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Glymphatic system

January 29, 2023

The glymphatic system (or glymphatic clearance pathway, or paravascular system) was described and named in 2013 as a system for waste clearance in the central nervous system (CNS) of vertebrates. According to this model, cerebrospinal fluid (CSF) flows into the paravascular space around cerebral arteries, combining with interstitial fluid (ISF) and parenchymal solutes, and exiting down venous paravascular spaces.[1] The pathway consists of a para-arterial influx route for 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[2] 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.[3]

Glymphatic system
Mammalian glymphatic system
Identifiers
MeSHD000077502
Anatomical terminology
[edit on Wikidata]

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.[4]

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

 
Astrocytes stained for GFAP (green) and aquaporin-4 (purple)

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 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.[8] 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.[citation needed]

Astrocytes extend long processes that interface with neuronal synapses, as well as projections referred to as 'end-feet' that completely ensheathe the brain's entire vasculature. Although the exact mechanism is not completely understood, astrocytes are known to facilitate changes in blood flow [9][10] and have long been thought to play a role in waste removal in the brain.[11] Researchers have long known that astrocytes express water channels called aquaporins.[12] Until recently, however, no physiological function had been identified that explained their presence in the astrocytes of the mammalian CNS. Aquaporins are membrane-bound channels that play critical roles in regulating the flux of water into and out of cells. Relative to simple diffusion, the presence of aquaporins in biological membranes facilitates a 3– to 10-fold increase in water permeability.[13] Two types of aquaporins are expressed in the CNS: aquaporin-1, which is expressed by specialized epithelial cells of the choroid plexus, and aquaporin-4 (AQP4), which is expressed by astrocytes.[14][15] Aquaporin-4 expression in astrocytes is highly polarized to the endfoot processes ensheathing the cerebral vasculature. Up to 50% of the vessel-facing endfoot surface that faces the vasculature is occupied by orthogonal arrays of AQP4.[12][14] In 2012, it was shown that AQP4 is essential for paravascular CSF–ISF exchange. Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow-dependent clearance of interstitial solutes decreases by 70% in the absence of AQP4. Based upon this role of AQP4-dependent glial water transport in the process of paravascular interstitial solute clearance, Iliff and Nedergaard termed this brain-wide glio-vascular pathway the "glymphatic system".

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.[16] 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.[citation needed]

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.[17] Led by M. Nedergaard, Thrane and colleagues also showed that the paravascular transport of lipids through the glymphatic pathway activated glial calcium signalling and that the depressurization of the cranial cavity, and thus impairment of the glymphatic circulation, led to unselective lipid diffusion, intracellular lipid accumulation, and pathological signalling among astrocytes. Although further experiments are needed to parse out the physiological significance of the connection between the glymphatic circulation, calcium signalling, and paravascular lipid transport in the brain, the findings point to the adoption of a function in the CNS similar to the capacity of the intestinal lymph vessels (lacteals) to carry lipids to the liver.

Clinical significance

Pathologically, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are all characterized by the progressive loss of neurons, cognitive decline, motor impairments, and sensory loss.[18][19] Collectively these diseases fall within a broad category referred to as proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins. According to the prevailing amyloid hypothesis of Alzheimer's disease, the aggregation of amyloid-beta (a peptide normally produced in and cleared from the healthy young brain) into extracellular plaques drives the neuronal loss and brain atrophy that is the hallmark of Alzheimer's dementia. Although the full extent of the involvement of the glymphatic system in Alzheimer's disease and other neurodegenerative disorders remains unclear, researchers have demonstrated through experiments with genetically modified mice that the proper function of the glymphatic clearance system was necessary to remove soluble amyloid-beta from the brain interstitium.[7] In mice that lack the AQP4 gene, amyloid-beta clearance is reduced by approximately 55 percent.

