CADASIL Affects Multiple Aspects of Cerebral Small Vessel Function on 7T-MRI.

OBJECTIVE: Cerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting-edge 7T-MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD. METHODS: We recruited 23 CADASIL patients (age 51.1 ± 10.1 years, 52% women) and 13 age- and sex-matched controls (46.1 ± 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities. RESULTS: Compared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference - 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference - 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood-oxygen-level dependent [BOLD] mean difference -0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference -0.29%, p = 0.02). INTERPRETATION: Multiple aspects of cerebral small vessel function on 7T-MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies. ANN NEUROL 2023;93:29-39.

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.

Effects of Cilostazol and Isosorbide Mononitrate on Cerebral Hemodynamics in the LACI-1 Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Cerebral small vessel disease-a major cause of stroke and dementia-is associated with cerebrovascular dysfunction. We investigated whether short-term isosorbide mononitrate (ISMN) and cilostazol, alone or in combination, improved magnetic resonance imaging-measured cerebrovascular function in patients with lacunar ischemic stroke. METHODS: Participants were randomized to ISMN alone, cilostazol alone, both ISMN and cilostazol, or no medication. Participants underwent structural, cerebrovascular reactivity (to 6% carbon dioxide) and phase-contrast pulsatility magnetic resonance imaging at baseline and after 8 weeks of medication. RESULTS: Of 27 participants (mean age, 68±7.7; 44% female), 22 completed cerebrovascular reactivity and pulsatility imaging with complete datasets. White matter cerebrovascular reactivity increased in the ISMN (ß=0.021%/mm Hg [95% CI, 0.003-0.040]) and cilostazol (ß=0.035%/mm Hg [95% CI, 0.014-0.056]) monotherapy groups and in those taking any versus no medication (ß=0.021%/mm Hg [95% CI, 0.005-0.037]). CONCLUSIONS: While limited by small sample size, we demonstrate that measuring cerebrovascular function with magnetic resonance imaging is feasible in clinical trials and that ISMN and cilostazol may improve cerebrovascular function. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481323. URL: www.isrctn.com; Unique identifier: ISRCTN12580546. URL: www.clinicaltrialsregister.eu; Unique identifier: EudraCT 2015-001953-33.

Choroid plexus tissue perfusion and blood to CSF barrier function in rats measured with continuous arterial spin labeling.

The choroid plexus (ChP) of the cerebral ventricles is a source of cerebrospinal fluid (CSF) production and also plays a key role in immune surveillance at the level of blood-to-CSF-barrier (BCSFB). In this study, we quantify ChP blood perfusion and BCSFB mediated water exchange from arterial blood into ventricular CSF using non-invasive continuous arterial spin labelling magnetic resonance imaging (CASL-MRI). Systemic administration of anti-diuretic hormone (vasopressin) was used to validate BCSFB water flow as a metric of choroidal CSF secretory function. To further investigate the coupling between ChP blood perfusion and BCSFB water flow, we characterized the effects of two anesthetic regimens known to have large-scale differential effects on cerebral blood flow. For quantification of ChP blood perfusion a multi-compartment perfusion model was employed, and we discovered that partial volume correction improved measurement accuracy. Vasopressin significantly reduced both ChP blood perfusion and BCSFB water flow. ChP blood perfusion was significantly higher with pure isoflurane anesthesia (2-2.5%) when compared to a balanced anesthesia with dexmedetomidine and low-dose isoflurane (1.0 %), and significant correlation between ChP blood perfusion and BCSFB water flow was observed, however there was no significant difference in BCSFB water flow. In summary, here we introduce a non-invasive, robust, and spatially resolved in vivo imaging platform to quantify ChP blood perfusion as well as BCSFB water flow which can be applied to study coupling of these two key parameters in future clinical translational studies.

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases.

Background and Purpose- Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods- We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results- Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%-18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (ß=0.468 [95% CI, 0.187-0.750]) and transverse sinus pulsatility (ß=0.547 [95% CI, 0.309-0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions- Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.

