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image of Functional and Clinical Relevance of the Crosstalk between the Glymphatic System and the Lymphatic System

Abstract

In this review, we describe the concept of the glymphatic system as a glial-dependent clearance pathway in the brain. The hypothesis of the glymphatic system function suggests that dural lymphatic vessels absorb the cerebrospinal fluid and brain interstitial fluid the glymphatic system and transport fluid into deep cervical lymph nodes. We present the accumulated data of various studies confirming the possible interconnection among the brain interstitial fluid, cerebrospinal fluid, and the glymphatic system. Anatomical features are discussed here together with a possible variety of glymphatic system functions, including the removal of waste products, transport of substances, and immune function. The glymphatic system is hypothesized to be involved in pathogenesis of many diseases, including Alzheimer's disease, stroke, and Parkinson’s disease. We also discuss the role of the glymphatic system in pathophysiology and the complications of brain tumors. Meningeal lymphatics is thoroughly analyzed as well. Finally, we propose new treatment approaches to brain tumors, Parkinson’s disease, and stroke using cervical lymph nodes and backward fluid flow in the meningeal lymphatic vessels.

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2025-06-03
2025-06-17
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References

  1. Thomas J.L. Jacob L. Boisserand L. Lymphatic system in central nervous system. Med. Sci. 2019 35 1 55 61 10.1051/medsci/2018309 30672459
    [Google Scholar]
  2. Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. Benveniste H. Vates G.E. Deane R. Goldman S.A. Nagelhus E.A. Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid &#946. Sci. Transl. Med. 2012 4 147 147ra111 10.1126/scitranslmed.3003748 22896675
    [Google Scholar]
  3. Ahn J.H. Cho H. Kim J.H. Kim S.H. Ham J.S. Park I. Suh S.H. Hong S.P. Song J.H. Hong Y.K. Jeong Y. Park S.H. Koh G.Y. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 2019 572 7767 62 66 10.1038/s41586‑019‑1419‑5 31341278
    [Google Scholar]
  4. Magistretti P.J. Allaman I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 2015 86 4 883 901 10.1016/j.neuron.2015.03.035 25996133
    [Google Scholar]
  5. Bacyinski A. Xu M. Wang W. Hu J. The paravascular pathway for brain waste clearance: Current understanding, significance and controversy. Front. Neuroanat. 2017 11 101 10.3389/fnana.2017.00101 29163074
    [Google Scholar]
  6. Rennels M.L. Gregory T.F. Blaumanis O.R. Fujimoto K. Grady P.A. 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 Res. 1985 326 1 47 63 10.1016/0006‑8993(85)91383‑6 3971148
    [Google Scholar]
  7. Mascagni P. Ciro S. Vasorum Lymphaticorum Corporis Humani Historia et Ichnographia. Siena, Italy Pazzini Carli 1787
    [Google Scholar]
  8. Virchow R. On the dilation of smaller vessels. Virchows Arch. 1851 3 3 427 462 10.1007/BF01960918
    [Google Scholar]
  9. Robin C. Research on some peculiarities of the structure of the capillaries of the brain. J. Physiol. Homme. Anim. 1859 2 537 548
    [Google Scholar]
  10. Koundal S. Elkin R. Nadeem S. Xue Y. Constantinou S. Sanggaard S. Liu X. Monte B. Xu F. Van Nostrand W. Nedergaard M. Lee H. Wardlaw J. Benveniste H. Tannenbaum A. Optimal mass transport with lagrangian workflow reveals advective and diffusion driven solute transport in the glymphatic system. Sci. Rep. 2020 10 1 1990 10.1038/s41598‑020‑59045‑9 32029859
    [Google Scholar]
  11. Aspelund A. Antila S. Proulx S.T. Karlsen T.V. Karaman S. Detmar M. Wiig H. Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 2015 212 7 991 999 10.1084/jem.20142290 26077718
