The glymphatic system and its role in cerebral homeostasis

Abstract

The brain's high bioenergetic state is paralleled by high metabolic waste production. Authentic lymphatic vasculature is lacking in brain parenchyma. Cerebrospinal fluid (CSF) flow has long been thought to facilitate central nervous system detoxification in place of lymphatics, but the exact processes involved in toxic waste clearance from the brain remain incompletely understood. Over the past 8 yr, novel data in animals and humans have begun to shed new light on these processes in the form of the "glymphatic system," a brain-wide perivascular transit passageway dedicated to CSF transport and interstitial fluid exchange that facilitates metabolic waste drainage from the brain. Here we will discuss glymphatic system anatomy and methods to visualize and quantify glymphatic system (GS) transport in the brain and also discuss physiological drivers of its function in normal brain and in neurodegeneration.

Keywords: MRI; cerebrospinal fluid; glymphatic system; interstitial space; state of arousal.

Fig. 1.

T2-weighted MRIs acquired on a 1.5T MRI instrument (GE Signa HDx 1.5using a T2 fast-spin-echo pulse sequence (4-mm thick slices) from the brain of a healthy 35-yr-old female. Perivascular spaces are clearly visible (yellow arrows) in a typical pattern. Data courtesy of Joanna Wardlaw.

Fig. 2.

Illustration of the glymphatic system of the brain. In principle, the glymphatic system comprise a periarterial influx pathway and a perivenous pathway for cerebrospinal fluid (CSF) transit that are coupled to the interstitial fluid space via the aquaporin 4 (APP4) water channels. The AQP4 water channels are positioned on the glial end feet that make up the outer perimeter of the perivascular space; the inner perimeter is the vascular basement membrane. CSF flows into the periarterial space and mixes with ISF whereby waste solutes (black particles) are propelled toward the perivenous conduits for ultimate drainage out of the brain.

Fig. 3.

Glymphatic transport visualized by optimal mass transport (OMT) analysis based on dynamic contrast enhanced MRIs obtained from a live rat after MR contrast administration into the cerebrospinal fluid (CSF). The OMT-based analysis derives “CSF transport pathlines,” which are shown as a color-coded map overlaid on the corresponding volume rendered anatomical MRI. We are showing the effect of increasing the diffusion term in the optimal transport algorithm. Specifically, with a minimal or absent diffusion term in the OMT analysis, the pattern of CSF parenchymal streamlines does not align well with physiological evidence of MR contrast uptake in live rodent brain (A, arrows on nonexisting CSF pathlines). However, with more diffusion “weighting” (B), the aberrant parenchymal CSF pathways have disappeared and the uptake pattern better matched what is observed on the MRI data, strongly suggesting that parenchymal glymphatic system transport is governed by both advection and diffusion. Scale bars = 3 mm.

Fig. 4.

A: the conventional visualization of glymphatic transport in whole rat brain based on dynamic contrast-enhanced MRIs expressed as “% signal increase from baseline” 1.5 h after administration of MR contrast into the cerebrospinal fluid (CSF) via cisterna magna. The color-coded map shows the spatial distribution of CSF tagged with MR contrast demonstrating that CSF and the contrast solute have penetrated into the cerebellum, midbrain, and olfactory bulb and along the perivascular space of the middle cerebral artery as highlighted in C. B: the same data set processed by the GlymphVis algorithm with advection and diffusion terms deriving CSF streamlines. These streamlines show brain parenchymal CSF flow patterns at a fixed point in time. Please note that the CSF streamlines including transport along the middle cerebral artery (D) are well matched to the contrast uptake in the original data (compare withA and C). Scale bars = 2 mm.