborhood deprivation was associated with poorer cognition (r = 0.36, p < 0.001), greater prevalence of modifiable risk factors (r = 0.36, p < 0.001), and greater SVD burden (β = 0.18, p = 0.008). Serial mediation showed that the effects of deprivation on cognition were indirect, possibly operating via lifestyle risk and SVD, explaining 20% of the total effect, whereas SVD alone explained 28%. DISCUSSION Neighborhood disadvantage relates to poorer cognition, possibly mediated through vascular risk factors and cerebrovascular disease. Highlights Neighborhood deprivation linked to poorer cognition in healthy midlife adults Deprivation linked to small vessel disease (SVD) and modifiable risk factors (chiefly cardiovascular risk) Association between deprivation and cognition mediated by modifiable risk and SVD Mediation was exclusive to hypertensive SVD, but not cerebral amyloid angiopathy (CAA)‐related SVD

Background Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30 mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions. Methods This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7 days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0–3). Results Of 499 enrolled patients, 300 had MRI at median 7.5 days (interquartile range 7–8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80 mm Hg in first 24 h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume ( p  = 0.03), decrease in SBP ≥ 80 mm Hg from admission to day 1 ( p  = 0.03), and moderate-to-severe white matter disease ( p  = 0.01). Patients with DWI lesions had higher odds of severe disability at 1 month ( p  = 0.04), 6 months ( p  = 0.036), and 12 months ( p  < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found. Conclusions In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24 h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted.

Background The benefit-risk of statins in patients with lobar intracerebral hemorrhage (ICH) is under investigation in the StATins Use in intRacerebral hemorrhage patieNts (SATURN) trial. The relationship between statin use in ICH survivors, MRI markers of cerebral small vessel disease (CSVD), and outcomes such as recurrent ICH or major adverse cardiovascular or cerebrovascular events (MACCE) is unclear. The ancillary study, SATURN-MRI, intends to evaluate the interrelationship between statin use, the progression of MRI markers of CSVD, and cognitive and functional outcomes. Additionally, SATURN-MRI aims to assess whether baseline MRI markers of CSVD interact with statin continuation for the outcomes of recurrent ICH or MACCE in patients with lobar ICH. Methods A target of 894 SATURN participants will undergo a baseline MRI within 7 days of randomization and a repeat MRI at the end of the 24-month follow-up period. Any SATURN subject without contraindication to MRI has the option to participate in SATURN MRI. MRIs will be reviewed by blinded central raters to assess for the presence and burden of markers of CSVD and their progression. The primary outcome is new cerebral microbleeds and/or sulci with cortical superficial siderosis identified on T2*-weighted (GRE, SWI or SWAN) images between baseline and end-study MRI. Additional outcomes include the progression of white matter hyperintensity and incidence of covert infarcts. Discussion The results will provide insights about the interrelationship between the effects of statins, progression of MRI markers of CSVD, and functional and cognitive outcomes. They might lead to the validation of MRI markers as tools to assist with individualized decision-making regarding the effects of statins continuation/discontinuation in patients with lobar ICH. Trial registration ClinicalTrials.gov NCT03936361. SATURN Trial was originally registered on May 1, 2019 and modified on February 28, 2022.

Cerebral small vessel disease (cSVD) is correlated with a high risk of stroke and cognitive impairment. Previous studies between heart rate variability (HRV) and cSVD revealed paradoxical results. The authors aimed to investigate the relationship between HRV and cSVD using Mendelian randomization analysis. Genetic instruments for HRV were obtained from previous genome‐wide association studies. They applied inverse variance‐weighted analysis, weighted median analysis, simple median analysis, and Mendelian randomization–Egger regression to evaluate the associations of HRV with white matter hyperintensity (WMH) and small vessel stroke (SVS) in the UK Biobank neuroimaging dataset and the MEGASTROKE genome‐wide association study dataset. Two genetically predicted traits of HRV (the root mean square of the successive differences of inter beat intervals [RMSSD] and the peak‐valley respiratory sinus arrhythmia or high frequency power [pvRSA/HF]) were suggestively associated with WMH (β 0.26, 95% confidence interval [CI] 0.04–0.49, p = .02; β 0.14, 95% CI 0.02–0.27, p = .03, respectively). Genetically predicted traits of HRV were not significantly associated with SVS. This study provides genetic support for a suggestive causal effect of HRV (RMSSD, pvRSA/HF) on WMH but not SVS.