Brain hyperintensities in magnetic resonance imaging of patients with mild acute focal neurology.

PURPOSE: Hyperintensities are common in neuroimaging scans of patients with mild acute focal neurology. However, their pathogenic role and clinical significance is not well understood. We assessed whether there was an association between hyperintensity score with diagnostic category and clinical assessments/measures. METHODS: One hundred patients (51 ± 12 years; 45:55 women:men), with symptomatology suggestive of short duration ischemia referred for magnetic resonance imaging, were prospectively recruited in NHS Grampian between 2012 and 2014. Hyperintensities were quantified, on T2 and FLAIR, using the Scheltens score. RESULTS: The most frequent diagnosis was minor stroke (33%), migraine (25%) and transient ischemic attack (17%). The mean total Scheltens score was 28.49 ± 11.93 with all participants having various loads of hyperintensities. Statistically significant correlations between hyperintensity scores and clinical assessments/measures (age, systolic blood pressure, pulse pressure, MoCA) at the global level were also reflected regionally. These provide further supporting data in terms of the robustness of the Scheltens scale. CONCLUSION: Hyperintensities could serve as a diagnostic and prognostic imaging biomarker for patients, presenting with mild acute focal neurology, warranting application of automated quantification methods. However, larger cohorts are required to provide a definitive answer especially as this is a heterogenous group of patients.

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress.

BACKGROUND: White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. METHODS AND RESULTS: We defined areas of stable normal-appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1-year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross-sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross-sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006-0.017]; -0.002 [95% CI, -0.008 to 0.003] and -0.003 [95% CI, -0.009 to 0.004]); in progressing and stable WMHs, FA decreased (-0.022 [95% CI, -0.027 to -0.017] and -0.009 [95% CI, -0.011 to -0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050-0.063], 0.058 [95% CI, 0.050 -0.066]; stable WMHs, 0.054 [95% CI, 0.045-0.063], 0.049 [95% CI, 0.039-0.058]); and in stable normal-appearing white matter, MD increased (0.004 [95% CI, 0.003-0.005]), whereas FA and T1 slightly decreased and increased (-0.002 [95% CI, -0.004 to -0.000] and 0.005 [95% CI, 0.001-0.009]). CONCLUSIONS: Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

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 ß [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.

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.

Blood-brain barrier leakage hotspots collocating with brain lesions due to sporadic and monogenic small vessel disease.

Blood-brain barrier (BBB) is known to be impaired in cerebral small vessel disease (SVD), and is measurable by dynamic-contrast enhancement (DCE)-MRI. In a cohort of 69 patients (42 sporadic, 27 monogenic SVD), who underwent 3T MRI, including DCE and cerebrovascular reactivity (CVR) sequences, we assessed the relationship of BBB-leakage hotspots to SVD lesions (lacunes, white matter hyperintensities (WMH), and microbleeds). We defined as hotspots the regions with permeability surface area product highest decile on DCE-derived maps within the white matter. We assessed factors associated with the presence and number of hotspots corresponding to SVD lesions in multivariable regression models adjusted for age, WMH volume, number of lacunes, and SVD type. We identified hotspots at lacune edges in 29/46 (63%) patients with lacunes, within WMH in 26/60 (43%) and at the WMH edges in 34/60 (57%) patients with WMH, and microbleed edges in 4/11 (36%) patients with microbleeds. In adjusted analysis, lower WMH-CVR was associated with presence and number of hotspots at lacune edges, and higher WMH volume with hotspots within WMH and at WMH edges, independently of the SVD type. In conclusion, SVD lesions frequently collocate with high BBB-leakage in patients with sporadic and monogenic forms of SVD.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia.

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder.

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

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

Prevalence and Significance of the Vessel-Cluster Sign on Susceptibility-Weighted Imaging in Patients With Severe Small Vessel Disease.

