The Brain’s Glymphatic System: Current Controversies

Abstract

The glymphatic concept along with the discovery of meningeal lymphatic vessels have, in recent years, highlighted that fluid is directionally transported within the central nervous system (CNS). Imaging studies, as well as manipulations of fluid transport, point to a key role of the glymphatic-lymphatic system in clearance of amyloid-β and other proteins. As such, the glymphatic-lymphatic system represents a new target in combating neurodegenerative diseases. Not unexpectedly, introduction of a new plumbing system in the brain has stirred controversies. This opinion article will highlight what we know about the brain's fluid transport systems, where experimental data are lacking, and what is still debated. The Interconnected Glymphatic-Lymphatic Fluid Transport SystemThe recent discoveries of the brain's glymphatic (glial-lymphatic) (see Glossary) system and the meningeal lymphatic vessels have stirred considerable debate [1][2][3]. An obvious question is why the existence of a brain-wide fluid transport system and the presence of lymphatic vessels in the meningeal layers remained under the radar until now? Before addressing this question, we will here discuss several of the most controversial points. The debates reflect, in part, the fact that critical sets of data have yet to be collected. Other points of controversy are based on debatable assumptions and misunderstandings of the fluid dynamics within the brain. In particular, it is important to stress that the analysis of tracer distribution in histological sections is prone to artifacts. Cardiac arrest or stroke abruptly initiate a pathological influx of cerebrospinal fluid (CSF) [4,5]. As a result, the microscopic localization of CSF tracers in postmortem tissue will inevitably reflect, in part, CSF movements that occurred after death. We will here outline recent developments and add our points to the ongoing debate.

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“…of reactive oxygen species (molecular level), regulation of neurogenesis, synapse formation, maintenance and elimination (cellular and network levels), regulation of blood flow, glycogen synthesis and storage (metabolic level), as well as control of the BBB and glymphatic clearance (whole brain level) (Hanisch and Kettenmann, 2007;Tay et al, 2017bTay et al, , 2019Verkhratsky et al, 2015bVerkhratsky et al, , 2016Verkhratsky et al, , 2020Verkhratsky and Nedergaard, 2018;Mestre et al, 2020;Mondo et al, 2020). Astrocytes further contribute to the regulation of energy balance and food intake, blood pH and Na + concentration, as well as of sleep homeostat (Verkhratsky and Nedergaard, 2018).…”

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“…These solutes are fundamental for normal brain function [ 2 ]. The CSF is also involved in the removal of waste products implicated in neurodegeneration and brain injury, for instance, as the vehicle of the brain’s “glymphatic system” [ 4 , 5 ]. Therefore, the volume, composition, and movement of the CSF are of the utmost physiological importance [ 6 ].…”

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“…PVS fluid movement is proposed to be highly driven by arterial pulsations [ 171 , 172 , 173 , 174 ]. Unfortunately, an exact anatomical description for the PVS remains contested and the reader is referred to other publications for further details [ 160 , 166 , 175 , 176 , 177 ]. Due to this uncertainty, the specific route CSF follows to enter the PVS is also unclear.…”

“…Parenchymal exit occurs via the perivenous PVS and tracts located alongside cranial nerves (perineural tracts, see [ 12 ] for example). A tenet of the glymphatic system is the massive impact of sleep and awake states (see [ 175 ] for a recent glymphatic description). However, the intraparenchymal bulk flow incorporated within the glymphatic hypothesis directly conflicts with data indicating diffusion as the singular driver of fluid and solute movement through most of the brain extracellular space.…”

“…However, the intraparenchymal bulk flow incorporated within the glymphatic hypothesis directly conflicts with data indicating diffusion as the singular driver of fluid and solute movement through most of the brain extracellular space. The ongoing debate on fluid movement between and within the parenchyma and the PVS is not a topic for the current work and the reader is referred to a trove of information in numerous reviews [ 160 , 166 , 175 , 176 , 179 , 180 , 181 , 182 , 183 , 184 , 185 ]. Additionally, differential movement of fluid in white and gray matter [ 179 ] plus intraparenchymal drainage sites (e.g., extrachoroidal CSF sources, ventricular mixing, etc.)…”