Project Summary/Abstract
The purpose of this US-China Biomedical Research Collaboration project is to understand the role of the
blood-brain barrier (BBB) in the pathogenesis of cerebral small vessel disease (SVD) and to validate BBB
permeability imaging as an early marker of SVD. SVD is a major cause of stroke, white matter (WM) disease
and dementia, but the mechanisms underlying brain damage and cognitive decline remain largely elusive. This
proposal will test the hypothesis that BBB breakdown initiates disease onset and progression in humans with
genetically defined SVD (NOTCH3 mutation carriers suffering from cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy or CADASIL). The proposal will use a unique cohort of
Chinese CADASIL patients already lined up for study inclusion at Xuanwu Hospital, Capital Medical University
in Beijing. With cutting-edge BBB permeability imaging techniques at 3 and 7 Tesla, using dynamic contrast
enhanced (DCE) MRI and diffusion-weighted arterial spin labeling (DW ASL), as well as other innovative
biomarkers of SVD as part of the MarkVCID consortium (www.markvcid.org), we will systematically investigate
the clinical, neuropsychological, and imaging changes during CADASIL progression. In 3 aims, we will first
evaluate the repeatability and correlation between BBB permeability to Gadolinium-based contrast agent
(GBCA) and water respectively in the cohort of Chinese CADASIL patients. Using a longitudinal study, we will
then determine the initiating role of BBB breakdown using DCE MRI and DW ASL in the cohort of Chinese
CADASIL patients to test the hypothesis that increased BBB permeability in NOTCH3 mutation carriers
initiates disease onset and progression, such as cerebral blood flow (CBF) reductions, development of WM
lesions and free water content, ischemic infracts and mircrohemorhages, and cognitive decline. We will further
develop and evaluate a multiparametric MRI protocol for CADASIL patients including BBB permeability
imaging at ultrahigh field of 7T. Leveraging a unique cohort of Chinese CADASIL patients, and applying
cutting-edge imaging approaches at 3 and 7T, this US-China Biomedical Collaboration project will define the
initiating role of BBB dysfunction in cerebral SVD, and will establish the BBB as a new key target for
therapeutic interventions in CADASIL and by extension SVD. This project will also result in cutting-edge BBB
permeability imaging protocols at 3 and 7T as early imaging markers of SVD.