The glymphatic system also may be impaired after acute brain injuries such as ischemic stroke, intracranial hemorrhage, or subarachnoid hemorrhage. In 2014, a group of researchers from the French Institute of Health and Medical Research (INSERM) demonstrated by MRI that the glymphatic system was impaired after subarachnoid hemorrhage, because of the presence of coagulated blood in the paravascular spaces.[20] Injection of tissue plasminogen activator (a fibrinolytic drug) in the CSF improved glymphatic functioning. In a parallel study, they also demonstrated that the glymphatic system was impaired after ischemic stroke in the ischemic hemisphere, although the pathophysiological basis of this phenomenon remains unclear. Notably, recanalization of the occluded artery also reestablished the glymphatic flow.

The glymphatic system may also be involved in the pathogenesis of amyotrophic lateral sclerosis.[21]

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 lymphatic system performs important immune functions and runs parallel to the blood circulatory system to provide a secondary circulation that transports excess interstitial fluid, proteins, and metabolic waste products from the systemic tissues back into the blood. The efficient removal of soluble proteins from the interstitial fluid is critical to the regulation of both colloidal osmotic pressure and homeostatic regulation of the fluid volume of the body. The importance of lymphatic flow is especially evident when the lymphatic system becomes obstructed. In lymphatic associated diseases, such as elephantiasis (where parasites occupying the lymphatic vessels block the flow of lymph), the impact of such an obstruction may be dramatic. The resulting chronic edema is due to the breakdown of lymphatic clearance and the accumulation of interstitial solutes.[citation needed]

In 2015, the presence of a meningeal lymphatic system was first identified.[5][6] Downstream of the glymphatic system's waste clearance from the ISF to the CSF, the meningeal lymphatic system drains fluid from the glymphatic system to the meningeal compartment and deep cervical lymph nodes. The meningeal lymphatics also carry immune cells. The extent to which these cells may interact directly with the brain or glymphatic system, is unknown.[citation needed]

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 choroid plexus and flows through the brain along a distinct pathway: moving through the cerebral ventricular system, into the subarachnoid space surrounding the brain, then draining into the systemic blood column via arachnoid granulations of the dural sinuses or to peripheral lymphatics along cranial nerve sheathes.[24][25] Many researchers have suggested that the CSF compartment constitutes a sink for interstitial solute and fluid clearance from the brain parenchyma.[citation needed] However, the distances between the interstitial fluid and the CSF in the ventricles and subarachnoid space are too great for the efficient removal of interstitial macromolecules and wastes by simple diffusion alone.[citation needed] Helen Cserr at Brown University calculated that mean diffusion times for large molecules, such as albumin, would exceed 100 hours to traverse 1 cm of brain tissue,[26] a rate that is not compatible with the intense metabolic demands of brain tissue. Additionally, a clearance system based on simple diffusion would lack the sensitivity to respond rapidly to deviations from homeostatic conditions.[citation needed]

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 convective bulk flow of interstitial fluid from the brain parenchyma to the CSF was responsible for efficient waste clearance.[26]

Progress in the field of CSF dynamics

Experiments conducted at the University of Maryland in the 1980s by Patricia Grady and colleagues postulated the existence of solute exchange between the interstitial fluid of the brain parenchyma and the CSF via paravascular spaces. In 1985, Grady and colleagues suggested that cerebrospinal fluid and interstitial fluid exchange along specific anatomical pathways within the brain, with CSF moving into the brain along the outside of blood vessels. Grady's group suggested that these 'paravascular channels' were functionally analogous to peripheral lymph vessels, facilitating the clearance of interstitial wastes from the brain.[8][28] However, other laboratories at the time did not observe such widespread paravascular CSF–ISF exchange.[26][29][30][31]

The continuity between the brain interstitial fluid and the CSF was confirmed by H. Cserr and colleagues from Brown University and King's College London.[31] The same group postulated that interstitial solutes in the brain parenchyma exchange with CSF via a bulk flow mechanism, rather than diffusion. However other work from this same laboratory indicated that the exchange of CSF with interstitial fluid was inconsistent and minor, contradicting the findings of Grady and colleagues.[29][30]

