Association of Cerebrovascular Reactivity With 1-Year Imaging and Clinical Outcomes in Small Vessel Disease: An Observational Cohort Study.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

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 (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-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 (BNAWM=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.

Cerebrovascular reactivity measurements using 3T BOLD MRI and a fixed inhaled CO2 gas challenge: Repeatability and impact of processing strategy.

Introduction: Cerebrovascular reactivity (CVR) measurements using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) are commonly used to assess the health of cerebral blood vessels, including in patients with cerebrovascular diseases; however, evidence and consensus regarding reliability and optimal processing are lacking. We aimed to assess the repeatability, accuracy and precision of voxel- and region-based CVR measurements at 3 T using a fixed inhaled (FI) CO2 stimulus in a healthy cohort. Methods: We simulated the effect of noise, delay constraints and voxel- versus region-based analysis on CVR parameters. Results were verified in 15 healthy volunteers (28.1±5.5 years, female: 53%) with a test-retest MRI experiment consisting of two CVR scans. CVR magnitude and delay in grey matter (GM) and white matter were computed for both analyses assuming a linear relationship between the BOLD signal and time-shifted end-tidal CO2 (EtCO2) profile. Results: Test-retest repeatability was high [mean (95% CI) inter-scan difference: -0.01 (-0.03, -0.00) %/mmHg for GM CVR magnitude; -0.3 (-1.2,0.6) s for GM CVR delay], but we detected a small systematic reduction in CVR magnitude at scan 2 versus scan 1, accompanied by a greater EtCO2 change [±1.0 (0.4,1.5) mmHg] and lower heart rate [-5.5 (-8.6,-2.4] bpm]. CVR magnitude estimates were higher for voxel- versus region-based analysis [difference in GM: ±0.02 (0.01,0.03) %/mmHg]. Findings were supported by simulation results, predicting a positive bias for voxel-based CVR estimates dependent on temporal contrast-to-noise ratio and delay fitting constraints and an underestimation for region-based CVR estimates. Discussion: BOLD CVR measurements using FI stimulus have good within-day repeatability in healthy volunteers. However, measurements may be influenced by physiological effects and the analysis protocol. Voxel-based analyses should be undertaken with care due to potential for systematic bias; region-based analyses are more reliable in such cases.

Retinal capillary microvessel morphology changes are associated with vascular damage and dysfunction in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is a cause of stroke and dementia. Retinal capillary microvessels revealed by optical coherence tomography angiography (OCTA) are developmentally related to brain microvessels. We quantified retinal vessel density (VD) and branching complexity, investigating relationships with SVD lesions, white matter integrity on diffusion tensor imaging (DTI) and cerebrovascular reactivity (CVR) to CO2 in patients with minor stroke. We enrolled 123 patients (mean age 68.1 ± SD 9.9 years), 115 contributed retinal data. Right (R) and left (L) eyes are reported. After adjusting for age, eye disease, diabetes, blood pressure and image quality, lower VD remained associated with higher mean diffusivity (MD) (standardized ß; R -0.16 [95%CI -0.32 to -0.01]) and lower CVR (L 0.17 [0.03 to 0.31] and R 0.19 [0.02 to 0.36]) in normal appearing white matter (NAWM). Sparser branching remained associated with sub-visible white matter damage shown by higher MD (R -0.24 [-0.08 to -0.40]), lower fractional anisotropy (FA) (L 0.17 [0.01 to 0.33]), and lower CVR (R 0.20 [0.02 to 0.38]) in NAWM. OCTA-derived metrics provide evidence of microvessel abnormalities that may underpin SVD lesions in the brain.

Corrigendum: Cerebrovascular reactivity measurement using magnetic resonance imaging: A systematic review.

[This corrects the article DOI: 10.3389/fphys.2021.643468.].

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BACKGROUND: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. SUMMARY: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Cerebrovascular Reactivity Measurement Using Magnetic Resonance Imaging: A Systematic Review.

Cerebrovascular reactivity (CVR) magnetic resonance imaging (MRI) probes cerebral haemodynamic changes in response to a vasodilatory stimulus. CVR closely relates to the health of the vasculature and is therefore a key parameter for studying cerebrovascular diseases such as stroke, small vessel disease and dementias. MRI allows in vivo measurement of CVR but several different methods have been presented in the literature, differing in pulse sequence, hardware requirements, stimulus and image processing technique. We systematically reviewed publications measuring CVR using MRI up to June 2020, identifying 235 relevant papers. We summarised the acquisition methods, experimental parameters, hardware and CVR quantification approaches used, clinical populations investigated, and corresponding summary CVR measures. CVR was investigated in many pathologies such as steno-occlusive diseases, dementia and small vessel disease and is generally lower in patients than in healthy controls. Blood oxygen level dependent (BOLD) acquisitions with fixed inspired CO2 gas or end-tidal CO2 forcing stimulus are the most commonly used methods. General linear modelling of the MRI signal with end-tidal CO2 as the regressor is the most frequently used method to compute CVR. Our survey of CVR measurement approaches and applications will help researchers to identify good practice and provide objective information to inform the development of future consensus recommendations.