Glymphatic system

Close metadata

Recommended articles:

Diagnosis of neuroinfections in children. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(11-2):51-59

The experience of diagnosing Alzheimer’s disease based on the study of cerebrospinal fluid biomarkers. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(1):91-97

Glymphatic system — is a recently discovered system for waste clearance and solute balance regulation in the brain. In this article we review the modern views on anatomy and physiology of glymphatic system, the factors known to regulate glymphatic flow, as well as the role of glyphatic dysfunction in the development of central nervous system pathology.

Keywords:

glymphatic system

peravascular spaces

glymphatic clearance

aquaporin-4

cerebrospinal fluid

Authors:

Dudchenko N.G.

Russian Medical Academy of Continuous Professional Education

ORCID: 0000-0001-8852-8587

Chimagomedova A.Sh.

Russian Medical Academy of Continuous Professional Education

Vasenina E.E.

Russian Medical Academy of Continuous Professional Education

Levin O.S.

Russian Medical Academy of Continuous Professional Education

SPIN RSCI: 5342-1373
Scopus AuthorID: 57147160800
ORCID: 0000-0003-3872-5923

Received:

08.02.2021

Accepted:

08.02.2021

List of references:

Ikomi F, Kawai Y, Ohhashi T. Recent Advance in Lymph Dynamic Analysis in Lymphatics and Lymph Nodes. Annals of Vascular Diseases. 2012;5(3):258-568. https://doi.org/10.3400/avd.ra.12.00046
Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochemistry International. 2004;45(4):545-552. https://doi.org/10.1016/j.neuint.2003.11.006
Cserr HF, Cooper DN, Suri PK, et al. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. American Journal of Physiology-Renal Physiology. 1981;240(4):319-328. https://doi.org/10.1152/ajprenal.1981.240.4.f319
Bradbury MW, Cserr HF, Westrop RJ. Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. American Journal of Physiology-Renal Physiology.1981;240(4):329-336. https://doi.org/10.1152/ajprenal.1981.240.4.f329
Bradbury MW, Westrop RJ. Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. The Journal of Physiology. 1983;339(1):519-534. https://doi.org/10.1113/jphysiol.1983.sp014731
Iliff JJ, Wang M, Liao Y, et al. A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid. Science Translational Medicine. 2012;4(147):147ra111-147ra111. https://doi.org/10.1126/scitranslmed.3003748
Louveau A, Harris TH, Kipnis J. Revisiting the Mechanisms of CNS Immune Privilege. Trends in Immunology. 2015;36(10):569-577. https://doi.org/10.1016/j.it.2015.08.006
Caversaccio M, Peschel O, Arnold W. Connections between the cerebrospinal fluid space and the lymphatic system of the head and neck in humans. Intracranial and Intralabyrinthine Fluids. 1996;2(19):123-128. https://doi.org/10.1007/978-3-642-80163-1_15
Damkier HH, Brown PD, Praetorius J. Epithelial Pathways in Choroid Plexus Electrolyte Transport. Physiology. 2010;25(4):239-249. https://doi.org/10.1152/physiol.00011.2010
Bulat M, Klarica M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Research Reviews. 2011;65(2):99-112. https://doi.org/10.1016/j.brainresrev.2010.08.002
Crone C. The Blood-Brain Barrier as a Tight Epithelium: Where Is Information Lacking? Annals of the New York Academy of Sciences. 1986;481(1):174-185. https://doi.org/10.1111/j.1749-6632.1986.tb27149.x
Kimelberg HK. Water homeostasis in the brain: Basic concepts. Neuroscience. 2004;129(4):851-860. https://doi.org/10.1016/j.neuroscience.2004.07.033
Milhorat TH, Hammock MK, Fenstermacher JD, et al. Cerebrospinal Fluid Production by the Choroid Plexus and Brain. Science. 1971;173(3994):330-332. https://doi.org/10.1126/science.173.3994.330
