Background Subtle blood-brain barrier (BBB) leakage has been detected in small vessel disease (SVD). While established methods rely on gadolinium-based contrast agents (GBCA), diffusion-weighted arterial spin labelling (DW-ASL) is a promising alternative which assesses water exchange rate (kw) without injected contrast. However, DW-ASL has not been widely applied in sporadic SVD. We aimed to determine how kw varied with GBCA BBB leakage measures, baseline and 1-year change in SVD burden. Methods We recruited patients with mild ischaemic stroke (lacunar or cortical) all characterised for SVD features. We assessed kw using DW-ASL and GBCA measures of BBB leakage (permeability-surface area product (PS), blood plasma volume and exchange rate of GBCA) using dynamic-contrast enhanced MRI. We used separate linear regression models to assess how kw varied with GBCA-derived metrics, baseline and 1-year change in WMH volume in co-variate-adjusted analyses. Results We included 24 with complete MRI (61±10 years; 71% male). Patients with higher kw tended to have more severe baseline SVD (e.g. subcortical grey matter (SGM): B=14.59 min-1/%WMH volume, 95% confidence interval (95%CI)=-1.00,28.18, p=0.04) and greater 1-year increase (B=0.0013 %WMH volume increase/min-1, 95%CI=-0.0001, 0.0026, p=0.06). We generally found kw and GBCA BBB leakage measures were not meaningfully associated (e.g. SGM kw∼PS: B=-0.23 min-1/10-4min-1, 95%CI=-7.47, 7.01, p=0.95). Conclusion BBB water exchange estimated using DW-ASL tended to be greater with higher WMH burden and progression, suggesting kw may be a sensitive measure of BBB dysfunction in SVD. However, non-concordance between kw and GBCA metrics suggests the two methods probe different aspects of BBB function.

The Diffusion Tensor Imaging along the Perivascular Space (DTI-ALPS) index has been proposed as a non-invasive marker of glymphatic function, but its specific utility in the context of SVD and cognition remains unclear. In 189 patients with mild ischaemic stroke (age 38.8-86.3 years), we computed DTI-ALPS and quantified imaging markers of SVD: enlarged perivascular spaces (PVS), white matter hyperintensities (WMH), and cerebral microbleeds. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA). Linear regression models were used to explore the associations between DTI-ALPS, SVD markers and cognition. We found that lower DTI-ALPS values were associated with higher volume of basal ganglia PVS (β = -0.026, 95% CI [-0.052, -0.001]) and with male sex (-0.058, [-0.105, -0.010]). DTI-ALPS was also negatively associated with fractional anisotropy (FA) (-0.062, [-0.084, -0.040]) and mean diffusivity (MD) (-0.056, [-0.092, -0.021]) and positively associated with both neurite density (NDI) (0.033 [0.001,0.065]) and orientation dispersion (ODI) (0.079 [0.061,0.097]) indices. Higher WMH volume predicted lower DTI-ALPS in patients with non-lacunar stroke (-0.079 [-0.118, -0.041]). No associations were observed between DTI-ALPS values and microbleeds or MoCA scores. These findings suggest that, in post-stroke SVD, the DTI-ALPS index may primarily reflect local tissue fluid changes and microstructure damage, rather than serving as a specific, direct indicator of glymphatic function or cognitive impairment. Future research using region-specific and physiologically dynamic imaging approaches may be better suited to capture the glymphatic contributions to stroke and SVD pathology.

Objective: Cranial artery stenosis and dilatation are distinct large artery phenotypes that often coexist with cerebral small vessel disease (cSVD), yet their downstream microvascular functional correlates remain unclear. Methods: In the prospective Mild Stroke Study 3, we recruited patients with lacunar or mild non-lacunar stroke. At baseline, large artery stenosis (LAS), basilar artery dolichoectasia (BADE), and intracranial arterial diameters were assessed. Multimodal MRI quantified cerebrovascular reactivity (CVR), blood-brain barrier (BBB) permeability, plasma volume fraction, and intracranial pulsatility. cSVD markers were evaluated at baseline and 1 year. Associations between large artery phenotypes and vascular function were examined with multivariable regression. Mediation analyses tested whether vascular dysfunction linked large artery pathology to cSVD progression. Results: Among 224 participants (mean age 66.0, SD 11.2 years; 66.5% men), BADE (n=36, 16.1%) was independently associated with lower CVR in normal-appearing white matter (NAWM; β −0.01, 95% CI −0.016 to −0.004, P=0.003). Larger mean intracranial arterial diameter was associated with lower CVR in NAWM and white matter hyperintensities (WMH), while showing a U-shaped association with BBB permeability. LAS (n=46, 20.5%) was unrelated to CVR, BBB permeability, or pulsatility, but was associated with higher plasma volume in WMH. CVR in NAWM partially mediated the association between BADE and both baseline cSVD burden and 1-year progression. Interpretation: Large artery dilatation may serve as a macroscopic signal of small-vessel dysfunction, being associated with lower CVR and altered BBB permeability. Reduced CVR in NAWM partially mediated the impact of dolichoectasia on cSVD progression and may represent a potential therapeutic target. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement UK Dementia Research Institute ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Southeast Scotland Regional Ethics Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors UK Dementia Research Institute

