Causes and Consequences of Leptomeningeal Bleeding in Cerebral Amyloid Angiopathy - Project Summary/Abstract: Cerebral amyloid angiopathy (CAA), a small vessel disease characterized by the deposition of amyloid-β in the walls of cortical and leptomeningeal blood vessels of the brain, is a leading cause of intracerebral hemorrhage (ICH) in the elderly. Patients with CAA present clinically with hemorrhagic lesions, including acute symptomatic lobar ICH, convexal subarachnoid hemorrhage (cSAH), and the chronic manifestation of cSAH, cortical superficial siderosis (cSS). There are currently no effective treatments for hemorrhage prevention in CAA, in part due to limitations in our understanding of the mechanisms leading to vessel rupture and hemorrhage. Recent studies suggest that leptomeningeal bleeding is an important risk factor in the development of lobar ICH. The proposed research focuses on the central hypothesis that severe leptomeningeal CAA and leptomeningeal bleeding (including cSAH and cSS) cause CAA-related lobar ICH. The applicant will use a multimodal approach including ex vivo MRI-targeted neuropathological examination of human brain tissue and complementary in vivo imaging of mouse models of CAA. Inflammatory-mediated leptomeningeal vascular remodeling will be explored as a putative cause of leptomeningeal bleeding and potentially lobar ICH. Additionally, the consequences of leptomeningeal bleeding for the underlying cortex and cortical vasculature will be investigated. Inflammation secondary to blood products is hypothesized to be a crucial mechanistic link between initial leptomeningeal bleeding and rupture of additional blood vessels leading to ICH. This hypothesis will be explored in human brain tissue and in two complementary animal models of cSAH/cSS developed by the applicant. Importantly, patients with CAA typically present to clinical attention when the underlying vessel pathology has significantly progressed, and bleeding events have begun to occur. The overarching goal of these studies is to identify novel, and urgently needed, treatment targets for hemorrhage prevention, accessible at the time of symptomatic patient presentation. The proposed experiments and career development plan build on the applicant’s strong background in in vivo optical imaging of rodent models, with the career development plan focused on expanding the applicant’s knowledge base in advanced neuropathology and neuroinflammation through experimental training, formal coursework, conferences, and mentorship. The excellent scientific environment and resources of Massachusetts General Hospital and Harvard Medical School as well as the applicant’s outstanding mentorship team (including mentor, co-mentor, and scientific advisory board) of internationally recognized leaders in the fields of CAA, ICH/SAH, in vivo optical imaging, neuropathology, and neuroinflammation, will be critical to the applicant’s career development and completion of the proposed work. This K08 award will be instrumental in the applicant’s progression to a successful independent career as a clinician-scientist focused on ICH.