Rapoport SI. A mathematical model for vasogenic brain edema. Journal of Theoretical Biology. 1978;74(3):439-467. https://doi.org/10.1016/0022-5193(78)90224-2
Cutler RWP, Page L, Galicich J, et al Formation and absorption of cerebrospinal flui in man. Brain. 1968;91(4):707-720. https://doi.org/10.1093/brain/91.4.707
Rubin RC, Henderson ES, Ommaya AK, et al. The Production of Cerebrospinal Fluid in Man and Its Modification by Acetazolamide. Journal of Neurosurgery. 1966;25(4):430-436. https://doi.org/10.3171/jns.1966.25.4.0430
Schroth G, Klose U. Cerebrospinal fluid flow. Neuroradiology. 1992;35(1):10-15. https://doi.org/10.1007/bf00588271
Johanson CE, Duncan JA, Klinge PM, et al. Multiplicity of cerebrospinal fluid functions: New challenges in health and disease. Cerebrospinal Fluid Research. 2008;5(1):10. https://doi.org/10.1186/1743-8454-5-10
Nilsson C, Stahlberg F, Thomsen C, et al. Circadian variation in human cerebrospinal fluid production measured by magnetic resonance imaging. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 1992;262(1):20-24. https://doi.org/10.1152/ajpregu.1992.262.1.r20
Lindvall M, Owman C. Autonomic Nerves in the Mammalian Choroid Plexus and Their Influence on the Formation of Cerebrospinal Fluid. Journal of Cerebral Blood Flow & Metabolism. 1981;1(3):245-266. https://doi.org/10.1038/jcbfm.1981.30
Damkier HH, Brown PD, Praetorius J. Cerebrospinal Fluid Secretion by the Choroid Plexus. Physiological Reviews. 2013;93(4):1847-1892. https://doi.org/10.1152/physrev.00004.2013
Bonnet MH, Arand DL. Heart rate variability: sleep stage, time of night, and arousal influences. Electroencephalography and Clinical Neurophysiology. 1997;102(5):390-396. https://doi.org/10.1016/s0921-884x(96)96070-1
Friese S, Hamhaber U, Erb M, et al. The Influence of Pulse and Respiration on Spinal Cerebrospinal Fluid Pulsation. Investigative Radiology. 2004;39(2):120-130. https://doi.org/10.1097/01.rli.0000112089.66448.bd
Wagshul ME, Eide PK, Madsen JR. The pulsating brain: A review of experimental and clinical studies of intracranial pulsatility. Fluids and Barriers of the CNS. 2011;8(1):5. https://doi.org/10.1186/2045-8118-8-5
Weller RO. Microscopic morphology and histology of the human meninges. Morphologie. 2005;89(284):22-34. https://doi.org/10.1016/s1286-0115(05)83235-7
Bakker ENTP, Bacskai BJ, Arbel-Ornath M, et al. Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases. Cellular and Molecular Neurobiology. 2016;36(2):181-194. https://doi.org/10.1007/s10571-015-0273-8
Weller RO, Djuanda E, Yow H-Y, et al. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathologica. 2008;117(1):1-14. https://doi.org/10.1007/s00401-008-0457-0
Jessen NA, Munk ASF, Lundgaard I, et al. The Glymphatic System: A Beginner’s Guide. Neurochemical Research. 2015;40(12):2583-2599. https://doi.org/10.1007/s11064-015-1581-6
Bedussi B, Almasian M, de Vos J, et al. Paravascular spaces at the brain surface: Low resistance pathways for cerebrospinal fluid flow. Journal of Cerebral Blood Flow & Metabolism. 2017;38(4):719-726. https://doi.org/10.1177/0271678x17737984
Bedussi B, van Lier MGJTB, Bartstra JW, et al. Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system. Fluids and Barriers of the CNS. 2015;12(1):34-39. https://doi.org/10.1186/s12987-015-0019-5
Morris AWJ, Sharp MM, Albargothy NJ, et al. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathologica. 2016;131(5):725-736. https://doi.org/10.1007/s00401-016-1555-z
Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. Journal of Clinical Investigation. 2013;123(3):1299-1309. https://doi.org/10.1172/jci67677
