Project Summary / Abstract Title project: “leptomeningeal vessel wall enhancement as an early pathophysiological marker of cerebral amyloid angiopathy” Cerebral amyloid angiopathy (CAA) is a significant contributor to cognitive impairment and dementia and a leading cause of intracerebral hemorrhage (ICH) in older individuals. CAA is characterized by the accumulation of Aβ in the walls of cortical and leptomeningeal vessels. It has been suggested that vascular Aβ deposition involves a self-reinforcing cycle of reduced vascular reactivity and impaired perivascular clearance of Aβ from the brain, eventually resulting in vessel wall breakdown and the formation of hemorrhages. Currently, CAA patients are only recognized during the late stages of the disease by the detection of hemorrhages on brain MRI. Bleeding from leptomeningeal vessels, recognized as superficial siderosis on MRI, has recently emerged as one of the strongest predictors for future symptomatic ICH. However, there are currently no in vivo tools available to identify vessels at risk for superficial siderosis. In this proposal, we aim to determine the potential of contrast agent leakage as an early detection strategy to predict future sites of bleeding. We will utilize high-resolution heavily T2-weighted post-contrast fluid-attenuated inversion recovery (FLAIR) MRI after intravenous gadolinium administration to detect leakage from individual leptomeningeal vessels at the surface of the brain. Leveraging the dataset acquired in this patient population, we will further assess the clearance of gadolinium after focal leakage into perivascular spaces to determine the feasibility of mapping perivascular clearance routes in humans non-invasively. The results will inform the design of future mechanistic studies looking at perivascular clearance dynamics in CAA and Alzheimer’s disease. The proposal builds on the applicants’ international leadership in CAA, their strong background in advanced neuroimaging, and translational research program involving ex vivo MRI-guided neuropathology and in vivo two-photon imaging in mouse models. Combined with the world-class resources and international collaborations with experts in the field to perform advanced image processing, the proposed set of experiments will likely yield much needed answers regarding the early pathophysiology in CAA. Novel insights resulting from this project may also yield promising new targets to prevent vascular cognitive impairment and dementia in the elderly.