BACKGROUND:Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small-vessel disease (cSVD) remain contentious. We investigated the associations of large-artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. METHODS:We prospectively recruited patients with lacunar or mild nonlacunar stroke, with demographic, stroke-related, cognitive, functional, and magnetic resonance imaging (index and incident infarcts, cSVD markers) assessments at baseline and 1 year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia was defined by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated from multivariable logistic, linear, and proportional odds regression models adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large-artery pathology and cSVD. RESULTS:Among 229 patients (mean age, 65.9±11.1 years; 131 [57.2%] lacunar stroke), LAS and basilar artery dolichoectasia were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio, 0.49 [95% CI, 0.23-0.99]) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, basilar artery dolichoectasia was strongly associated with lacunar stroke (odds ratio, 4.67 [95% CI, 1.87-13.14]), higher cSVD scores (ordinal analysis; odds ratio, 2.57 [95% CI, 1.28-5.25]), incident infarcts (75% subcortical; odds ratio, 2.29 [95% CI, 1.01-5.14]), and greater progression of white matter hyperintensities over 1 year (β, 0.15 [95% CI, 0.01-0.29] per log10-transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. CONCLUSIONS:cSVD, including lacunar stroke, was unrelated to LAS but strongly associated with dolichoectasia and wider arteries. These findings support a nonatheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted.

Cerebrovascular reactivity (CVR), a promising marker of neurovascular responsiveness, is commonly measured using blood-oxygenation-level-dependent magnetic resonance imaging (BOLD-MRI) during a vasoactive gas challenge. While CVR magnitude (vascular response strength) has been widely studied, CVR delay (response time) is comparatively underexplored yet may provide valuable insight into vascular dysfunction across several neurological conditions. We systematically reviewed publications assessing delay using gas-challenge BOLD-MRI up to October 2025, identifying 200 relevant papers. Only 44 (22%) papers investigated delay in detail; the remainder only applied delay correction to improve CVR magnitude accuracy. Findings in disease were mixed and often limited by small sample sizes and methodological differences. Hypercapnic stimuli, typically delivered via fixed-inspired or fixed-expired methods, were most commonly used. While cross-correlation was the most popular delay estimation method, several alternatives, including haemodynamic response function fitting and Fourier analysis, have been proposed, but systematic comparisons against standard delay estimation methods remain limited, especially in clinical populations. Our review highlights inconsistencies in delay measurement and interpretation, with delay mostly treated as a confounder rather than a meaningful physiological parameter. Greater methodological validation and harmonisation are needed to realise the potential of CVR delay as a novel biomarker of brain health and disease.

BACKGROUND AND OBJECTIVES:Disturbed sleep is common after stroke, yet its relationship with cerebral small vessel disease (SVD) and cognitive performance in the stroke population, particularly patients with TIA/mild stroke who are on the milder end of the cerebrovascular spectrum, remains understudied. We aim to examine the associations of self-reported sleep metrics with neuroimaging markers of SVD and cognitive performance in patients with TIA/mild stroke from 2 prospective stroke cohorts. METHODS:We studied adult patients with TIA/mild stroke (NIH Stroke Scale [NIHSS] score <7) who were consecutively recruited from Mild Stroke Study 3 (MSS3, University of Edinburgh) and the stroke cohort (the University of Hong Kong, HKU) during 2018-2022. Both MSS3 (N = 211) and HKU (N = 211) cohorts assessed SVD burden visually on brain MRI, cognitive performance using Montreal Cognitive Assessment (MoCA), and sleep quality using a structured sleep questionnaire at baseline visit. The primary outcomes were SVD markers, and the secondary outcome was total MoCA score. The associations of sleep metrics with SVD markers and cognitive performance were assessed using regression models, adjusted for demographics, vascular risk factors, history of depression and stroke, and study sites. RESULTS:In 422 patients (65.6 ± 11.8 years, 67% male, median NIHSS score 1.0), longer in-bed time was independently associated with greater global SVD and Fazekas periventricular white matter hyperintensity (WMH) burden: odds ratio (OR)summary SVD score = 1.27 per 1-SD increase (95% CI 1.05-1.53), false discovery rate (FDR)-adjusted p = 0.04; ORperiventricular WMH = 1.53 per 1-SD increase (95% CI 1.18-2.00), p = 0.003. Longer sleep duration was independently associated with presence of cerebral microbleeds: OR = 1.42 per 1-SD increase (95% CI 1.09-1.87), p = 0.04. Longer in-bed time was associated with a lower total MoCA score after covariate adjustment: standardized β = -0.58 (95% CI -0.99 to -0.16), p = 0.02. DISCUSSION:Disturbed sleep, including longer in-bed time and longer sleep duration, was cross-sectionally associated with greater SVD burden and worse cognitive performance in patients with TIA/mild stroke. Future longitudinal studies are warranted to validate our findings.

Background White matter hyperintensity (WMH) progression is well documented; WMH regression is more contentious, which might reflect differences in defining WMH change. We compared four existing WMH change definitions in one population to determine the effect of definition on WMH regression.Methods We recruited patients with minor non-disabling ischaemic stroke who underwent MRI 1-3 months after stroke and 1 year later. We assessed WMH volume (in absolute mL and % intracranial volume) and applied four different definitions, including two thresholds (based on SD or mL), percentile and quintile approaches.Results In 198 participants, mean age 65.5 (SD=11.13), baseline WMH volume was 15.46 mL (SD=19.2), the mean net WMH volume change was 0.98 mL (SD=2.84), range -7.98 to +12.84 mL. Proportion regressing/stable/progressing WMH were threshold 1 (SD), 29.8%/55.6%/14.6%; threshold 2(mL), 29.8%/16.7%/53.5%; percentile approach, 28.3%/21.2%/50.5%. The quintile approach includes five groups with quintile 3 reflecting no change (N=40), quintiles 1 and 2 any WMH decrease (N=80) and quintiles 4 and 5 any WMH increase (N=78).Conclusions Different WMH change definitions cause big differences in how participants are categorised; additionally, non-normal WMH distribution precludes use of some definitions. Consistent use of an appropriate definition would facilitate data comparisons, particularly in clinical trials of potential WMH treatments.

Cerebral small vessel disease (cSVD) is characterised by white matter hyperintensities (WMH) and contributes to stroke and dementia. Cerebrovascular reactivity (CVR) declines with worsening cSVD but estimates of CVR from brain scans give limited information about the coordination of individual arterioles or venules. Retinovascular reactivity can provide separate data about arterioles and venules, but it is not known if retinovascular reactivity correlates with CVR in people with cSVD. We aimed to assess retinal vascular reactivity in people with cSVD and explore associations with WMH and CVR in a cross-sectional study. Participants had retinal photographs and magnetic resonance brain imaging (MRI) before and during inhalation of 6% CO 2 in air. We recruited 60 participants. 48 provided analysable retinal vessel reactivity data. Retinal arteriole/venule ratio was inversely related to WMH severity (adjusted R2 = 0.47 β–5.2 95%CI–7.9 to −2.5) and directly related to CVR (adjusted R2 = 0.21 β0.15 95%CI 0.04 to 0.25). In general, participants whose arteriole/venule ratio increased with CO 2 had milder WMH and higher (better) CVR, while participants whose arteriole/venule ratio decreased had more severe WMH and lower (worse) CVR. Retinovascular reactivity to CO 2 inhalation in people with cSVD suggests loss of normal arteriovenous coordination and inefficient perfusion of the capillary bed.

BACKGROUND:Cerebral small vessel disease (SVD) causes up to 45% of dementias and 25% of ischemic strokes, but the understanding of vascular pathophysiology is limited. We aimed to investigate the contribution of pulsatility of intracranial arteries, veins, and cerebrospinal fluid (CSF) and cerebral blood flow to long-term imaging and clinical outcomes in SVD. METHODS:We prospectively recruited participants in Edinburgh/Lothian, Scotland, with lacunar or nonlacunar ischemic stroke (modified Rankin Scale score ≤2, as controls) and assessed medical and brain magnetic resonance imaging characteristics at baseline and 1 year (2018-2022). We used phase-contrast magnetic resonance imaging to measure flow and pulsatility in major cerebral vessels and CSF to investigate independent associations with baseline white matter hyperintensity (WMH) and perivascular space (PVS) volumes and their progression, as well as with recurrent stroke, functional, and cognitive outcomes at 1 year. We applied linear, logistic, and ordinal regression models in our analysis. RESULTS:We recruited 210 participants; 205 (66.8% male; aged 66.4±11.1 years) had useable data. In covariate-adjusted analyses, higher baseline arterial pulsatility was associated with larger volumes of baseline WMH (B=0.26 [95% CI, 0.08-0.44]; P=0.01) and basal ganglia PVS (B=0.12 [95% CI, 0.04-0.20]; P<0.01) but not with their change at 1 year (WMH: B=0.01 [95% CI, -0.05 to 0.06]; P=0.78; basal ganglia PVS: B=0.02 [95% CI, -0.04 to -0.07]; P=0.62) or cognition, dependency, or recurrent stroke at 1 year. Neither cerebral blood flow nor CSF pulsatility was related to baseline SVD severity, WMH/PVS progression, or clinical outcomes at 1 year. CONCLUSIONS:Associations between vascular/CSF pulsatility, cerebral blood flow, WMH/PVS, and clinical SVD features are complex. The lack of association between intracranial arterial, venous, or CSF pulsatility, cerebral blood flow, and WMH or PVS longitudinal change in this large, covariate-adjusted analysis questions the presumption that high intracranial vascular pulsatility causes SVD and its progression, consistent with other recent longitudinal studies. Intracranial pulsatility may differ from systemic vascular measures in their cause-pathogenic role(s) in SVD and should be considered separately.

BACKGROUND AND OBJECTIVES:White matter hyperintensities (WMHs) are the commonest imaging marker of cerebral small vessel disease (SVD) and a major cause of cognitive decline and vascular dementia. WMHs typically accumulate over time, but recent studies show they can also regress, but potential clinical benefits have received little attention. We examined progressing, stable, and regressing WMH in people with stroke-related SVD and the effect on cognitive outcomes. METHODS:We recruited patients with minor nondisabling ischemic stroke (modified Rankin score ≤2) from stroke services into our prospective longitudinal observational study. Participants underwent cognitive assessment and brain MRI within 3-month poststroke and 1 year later. We gathered information on vascular risk factors, stroke severity, global cognition (Montreal Cognitive Assessment [MoCA]), processing speed and executive functioning (Trail Making Test [TMT] A and B, and the B/A ratio with ratio ≥3 reflecting executive dysfunction), and the Letter Digit Substitution Test. We measured WMH volumes at baseline and 1 year and categorized net WMH volume change into quintiles: Q1 (most regression), Q3 (stable), and Q5 (most progression). We applied repeated-measures linear mixed models to analyze longitudinal WMH and cognitive changes, adjusting for age, sex, premorbid intelligence, stroke severity, disability, white matter structural integrity, and baseline WMH volume. RESULTS:One hundred ninety-eight of 229 participants had WMH volumes available at both time-points. At baseline, the mean age was 67.5 years (SD = 10.9), with 33% female. Mean net WMH volume change per quintile was Q1 -1.79 mL (SD = 1.54), Q2 -0.27 mL (0.20), Q3 0.35 mL (0.18), Q4 1.43 mL (0.48), and Q5 5.31 mL (3.07). MoCA deteriorated the most in participants with most WMH progression (Q5) (estimated β -0.428 [95% CI -0.750 to -0.106]), compared with stable WMH (Q3), with no clear deterioration in those with most WMH regression (Q1). TMT B/A ratio improved in participants with most WMH regression (Q1; -0.385 [-0.758 to -0.012]). DISCUSSION:WMH regression was associated with preserved global cognition and improved executive function, compared with stable WMH, while WMH progression was associated with global cognitive decline. Cognitive benefits of WMH regression suggest that WMH-affected tissue can recover, may explain variance in cognitive outcomes, offer an important intervention target, and should be assessed in other populations and longer follow-up times.

ObjectiveAfter a recent small subcortical infarct (RSSI), some patients develop perilesional or remote hyperintensities (‘caps/tracks’) to the index infarct on T2/FLAIR MRI. However, their clinical relevance remains unclear. We investigated the clinicoradiological correlates of ‘caps/tracks’, and their impact on long‐term outcomes following RSSI.MethodsWe identified participants with lacunar stroke and MRI‐confirmed RSSI from 3 prospective studies. At baseline, we collected risk factors, RSSI characteristics, small vessel disease (SVD) features, and microstructural integrity on diffusion imaging. Over 1‐year, we repeated MRI and recorded ‘caps/tracks’ blinded to other data. We evaluated predictors of ‘caps/tracks’, and their association with 1‐year functional (modified Rankin Scale score ≥2), mobility (Timed Up‐and‐Go), cognitive outcomes (Montreal Cognitive Assessment [MoCA] score <26), and recurrent cerebrovascular events (stroke/transient ischemic attack/incident infarct) using multivariable regression.ResultsAmong 185 participants, 93 (50.3%) developed ‘caps/tracks’ first detected at median 198 days after stroke. ‘Caps/tracks’ were independently predicted by baseline factors: larger RSSI, RSSI located in white matter, higher SVD score, and higher mean diffusivity in normal‐appearing white matter (odds ratio [OR] [95% confidence interval {CI}], 1.15 [1.07–1.25], 6.01 [2.80–13.57], 1.77 [1.31–2.44], 1.42 [1.01–2.03]). At 1 year, ‘cap/track’ formation was associated with worse functional outcome (OR: 3.17, 95% CI: 1.28–8.22), slower gait speed (β: 0.13, 95% CI: 0.01–0.25), and recurrent cerebrovascular events (hazard ratio [HR]: 2.05, 95% CI: 1.05–4.02), but not with cognitive impairment.Interpretation‘Caps/tracks’ after RSSI are associated with worse clinical outcomes, and may reflect vulnerability to progressive SVD‐related injury. Reducing ‘caps/tracks’ may offer early efficacy markers in trials aiming to improve outcome after lacunar stroke. ANN NEUROL 2025

Background and ObjectivesWhite matter hyperintensities (WMHs) are the commonest imaging marker of cerebral small vessel disease (SVD) and a major cause of cognitive decline and vascular dementia. WMHs typically accumulate over time, but recent studies show they can also regress, but potential clinical benefits have received little attention. We examined progressing, stable, and regressing WMH in people with stroke-related SVD and the effect on cognitive outcomes.MethodsWe recruited patients with minor nondisabling ischemic stroke (modified Rankin score <= 2) from stroke services into our prospective longitudinal observational study. Participants underwent cognitive assessment and brain MRI within 3-month poststroke and 1 year later. We gathered information on vascular risk factors, stroke severity, global cognition (Montreal Cognitive Assessment [MoCA]), processing speed and executive functioning (Trail Making Test [TMT] A and B, and the B/A ratio with ratio >= 3 reflecting executive dysfunction), and the Letter Digit Substitution Test. We measured WMH volumes at baseline and 1 year and categorized net WMH volume change into quintiles: Q1 (most regression), Q3 (stable), and Q5 (most progression). We applied repeated-measures linear mixed models to analyze longitudinal WMH and cognitive changes, adjusting for age, sex, premorbid intelligence, stroke severity, disability, white matter structural integrity, and baseline WMH volume.ResultsOne hundred ninety-eight of 229 participants had WMH volumes available at both time-points. At baseline, the mean age was 67.5 years (SD = 10.9), with 33% female. Mean net WMH volume change per quintile was Q1 -1.79 mL (SD = 1.54), Q2 -0.27 mL (0.20), Q3 0.35 mL (0.18), Q4 1.43 mL (0.48), and Q5 5.31 mL (3.07). MoCA deteriorated the most in participants with most WMH progression (Q5) (estimated beta -0.428 [95% CI -0.750 to -0.106]), compared with stable WMH (Q3), with no clear deterioration in those with most WMH regression (Q1). TMT B/A ratio improved in participants with most WMH regression (Q1; -0.385 [-0.758 to -0.012]).DiscussionWMH regression was associated with preserved global cognition and improved executive function, compared with stable WMH, while WMH progression was associated with global cognitive decline. Cognitive benefits of WMH regression suggest that WMH-affected tissue can recover, may explain variance in cognitive outcomes, offer an important intervention target, and should be assessed in other populations and longer follow-up times.

BACKGROUND AND OBJECTIVES:MRI-visible brain perivascular spaces (PVSs) represent an imaging feature of cerebral small vessel disease that is associated with hypertension, diabetes, and poor sleep quality and correlated with cognitive impairment and dementia. Although research shows that sleep apnea and sleep disruption are associated with PVS volumes, few studies have investigated whether sleep apnea treatment can modify this association. We aimed to test the hypothesis that continuous positive airway pressure (CPAP) therapy can change the trajectory of PVS progression in adults with sleep apnea. METHODS:In this longitudinal observational treatment study, we recruited participants from sleep clinics at the Royal Infirmary of Edinburgh and Sunnybrook Health Sciences Centre with moderate-to-severe hypoxemic sleep apnea (apnea hypopnea index ≥15 and oxygen desaturation index ≥10). Before and after a minimum 4 months of CPAP, we obtained pulse oximetry (WatchPAT) and performed brain MRI, with quantification of PVS volumes in the basal ganglia (BG) and centrum semiovale (CSO). We used linear mixed-effects models to test for associations between CPAP usage, changes in PVS volumes, and baseline sleep apnea severity. RESULTS:Among 64 participants (mean age 54.7 years old, 31% female) who were followed for more than a median (interquartile range) of 140 (124-163) days, there were 2 subgroups: 37 participants who used CPAP optimally (≥4 hours a night ≥70% of nights) and 27 participants who did not. Optimal CPAP usage modified the association between visit and BG PVS volumes (interaction estimate = -0.007, SE = 0.002, p = 0.007). Participants with the poor CPAP adherence experienced an increase in BG PVS (estimate = +0.005, SE = 0.001, p = 0.002). Participants with consistent CPAP adherence experienced stabilization of BG PVS volumes (estimate = -0.001, SE = 0.001, p = 0.42). This benefit was more pronounced with increased hypoxemia (mean interaction estimate = +0.004, SE = 0.001, p = 0.0009) and increased AHI (interaction estimate = -0.002, SE = 0.00009, p = 0.008). DISCUSSION:Optimal CPAP use may moderate the effects of sleep apnea on trajectories of MRI-visible PVS volumes. Although the observational nonrandomized nature of this study is a limitation, these data suggest that CPAP may be an effective means of slowing PVS dysfunction progression, a key correlate of aging and dementia, in adults with sleep apnea. TRIAL REGISTRATION INFORMATION:NCT03410095. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that, in patients with moderate-to-severe sleep apnea, optimal adherence to CPAP treatment stabilizes the progression of BG PVS volume.

Cerebral small vessel diseases (cSVDs) contribute significantly to stroke and dementia. Advanced 7 T MRI techniques have revealed small vessel dysfunction in cSVD patients, linked to global white matter damage cross-sectionally. However, it remains unclear whether these vascular deficits predict progressive tissue damage. This longitudinal study examined the spatial relationship between local vascular function and white matter damage progression in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Twenty-two patients underwent baseline small vessel function assessment using 7 T MRI. Voxelwise blood-oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR) to a hypercapnic was evaluated. White matter changes were assessed on 3 T MRI over two years, analyzing mean diffusivity changes and conversion of normal-appearing white matter to white matter hyperintensities (WMH). Results showed significant global increases in white matter damage over time. Voxelwise analysis revealed that lower baseline BOLD-CVR magnitude and higher dispersion were associated with increased white matter damage and WMH progression at specific locations at follow-up. However, whole-brain vascular function measures did not predict white matter changes at a global level. These findings suggest that local vascular function plays a key role in white matter damage progression in CADASIL, highlighting the importance of regional vascular health in cSVDs.

BACKGROUND AND OBJECTIVES:Factors associated with cerebral small vessel disease (SVD) progression, including incident infarcts, are unclear. We aimed to determine the frequency of incident infarcts over 1 year after minor stroke and their relation to baseline SVD burden, vascular risks, and recurrent stroke and cognitive outcomes. METHODS:We recruited patients with lacunar or nondisabling cortical stroke. After diagnostic imaging, we repeated structural MRI at 3-6 monthly intervals for 12 months, visually assessing incident infarcts on diffusion-weighted imaging or FLAIR. We used logistic regression to determine associations of baseline vascular risks, SVD score, and index stroke subtype with subsequent incident infarcts. We assessed cognitive and functional outcomes at 1 year using Montreal Cognitive Assessment (MoCA) and modified Rankin scale (mRS), adjusting for baseline age, mRS, MoCA, premorbid intelligence, and SVD score. RESULTS:We recruited 229 participants, mean age 65.9 (SD 11.1). Over half of all participants, 131 of 229 (57.2%) had had an index lacunar stroke. From baseline to 1-year MRI, we detected 117 incident infarcts in n = 57/229 (24.8%) participants. Incident infarcts were mainly of the small subcortical (86/117 [73.5%] in n = 38/57 [66.7%]) vs cortical infarct subtype (n = 19/57 [33.3%]). N = 39/57 participants had incident infarcts at 1 visit; 18 of 57 at 2 or more visits; and 19 of 57 participants had multiple infarcts at a single visit. Only 7 of 117 incident infarcts corresponded temporally to clinical stroke syndromes. The baseline SVD score was the strongest predictor of incident infarcts (adjusted odds ratio [OR] 1.87, 95% CI 1.39-2.58), while mean arterial pressure was not associated. All participants with incident infarcts were prescribed an antiplatelet or anticoagulant. Lower 1-year MoCA was associated with lower baseline MoCA (β 0.47, 95% CI 0.33-0.61), lower premorbid intelligence, and older age. Higher 1-year mRS was associated with higher baseline mRS only (OR 5.57 [3.52-9.10]). Neither outcome was associated with incident infarcts. DISCUSSION:In the year after stroke in a population enriched for lacunar stroke, incident infarcts occurred in one-quarter and were associated with worse baseline SVD. Most incident infarcts detected on imaging did not correspond to clinical stroke/transient ischemic attack. Worse 1-year cognition and function were not associated with incident infarcts.

OBJECTIVE:Cerebral small vessel diseases (SVDs) are associated with cerebrovascular dysfunction, such as increased blood-brain barrier leakage (permeability surface area product), vascular pulsatility, and decreased cerebrovascular reactivity (CVR). No studies assessed all 3 functions concurrently. We assessed 3 key vascular functions in sporadic and genetic SVD to determine associations with SVD severity, subtype, and interrelations. METHODS:In this prospective, cross-sectional, multicenter INVESTIGATE-SVDs study, we acquired brain magnetic resonance imaging in patients with sporadic SVD/cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), including structural, quantitative microstructural, permeability surface area product, blood plasma volume fraction, vascular pulsatility, and CVR (in response to CO2) scans. We determined vascular function and white matter hyperintensity (WMH) associations, using covariate-adjusted linear regression; normal-appearing white matter and WMH differences, interrelationships between vascular functions, using linear mixed models; and major sources of variance using principal component analyses. RESULTS:We recruited 77 patients (45 sporadic/32 CADASIL) at 3 sites. In adjusted analyses, patients with worse WMH had lower CVR (B = -1.78, 95% CI -3.30, -0.27) and blood plasma volume fraction (B = -0.594, 95% CI -0.987, -0.202). CVR was worse in WMH than normal-appearing white matter (eg, CVR: B = -0.048, 95% CI -0.079, -0.017). Adjusting for WMH severity, SVD subtype had minimal influence on vascular function (eg, CVR in CADASIL vs sporadic: B = 0.0169, 95% CI -0.0247, 0.0584). Different vascular function mechanisms were not generally interrelated (eg, permeability surface area product~CVR: B = -0.85, 95% CI -4.72, 3.02). Principal component analyses identified WMH volume/quantitative microstructural metrics explained most variance in CADASIL and arterial pulsatility in sporadic SVD, but similar main variance sources. INTERPRETATION:Vascular function was worse with higher WMH, and in WMH than normal-appearing white matter. Sporadic SVD-CADASIL differences largely reflect disease severity. Limited vascular function interrelations may suggest disease stage-specific differences. ANN NEUROL 2025;97:483-498.

Optical coherence tomography angiography (OCT-A) retinal imaging enables in vivo visualization of the retinal microvasculature that is developmentally related to the brain and can offer insight on cerebrovascular health. We investigated retinal phenotypes and neuroimaging markers of small vessel disease (SVD) in individuals with obstructive sleep apnoea (OSA). We enrolled 44 participants (mean age 50.1 ± SD 9.1 years) and performed OCT-A imaging before and after continuous positive airway pressure (CPAP) therapy. Pre-treatment analyses using a generalized estimating equations model adjusted for relevant covariates, revealed perivascular spaces (PVS) volume in basal ganglia associated with greater foveal vessel density (fVD) (p-value < 0.001), and smaller foveal avascular zone area (p-value = 0.01), whereas PVS count in centrum semiovale associated with lower retinal vessel radius (p-value = 0.02) and higher vessel tortuosity (p-value = 0.01). A reduction in retinal vessel radius was also observed with increased OSA severity (p-value = 0.05). Post-treatment analyses showed greater CPAP usage was associated with a decrease in fVD (p-value = 0.02), and increased retinal vessel radius (p-value = 0.01). The findings demonstrate for the first time the potential use of OCT-A to monitor CPAP treatment and its possible impact on both retinal and brain vascular health.

Introduction White matter hyperintensities (WMH) are related to cognitive decline, particularly processing speed and executive functioning (EF). However, all cognitive domains might be affected. WMH can regress and this might have positive consequences for cognition, but the effects of WMH regression on cognition are unknown. This study aims to assess whether changes in global cognition, processing speed and EF are related to progressing and regressing WMH. Methods We recruited mild, non-disabling, ischemic stroke patients with sporadic small vessel disease. They underwent MRI and cognitive assessment within 3 months post-stroke and 1 year later. Cognitive assessment included MoCA (global cognition; score 0-30), trail making test (TMT) A (processing speed; seconds) and TMT B (EF; seconds). WMH volumes are reported as % intracranial volume (ICV). WMH volume change (%ICV) is defined as WMH volume difference between baseline and 1 year. We calculated quintiles (Q) of WMH volume change to group volume change. We performed three linear mixed models, with MoCA, TMT-A and B as outcomes, to assess relationships over time with quintile of WMH volume change. Predictors in addition to quintile are age, sex, premorbid intelligence (NART), stroke severity (NIHSS). Extra predictor for TMT-B analysis is the TMT-A time to correct for speed. Results 202 participants had WMH change volumes available (mean age: 66.03 years [SD=11.15), 33% female]. Q1 reflect greatest WMH volume reduction and Q5 greatest volume increase, while Q3 is lowest overall volume change (Figure 1). MoCA score increased over time (Figure 2). Older age (std. B [std. 95%CI]: -0.303 [-0.400, -0.206]), worse NART (-0.463 [-0.557, -0.368]), increasing NIHSS (-0.208 [-0.286, -0.130]) and more WMH increase (Q5; -0.513 [-0.814, -0.211]) predict lower MoCA. Older age (0.257 [0.135, 0.380]), worse NART (0.259 [0.139, 0.378]) and higher NIHSS (0.152 [0.078, 0.226]) predict worse TMT-A time (Figure 3A). Older age (0.224 [0.132, 0.316]), worse NART (0.295 [0.207, 0.383]), worse TMT-A (0.469 [0.384, 0.555]), worsening WMH volume (Q2; 0.382 [0.115, 0.0.649] and Q5; 0.425 [0.150, 0.699]) predict worse TMT-B time (Figure 3B). Discussion More WMH progression independently predicts worse global cognition and EF but not processing speed. WMH regression (Q1) was not related to worsening or improving global cognition, processing speed and EF. Cognitive consequences of WMH regression might be comparable to stable WMH (Q3).

Background and Objectives A quarter of ischemic strokes are of lacunar clinical subtype and have an underlying recent small subcortical infarct (RSSI), but their long-term outcomes remain poorly characterized. Hemosiderin deposits (HDs) have been noted in RSSIs at chronic stages and might mimic primary hemorrhage. We characterized HDs' morphology, frequency, and clinical relevance. Methods Participants with RSSIs were identified from a prospective longitudinal study and evaluated on 3T MRI including susceptibility-weighted imaging (SWI) from stroke diagnosis to 12 months. We categorized HDs in RSSIs on SWI at all available time points into 4 types (spots, smudge, rim, cluster) and assessed their associations with demographic factors, stroke-related factors, and image markers with adjusted logistic regression. Results HDs were observed in 43 (55.0%) of 108 participants within 3 months and 83 (76.9%) of 108 within 12 months after stroke onset. The mean time to first detection of HDs was 87 (interquartile range 53-164) days. A "rim" pattern (similar to late appearance of primary hemorrhage) occurred in at least 26.5% of RSSIs at all follow-up time points, mainly those located in the lentiform/internal capsule (50.0%) or thalamus (36.4%). Infarct volume (odds ratio [OR] 1.003, 95% CI 1.001-1.006; p = 0.004) and the total small vessel disease (SVD) score at baseline (OR 2.50, 95% CI 1.28-4.86, p = 0.007) independently predicted HDs at 12 months. HDs were positively associated with more lacunes (OR 1.60, 95% CI 1.13-2.26, p < 0.01), but not the Fazekas score, number of microbleeds, basal ganglia mineral deposit score, or clinical outcomes. Discussion HDs occur commonly in RSSIs and may be associated with infarct volume and SVD score. Hemosiderin "rim" is common in RSSIs, urging caution to avoid mistaking ischemic RSSI for primary hemorrhage in subacute and chronic stages.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized beta [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke. Jochems et al. report that mobility and dexterity are affected by white matter hyperintensity volume longitudinal change after minor ischaemic stroke, independently of stroke severity. Dominant and non-dominant hands might be differently affected. In-person measures of dexterity and mobility are associated with self-reported experience 1 year after stroke. Graphical abstract