Vascular Pathology in Early and Asymptomatic Cerebral Amyloid Angiopathy

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PROJECT SUMMARY/ABSTRACT Cerebral amyloid angiopathy (CAA) is an age-related cerebral small vessel disease that is common in elderly. CAA causes two principle, potentially devastating, outcomes in this population: lobar intracerebral hemorrhage (ICH) and vascular cognitive impairment and dementia (VCID). CAA is characterized by progressive deposition of β-amyloid (Aβ) in the walls of cortical and leptomeningeal arteries leading to vascular dysfunction. Vascular dysfunction underlies the lesions of small vessel disease typically seen in CAA such as lobar microbleeds (MB) and cortical superficial siderosis (cSS). In addition to exhibiting vascular dysfunction, a significant proportion of CAA patients harbor the amyloid plaques and tau-based neurofibrillary tangles typical of Alzheimer’s pathology which may also influence disease course. Although CAA is often identified in patients after they develop lobar ICH or dementia, neuropathological and epidemiologic studies suggest that early, yet pathologically advanced pre-clinical forms of CAA are common. Data generated from this project during the initial funding period have shown that these previously understudied patients can now be reliably identified with high specificity using MRI-based biomarkers. The critical next step is to identify modifiable risk factors that may influence early disease course in CAA. In contrast to other forms of stroke, modifiable risk factors to prevent CAA-related outcomes have not been identified. Preliminary evidence suggests that in CAA patients with lobar ICH, elevated mean blood pressure (BP) predicts increased risk of ICH recurrence. Emerging evidence has linked increased BP variability to elevated risk of cerebral small vessel disease, stroke and dementia above and beyond the role of mean BP levels. It is, however, unknown whether BP variability may also contribute to subclinical disease course in CAA patients. In early CAA patients who do not develop incident ICH, nearly a third develop dementia over 2 years. Is dementia caused by progressive vascular dysfunction or tau or amyloid pathology in the disease? Our preliminary data suggests that BP variability influences tau accumulation. The underlying biologic mechanisms are poorly understood. Using a prospective cohort of patients with CAA without previous history of ICH, we will answer the following three key questions: 1) Does abnormal BP, characterized by elevated BP level and variability, increase the risk of bleeding events in patients with early CAA? 2) Does BP affect progression of CAA-related vascular or tau or amyloid pathology? 3) In patients with early CAA does BP influence development of cognitive impairment and dementia?