Repository logo

New insights into mechanisms of small vessel disease stroke from genetics

Accepted version



Change log


Tan, Y 
Rutten-Jacobs, L 


Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood–brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and ‘sporadic’ SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in ‘sporadic’ SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in ‘sporadic’ SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.



cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral small vessel disease, extracellular matrix, genetics, lacunar stroke, matrisome, Alopecia, Blood-Brain Barrier, CADASIL, Cerebral Infarction, Cerebral Small Vessel Diseases, Collagen, Extracellular Matrix, Extracellular Matrix Proteins, Genetic Predisposition to Disease, Humans, Leukoencephalopathies, Spinal Diseases

Journal Title

Clinical Science

Conference Name

Journal ISSN


Volume Title



Portland Press
British Heart Foundation (FS/15/61/31626)
Rhea Tan is supported by the Agency for Science, Technology and Research Singapore. Matthew Traylor is funded by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Loes Rutten-Jacobs is supported by a British Heart Foundation Immediate Research Fellowship (FS/15/61/31626). Hugh Markus is supported by an NIHR Senior Investigator award. His work is supported by the Cambridge Universities Trust NIHR Comprehensive Biomedical Research Centre.