References

  1. ^ Bacyinski A, Xu M, Wang W, Hu J (2017). "The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy". Frontiers in Neuroanatomy. 11: 101. doi:10.3389/fnana.2017.00101. PMC 5681909. PMID 29163074.
  2. ^ Kiviniemi V, Wang X, Korhonen V, Keinänen T, Tuovinen T, Autio J, et al. (June 2016). "Ultra-fast magnetic resonance encephalography of physiological brain activity - Glymphatic pulsation mechanisms?". Journal of Cerebral Blood Flow and Metabolism. 36 (6): 1033–45. doi:10.1177/0271678X15622047. PMC 4908626. PMID 26690495.
  3. ^ Bohr T, Hjorth PG, Holst SC, Hrabětová S, Kiviniemi V, Lilius T, Lundgaard I, Mardal KA, Martens EA, Mori Y, Nägerl UV, Nicholson C, Tannenbaum A, Thomas JH, Tithof J, Benveniste H, Iliff JJ, Kelley DH, Nedergaard M (September 2022). "The glymphatic system: Current understanding and modeling". iScience. 25 (9): 104987. doi:10.1016/j.isci.2022.104987. PMC 9460186. PMID 36093063.
  4. ^ 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
  5. ^ a b Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. (July 2015). "Structural and functional features of central nervous system lymphatic vessels". Nature. 523 (7560): 337–41. Bibcode:2015Natur.523..337L. doi:10.1038/nature14432. PMC 4506234. PMID 26030524.
  6. ^ a b Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. (June 2015). "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules". The Journal of Experimental Medicine. 212 (7): 991–9. doi:10.1084/jem.20142290. PMC 4493418. PMID 26077718.
  7. ^ a b c Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. (August 2012). "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β". Science Translational Medicine. 4 (147): 147ra111. doi:10.1126/scitranslmed.3003748. PMC 3551275. PMID 22896675.
  8. ^ a b Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (February 1985). "Evidence for a 'paravascular' fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space". Brain Research. 326 (1): 47–63. doi:10.1016/0006-8993(85)91383-6. PMID 3971148. S2CID 23583877.
  9. ^ Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (February 2006). "Astrocyte-mediated control of cerebral blood flow". Nature Neuroscience. 9 (2): 260–7. doi:10.1038/nn1623. PMID 16388306. S2CID 6140428.
  10. ^ Schummers J, Yu H, Sur M (June 2008). "Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex". Science. 320 (5883): 1638–43. Bibcode:2008Sci...320.1638S. doi:10.1126/science.1156120. PMID 18566287. S2CID 16895889.
  11. ^ Yuhas D (2012). "How the brain cleans itself". Nature. doi:10.1038/nature.2012.11216. ISSN 1476-4687. S2CID 183462941.
  12. ^ a b Amiry-Moghaddam M, Ottersen OP (December 2003). "The molecular basis of water transport in the brain". Nature Reviews. Neuroscience. 4 (12): 991–1001. doi:10.1038/nrn1252. PMID 14682361. S2CID 23975497.
  13. ^ Verkman AS, Mitra AK (January 2000). "Structure and function of aquaporin water channels". American Journal of Physiology. Renal Physiology. 278 (1): F13-28. doi:10.1152/ajprenal.2000.278.1.F13. PMID 10644652.
  14. ^ a b Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC (August 2006). "Three distinct roles of aquaporin-4 in brain function revealed by knockout mice". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1758 (8): 1085–93. doi:10.1016/j.bbamem.2006.02.018. PMID 16564496.
  15. ^ Yool AJ (October 2007). "Aquaporins: multiple roles in the central nervous system". The Neuroscientist. 13 (5): 470–85. doi:10.1177/1073858407303081. PMID 17901256. S2CID 46231509.
