71 - Extracellular Fluid Movement and Clearance in the Brain: The Glymphatic Pathway

Abstract

Fluid movement between the fluid compartments of the brain and spinal cord, including the blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), and the extracellular and intracellular compartments, is tightly controlled by barrier structures such as the blood-brain barrier (BBB) and the blood-CSF barrier. Recent investigations into the physiologic movement of fluid within and around the brain have led to the description of the glymphatic pathway, a brainwide network of perivascular spaces that supports the exchange of CSF and ISF and facilitates the clearance of interstitial solutes. Perivascular fluid exchange is dependent on the astroglial water channel aquaporin 4, which is localized to perivascular astrocytic end-feet surrounding the cerebral microcirculation. Glymphatic pathway function plays a key role in interstitial waste clearance, solute distribution, and peripheral immune surveillance within the intact brain. During sleep, the flow rate increases and facilitates waste removal. Impairment of glymphatic pathway function occurs in the aging brain, after ischemic or traumatic brain injury, and after subarachnoid hemorrhage. Neurodegenerative conditions such as Alzheimer disease or Parkinson disease are proposed to be characterized by glymphatic pathway impairment. Because the ISF is the fluid compartment through which CNS-targeting therapeutics must move and because the perivascular glymphatic pathway provides a low-resistance pathway for the exchange of CSF and ISF, the biology of the glymphatic system and its dysfunction in disease have important implications for the delivery of CNS therapeutics by intrathecal delivery, intracerebroventricular (ICV) injection, and convection-enhanced delivery (CED).