Efflux Route Responses of Cerebral Waste Clearance During Progression of Alzheimer’s Disease - ABSTRACT The objectives of this proposal are to optimize and validate detection of microvessels in the cerebral vascular, glymphatic and meningeal lymphatic (ML) systems using superparamagnetic iron oxide (SPIO)-enhanced susceptibility weighted imaging (SWI, SPIO-SWI), and then to investigate the cerebral waste clearance in the vascular, glymphatic and ML systems during progression of Alzheimer’s Disease (AD). Emerging data indicate that the waste clearance from the brain parenchyma plays an important role in neurological diseases, especially neurodegenerative diseases1-9. Waste clearance from brain is closely related to alterations in small blood and lymphatic vessels and perivascular spaces of the brain7-9. The glymphatic system and its peri-vascular pathway for waste clearance have been shown to be sensitive biomarkers for neurological diseases8,10-15. Despite many milestone achievements, conclusive findings on the brain waste clearance relationships among the blood and lymphatic vessels, and perivascular spaces and their contributions to AD are absent. The paucity of research into the relationships among the changes in cerebral blood vessels, lymphatic vessels, perivascular spaces, and the outcomes of diseases may be attributed, in part, to technical difficulties. Although the currently used two-photon imaging (TPI) is excellent for vessel detection in small surface areas, it is invasive and is not suitable for whole brain studies. MRI can overcome the weak points of TPI and provide non-invasive whole brain real-time imaging of the vascular, glymphatic and lymphatic systems. However, conventional MRI sensitivity is insufficient to investigate microvessels of the vascular, glymphatic and lymphatic systems. We have optimized highly sensitive MRI methods using the SPIO-SWI to detect ~10 micrometer cerebral microvessels (Fig. 1-4)16,17. Our preliminary data indicate that clearance of intracisternal injected MRI contrast agent decreases with AD severity and concomitantly with increased beta-amyloid around the vasculature and with functional deficits in a rat model of AD. Based on our novel preliminary data, we posit that the SPIO-SWI technique will significantly increase detection sensitivity of microvessels in vascular, glymphatic and ML systems and thereby permit detailed investigation of the interaction among the changes in cerebral blood vessels, lymphatic vessels, and perivascular spaces during progression of AD. To test these hypotheses, we will first (Aim 1) optimize and validate our approach to enhance the detection sensitivity for both glymphatic and ML microvessels. In Aim 2, using the optimized SPIO-SWI technique, we will perform longitudinal measurements to investigate the interaction among vascular, glymphatic and ML systems for waste clearance during progression of AD. Data generated from this application will provide new insights into the efflux pathways of brain waste clearance with progression of AD.