    [Google Scholar]
  12. Raper D. Louveau A. Kipnis J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 2016 39 9 581 586 10.1016/j.tins.2016.07.001 27460561
    [Google Scholar]
  13. Hladky S.B. Barrand M.A. The glymphatic hypothesis: The theory and the evidence. Fluids Barriers CNS 2022 19 1 9 10.1186/s12987‑021‑00282‑z 35115036
    [Google Scholar]
  14. Abbott N.J. Pizzo M.E. Preston J.E. Janigro D. Thorne R.G. The role of brain barriers in fluid movement in the CNS: Is there a ‘glymphatic’ system? Acta Neuropathol. 2018 135 3 387 407 10.1007/s00401‑018‑1812‑4 29428972
    [Google Scholar]
  15. Bakker E.N.T.P. Bacskai B.J. Arbel-Ornath M. Aldea R. Bedussi B. Morris A.W.J. Weller R.O. Carare R.O. Lymphatic clearance of the brain: Perivascular, paravascular and significance for neurodegenerative diseases. Cell. Mol. Neurobiol. 2016 36 2 181 194 10.1007/s10571‑015‑0273‑8 26993512
    [Google Scholar]
  16. Moore J.E. Jr Bertram C.D. Lymphatic system flows. Annu. Rev. Fluid Mech. 2018 50 1 459 482 10.1146/annurev‑fluid‑122316‑045259 29713107
    [Google Scholar]
  17. Lee H. Xie L. Yu M. Kang H. Feng T. Deane R. Logan J. Nedergaard M. Benveniste H. The effect of body posture on brain glymphatic transport. J. Neurosci. 2015 35 31 11034 11044 10.1523/JNEUROSCI.1625‑15.2015 26245965
    [Google Scholar]
  18. Mestre H. Tithof J. Du T. Song W. Peng W. Sweeney A.M. Olveda G. Thomas J.H. Nedergaard M. Kelley D.H. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat. Commun. 2018 9 1 4878 10.1038/s41467‑018‑07318‑3 30451853
    [Google Scholar]
  19. He X. Liu D. Zhang Q. Liang F. Dai G. Zeng J. Pei Z. Xu G. Lan Y. Voluntary exercise promotes glymphatic clearance of Crosstalk between the Glymphatic System and the Lymphatic System amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Front. Mol. Neurosci. 2017 10 144 10.3389/fnmol.2017.00144 28579942
    [Google Scholar]
  20. Roy B. Nunez A. Aysola R.S. Kang D.W. Vacas S. Kumar R. Impaired glymphatic system actions in obstructive sleep apnea adults. Front. Neurosci. 2022 16 884234 10.3389/fnins.2022.884234 35600625
    [Google Scholar]
  21. Thrane V.R. Thrane A.S. Plog B.A. Thiyagarajan M. Iliff J.J. Deane R. Nagelhus E.A. Nedergaard M. Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci. Rep. 2013 3 1 2582 10.1038/srep02582 24002448
    [Google Scholar]
  22. Lundgaard I. Li B. Xie L. Kang H. Sanggaard S. Haswell J.D.R. Sun W. Goldman S. Blekot S. Nielsen M. Takano T. Deane R. Nedergaard M. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat. Commun. 2015 6 1 6807 10.1038/ncomms7807 25904018
    [Google Scholar]
  23. Achariyar T.M. Li B. Peng W. Verghese P.B. Shi Y. McConnell E. Benraiss A. Kasper T. Song W. Takano T. Holtzman D.M. Nedergaard M. Deane R. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol. Neurodegener. 2016 11 1 74 10.1186/s13024‑016‑0138‑8 27931262
    [Google Scholar]
  24. von Bartheld C.S. Bahney J. Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting. J. Comp. Neurol. 2016 524 18 3865 3895 10.1002/cne.24040 27187682
    [Google Scholar]
  25. Clark D.D. Sokoloff L. Circulation and energy metabolism of the brain. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Siegel G.J. Agranoff B.W. Albers R.W. Fisher S.K. Uhler M.D. Philadelphia Lippincott-Raven 1999 637 670
    [Google Scholar]
  26. Jiménez A.J. Domínguez-Pinos M.D. Guerra M.M. Fernández- Llebrez, P.; Pérez-Fígares, J.M. Structure and function of the ependymal barrier and diseases associated with ependyma disruption. Tissue Barriers 2014 2 1 e28426 10.4161/tisb.28426 25045600
    [Google Scholar]
