Non-invasive MRI mapping of BBB water exchange rate and permeability

Project Summary/Abstract The blood-brain barrier (BBB) plays a crucial role in protecting the central nervous system (CNS) from harmful substances such as plasma proteins and inorganic solutes. A non-invasive MRI technique to detect subtle BBB dysfunction could be an extremely valuable tool for early diagnosis of neurodegenerative disorders. Our team has developed a diffusion prepared pseudo-continuous arterial spin labeling (OP-pCASL) technique for mapping BBB water exchange rate (kw), which has been validated by preclinical studies and found to be associated with aging, small vascular disease, APOE epsilon4 genotype, amyloid PET, and CSF Aβ-42 in cognitively normal subjects. However, the OP-pCASL technique currently has low spatial resolution and cannot estimate the permeability surface area product of water (PSw) due to a lack of venous compartment in its modeling. Mapping both kw and PSw is significant because they assess different aspects of the BBB and provide comprehensive information about its function. Changes in PSw can indicate a combination of changes in capillary surface and permeability, making it a potential biomarker for subtle BBB leakage across endothelial cells. In contrast, kw measures the exchange rate between blood and tissue and can be more sensitive to transport mechanisms, e.g. AQP4 function, and potentially linked to the glymphatic function. However, the exact neurophysiological mechanisms of kw and PSw are still unclear. The proposed project aims to develop and optimize a highresolution diffusion-weighted arterial spin labeling (OW-ASL) technique and mathematical models to non-invasively quantify BBB kw and PSw simultaneously. The individual BBB kw and PSw measurements will be evaluated for test-retest repeatability. The age-related changes of BBB function and BBB dysfunction in cerebral small vessel disease (cSVO) will be investigated by measuring kw and PSw in a cohort of healthy subjects across the lifespan of 18-90 years and elderly subjects (age> 60 years) with cSVO from USC VCIO study. Finally, the mechanisms of BBB water exchange will be studied in AQP4-knockout mice and in models of mannitol-induced BBB disruption. The outcome of this project will be a cutting-edge OW-ASL pulse sequence and post-processing pipeline that allows for high-resolution mapping of kw and PSw, with an understanding of their neurophysiological mechanisms.