The glymphatic system (or glymphatic clearance pathway, or paravascular system) is a functional waste clearance pathway for the vertebrate central nervous system (CNS). The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between CSF and ISF is driven primarily by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space. Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.

The name "glymphatic system" was coined by the Danish neuroscientist Maiken Nedergaard in recognition of its dependence upon glial cells and the similarity of its functions to those of the peripheral lymphatic system.

While glymphatic flow initially was believed to be the complete answer to the long-standing question of how the sensitive neural tissue of the CNS functions in the perceived absence of a lymphatic drainage pathway for extracellular proteins, excess fluid, and metabolic waste products, two subsequent articles by Louveau et al. from the University of Virginia School of Medicine and Aspelund et al. from the University of Helsinki, reported independently the discovery that, in fact, the dural sinuses and meningeal arteries are lined with conventional lymphatic vessels, and that this long-elusive vasculature forms a connecting pathway to the glymphatic system.

In a study published in 2012, a group of researchers from the University of Rochester, headed by M. Nedergaard, used in-vivo two-photon imaging of small fluorescent tracers to monitor the flow of subarachnoid CSF into and through the brain parenchyma. The two-photon microscopy allowed the Rochester team to visualize the flux of CSF in living mice, in real time, without needing to puncture the CSF compartment (imaging was performed through a closed cranial window). According to findings of that study, subarachnoid CSF enters the brain rapidly, along the paravascular spaces surrounding the penetrating arteries, then exchanges with the surrounding interstitial fluid. Similarly, interstitial fluid is cleared from the brain parenchyma via the paravascular spaces surrounding large draining veins.

Paravascular spaces are CSF-filled channels formed between the brain blood vessels and leptomeningeal sheathes that surround cerebral surface vessels and proximal penetrating vessels. Around these penetrating vessels, paravascular spaces take the form of Virchow-Robin spaces. Where the Virchow-Robin spaces terminate within the brain parenchyma, paravascular CSF can continue traveling along the basement membranes surrounding arterial vascular smooth muscle, to reach the basal lamina surrounding brain capillaries. CSF movement along these paravascular pathways is rapid and arterial pulsation has long been suspected as an important driving force for paravascular fluid movement. In a study published in 2013, J. Iliff and colleagues demonstrated this directly. Using in vivo 2-photon microscopy, the authors reported that when cerebral arterial pulsation was either increased or decreased, the rate of paravacular CSF flux in turn increased or decreased, respectively.

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