  27. Brøchner C.B. Holst C.B. Møllgård K. Outer brain barriers in rat and human development. Front. Neurosci. 2015 9 75 10.3389/fnins.2015.00075 25852456
    [Google Scholar]
  28. Nakada T. Kwee I.L. Fluid dynamics inside the brain barrier: Current concept of interstitial flow, glymphatic flow, and cerebrospinal fluid circulation in the brain. Neuroscientist 2019 25 2 155 166 10.1177/1073858418775027 29799313
    [Google Scholar]
  29. Zhao Z. Nelson A.R. Betsholtz C. Zlokovic B.V. Establishment and dysfunction of the blood-brain barrier. Cell 2015 163 5 1064 1078 10.1016/j.cell.2015.10.067 26590417
    [Google Scholar]
  30. Serlin Y. Shelef I. Knyazer B. Friedman A. Anatomy and physiology of the blood-brain barrier. Semin. Cell Dev. Biol. 2015 38 2 6 10.1016/j.semcdb.2015.01.002 25681530
    [Google Scholar]
  31. Ineichen B.V. Okar S.V. Proulx S.T. Engelhardt B. Lassmann H. Reich D.S. Perivascular spaces and their role in neuroinflammation. Neuron 2022 110 21 3566 3581 10.1016/j.neuron.2022.10.024 36327898
    [Google Scholar]
  32. Haider L. Hametner S. Endmayr V. Mangesius S. Eppensteiner A. Frischer J.M. Iglesias J.E. Barkhof F. Kasprian G. Post-mortem correlates of Virchow-Robin spaces detected on in vivo MRI. J. Cereb. Blood Flow Metab. 2022 42 7 1224 1235 10.1177/0271678X211067455 35581687
    [Google Scholar]
  33. Mathiisen T.M. Lehre K.P. Danbolt N.C. Ottersen O.P. The perivascular astroglial sheath provides a complete covering of the brain microvessels: An electron microscopic 3D reconstruction. Glia 2010 58 9 1094 1103 10.1002/glia.20990 20468051
    [Google Scholar]
  34. MacVicar B.A. Newman E.A. Astrocyte regulation of blood flow in the brain. Cold Spring Harb. Perspect. Biol. 2015 7 5 a020388 10.1101/cshperspect.a020388 25818565
    [Google Scholar]
  35. Iliff J.J. Wang M. Zeppenfeld D.M. Venkataraman A. Plog B.A. Liao Y. Deane R. Nedergaard M. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 2013 33 46 18190 18199 10.1523/JNEUROSCI.1592‑13.2013 24227727
    [Google Scholar]
  36. Takano T. Tian G.F. Peng W. Lou N. Libionka W. Han X. Nedergaard M. Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 2006 9 2 260 267 10.1038/nn1623 16388306
    [Google Scholar]
  37. Kubotera H. Ikeshima-Kataoka H. Hatashita Y. Allegra Mascaro A.L. Pavone F.S. Inoue T. Astrocytic endfeet re-cover blood vessels after removal by laser ablation. Sci. Rep. 2019 9 1 1263 10.1038/s41598‑018‑37419‑4 30718555
    [Google Scholar]
  38. Ikeshima-Kataoka H. Neuroimmunological implications of AQP4 in astrocytes. Int. J. Mol. Sci. 2016 17 8 1306 10.3390/ijms17081306 27517922
    [Google Scholar]
  39. Kim S.H. Turnbull J. Guimond S. Extracellular matrix and cell signalling: The dynamic cooperation of integrin, proteoglycan and growth factor receptor. J. Endocrinol. 2011 209 2 139 151 10.1530/JOE‑10‑0377 21307119
    [Google Scholar]
  40. Timpl R. Structure and biological activity of basement membrane proteins. Eur. J. Biochem. 1989 180 3 487 502 10.1111/j.1432‑1033.1989.tb14673.x 2653817
    [Google Scholar]
  41. Engelhardt B. Sorokin L. The blood-brain and the bloodcerebrospinal fluid barriers: Function and dysfunction. Semin. Immunopathol. 2009 31 4 497 511 10.1007/s00281‑009‑0177‑0 19779720
    [Google Scholar]
  42. Butt A.M. Jones H.C. Abbott N.J. Electrical resistance across the blood-brain barrier in anaesthetized rats: A developmental study. J. Physiol. 1990 429 1 47 62 10.1113/jphysiol.1990.sp018243 2277354
    [Google Scholar]
  43. Pardridge W.M. 2003
  44. Bae Y.H. Park K. Advanced drug delivery 2020 and beyond: Perspectives on the future. Adv. Drug Deliv. Rev. 2020 158 4 16 10.1016/j.addr.2020.06.018 32592727
    [Google Scholar]
