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.

Image processing approaches to enhance perivascular space visibility and quantification using MRI

“…Many recent studies have shown pathological alteration of PVS in a range of neurological disorders (Bacyinski et al, 2017;Banerjee et al, 2017;Brown et al, 2018;Cavallari et al, 2018;Feldman et al, 2018;Kalaria, 2018;Krueger and Bechmann, 2010;Laveskog et al, 2018;Park et al, 2017). It is also believed that PVS plays a major role in the clearance system, accommodating the influx of CSF to brain parenchyma through peri-arterial space, and the efflux of interstitial fluid to the lymphatic system through peri-venous space (Rasmussen et al, 2018;Tarasoff-Conway et al, 2015;Bacyinski et al, 2017;Iliff et al, 2012). MRI is a powerful tool that enables in vivo, non-invasive imaging of this less-known glia-lymphatic pathway.…”

Landmarks and frontiers in biological fluid dynamics

“…Bacyinski, Xu, Wang, and Hu. Frontiers in Neuroanatomy 11: 101 (2017) [6] "Unidirectional pulmonary airflow in vertebrates: a review of structure, function, and evolution." Cieri and Farmer.…”

Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis

“…There has been great interest surrounding cerebrospinal fluid (CSF) dynamics since the existence of the glymphatic system was proposed in 2012 (1)(2)(3)(4). The glymphatic system has been suggested as being largely responsible for the clearance of waste from the brain (1,5).…”

“…This system is thought to be analogous to the body's peripheral lymphatic system with the additional involvement of glial cells (1). Although there is still debate over the exact mechanism underlying the glymphatic system (2,3,(6)(7)(8), there is an overall agreement that a para-and/or peri-vascular clearance system of the brain exists and that it is closely linked to the production and flow of CSF. CSF is predominantly produced by the choroid plexuses of the lateral, third, and fourth ventricles.…”