BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (B_NAWM=−0.0073 [95% CI, −0.0133 to −0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (B_NAWM=−0.00129 [95% CI, −0.00215 to −0.00043] %/mm Hg per lacune), more microbleeds (B_NAWM=−0.00083 [95% CI, −0.00130 to −0.00036] %/mm Hg per microbleed), higher deep atrophy score (B_NAWM=−0.00218 [95% CI, −0.00417 to −0.00020] %/mm Hg per score point increase), higher perivascular space score (B_NAWM=−0.0034 [95% CI, −0.0066 to −0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (B_NAWM=−0.0048 [95% CI, −0.0075 to −0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (B_NAWM=0.00065 [95% CI, −0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Small vessel disease (SVD) is a highly prevalent disorder of the brain’s microvessels and a common cause of dementia as well as ischaemic and haemorrhagic strokes. Though much about the underlying pathophysiology of SVD remains poorly understood, a wealth of recently published evidence strongly suggests a key role of microvessel endothelial dysfunction and a compromised blood–brain barrier (BBB) in the development and progression of the disease. Understanding the causes and downstream consequences associated with endothelial dysfunction in this pathological context could aid in the development of effective diagnostic and prognostic tools and provide promising avenues for potential therapeutic interventions. In this scoping review, we aim to summarise the findings from clinical studies examining the role of the molecular mechanisms underlying endothelial dysfunction in SVD, focussing on biochemical markers of endothelial dysfunction detectable in biofluids, including cell adhesion molecules, BBB transporters, cytokines/chemokines, inflammatory markers, coagulation factors, growth factors, and markers involved in the nitric oxide cascade.

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. 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. 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]). 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.

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. 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. 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). 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. NCT03410095. 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.

In patients with cerebral small vessel disease (SVD), impaired cerebrovascular reactivity (CVR) is related to worse concurrent SVD burden, but less is known about cerebrovascular reactivity and long-term SVD lesion progression and clinical outcomes. We investigated associations between cerebrovascular reactivity and 1-year progression of SVD features and clinical outcomes. Between 2018 and 2021, we recruited patients from the Edinburgh/Lothian stroke services presenting with minor ischemic stroke and SVD features as part of the Mild Stroke Study 3, a prospective observational cohort study (ISRCTN 12113543). We acquired 3T brain MRI at baseline and 1 year. At baseline, we measured cerebrovascular reactivity to 6% inhaled CO₂ in subcortical gray matter, normal-appearing white matter, and white matter hyperintensities (WMH). At baseline and 1 year, we quantified SVD MRI features, incident infarcts, assessed stroke severity (NIH Stroke Scale), recurrent stroke, functional outcome (modified Rankin Scale), and cognition (Montreal Cognitive Assessment). We performed linear and logistic regressions adjusted for age, sex, and vascular risk factors, reporting the regression coefficients and odds ratios with 95% CIs. We recruited 208 patients of whom 163 (mean age and SD: 65.8 ± 11.2 years, 32% female) had adequate baseline CVR and completed the follow-up structural MRI. The median increase in WMH volume was 0.32 mL with (Q1, Q3) = (−0.48, 1.78) mL; 29% had a recurrent stroke or incident infarct on MRI. At 1 year, patients with lower baseline cerebrovascular reactivity in normal-appearing tissues had increased WMH (regression coefficient: B = −1.14 [−2.13, −0.14] log₁₀ (%ICV) per %/mm Hg) and perivascular space volumes (B = −1.90 [−3.21, −0.60] log₁₀ (%ROIV) per %/mm Hg), with a similar trend in WMH. CVR was not associated with clinical outcomes at 1 year. Lower baseline cerebrovascular reactivity predicted an increase in WMH and perivascular space volumes after 1 year. CVR should be considered in SVD future research and intervention studies.

INTRODUCTION: This study explored the relationship between blood biomarkers of cerebrovascular function and small vessel disease (SVD) neuroimaging markers and cognitive outcomes in highly‐phenotyped participants.METHODS: We conducted cross‐sectional and 1‐year longitudinal analyses on 181 patients with mild ischemic stroke, enriched for SVD features. We examined relationships between a panel of 13 blood biomarkers and magnetic resonance imaging (MRI) markers of SVD (structural lesions, diffusion‐weighted imaging [DWI]‐positive lesions, blood‐brain barrier (BBB) permeability, and cerebrovascular reactivity (CVR), and cognition.RESULTS: In linear mixed models, vascular endothelial growth factor was significantly associated with incident DWI‐positive lesions over 1 year. Intercellular adhesion molecule‐1 was linked with lower CVR while platelet‐derived growth factor‐subunit B and Endothelin‐1 were associated with higher CVR. Platelet‐Selectin levels were associated with mild cognitive impairment at 1 year.DISCUSSION: Our results support the role of endothelial and pericyte dysfunction in SVD burden and progression and suggest that specific biomarkers relate to distinct SVD manifestations.Highlights: Small vessel disease (SVD) lacks specific or predictive biomarker signatures. Vascular endothelial growth factor levels were linked to incident lesions detected over 1 year. Circulating intercellular adhesion molecule‐1 related to lower cerebrovascular reactivity. Platelet‐selectin levels were associated with mild cognitive impairment longitudinally. These findings could help stratify patients at high‐risk of rapid‐progression SVD.