  16. ^ Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. (October 2013). "Sleep drives metabolite clearance from the adult brain". Science. 342 (6156): 373–7. Bibcode:2013Sci...342..373X. doi:10.1126/science.1241224. PMC 3880190. PMID 24136970.
  17. ^ Rangroo Thrane V, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ, Deane R, et al. (2013). "Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain". Scientific Reports. 3: 2582. Bibcode:2013NatSR...3E2582T. doi:10.1038/srep02582. PMC 3761080. PMID 24002448.
  18. ^ Mehler MF, Gokhan S (December 2000). "Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat". Trends in Neurosciences. 23 (12): 599–605. doi:10.1016/s0166-2236(00)01705-7. PMID 11137149. S2CID 21302044.
  19. ^ Narasimhan K (March 2006). "Quantifying motor neuron loss in ALS". Nature Neuroscience. 9 (3): 304. doi:10.1038/nn0306-304. PMID 16498424. S2CID 1933099.
  20. ^ Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, et al. (October 2014). "Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis?". Stroke. 45 (10): 3092–6. doi:10.1161/STROKEAHA.114.006617. PMID 25190438.
  21. ^ Ng Kee Kwong KC, Mehta AR, Nedergaard M, Chandran S (August 2020). "Defining novel functions for cerebrospinal fluid in ALS pathophysiology". Review. Acta Neuropathologica Communications. 8 (1): 140. doi:10.1186/s40478-020-01018-0. PMC 7439665. PMID 32819425.
  22. ^ a b c Hajdu S (2003). "A Note from History: Discovery of the Cerebrospinal Fluid" (PDF). Annals of Clinical and Laboratory Science. 33 (3).
  23. ^ Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG (March 2018). "The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system?". Acta Neuropathologica. 135 (3): 387–407. doi:10.1007/s00401-018-1812-4. PMID 29428972.
  24. ^ Abbott NJ (September 2004). "Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology". Neurochemistry International. 45 (4): 545–52. doi:10.1016/j.neuint.2003.11.006. PMID 15186921. S2CID 10441695.
  25. ^ Bradbury MW, Cserr HF, Westrop RJ (April 1981). "Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit". The American Journal of Physiology. 240 (4): F329-36. doi:10.1152/ajprenal.1981.240.4.F329. PMID 7223890.
  26. ^ a b c Cserr HF (April 1971). "Physiology of the choroid plexus". Physiological Reviews. 51 (2): 273–311. doi:10.1152/physrev.1971.51.2.273. PMID 4930496.
  27. ^ Nicholson C, Phillips JM (December 1981). "Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum". The Journal of Physiology. 321: 225–57. doi:10.1113/jphysiol.1981.sp013981. PMC 1249623. PMID 7338810.
  28. ^ Rennels ML, Blaumanis OR, Grady PA (1990). "Rapid solute transport throughout the brain via paravascular fluid pathways". Advances in Neurology. 52: 431–9. PMID 2396537.
  29. ^ a b Pullen RG, DePasquale M, Cserr HF (September 1987). "Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality". The American Journal of Physiology. 253 (3 Pt 2): F538-45. doi:10.1152/ajprenal.1987.253.3.F538. PMID 3115117.
  30. ^ a b Ichimura T, Fraser PA, Cserr HF (April 1991). "Distribution of extracellular tracers in perivascular spaces of the rat brain". Brain Research. 545 (1–2): 103–13. doi:10.1016/0006-8993(91)91275-6. PMID 1713524. S2CID 41924137.
  31. ^ a b Cserr HF, Cooper DN, Suri PK, Patlak CS (April 1981). "Efflux of radiolabeled polyethylene glycols and albumin from rat brain". The American Journal of Physiology. 240 (4): F319-28. doi:10.1152/ajprenal.1981.240.4.F319. PMID 7223889.