  45. Armulik A. Genové G. Mäe M. Nisancioglu M.H. Wallgard E. Niaudet C. He L. Norlin J. Lindblom P. Strittmatter K. Johansson B.R. Betsholtz C. Pericytes regulate the blood-brain barrier. Nature 2010 468 7323 557 561 10.1038/nature09522 20944627
    [Google Scholar]
  46. Sengillo J.D. Winkler E.A. Walker C.T. Sullivan J.S. Johnson M. Zlokovic B.V. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol. 2013 23 3 303 310 10.1111/bpa.12004 23126372
    [Google Scholar]
  47. Cai C. Fordsmann J.C. Jensen S.H. Gesslein B. Lønstrup M. Hald B.O. Zambach S.A. Brodin B. Lauritzen M.J. Stimulation- induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses. Proc. Natl. Acad. Sci. USA 2018 115 25 E5796 E5804 10.1073/pnas.1707702115 29866853
    [Google Scholar]
  48. Hall C.N. Reynell C. Gesslein B. Hamilton N.B. Mishra A. Sutherland B.A. O’Farrell F.M. Buchan A.M. Lauritzen M. Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 2014 508 7494 55 60 10.1038/nature13165 24670647
    [Google Scholar]
  49. Alarcon-Martinez L. Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection. eLife 2018 7 e34861 10.7554/eLife.34861 29561727
    [Google Scholar]
  50. Gonzales A.L. Klug N.R. Moshkforoush A. Lee J.C. Lee F.K. Shui B. Tsoukias N.M. Kotlikoff M.I. Hill-Eubanks D. Nelson M.T. Contractile pericytes determine the direction of blood flow at capillary junctions. Proc. Natl. Acad. Sci. USA 2020 117 43 27022 27033 10.1073/pnas.1922755117 33051294
    [Google Scholar]
  51. Kress B.T. Iliff J.J. Xia M. Wang M. Wei H.S. Zeppenfeld D. Xie L. Kang H. Xu Q. Liew J.A. Plog B.A. Ding F. Deane R. Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. 2014
    [Google Scholar]
  52. Reeves B.C. Karimy J.K. Kundishora A.J. Mestre H. Cerci H.M. Matouk C. Alper S.L. Lundgaard I. Nedergaard M. Kahle K.T. Glymphatic system impairment in Alzheimer’s disease and idiopathic normal pressure hydrocephalus. Trends Mol. Med. 2020 26 3 285 295 10.1016/j.molmed.2019.11.008 31959516
    [Google Scholar]
  53. Storck S.E. Meister S. Nahrath J. Meißner J.N. Schubert N. Di Spiezio A. Baches S. Vandenbroucke R.E. Bouter Y. Prikulis I. Korth C. Weggen S. Heimann A. Schwaninger M. Bayer T.A. Pietrzik C.U. Endothelial LRP1 transports amyloid- β1-42 across the blood-brain barrier. J. Clin. Invest. 2015 126 1 123 136 10.1172/JCI81108 26619118
    [Google Scholar]
  54. Storck S.E. Hartz A.M.S. Bernard J. Wolf A. Kachlmeier A. Mahringer A. Weggen S. Pahnke J. Pietrzik C.U. The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM. Brain Behav. Immun. 2018 73 21 33 10.1016/j.bbi.2018.07.017 30041013
    [Google Scholar]
  55. Møllgård K. Beinlich F.R.M. Kusk P. Miyakoshi L.M. Delle C. Plá V. Hauglund N.L. Esmail T. Rasmussen M.K. Gomolka R.S. Mori Y. Nedergaard M. A mesothelium divides the subarachnoid space into functional compartments. Science 2023 379 6627 84 88 10.1126/science.adc8810 36603070
    [Google Scholar]
  56. Hartmann K. Neyazi B. Stein K.P. Haghikia A. Sandalcioglu I.E. Is the central nervous system enclosed by a mesothel? Ther. Adv. Neurol. Disord. 2023 16 17562864231180335 10.1177/17562864231180335 37434877
    [Google Scholar]
  57. Plá V. Bitsika S. Giannetto M.J. Ladron-de-Guevara A. Gahn- Martinez, D.; Mori, Y.; Nedergaard, M.; Møllgård, K. Structural characterization of SLYM—a 4th meningeal membrane. Fluids Barriers CNS 2023 20 1 93 10.1186/s12987‑023‑00500‑w 38098084
    [Google Scholar]
  58. Verkman A.S. Smith A.J. Phuan P. Tradtrantip L. Anderson M.O. The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin. Ther. Targets 2017 21 12 1161 1170 10.1080/14728222.2017.1398236 29072508
    [Google Scholar]
  59. Badaut J. Lasbennes F. Magistretti P.J. Regli L. Aquaporins in brain: distribution, physiology, and pathophysiology. J. Cereb. Blood Flow Metab. 2002 22 4 367 378 10.1097/00004647‑200204000‑00001 11919508
