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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; p overall =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; p overall =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., Competing Interests: Declaration of interests MD has received consultancy and advisory board fees from Bayer Vital, and speaker's fees from Bayer Vital. MDu reports no competing interests directly related to this work, but declares the following interests outside the submitted work: MIAC (employment), Roche (consultant), Biogen (scientific advisory board), Hovid Berhad (adjudication board), Bayer Vital, and Sanofi Genzyme (speaker honoraria). BN has received consultancy fees from Simbec-Orion for data monitoring committee work. KWM has received consultancy fees from Boehringer Ingelheim, Biogen, Abbvie, Lumosa, and Woolsey, advisory board fees from Boehringer Ingelheim, and speaker's fees from Boehringer Ingelheim. PMR has received consultancy and advisory board fees from Bayer, Bristol Myers Squibb, Sanofi, and Abbott, and speaker fees from Sanofi and Abbott. RvO reports financial support by the European Union's Horizon 2020 project ‘CRUCIAL’ (grant number 848109), and the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium (financed by the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation, the Netherlands Brain Foundation, Stryker, Medtronic, and Cerenovus). JMW is part funded by the UK Dementia Research Institute (funded by the Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK) but has no competing interests. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: 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 multicenter 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 lesion 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 a reference., Results: Among the 77 patients enrolled, 76 had usable SWI sequences, 45 with sporadic SVD (mean age 64 years [SD 11], 26 men [58%]) and 31 with CADASIL (53 years [11], 15 men [48%]). We identified 94 vessel-clusters in 36 of the 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), and lower CVR in normal appearing white matter (per %/mm Hg, 0.77, 0.60-0.99), compared with patients without vessel-clusters. Fifty-seven of the 94 vessel-clusters (61%) corresponded to noncavitated or partially cavitated WMH on fluid-attenuated inversion recovery, and 37 of 94 (39%) to complete cavities. CVR magnitude was lower than in the corresponding contralateral volumes (mean difference [SD], t , p ) within vessel-cluster volumes (-0.00046 [0.00088], -3.021, 0.005) and in the surrounding volume expansion shells up to 4 voxels (-0.00011 [0.00031], -2.140, 0.039; -0.00010 [0.00027], -2.295, 0.028) in vessel-clusters with complete cavities, but not in vessel-clusters without complete cavitation., Discussion: Vessel-clusters might correspond to maximally dilated vessels in white matter that are approaching complete tissue injury and cavitation. The pathophysiologic significance of this new feature warrants further longitudinal investigation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Cognitive impairment is an inevitable feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affecting executive function, attention and processing speed from an early stage. Impairment is associated with structural markers such as lacunes, but associations with functional connectivity have not yet been reported. Twenty-two adults with genetically-confirmed CADASIL (11 male; aged 49.8 ± 11.2 years) underwent functional magnetic resonance imaging at rest. Intrinsic attentional/executive networks were identified using group independent components analysis. A linear regression model tested voxel-wise associations between cognitive measures and component spatial maps, and Pearson correlations were performed with mean intra-component connectivity z-scores. Two frontoparietal components were associated with cognitive performance. Voxel-wise analyses showed an association between one component cluster and processing speed (left middle temporal gyrus; peak -48, -18, -14; ZE = 5.65, pFWE corr = 0.001). Mean connectivity in both components correlated with processing speed (r = 0.45, p = 0.043; r = 0.56, p = 0.008). Mean connectivity in one component correlated with faster Trailmaking B minus A time (r = -0.77, p < 0.001) and better executive performance (r = 0.56, p = 0.011). This preliminary study provides evidence for associations between cognitive performance and attentional network connectivity in CADASIL. Functional connectivity may be a useful biomarker of cognitive performance in this population., (© The Author(s) 2016.)