BACKGROUND: Magnetic resonance susceptibility-weighted imaging (SWI) can identify small brain blood vessels that contain deoxygenated blood due to its induced magnetic field disturbance. We observed focal clusters of possible dilated small vessels on SWI in white matter in severe small vessel disease (SVD). We assessed their prevalence, associations with SVD lesions and vascular reactivity in patients with sporadic SVD and in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). METHODS: Secondary cross-sectional analysis of a prospective multicentre observational study of patients with either sporadic SVD or CADASIL (INVESTIGATE-SVD) studied with 3 Tesla MRI including blood-oxygen-level-dependent-MRI cerebrovascular reactivity (CVR). Two independent raters evaluated SWI sequences to identify "vessel-clusters" in white matter as focal low-signal dots/lines with small vessel appearance (interrater agreement, kappa statistic= 0.66). We assessed per-patient and per-cluster associations with SVD lesions type and severity on structural MRI sequences. We also assessed CVR within and at 2-voxel concentric intervals around the vessel-clusters using contralateral volumes as reference. RESULTS: Amongst the 77 patients enrolled, 76 had usable SWI sequences, 45 with sporadic SVD [mean age 64 years (SD 11), 26 males (58%)] and 31 with CADASIL [53 years (11), 15 males (48%)]. We identified 94 vessel-clusters in 36/76 patients (15/45 sporadic SVD, 21/31 CADASIL). In covariate-adjusted analysis, patients with vessel-clusters had more lacunes (OR, 95%CI) (1.30, 1.05-1.62), higher white matter hyperintensity (WMH) volume (per-log10 increase, 1.92, 1.04-3.56), lower CVR in normal appearing white matter (per %/mmHg, 0.77 (0.60-0.99), compared with patients without vessel-clusters. Fifty-seven of 94 vessel-clusters (61%) corresponded to non-cavitated or partially-cavitated WMH on Fluid Attenuated Inversion Recovery, and 37/94 (39%) to complete cavities. CVR magnitude was lower than in corresponding contralateral volumes [mean difference (SD), t, p] within vessel-cluster volumes [-0.00046 (0.00088), -3.021, 0.005) and in surrounding volume expansion shells up to 4 voxels [-0.00011 (0.00031), -2.140, 0.039; and -0.00010 (0.00027), -2.295, 0.028] in vessel-clusters with complete cavities, but not in vessel-clusters without complete cavitation. CONCLUSIONS: Vessel-clusters might correspond to maximally dilated vessels in white matter that are approaching complete tissue injury and cavitation. The pathophysiological significance of this new feature warrants further longitudinal investigation.

Topological relationships between perivascular spaces and progression of white matter hyperintensities: A pilot study in a sample of the Lothian Birth Cohort 1936.

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves-1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves-1-2: 73%; 2-3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear.

Contribution of white matter hyperintensities to ventricular enlargement in older adults.

Lateral ventricles might increase due to generalized tissue loss related to brain atrophy. Alternatively, they may expand into areas of tissue loss related to white matter hyperintensities (WMH). We assessed longitudinal associations between lateral ventricle and WMH volumes, accounting for total brain volume, blood pressure, history of stroke, cardiovascular disease, diabetes and smoking at ages 73, 76 and 79, in participants from the Lothian Birth Cohort 1936, including MRI data from all available time points. Lateral ventricle volume increased steadily with age, WMH volume change was more variable. WMH volume decreased in 20% and increased in remaining subjects. Over 6 years, lateral ventricle volume increased by 3% per year of age, 0.1% per mm Hg increase in blood pressure, 3.2% per 1% decrease of total brain volume, and 4.5% per 1% increase of WMH volume. Over time, lateral ventricle volumes were 19% smaller in women than men. Ventricular and WMH volume changes are modestly associated and independent of general brain atrophy, suggesting that their underlying processes do not fully overlap.