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. AAN. 15 (13): 1. doi:10.1097/01.NT.0000469526.77988.9e. 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. doi:10.1007/s11064-015-1581-6. PMC 4636982. PMID 25947369.

January 29, 2023
glymphatic, system, glymphatic, system, glymphatic, clearance, pathway, paravascular, system, described, named, 2013, system, waste, clearance, central, nervous, system, vertebrates, according, this, model, cerebrospinal, fluid, flows, into, paravascular, spac. The glymphatic system or glymphatic clearance pathway or paravascular system was described and named in 2013 as a system for waste clearance in the central nervous system CNS of vertebrates According to this model cerebrospinal fluid CSF flows into the paravascular space around cerebral arteries combining with interstitial fluid ISF and parenchymal solutes and exiting down venous paravascular spaces 1 The pathway consists of a para arterial influx route for 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 2 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 3 Glymphatic system source source source source source source source source source source source source source source source Mammalian glymphatic systemIdentifiersMeSHD000077502Anatomical terminology edit on Wikidata 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 4 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 Contents 1 Proposed structure 2 Function 2 1 Waste clearance during sleep 2 2 Lipid transport 3 Clinical significance 4 History 4 1 Description of the cerebrospinal fluid 4 2 CNS lymphatics 4 3 Diffusion hypothesis 4 4 Progress in the field of CSF dynamics 5 References 6 Further readingProposed structure Edit Astrocytes stained for GFAP green and aquaporin 4 purple 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 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 8 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 citation needed Astrocytes extend long processes that interface with neuronal synapses as well as projections referred to as end feet that completely ensheathe the brain s entire vasculature Although the exact mechanism is not completely understood astrocytes are known to facilitate changes in blood flow 9 10 and have long been thought to play a role in waste removal in the brain 11 Researchers have long known that astrocytes express water channels called aquaporins 12 Until recently however no physiological function had been identified that explained their presence in the astrocytes of the mammalian CNS Aquaporins are membrane bound channels that play critical roles in regulating the flux of water into and out of cells Relative to simple diffusion the presence of aquaporins in biological membranes facilitates a 3 to 10 fold increase in water permeability 13 Two types of aquaporins are expressed in the CNS aquaporin 1 which is expressed by specialized epithelial cells of the choroid plexus and aquaporin 4 AQP4 which is expressed by astrocytes 14 15 Aquaporin 4 expression in astrocytes is highly polarized to the endfoot processes ensheathing the cerebral vasculature Up to 50 of the vessel facing endfoot surface that faces the vasculature is occupied by orthogonal arrays of AQP4 12 14 In 2012 it was shown that AQP4 is essential for paravascular CSF ISF exchange Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow dependent clearance of interstitial solutes decreases by 70 in the absence of AQP4 Based upon this role of AQP4 dependent glial water transport in the process of paravascular interstitial solute clearance Iliff and Nedergaard termed this brain wide glio vascular pathway the glymphatic system Function EditWaste clearance during sleep Edit 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 16 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 citation needed Lipid transport Edit 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 17 Led by M Nedergaard Thrane and colleagues also showed that the paravascular transport of lipids through the glymphatic pathway activated glial calcium signalling and that the depressurization of the cranial cavity and thus impairment of the glymphatic circulation led to unselective lipid diffusion intracellular lipid accumulation and pathological signalling among astrocytes Although further experiments are needed to parse out the physiological significance of the connection between the glymphatic circulation calcium signalling and paravascular