A clinical primer for the glymphatic system

Abstract

Abstract The complex and dynamic system of fluid flow through the perivascular and interstitial spaces of the central nervous system has new-found implications for neurological diseases. Cerebrospinal fluid movement throughout the CNS parenchyma is more dynamic than could be explained via passive diffusion mechanisms alone. Indeed, a semi-structured glial-lymphatic (glymphatic) system of astrocyte-supported extracellular perivascular channels serves to directionally channel extracellular fluid, clearing metabolites and peptides to optimize neurologic function. Clinical studies of the glymphatic network has to date proven challenging, with most data gleaned from rodent models and post-mortem investigations. However, increasing evidence suggests that disordered glymphatic function contributes to the pathophysiology of CNS aging, neurodegenerative disease, and CNS injuries, as well as normal pressure hydrocephalus. Unlocking such pathophysiology could provide important avenues toward novel therapeutics. We here provide a multidisciplinary overview of glymphatics and critically review accumulating evidence regarding its structure, function, and hypothesized relevance to neurological disease. We highlight emerging technologies of relevance to the longitudinal evaluation of glymphatic function in health and disease. Finally, we discuss the translational opportunities and challenges of studying glymphatic science.