Intracerebral Hemorrhage and Cerebral Amyloid Angiopathy

Intracerebral hemorrhage (ICH) is the acute manifestation of chronic cerebral small vessel disease. ICH is classified according to the affected brain region as lobar ICH, most often caused by cerebral amyloid angiopathy (CAA), or deep ICH, most often caused by chronic hypertension. Although multiple autosomal dominant genetic ICH syndromes exist, the vast majority of ICH is sporadic with substantial heritability, the variance explained by common genetic variation being ~44%. Sporadic CAA accounts for the vast majority of lobar ICH in the general population. While definitive diagnosis requires pathological examination, CAA can be diagnosed reliably according to the Boston or Edinburgh criteria using neuroimaging and clinical data. The most important and most extensively studied locus of common genetic variation in CAA is APOE with both the ε(epsilon)2 and ε(epsilon)4 alleles associated with lobar ICH risk, and ε(epsilon)2 associated with ICH volume, ICH expansion on follow-up imaging, and 3-month outcomes after ICH. Rare mutations within the amyloid precursor protein (APP) responsible for most forms of familial CAA. These autosomal dominant disorders have an earlier age of onset and more severe clinical course than sporadic CAA. The alpha1 and alpha2 chains of type IV collagen (COL4A1/COL4A2) genes are involved in both familial and sporadic forms of ICH in all anatomical locations. For deep ICH, common genetic risk exists mainly at the 1q22 locus, with PMF1 and SLC25A44 being of highest interest for further biological dissection. Future studies are urgently needed to better understand the genetic architecture of ICH in order to ultimately develop therapeutics for this devastating disease.