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Amyloid-related Disorders Update on Amyloid-associated Intracerebral Hemorrhage Rebbeca Grysiewicz, DO 1 and Philip B Gorelick, MD, MPH, FACP 2 1. Assistant Professor of Neurology, Section of Cerebrovascular Disease and Neurological Critical Care, University of Illinois College of Medicine at Chicago, Illinois, US; 2. Medical Director, Hauenstein Neuroscience Center, Saint Mary’s Health Care and Clinical Professor, Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, US Abstract Cerebral congophilic or amyloid angiopathy (CAA) is a clinicopathological entity that is considered a common cause of primary non-traumatic brain hemorrhage in the elderly. CAA is frequently associated with Alzheimer’s disease (AD) and has become a primary focus of scientific inquiry. The spectrum of intracerebral hemorrhage (ICH) that may occur in CAA includes: cerebral lobar hemorrhages, deep hemorrhages, purely subarachnoid and subdural hemorrhages and cerebral microbleeds. CAA is also associated with microinfarcts, leukoencephalopathy and superficial siderosis. This brief article will provide an update on the advances in our understanding of CAA-associated ICH with a focus on the following topics: neuropathology and mechanism of CAA-related hemorrhage; epidemiology, including genetic and other possible risk factors; clinical presentation; diagnosis, including newer imaging modalities; and prospects for prevention and treatment. Keywords Cerebral amyloid angiopathy, intracerebral hemorrhage, cerebral microbleeds, lobar hemorrhage, Alzheimer’s disease Disclosure: The authors have no conflicts of interest to declare. Received: November 2, 2011 Accepted: February 1, 2012 Citation: US Neurology, 2012;8(1):20–3 Correspondence: Rebbeca Grysiewicz, DO, Assistant Professor of Neurology, Section of Cerebrovascular Disease and Neurological Critical Care, University of Illinois College of Medicine at Chicago, 912 South Wood Street, Room 855N, Chicago, IL 60612, US. E: grysiewi@uic.edu Cerebral congophilic or amyloid angiopathy (CAA) is a clinicopathologic entity that has been recognised since the early part of the 20th century. 1 It is now considered a common cause of primary non-traumatic brain hemorrhage and traditionally it was described in elderly patients who were thought to be normotensive. Because of its frequent association with Alzheimer’s disease (AD), CAA has become a primary focus of scientific inquiry. The spectrum of intracerebral hemorrhage (ICH) that may occur in CAA includes: cerebral lobar hemorrhage in which several lobes on both sides of the brain may be involved over time; on rare occasions, hemorrhage in deep brain central grey nuclei, the corpus callosum and cerebellum, locations more typically involved when there is hypertensive ICH; the rare purely subarachnoid and subdural hemorrhages, as meningeal vessels may be heavily involved by CAA; and miliary and petechial or cerebral microbleeds. 1,2 In addition, there may be scattered associated microinfarcts, an inflammatory type of CAA, leukoencephalopathy, AD-associated changes of the brain and superficial siderosis (SS). 3 In this brief article we provide an update on advances in our understanding of CAA-associated ICH. We will focus on the following topics: neuropathology and mechanism of CAA-related hemorrhage; epidemiology, including genetic and other possible risk factors; clinical presentation; diagnosis, including newer imaging modalities; and prospects for prevention and treatment. 20 Neuropathology and Mechanism of Cerebral Amyloid Angiopathy-associated Brain Hemorrhage Amyloid-β (AB) deposition in the vascular media and adventitia provides a critical link whereby ICH may occur. AB is generated by proteolytic cleavage of the amyloid precursor proteins β-secretase and γ-secretase to yield a family of AB peptides with 40- and 42-amino acid species (AB40 and AB42, respectively). 4 These peptides may undergo degradation by other proteolytic enzymes (e.g., neprilysin, insulin-degrading enzyme), remain in solution and enter the plasma or efflux across the blood–brain barrier, or polymerise to form soluble oligomers or insoluble amyloid fibrils as senile plaques in the brain parenchyma or as deposition in the vascular media and adventitia, as occurs in CAA. AB deposition occurs in the vascular media and adventitia of small arteries of the leptomeninges and cerebral cortex, with heavy involvement of the occipital regions, whereas white-matter brain vessels are much less frequently affected. 4 The predominant AB species in CAA is the relatively more soluble AB40. AB is thought to be generated by neurons and possibly in the liver. Microscopically, CAA is characterized by acellular thickening of the walls of small and medium-sized arteries, including arterioles, but less often veins, by an amorphous, intensely eosinophilic material. 1 Microvascular amyloid may be identified by periodic acid–Schiff, toluidine blue, crystal violet, thioflavin S or T (fluorescence under ultraviolet light) © TOUCH BRIEFINGS 2012