Associations of Peak-Width Skeletonized Mean Diffusivity and Post-Stroke Cognition.

Post-stroke cognitive impairment is common and can have major impact on life after stroke. Peak-width of Skeletonized Mean Diffusivity (PSMD) is a diffusion imaging marker of white matter microstructure and is also associated with cognition. Here, we examined associations between PSMD and post-stroke global cognition in an ongoing study of mild ischemic stroke patients. We studied cross-sectional associations between PSMD and cognition at both 3-months (N = 229) and 1-year (N = 173) post-stroke, adjusted for premorbid IQ, sex, age, stroke severity and disability, as well as the association between baseline PSMD and 1-year cognition. At baseline, (mean age = 65.9 years (SD = 11.1); 34% female), lower Montreal Cognitive Assessment (MoCA) scores were associated with older age, lower premorbid IQ and higher stroke severity, but not with PSMD (ßstandardized = −0.116, 95% CI −0.241, 0.009; p = 0.069). At 1-year, premorbid IQ, older age, higher stroke severity and higher PSMD (ßstandardized = −0.301, 95% CI −0.434, −0.168; p < 0.001) were associated with lower MoCA. Higher baseline PSMD was associated with lower 1-year MoCA (ßstandardized = −0.182, 95% CI −0.308, −0.056; p = 0.005). PSMD becomes more associated with global cognition at 1-year post-stroke, possibly once acute effects have settled. Additionally, PSMD in the subacute phase after a mild stroke could help predict long-term cognitive impairment.

Associations Between White Matter Hyperintensity Burden, Cerebral Blood Flow and Transit Time in Small Vessel Disease: An Updated Meta-Analysis.

Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional (n = 2,956) and 3 longitudinal (n = 440). Cross-sectionally, 10/27 new studies (n = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies (n = 1,161), total 34 (n = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): -0.45, 95% confidence interval (CI): -0.64, -0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, n = 252) found no associations, while another small study (4.5 years, n = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; n = 295; SMD: -1.51, 95% CI: -1.94, -1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.

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.

A Comparison of CVR Magnitude and Delay Assessed at 1.5 and 3T in Patients With Cerebral Small Vessel Disease.

BACKGROUND: Cerebrovascular reactivity (CVR) measures blood flow change in response to a vasoactive stimulus. Impairment is associated with several neurological conditions and can be measured using blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). Field strength affects the BOLD signal, but the effect on CVR is unquantified in patient populations. METHODS: We recruited patients with minor ischemic stroke and assessed CVR magnitude and delay time at 3 and 1.5 Tesla using BOLD MRI during a hypercapnic challenge. We assessed subcortical gray (GM) and white matter (WM) differences using Wilcoxon signed rank tests and scatterplots. Additionally, we explored associations with demographic factors, WM hyperintensity burden, and small vessel disease score. RESULTS: Eighteen of twenty patients provided usable data. At 3T vs. 1.5T: mean CVR magnitude showed less variance (WM 3T: 0.062 ± 0.018%/mmHg, range 0.035, 0.093; 1.5T: 0.057 ± 0.024%/mmHg, range 0.016, 0.094) but was not systematically higher (Wilcoxon signal rank tests, WM: r = -0.33, confidence interval (CI): -0.013, 0.003, p = 0.167); delay showed similar variance (WM 3T: 40 ± 12 s, range: 12, 56; 1.5T: 31 ± 13 s, range 6, 50) and was shorter in GM (r = 0.33, CI: -2, 9, p = 0.164) and longer in WM (r = -0.59, CI: -16, -2, p = 0.010). Patients with higher disease severity tended to have lower CVR at 1.5 and 3T. CONCLUSION: Mean CVR magnitude at 3T was similar to 1.5T but showed less variance. GM/WM delay differences may be affected by low signal-to-noise ratio among other factors. Although 3T may reduce variance in CVR magnitude, CVR is readily assessable at 1.5T and reveals comparable associations and trends with disease severity.