Vascular breakdown in Alzheimers disease with cerebrovascular disease

Microhemorrhages and vasogenic edema are pathological phenomenon that occur in both cerebrovascular disease (CBVD) and Alzheimer’s disease (AD). In CBVD these can occur throughout the brain, yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and / or vasogenic edema. Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly, we propose to do T2* MRI imaging with FLAIR and SWI during the studies to assess vasogenic edema and microhemorrhages as well as any other brain changes occurring through the course of the studies. We will also perform arteriole spin label scans to measure blood flow and contrast agents as an additional measure of vascular leakage immediately prior to tissue harvest.