lipid transport in the brain the findings point to the adoption of a function in the CNS similar to the capacity of the intestinal lymph vessels lacteals to carry lipids to the liver Clinical significance EditPathologically neurodegenerative diseases such as amyotrophic lateral sclerosis Alzheimer s disease Parkinson s disease and Huntington s disease are all characterized by the progressive loss of neurons cognitive decline motor impairments and sensory loss 18 19 Collectively these diseases fall within a broad category referred to as proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins According to the prevailing amyloid hypothesis of Alzheimer s disease the aggregation of amyloid beta a peptide normally produced in and cleared from the healthy young brain into extracellular plaques drives the neuronal loss and brain atrophy that is the hallmark of Alzheimer s dementia Although the full extent of the involvement of the glymphatic system in Alzheimer s disease and other neurodegenerative disorders remains unclear researchers have demonstrated through experiments with genetically modified mice that the proper function of the glymphatic clearance system was necessary to remove soluble amyloid beta from the brain interstitium 7 In mice that lack the AQP4 gene amyloid beta clearance is reduced by approximately 55 percent The glymphatic system also may be impaired after acute brain injuries such as ischemic stroke intracranial hemorrhage or subarachnoid hemorrhage In 2014 a group of researchers from the French Institute of Health and Medical Research INSERM demonstrated by MRI that the glymphatic system was impaired after subarachnoid hemorrhage because of the presence of coagulated blood in the paravascular spaces 20 Injection of tissue plasminogen activator a fibrinolytic drug in the CSF improved glymphatic functioning In a parallel study they also demonstrated that the glymphatic system was impaired after ischemic stroke in the ischemic hemisphere although the pathophysiological basis of this phenomenon remains unclear Notably recanalization of the occluded artery also reestablished the glymphatic flow The glymphatic system may also be involved in the pathogenesis of amyotrophic lateral sclerosis 21 History EditDescription of the cerebrospinal fluid Edit 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 Edit In the peripheral organs the lymphatic system performs important immune functions and runs parallel to the blood circulatory system to provide a secondary circulation that transports excess interstitial fluid proteins and metabolic waste products from the systemic tissues back into the blood The efficient removal of soluble proteins from the interstitial fluid is critical to the regulation of both colloidal osmotic pressure and homeostatic regulation of the fluid volume of the body The importance of lymphatic flow is especially evident when the lymphatic system becomes obstructed In lymphatic associated diseases such as elephantiasis where parasites occupying the lymphatic vessels block the flow of lymph the impact of such an obstruction may be dramatic The resulting chronic edema is due to the breakdown of lymphatic clearance and the accumulation of interstitial solutes citation needed In 2015 the presence of a meningeal lymphatic system was first identified 5 6 Downstream of the glymphatic system s waste clearance from the ISF to the CSF the meningeal lymphatic system drains fluid from the glymphatic system to the meningeal compartment and deep cervical lymph nodes The meningeal lymphatics also carry immune cells The extent to which these cells may interact directly with the brain or glymphatic system is unknown citation needed Diffusion hypothesis Edit 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 choroid plexus and flows through the brain along a distinct pathway moving through the cerebral ventricular system into the subarachnoid space surrounding the brain then draining into the systemic blood column via arachnoid granulations of the dural sinuses or to peripheral lymphatics along cranial nerve sheathes 24 25 Many researchers have suggested that the CSF compartment constitutes a sink for interstitial solute and fluid clearance from the brain parenchyma citation needed However the distances between the interstitial fluid and the CSF in the ventricles and subarachnoid space are too great for the efficient removal of interstitial macromolecules and wastes by