Project Summary/Abstract I am a clinically focused neuroscientist with doctoral training in the neurobiology of aging and post-doctoral training in magnetic resonance imaging (MRI) methods of identifying structural and functional changes in neurodegeneration. A long-term research goal is to understand the dynamic relationship between brain and vascular function in the setting of Alzheimer's disease pathophysiology, with a specific focus on elucidating the role of the perivascular compartment in linking these systems and its potential as a therapeutic target. The brain perivascular space is well demonstrated to be a route of fluid flow serving to maintain brain homeostasis, and studies have shown clearance of interstitial wastes including amyloid by way of the perivascular compartment. There is mounting evidence that enlargement of this space (ePVS) is associated with clinical and diagnostic features of Alzheimer's disease and cerebrovascular pathology. Post mortem evaluation has linked ePVS with vessel-bound amyloid in the form of cerebral amyloid angiopathy (CAA) and with increased amyloid burden within the parenchyma. In vivo work has identified a strong correlation between radiologically visible (and thus enlarged) PVS and Alzheimer's disease, cerebral small vessel disease, and CAA. While the perivascular space is at the intersection of vascular, astro-glial, and amyloid-based pathologies, the relative and/or synergistic contribution to the development of ePVS is not understood. This is due in part to lack of sensitive methods to track subtle differences or changes in ePVS burden in clinical imaging and the lack of radiological/pathological association studies of ePVS. My objective is to apply innovative, multi-faceted approaches to understanding the clinical relevance and etiology of ePVS, with the long-term goal of identifying a novel preventative or therapeutic target to Alzheimer's disease and related dementias. The current proposal is a first step towards those goals. I have assembled a dynamic and cohesive team of mentors and collaborators and together we have developed a training plan that combines direct mentored training, lab meetings, departmental seminars, national and international scientific meetings, didactics, and workshops. These activities will facilitate my understanding the clinical and pathological features of Alzheimer's disease and vascular dementia (VaD) and how these disease processes intersect and interact. In addition, the proposed plan will allow me to expand my research toolbox to include methods characterizing in vivo evidence of cerebrovascular disease (perfusion MRI and white matter hyperintensity burden) and of amyloid deposition (amyloid positron emission tomography) and direct quantification of related pathologies and proteins of interest (immunohistochemistry and immunofluorescent imaging). Finally, at the completion of this training period, I will have developed proficiency in identifying the clinical features of Alzheimer's disease and VaD and in managing and analyzing multi-dimensional datasets. This would be the first study of its kind to combine in vivo, post mortem, and targeted histopathological characterization of ePVS, the lack of which is regarded as a key limitation to understanding their clinical relevance. The proposal comes at a unique time; the merging fields of Alzheimer's and cerebrovascular disease converge and focus on the perivascular space. Through this training plan, I will generate a body of data that will elucidate the clinical and biological correlates of ePVS, which will form the foundation for additional proposals aimed at more completely understanding the mechanistic underpinnings of ePVS and to explore novel diagnostic and therapeutic approaches to prevent and treat Alzheimer's disease and related dementias.