PROJECT SUMMARY Perivascular spaces (PVS) are the area around arterioles, venules and capillaries which accommodate the clearance of the metabolic waste via Aquaporin-4 channels expressed on astrocytic endfeet and are involved in blood-brain barrier transport. PVS have come to prominence recently through potential roles in brain interstitial fluid drainage and waste clearance, and in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders. While animal studies have precisely clarified this mechanism, data from humans are relatively crude and limited to visual counting of visible PVS on clinical magnetic resonance images, and this limits our understands of the morphology, biophysical properties and distribution of the PVS in human aging and AD. The long-term goal is to understand the role of PVS in brain health and the degree to which it alters in AD. The objective of this project is to map morphologic and diffusion characteristics of the PVS fluid in healthy aging, and how it is altered in the early stages of AD. The central hypothesis is that imaging-derived PVS fluid characteristics, such as volume occupied and diffusion properties, are differentially and selectively altered in cognitive decline and AD in comparison with normal aging. The rationale underlying this proposal is that in vivo noninvasive mapping of the PVS provides mechanistic insight about AD pathophysiology. The proposed work will also develop widely applicable open resources to map PVS morphologic and diffusion properties that can be applied to a wide range of neurological disorders. The central hypothesis will be tested by pursuing three specific aims: 1) Characterize changes in PVS fluid in normal aging individuals with no cognitive decline nor evidence of AD pathology and evaluate the effect of image acquisition strategy on outcome measures; 2) Identify PVS alteration in cognitive decline and in individuals with AD pathology; and 3) Determine the extent to which PVS is associated with cardiovascular risk factors versus AD pathology. We will pursue these aims by applying innovative MRI-based computational techniques on recently available data of normal aging and patients with cognitive decline from multiple large NIH-funded studies. Computational techniques include both recently developed neuroimaging techniques sensitized to the PVS and more established structural image analysis techniques. The proposed research is significant, because it will aid in the understanding of AD pathophysiological mechanisms and consequently assist in the early diagnosis and disease monitoring of AD. It is also significant because it will make public resources available that can be used to study other neurological disorders characterized by impaired PVS in the brain. The results will have an important positive impact immediately because they will identify and map, for the first time, PVS alteration in human brain across aging, cognitively impaired and AD individuals. Our...