simple diffusion alone citation needed Helen Cserr at Brown University calculated that mean diffusion times for large molecules such as albumin would exceed 100 hours to traverse 1 cm of brain tissue 26 a rate that is not compatible with the intense metabolic demands of brain tissue Additionally a clearance system based on simple diffusion would lack the sensitivity to respond rapidly to deviations from homeostatic conditions citation needed 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 convective bulk flow of interstitial fluid from the brain parenchyma to the CSF was responsible for efficient waste clearance 26 Progress in the field of CSF dynamics Edit Experiments conducted at the University of Maryland in the 1980s by Patricia Grady and colleagues postulated the existence of solute exchange between the interstitial fluid of the brain parenchyma and the CSF via paravascular spaces In 1985 Grady and colleagues suggested that cerebrospinal fluid and interstitial fluid exchange along specific anatomical pathways within the brain with CSF moving into the brain along the outside of blood vessels Grady s group suggested that these paravascular channels were functionally analogous to peripheral lymph vessels facilitating the clearance of interstitial wastes from the brain 8 28 However other laboratories at the time did not observe such widespread paravascular CSF ISF exchange 26 29 30 31 The continuity between the brain interstitial fluid and the CSF was confirmed by H Cserr and colleagues from Brown University and King s College London 31 The same group postulated that interstitial solutes in the brain parenchyma exchange with CSF via a bulk flow mechanism rather than diffusion However other work from this same laboratory indicated that the exchange of CSF with interstitial fluid was inconsistent and minor contradicting the findings of Grady and colleagues 29 30 References Edit Bacyinski A Xu M Wang W Hu J 2017 The Paravascular Pathway for Brain Waste Clearance Current Understanding Significance and Controversy Frontiers in Neuroanatomy 11 101 doi 10 3389 fnana 2017 00101 PMC 5681909 PMID 29163074 Kiviniemi V Wang X Korhonen V Keinanen T Tuovinen T Autio J et al June 2016 Ultra fast magnetic resonance encephalography of physiological brain activity Glymphatic pulsation mechanisms Journal of Cerebral Blood Flow and Metabolism 36 6 1033 45 doi 10 1177 0271678X15622047 PMC 4908626 PMID 26690495 Bohr T Hjorth PG Holst SC Hrabetova S Kiviniemi V Lilius T Lundgaard I Mardal KA Martens EA Mori Y Nagerl UV Nicholson C Tannenbaum A Thomas JH Tithof J Benveniste H Iliff JJ Kelley DH Nedergaard M September 2022 The glymphatic system Current understanding and modeling iScience 25 9 104987 doi 10 1016 j isci 2022 104987 PMC 9460186 PMID 36093063 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 a b Louveau A Smirnov I Keyes TJ Eccles JD Rouhani SJ Peske JD et al July 2015 Structural and functional features of central nervous system lymphatic vessels Nature 523 7560 337 41 Bibcode 2015Natur 523 337L doi 10 1038 nature14432 PMC 4506234 PMID 26030524 a b Aspelund A Antila S Proulx ST Karlsen TV Karaman S Detmar M et al June 2015 A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules The Journal of Experimental Medicine 212 7 991 9 doi 10 1084 jem 20142290 PMC 4493418 PMID 26077718 a b c Iliff JJ Wang M Liao Y Plogg BA Peng W Gundersen GA et al August 2012 A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes including amyloid b Science Translational Medicine 4 147 147ra111 doi 10 1126 scitranslmed 3003748 PMC 3551275 PMID 22896675 a b Rennels ML Gregory TF Blaumanis OR Fujimoto K Grady PA February 1985 Evidence for a paravascular fluid circulation in the mammalian central nervous system provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space Brain Research 326 1 47 63 doi 10 1016 0006 8993 85 91383 6 PMID 3971148 S2CID 23583877 Takano T Tian GF Peng W Lou N Libionka W Han X Nedergaard M February 2006 Astrocyte mediated control of cerebral blood flow Nature Neuroscience 9 2 260 7 doi 10 1038 nn1623 PMID 16388306 S2CID 6140428 Schummers J Yu H Sur M June 2008 Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex Science 320 5883 1638 43 Bibcode 2008Sci 320 1638S doi 10 1126 science 1156120 PMID 18566287 S2CID 16895889 Yuhas D 2012 How the brain cleans itself Nature doi 10 1038 nature 2012 11216 ISSN 1476 4687 S2CID 183462941 a b Amiry Moghaddam M Ottersen OP December 2003 The molecular