Cerebral Waste Clearance: Measurements and Applications

Cerebral Waste clearance (CWC) is an essential process for brain homeostasis, which is required for the healthy functioning of all cerebrovascular and parenchymal brain cells. This dissertation features our current understanding of CWC, both within and external to the brain parenchyma. We describe the role of the cerebrospinal fluid (CSF) and its exit routes in mediating CWC. Recent discoveries of the glymphatic system and meningeal lymphatic vessels (mLVs), and their relevance to CWC and various neurological conditions are highlighted. Controversies related to CWC research and potential future directions are presented. This dissertation is divided into seven chapters that discuss investigations that used magnetic resonance imaging (MRI) and confocal microscopy imaging to evaluate the recently identified CWC routes, namely the glymphatic system and the mLVs. The dissertation begins with an introduction (Chapter- 1). It proceeds with background (Chapter- 2) based on two published peer-reviewed ‘review’ articles, and three research projects based on one submitted, one published ‘original research’ articles (Chapters- 3, 4) and one project with negative results (Chapter- 5). Among the three projects described in this dissertation, the first project (Chapter- 3) aimed to investigate the controversy of glymphatic convective bulk flow in the interstitial spaces and explore the association of perivascular macrophages (PVMs) in assisting the glymphatic system for CWC. Our findings solidify the glymphatic system hypothesis and indicate the interaction of PVMs with the glymphatic CSF influx along the arteries and glymphatic CSF efflux along the veins. The second project (Chapter- 4) aimed to examine the changes in the glymphatic system in rats with glioblastoma multiforme (GBM) and our results identify reduced glymphatic influx and clearance due to GBM. The third project (Chapter- 5) aimed to assess the mLVs as a potential efflux pathway of the glymphatic system under healthy and diabetic mellitus (DM) conditions. Our results suggest that mLVs are not the major efflux pathway of the glymphatic system, which is a negative result. The dissertation then discusses a translational issue for clinical MRI evaluation of the glymphatic system (Chapter- 6) based on a submitted ‘review’ article and concludes with a summary and future directions (Chapter- 7).