Glymphatic system
Glymphatic system | |
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Identifiers | |
MeSH | D000077502 |
Anatomical terminology |
The glymphatic system (or glymphatic clearance pathway, or paravascular system) is a system for waste clearance in the
The name "glymphatic system" was coined by the
Glymphatic flow was initially 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. However, 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 that 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.[5][6]
Proposed structure
In a study published in 2012,[7] 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.[7] Similarly, interstitial fluid is cleared from the brain parenchyma via the paravascular spaces surrounding large draining veins.[citation needed]
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
Function
Waste clearance during sleep
A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Using a combination of diffusion iontophoresis techniques pioneered by Nicholson and colleagues, in vivo 2-photon imaging, and electroencephalography to confirm the wake and sleep states, Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta. On the basis of these findings, they hypothesized that the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain.[16]
Lipid transport
Another key function of the glymphatic system was documented by Thrane et al., who, in 2013, demonstrated that the brain's system of paravascular pathways plays an important role in transporting small lipophilic molecules.
Clinical significance
Pathologically,
The glymphatic system also may be impaired after acute brain injuries such as
The glymphatic system may also be involved in the
History
Description of the cerebrospinal fluid
Although the first known observations of the CSF date back to Hippocrates (460–375 BCE) and later, to Galen (130–200 CE), its discovery is credited to Emanuel Swedenborg (1688–1772 CE), who, being a devoutly religious man, identified the CSF during his search for the seat of the soul.[22] The 16 centuries of anatomists who came after Hippocrates and Galen may have missed identifying the CSF due to the prevailing autopsy technique of the time, which included severing the head and draining the blood before dissecting the brain.[22] Although Swedenborg's work (in translation) was not published until 1887 due to his lack of medical credentials, he also may have made the first connection between the CSF and the lymphatic system. His description of the CSF was of a "spirituous lymph".[22]
CNS lymphatics
In the peripheral organs, the
In 2015, the presence of a
Diffusion hypothesis
For more than a century the prevailing hypothesis was that the flow of cerebrospinal fluid (CSF), which surrounds, but does not come in direct contact with the parenchyma of the CNS, could replace peripheral lymphatic functions and play an important role in the clearance of extracellular solutes.[23] The majority of the CSF is formed in the
Key determinants of diffusion through the brain interstitial spaces are the dimensions and composition of the extracellular compartment. In a series of elegantly designed experiments in the 1980s and 1990s, C. Nicholson and colleagues from New York University explored the microenvironment of the extracellular space using ion-selective micropipettes and ionophoretic point sources. Using these techniques Nicholson showed that solute and water movement through the brain parenchyma slows as the extracellular volume fraction decreases and becomes more tortuous.[27]
As an alternative explanation to diffusion, Cserr and colleagues proposed that
Research
Studies in 1985 indicated that cerebrospinal fluid and interstitial fluid may flow along specific anatomical pathways within the brain, with CSF moving into the brain along the outside of blood vessels; such 'paravascular channels' were possibly analogous to peripheral lymph vessels, facilitating the clearance of interstitial wastes from the brain.[8][28] However, other studies did not observe such widespread paravascular CSF–ISF exchange.[29][30] The continuity between the brain interstitial fluid and the CSF was confirmed by evidence that interstitial solutes in the brain exchange with CSF via a bulk flow mechanism, rather than by diffusion.[30]
References
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- ^ Konnikova M (11 January 2014). "Goodnight. Sleep Clean". The New York Times. Retrieved 18 February 2014.
She called it the glymphatic system, a nod to its dependence on glial cells
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Further reading
- Konnikova M (2014-01-11). "Goodnight. Sleep Clean". New York Times. Retrieved 2014-01-20.
- Shaw G (2015-07-10). "New Study Suggests Brain Is Connected to the Lymphatic System: What the Discovery Could Mean for Neurology". Neurology Today. 15 (13). S2CID 74857111. Retrieved 2015-07-10.
- Jessen NA, Munk AS, Lundgaard I, Nedergaard M (December 2015). "The Glymphatic System: A Beginner's Guide". Neurochemical Research. 40 (12): 2583–99. PMID 25947369.