The Genetics of Cerebral Microbleeds

Cerebral microbleeds are a radiological marker of small areas of haemorrhage in the brain, seen on magnetic resonance imaging sequences sensitive to the paramagnetic properties of blood and its breakdown products. In this chapter, we review both the monogenetic disorders and more common genetic variants associated with cerebral microbleeds. We first introduce cerebral microbleeds, including how they can be identified and quantified and a brief overview of their clinical associations and relevance. We then explore these monogenetic conditions associated with cerebral microbleeds; we consider those associated with cerebrovascular amyloid deposition (first amyloid-beta, and then other forms of amyloid). We focus on familial amyloid-beta CAA (and Alzheimer’s disease) caused by autosomal dominant mutations in three genes: APP, which encodes the amyloid precursor protein; PSEN1, which encodes presenilin-1, the catalytic subunit of the gamma-secretase enzyme which cleaves the amyloid precursor protein to produce amyloid-beta; and PSEN2, which encodes presenilin-2, a homologue of presenilin-1 which can also act as the catalytic subunit of gamma-secretase. We then describe genetic conditions associated with other forms of amyloid (familial British Dementia, gelsolin amyloidosis, and familial leptomeningeal (transthyretin) amyloidosis) and then other non-amyloid mutations causing cerebral small vessel diseases (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), collagen gene mutations, Fabry disease, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS), and laminin gene mutations). Finally, we review common gene variants associated with cerebral microbleeds in genome-wide association studies.