Imaging neurovascular, endothelial and structural integrity in preparation to treat small vessel diseases. The INVESTIGATE-SVDs study protocol. Part of the SVDs@Target project

Abstract

Background: Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres.

Methods: We will recruit participants with sporadic SVDs (ischaemic stroke or vascular cognitive impairment) and CADASIL in Edinburgh, Maastricht and Munich. We will perform detailed clinical and neuropsychological phenotyping of the participants, and neuroimaging including structural MRI, cerebrovascular reactivity MRI (CVR: using carbon dioxide challenge), phase contrast MRI (arterial, venous and CSF flow and pulsatility), dynamic contrast-enhanced MRI (blood brain barrier (BBB) leakage) and multishell diffusion imaging. Participants will measure their blood pressure (BP) and its variability over seven days using a telemetric device.

Discussion: INVESTIGATE-SVDs will assess the relationships of BBB integrity, CVR, pulsatility and CSF flow in sporadic SVD and CADASIL using a multisite, multimodal MRI protocol. We aim to establish associations between these measures of vascular function, risk factors particularly BP and its variability, and brain parenchymal lesions in these two SVD phenotypes. Additionally we will test feasibility of complex multisite MRI, provide reliable intermediary outcome measures and sample size estimates for future trials.

Keywords: BBB, blood brain barrier; BOLD, blood oxygen level dependent; BP, blood pressure; BPv, blood pressure variability; Blood-brain barrier permeability; CADASIL; CADASIL, cerebral autosomal dominant arteriopathy with leukoencephalopathy and subcortical infarcts; CBF, cerebral blood flow; CERAD+, consortium to establish a disease registry for Alzheimer's disease plus battery; CO2, carbon dioxide; CSF, cerebrospinal fluid; CVR, cerebrovascular reactivity; Cerebral small vessel disease; Cerebrovascular reactivity; DCE, dynamic contrast enhanced; EtCO2, end-tidal carbon dioxide; GM, grey matter; MMSE, mini-mental state examination; MRI; MoCA, Montreal cognitive exam; NIHSS, national institute for health stroke scale; PI, pulsatility index; PVS, perivascular space; RSSI, recent small subcortical infarct; SVDs, small vessel diseases; WM, white matter; WMH, white matter hyperintensity.