The integrity of perivascular spaces is absolutely essential for proper function of the glymphatic system waste and excess water removal from the brain.

Interest in normal perivascular spaces (PVS) and their evolution to a pathogenic, remodeled enlarged perivascular spaces (EPVS) have increased in parallel with the recently described glymphatic system pathway (GS) during the past decade. EPVS on magnetic resonance images have been shown to be a biomarker for neurovascular, neuroinflammatory, and neurodegenerative diseases. Thus, the integrity of the PVS is absolutely essential for the proper function of the GS. The mechanisms involved in the evolution of PVS to EPVS are a hot topic in research and as we better understand the pericapillary venules and vein's role regarding the GS via higher resolution imaging some of the missing pieces of this puzzle will evolve. The GS is currently known to absolutely depend on the brain's existing PVS to provide a channel for the efflux of neurotoxic substances such as accumulated neurodegenerative misfolded proteins, proinflammatory cytokines/chemokines, leukocytes, and metabolic, proteolytic debris. The perivascular unit contains both the normal PVS and the pathologic remodeled EPVS and allows for a space to house incoming leukocytes to undergo excessive cellular crosstalk of leukocytes and the resident perivascular macrophage to result in neuroinflammation. Additionally, the polarized aquaporin 4 water channels are essential in waste and excess water removal by the GS.