The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy

Abstract

The paravascular pathway, also known as the "glymphatic" pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted.

Keywords: amyloid-beta; brain waste clearance; glymphatic system; paravascular pathway; perivascular pathway.

Figure 1

Anatomy of the paravascular and perivascular spaces. The arterial paravascular space is bounded internally by the pial sheath (4) and externally by the basement membrane of glia limitans (5). The venous paravascular space is bounded internally by the vein wall (6) and externally by the glia limitans. The perivascular space is found within the middle layers of the basement membrane of arterial smooth muscle cells (3). No perivascular space is present in venous vasculature. In each space, the direction of fluid flow and waste clearance, such as amyloid beta (Aβ), is depicted with arrows. Reprinted with permission © Bakker et al. (2016).

Figure 2

Schematic of glymphatic and perivascular waste clearance routes. According to the glymphatic model, cerebrospinal fluid (CSF) flows along para-arterial spaces (1), mixes with interstitial fluid (ISF) and solutes (2), and is cleared from the brain along para-venous spaces (3). Efficient glymphatic clearance of waste and solutes is dependent on fluid movement across aquaporin-4 (AQP4) channels located on astrocytic endfeet surrounding the parenchymal vasculature. In contrast, perivascular drainage of ISF and solutes occurs along the middle layers of the basement membrane of arterial smooth muscle cells and, as indicated by arrows, flows in a direction opposite to that of glymphatic clearance. Reprinted with permission from Macmillan Publishers Ltd: © Tarasoff-Conway et al. (2015).