basis of water transport in the brain Nature Reviews Neuroscience 4 12 991 1001 doi 10 1038 nrn1252 PMID 14682361 S2CID 23975497 Verkman AS Mitra AK January 2000 Structure and function of aquaporin water channels American Journal of Physiology Renal Physiology 278 1 F13 28 doi 10 1152 ajprenal 2000 278 1 F13 PMID 10644652 a b Verkman AS Binder DK Bloch O Auguste K Papadopoulos MC August 2006 Three distinct roles of aquaporin 4 in brain function revealed by knockout mice Biochimica et Biophysica Acta BBA Biomembranes 1758 8 1085 93 doi 10 1016 j bbamem 2006 02 018 PMID 16564496 Yool AJ October 2007 Aquaporins multiple roles in the central nervous system The Neuroscientist 13 5 470 85 doi 10 1177 1073858407303081 PMID 17901256 S2CID 46231509 Xie L Kang H Xu Q Chen MJ Liao Y Thiyagarajan M et al October 2013 Sleep drives metabolite clearance from the adult brain Science 342 6156 373 7 Bibcode 2013Sci 342 373X doi 10 1126 science 1241224 PMC 3880190 PMID 24136970 Rangroo Thrane V Thrane AS Plog BA Thiyagarajan M Iliff JJ Deane R et al 2013 Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain Scientific Reports 3 2582 Bibcode 2013NatSR 3E2582T doi 10 1038 srep02582 PMC 3761080 PMID 24002448 Mehler MF Gokhan S December 2000 Mechanisms underlying neural cell death in neurodegenerative diseases alterations of a developmentally mediated cellular rheostat Trends in Neurosciences 23 12 599 605 doi 10 1016 s0166 2236 00 01705 7 PMID 11137149 S2CID 21302044 Narasimhan K March 2006 Quantifying motor neuron loss in ALS Nature Neuroscience 9 3 304 doi 10 1038 nn0306 304 PMID 16498424 S2CID 1933099 Gaberel T Gakuba C Goulay R Martinez De Lizarrondo S Hanouz JL Emery E et al October 2014 Impaired glymphatic perfusion after strokes revealed by contrast enhanced MRI a new target for fibrinolysis Stroke 45 10 3092 6 doi 10 1161 STROKEAHA 114 006617 PMID 25190438 Ng Kee Kwong KC Mehta AR Nedergaard M Chandran S August 2020 Defining novel functions for cerebrospinal fluid in ALS pathophysiology Review Acta Neuropathologica Communications 8 1 140 doi 10 1186 s40478 020 01018 0 PMC 7439665 PMID 32819425 a b c Hajdu S 2003 A Note from History Discovery of the Cerebrospinal Fluid PDF Annals of Clinical and Laboratory Science 33 3 Abbott NJ Pizzo ME Preston JE Janigro D Thorne RG March 2018 The role of brain barriers in fluid movement in the CNS is there a glymphatic system Acta Neuropathologica 135 3 387 407 doi 10 1007 s00401 018 1812 4 PMID 29428972 Abbott NJ September 2004 Evidence for bulk flow of brain interstitial fluid significance for physiology and pathology Neurochemistry International 45 4 545 52 doi 10 1016 j neuint 2003 11 006 PMID 15186921 S2CID 10441695 Bradbury MW Cserr HF Westrop RJ April 1981 Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit The American Journal of Physiology 240 4 F329 36 doi 10 1152 ajprenal 1981 240 4 F329 PMID 7223890 a b c Cserr HF April 1971 Physiology of the choroid plexus Physiological Reviews 51 2 273 311 doi 10 1152 physrev 1971 51 2 273 PMID 4930496 Nicholson C Phillips JM December 1981 Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum The Journal of Physiology 321 225 57 doi 10 1113 jphysiol 1981 sp013981 PMC 1249623 PMID 7338810 Rennels ML Blaumanis OR Grady PA 1990 Rapid solute transport throughout the brain via paravascular fluid pathways Advances in Neurology 52 431 9 PMID 2396537 a b Pullen RG DePasquale M Cserr HF September 1987 Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality The American Journal of Physiology 253 3 Pt 2 F538 45 doi 10 1152 ajprenal 1987 253 3 F538 PMID 3115117 a b Ichimura T Fraser PA Cserr HF April 1991 Distribution of extracellular tracers in perivascular spaces of the rat brain Brain Research 545 1 2 103 13 doi 10 1016 0006 8993 91 91275 6 PMID 1713524 S2CID 41924137 a b Cserr HF Cooper DN Suri PK Patlak CS April 1981 Efflux of radiolabeled polyethylene glycols and albumin from rat brain The American Journal of Physiology 240 4 F319 28 doi 10 1152 ajprenal 1981 240 4 F319 PMID 7223889 Further reading EditKonnikova 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 AAN 15 13 1 doi 10 1097 01 NT 0000469526 77988 9e 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 doi 10 1007 s11064 015 1581 6 PMC 4636982 PMID 25947369 Retrieved from https en wikipedia org w index php title Glymphatic system amp oldid 1126930734, wikipedia, wiki, book, books, library,

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