    [Google Scholar]
  60. Papadopoulos M.C. Manley G.T. Krishna S. Verkman A.S. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J. 2004 18 11 1291 1293 10.1096/fj.04‑1723fje 15208268
    [Google Scholar]
  61. Rash J.E. Yasumura T. Hudson C.S. Agre P. Nielsen S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc. Natl. Acad. Sci. USA 1998 95 20 11981 11986 10.1073/pnas.95.20.11981 9751776
    [Google Scholar]
  62. Potokar M. Jorgačevski, J.; Zorec, R. Astrocyte aquaporin dynamics in health and disease. Int. J. Mol. Sci. 2016 17 7 1121 10.3390/ijms17071121 27420057
    [Google Scholar]
  63. Badaut J. Hirt L. Granziera C. Bogousslavsky J. Magistretti P.J. Regli L. Astrocyte-specific expression of aquaporin-9 in mouse brain is increased after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001 21 5 477 482 10.1097/00004647‑200105000‑00001 11333357
    [Google Scholar]
  64. Satoh J. Tabunoki H. Yamamura T. Arima K. Konno H. Human astrocytes express aquaporin-1 and aquaporin-4 in vitro and in vivo. Neuropathology 2007 27 3 245 256 10.1111/j.1440‑1789.2007.00774.x 17645239
    [Google Scholar]
  65. Misawa T. Arima K. Mizusawa H. Satoh J. Close association of water channel AQP1 with amyloid-β deposition in Alzheimer disease brains. Acta Neuropathol. 2008 116 3 247 260 10.1007/s00401‑008‑0387‑x 18509662
    [Google Scholar]
  66. Pérez E. Barrachina M. Rodríguez A. Torrejón-Escribano B. Boada M. Hernández I. Sánchez M. Ferrer I. Aquaporin expression in the cerebral cortex is increased at early stages of Alzheimer disease. Brain Res. 2007 1128 1 164 174 10.1016/j.brainres.2006.09.109 17123487
    [Google Scholar]
  67. Jorgačevski, J.; Zorec, R.; Potokar, M. Insights into cell surface expression, supramolecular organization, and functions of aquaporin 4 isoforms in astrocytes. Cells 2020 9 12 2622 10.3390/cells9122622 33297299
    [Google Scholar]
  68. Lisjak M. Potokar M. Rituper B. Jorgačevski, J.; Zorec, R. AQP4e-based orthogonal arrays regulate rapid cell volume changes in astrocytes. J. Neurosci. 2017 37 44 10748 10756 10.1523/JNEUROSCI.0776‑17.2017 28978666
    [Google Scholar]
  69. Jin B.J. Rossi A. Verkman A.S. Model of aquaporin-4 supramolecular assembly in orthogonal arrays based on heterotetrameric association of M1-M23 isoforms. Biophys. J. 2011 100 12 2936 2945 10.1016/j.bpj.2011.05.012 21689527
    [Google Scholar]
  70. MacAulay N. Molecular mechanisms of brain water transport. Nat. Rev. Neurosci. 2021 22 6 326 344 10.1038/s41583‑021‑00454‑8 33846637
    [Google Scholar]
  71. Nagelhus E.A. Ottersen O.P. Physiological roles of aquaporin-4 in brain. Physiol. Rev. 2013 93 4 1543 1562 10.1152/physrev.00011.2013 24137016
    [Google Scholar]
  72. Smith A.J. Yao X. Dix J.A. Jin B.J. Verkman A.S. Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4- independent solute transport in rodent brain parenchyma. eLife 2017 6 e27679 10.7554/eLife.27679 28826498
    [Google Scholar]
  73. Mestre H. Hablitz L.M. Xavier A.L.R. Feng W. Zou W. Pu T. Monai H. Murlidharan G. Castellanos Rivera R.M. Simon M.J. Pike M.M. Plá V. Du T. Kress B.T. Wang X. Plog B.A. Thrane A.S. Lundgaard I. Abe Y. Yasui M. Thomas J.H. Xiao M. Hirase H. Asokan A. Iliff J.J. Nedergaard M. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 2018 7 e40070 10.7554/eLife.40070 30561329
    [Google Scholar]
  74. Yang B. Zhang H. Verkman A.S. Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides. Bioorg. Med. Chem. 2008 16 15 7489 7493 10.1016/j.bmc.2008.06.005 18572411
    [Google Scholar]
  75. Amiry-Moghaddam M. Ottersen O.P. The molecular basis of water transport in the brain. Nat. Rev. