Prenatal maternal stress is linked to neurodevelopmental outcomes. Maternal hair cortisol concentration in pregnancy is associated with neonatal amygdala microstructure and structural connectivity, suggesting that amygdala is sensitive to antenatal stress. We investigated whether amygdala microstructure and/or connectivity associate with neurodevelopmental outcomes. 174 participants (105 preterm) underwent brain MRI at term-equivalent age and assessment of neurodevelopment, autistic traits, temperament, and executive function at 2 years corrected age. We calculated amygdala microstructure (fractional anisotropy, mean diffusivity, neurite density index, orientation dispersion index) and structural connectivity (mean fractional anisotropy) to 6 regions (insula, putamen, thalamus, inferior temporal gyrus, medial orbitofrontal cortex, rostral anterior cingulate cortex). We used linear regression to model amygdala-outcome associations, adjusting for gestational age at birth and at scan, sex, maternal education and postnatal depression score, and network-based statistics (NBS) for whole-brain analyses. Following correction for multiple comparisons, lower amygdala mean diffusivity (left: β = -0.32, p = 0.026, right: β = -0.38, p = 0.012), higher left amygdala neurite density index (β = 0.35, p = 0.026), and increased left amygdala-putamen connectivity (β = 0.31, p = 0.026) associated with higher autistic traits across the whole sample. NBS additionally revealed amygdala-involving networks associated with cognition and surgency among preterms, and gestation-dependent associations with autistic traits. Findings indicate that neonatal amygdala microstructure may be important in the development of autistic traits.

Abstract Background and aims Larger lacunar strokes are often attributed to branch atheromatous disease (BAD), especially in Asian populations. We aimed to classify BAD in European patients, and explored its association with large artery phenotypes and small vessel disease (SVD). Methods We recruited patients prospectively with acute clinical lacunar and mild cortical ischaemic strokes. We defined BAD using two common criteria: 1) slice/shape: tubular-like lesions coronally or axial thickness >15mm; 2) size: >20mm within or >15mm after one month. We assessed associations between BAD and large cranial artery stenosis or widening, and SVD markers using adjusted logistic regression. Results Amongst 229 participants, 114 with lacunar stroke, 42/114 (criteria1) and 21/114 (criteria2) had BAD (kappa=0.439). Lacunar-BAD had fewer lacunes (criteria1: adjusted odds ratio (aOR) 0.839, 95%CI 0.718-0.980, p=0.027; criteria2: aOR 0.717, 0.546-0.943, p=0.017), lower SVD score (criteria1: aOR 0.522, 0.327-0.833, p=0.007; criteria2: aOR 0.405, 0.185-0.887, p=0.024), and lower white matter hyperintensity volumes (criteria1 only (p<0.001)) compared to lacunar-non-BAD strokes. Neither large artery stenosis nor widening differed between lacunar-BAD and lacunar-non-BAD stroke (any stenosis 16.7% vs 22.9%; basilar widening 21.4% vs 23.6%) , all p>0.05). Amongst 42/229 lacunar-BAD (criteria1), basilar artery diameter was wider (aOR 1.843, 1.085-3.129, p=0.024) and amongst 21/229 lacunar-BAD (criteria2), middle cerebral artery diameter was smaller (aOR 0.107, 0.017-0.661, p=0.016) than in all non-BAD strokes . Conclusions BAD occurs in Europeans, but current definitions are very inconsistent. Lacunar-BAD had fewer SVD markers but similar associations with large artery widening and few stenoses as in lacunar-non-BAD strokes, suggesting a non-atheromatous etiology of BAD. Conflict of interest All authors: nothing to disclose

BACKGROUND:The Fazekas score is widely used to grade white matter hyperintensities (WMHs) in cerebral small vessel disease, yet the equivalent volume of each grade is unclear. We quantified the correspondence between Fazekas scores and WMH volume, normalized ratios, and derived conversion equations across populations. METHODS:We analyzed 1220 participants from 4 mostly United Kingdom-based cohorts representing different cerebral small vessel disease severities: community-dwelling (LBC1936 [Lothian Birth Cohort 1936]), stroke (MSS2 [Mild Stroke Study 2] and MSS3 [Mild Stroke Study 3]), and a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy-enriched cohort (INVESTIGATE [Imaging Neuro-Vascular, Endothelial and Structural Integrity in Preparation to Treat Small Vessel Diseases]). WMH burden was quantified as absolute WMH volume and as normalized ratios: WMH volume as a percentage of brain volume and WMH volume as a percentage of intracranial volume. Transition zones were defined as the overlap of WMH volume interquartile ranges between adjacent Fazekas scores. Linear, exponential (nonlinear least squares), and log-linear (ln WMH≈Fazekas score and zeros excluded) models were fitted; model fit was assessed using mean squared error, (pseudo-)R2, and Vuong tests. Periventricular-versus-deep WMH patterns within each total Fazekas score were compared using the Kruskal-Wallis test. RESULTS:The pooled cohort had a mean age of 69.4±8.9 years; 700 of 1227 records (57.1%) were male. WMH burden increased monotonically with a Fazekas score in all cohorts. Adjacent-grade separation was strongest in LBC1936 (all P≤0.002) but weaker at lower grades in MSS2, MSS3, and INVESTIGATE. The widest transition zones occurred between Fazekas grades of 3 to 4 and 4 to 5, whereas a clear WMH volume gap separated grades 5 and 6. Exponential models generally fit better than linear models, with lower mean squared error and supportive Vuong tests in most cohorts. Log-linear sensitivity analyses showed similar fitted trajectories after back-transformation. WMH burden did not differ consistently by periventricular-versus-deep distribution within Fazekas grades. CONCLUSIONS:WMH burden followed an exponential trajectory across Fazekas scores, with population-dependent progression. The resulting conversion equations enabled bidirectional translation between visual Fazekas score and quantitative WMH volume, facilitating cross-study comparison, large-scale epidemiology, and might facilitate clinical decision-making in cerebral small vessel disease.

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

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: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.

BACKGROUND:Novel risk factors for stroke, such as occupation, are increasingly under exploration. We investigate if specific occupational exposures and settings increase the risk of developing small-vessel disease (SVD), including SVD-related strokes. METHODS:We performed a systematic review on stroke-occupation associations and then analyzed data from patients presenting to Lothian stroke services with mild ischemic stroke (modified Rankin Scale score ≤2). We performed magnetic resonance imaging and inquired about occupational status. We assessed relationships between high-risk occupations (per Control to Substances Hazardous to Health guidelines) and standard occupational classifications (per Standard Occupational Classifications criteria) against white matter hyperintensity volumes, SVD score, and stroke subtype. RESULTS:Our systematic review identified 37 papers assessing occupations/broad occupational classifications (n=13), psychosocial work-related factors (n=11), and occupational exposure to hazardous substances (n=13). We then analyzed data from 414 participants and found, after adjustment for age, hypercholesterolemia, socioeconomic status, years of education, hypertension, diabetes, and smoking history, that high-risk occupations were associated with higher SVD scores (odds ratio, 1.64 [95% CI, 1.07-2.54]; n=357; P=0.02) but not for lacunar stroke subtype (odds ratio, 1.03 [95% CI, 0.64-1.67]; n=358; P=0.90) or white matter hyperintensity volume (% intracranial volume) (β=-0.003 [95% CI, -0.015 to 0.008]; n=357; P=0.60). Examples of high-risk occupations include drivers, engineers, and skilled trade workers. No associations were found for standard occupational classifications. CONCLUSIONS:This systematic review shows limited data on stroke-occupation associations. Our analysis showed that high-risk occupations are associated with higher SVD scores but not stroke subtype. REGISTRATION:URL: www.crd.york.ac.uk/PROSPERO; Unique Identifier: 42024466671.

Abstract Background and aims 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 poorly characterized. Methods In the prospective Mild Stroke Study, we recruited patients with lacunar or mild non-lacunar stroke. 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 assessed at baseline and 1 year. Associations between large artery phenotypes and vascular function were examined with multivariable regression adjusted for risk factors, and mediation analyses tested whether vascular dysfunction linked large artery pathology to cSVD progression. Results A total of 224 participants (66.0 ± 11.2 years; 66.5% men) were included. 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, but not with pulsatility. Arterial diameter showed a U-shaped association with BBB permeability. LAS (n=46, 20.5%) was 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. Conclusions 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 to slow disease progression. Conflict of interest Nothing to disclose

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.

MR imaging-visible PVS are an important neuroradiological marker of brain clearance which assessments can be compounded by clinically relevant imaging features, imaging artifacts, and imaging protocols alike. While combining PVS measurements from different sources, harmonization of these measurements prior to their use in clinical analyses is necessary. Given the lack of data to inform these procedures, we compared PVS assessments from MR imaging of 100 adult volunteers acquired at 2 different scanners with magnets of the 2 field strengths most used in hospitals and research institutions across the globe. Computational assessments were biased with PVS counts and volumes consistently higher at 3T than at 1.5T, and median lengths longer at 1.5T than at 3T. Adjusting the counts and volumes by the volume of the region of interest was not effective for compensating the differences introduced by the different magnetic field strengths. Applying ComBat harmonization and converting the measurements to Z-scores did compensate for these differences. Visual scoring was not more resilient to these differences than computationally-derived measurements after applying these harmonization methods. The poor agreement in the visual assessment that involved images of lower quality was an evidence of the vulnerabilities of observer's manual annotations in relation to PVS. Therefore, it is possible that manually rectifying the computational output would even worsen the agreements between the measurements done in images acquired at 1.5T versus those done in images acquired at 3T.

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.