Hubbard JA, Hsu MS, Seldin MM, et al. Expression of the Astrocyte Water Channel Aquaporin-4 in the Mouse Brain. ASN Neuro. 2015;7(5):175909141560548. https://doi.org/10.1177/1759091415605486
Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain — implications for Alzheimer disease. Nature Reviews. 2015;11(8):457-470. https://doi.org/10.1038/nrneurol.2015.119
Louveau A, Da Mesquita S, Kipnis J. Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease? Neuron. 2016;91(5):957-973. https://doi.org/10.1016/j.neuron.2016.08.027
Lee H, Xie L, Yu M, et al. The Effect of Body Posture on Brain Glymphatic Transport. Journal of Neuroscience. 2015;35(31):11034-11044. https://doi.org/10.1523/jneurosci.1625-15.2015
Kiviniemi V, Wang X, Korhonen V, et al. Ultra-fast magnetic resonance encephalography of physiological brain activity — Glymphatic pulsation mechanisms? Journal of Cerebral Blood Flow & Metabolism. 2015;36(6):1033-1045. https://doi.org/10.1177/0271678x15622047
Hladky SB, Barrand MA. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids and Barriers of the CNS. 2014;11(1):26. https://doi.org/10.1186/2045-8118-11-26
Asgari M, de Zélicourt D, Kurtcuoglu V. Glymphatic solute transport does not require bulk flow. Scientific Reports. 2016;6(1):23-28. https://doi.org/10.1038/srep38635
Bradbury MW, Cole DF. The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour. The Journal of Physiology. 1980;299(1):353-365. https://doi.org/10.1113/jphysiol.1980.sp013129
Guseva MR, Beslaneeva MA, Mishchenko NV, Khurai AR. penetration of the antioxidant drug Histochrome through the hematothalmic barrier (experimental study). Vestnik ofthalmology. 2007;123(6):38-40. (In Russ.).
Dixon WE, Halliburton WD. The cerebro-spinal fluid. The Journal of Physiology. 1914;48(2-3):128-153. https://doi.org/10.1113/jphysiol.1914.sp001652
Matsumae M, Sato O, Hirayama A, et al. Research into the Physiology of Cerebrospinal Fluid Reaches a New Horizon: Intimate Exchange between Cerebrospinal Fluid and Interstitial Fluid May Contribute to Maintenance of Homeostasis in the Central Nervous System. Neurologia medico-chirurgica. 2016;56(7):416-441. https://doi.org/10.2176/nmc.ra.2016-0020
Achariyar TM, Li B, Peng W, et al. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Molecular Neurodegeneration. 2016;11(1):12-18. https://doi.org/10.1186/s13024-016-0138-8
Kress BT, Iliff JJ, Xia M, et al. Impairment of paravascular clearance pathways in the aging brain. Annals of Neurology. 2014;76(6):845-861. https://doi.org/10.1002/ana.24271
Xie L, Kang H, Xu Q, et al. Sleep Drives Metabolite Clearance from the Adult Brain. Science. 2013;342(6156):373-377. https://doi.org/10.1126/science.1241224
Xia M, Yang L, Sun G, Qi S, Li B. Mechanism of depression as a risk factor in the development of Alzheimer’s disease: the function of AQP4 and the glymphatic system. Psychopharmacology. 2016;234(3):365-379. https://doi.org/10.1007/s00213-016-4473-9
Ju Y-ES, Finn MB, Sutphen CL, et al. Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Annals of Neurology. 2016;80(1):154-159. https://doi.org/10.1002/ana.24672
He X, Liu D, Zhang Q, et al. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice. Neuroscience. 2017;10:23-27. https://doi.org/10.3389/fnmol.2017.00144
Simon MJ, Iliff JJ. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. Biochimica et Biophysica Acta (BBA). Molecular Basis of Disease. 2016;1862(3):442-451. https://doi.org/10.1016/j.bbadis.2015.10.014
Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiology of Disease. 2016;93:215-225. https://doi.org/10.1016/j.nbd.2016.05.015
Yang L, Kress BT, Weber HJ, et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. Journal of Translational Medicine. 2013;11(1):107. https://doi.org/10.1186/1479-5876-11-107
