Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.

Keywords: amyloid β; cerebral amyloid angiopathy; cerebral microbleeds; intracerebral hemorrhage; proteomic analyses; superficial siderosis.

Figure 1

Histopathological and radiological imaging of CAA (cerebral amyloid angiopathy). Representative histopathological images from a patient with severe CAA. Congo red-positive leptomeningeal arteries (A) and those same arteries viewed under polarized light (B). SWI (susceptibility-weighted imaging) MRI shows a strictly lobar distribution of lobar microbleeds (arrowheads) (C). SWI shows cSS (cortical superficial siderosis) as hypointense curvilinear signals along the cortical gyri (arrows) (D). Scale bars = 1 mm.