Monogenic causes of cerebral small vessel disease- models for vascular cognitive impairment and dementia?

Abstract

Purpose of review: Recent advancements in molecular biomarkers and therapeutic options for Alzheimer's disease have brought into focus the need for greater progress in the second most common cause of dementia, vascular cognitive impairment and dementia (VCID). We examine how the study of monogenic causes of VCID has contributed to the understanding of its pathophysiology and potential biomarker and treatment research.

Recent findings: It is widely accepted that conditions which disrupt the cerebral small vessels contribute to vascular pathologies including stroke and cerebral microbleeds, ultimately leading to vascular cognitive impairment and dementia. Among these conditions are a range of monogenic small vessel diseases (SVDs) such as CADASIL, CARASIL, Fabry disease and COL4A-related disorders.

Summary: This review indicates the importance of furthering research into monogenic SVDs in order to gain insight into the pathomechanisms of VCID more broadly. Monogenic conditions are easier to model than sporadic VCID and can serve as a guide for identifying biomarkers for diagnosis, monitoring and intervention outcomes.

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FIGURE 1

Monogenic causes of cerebral small vessel disease (cSVD) leading to vascular cognitive impairment and dementia (VCID), their common symptoms and associated genes. Icon adapted from BioRender. CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL, cathepsin-A related arteriopathy with strokes and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; COL4A1/A2, collagen type IV alpha 1 and 2; CTSA, cathepsin A; GLA, galactosidase alpha; HTRA1, high temperature requirement serine peptidase A1; RVCL-S, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; TIA, transient ischaemic attack.