Lundgaard I, Lu ML, Yang E, et al. Glymphatic clearance controls state-dependent changes in brain lactate concentration. Journal of Cerebral Blood Flow & Metabolism. 2016;37(6):2112-2124. https://doi.org/10.1177/0271678x16661202
Iliff JJ, Chen MJ, Plog BA, et al. Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury. The Journal of Neuroscience. 2014;34(49):16180-16193. https://doi.org/10.1523/jneurosci.3020-14.2014
Valdinocci D, Radford R, Siow S, et al. Potential Modes of Intercellular α-Synuclein Transmission. International Journal of Molecular Sciences. 2017;18(2):469. https://doi.org/10.3390/ijms18020469
Rennels ML, Gregory TF, Blaumanis OR, et al. 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. 1985;326(1):47-63. https://doi.org/10.1016/0006-8993(85)91383-6
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377. https://doi.org/10.1126/science.1241224
Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nature Reviews Neuroscience. 2013;14(4):265-277. https://doi.org/10.1038/nrn3468
Hoffmann J, Goadsby PJ. Update on intracranial hypertension and hypotension. Current Opinion in Neurology. 2013;26(3):240-247. https://doi.org/10.1097/wco.0b013e328360eccc
Gaberel T, Gakuba C, Goulay R, et al. Impaired Glymphatic Perfusion After Strokes Revealed by Contrast-Enhanced MRI. Stroke. 2014;45(10):3092-3096. https://doi.org/10.1161/strokeaha.114.006617
Mestre H, Kostrikov S, Mehta RI, Nedergaard M. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clinical Science. 2017;131(17):2257-2274. https://doi.org/10.1042/cs20160381
MacLullich AMJ. Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. Journal of Neurology. Neurosurgery & Psychiatry. 2004;75(11):1519-1523. https://doi.org/10.1136/jnnp.2003.030858
Tomassoni D, Bramanti V, Amenta F. Expression of aquaporins 1 and 4 in the brain of spontaneously hypertensive rats. Brain Research. 2010;1325:155-163. https://doi.org/10.1016/j.brainres.2010.02.023
Eide PK, Ringstad G. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study. Journal of Cerebral Blood Flow & Metabolism. 2018;0271678X1876097. https://doi.org/10.1177/0271678x18760974
Ren Z, Iliff JJ, Yang L, et al. «Hit & Run» Model of Closed-Skull Traumatic Brain Injury (TBI) Reveals Complex Patterns of Post-Traumatic AQP4 Dysregulation. Journal of Cerebral Blood Flow & Metabolism. 2013;33(6):834-845. https://doi.org/10.1038/jcbfm.2013.30
Lowe J, Mirra S, Hyman B, Dickson D. Ageing and dementia. Greenfield’s Neuropathology. 2008;2(6)1031-1152.
Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor—related protein-1 at the blood-brain barrier. Journal of Clinical Investigation. 2000;106(12):1489-1499. https://doi.org/10.1172/jci10498
Cirrito JR. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-deposition in an Alzheimer disease mouse model. Journal of Clinical Investigation. 2005;115(11):3285-3290. https://doi.org/10.1172/jci25247
Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiology of disease. 2016; 93:215-225.
Venkat P, Chopp M, Zacharek A, et al. White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies. Neurobiology of Aging. 2017;50:96-106. https://doi.org/10.1016/j.neurobiolaging.2016.11.002
Zeppenfeld DM, Simon M, Haswell JD, et al. Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains. JAMA Neurology. 2017;74(1):91. https://doi.org/10.1001/jamaneurol.2016.4370
Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560(7717):185-191. https://doi.org/10.1038/s41586-018-0368-8
Louveau A, Herz J, Alme MN, et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nature Neuroscience. 2018;21(10):1380-1391.

Close metadata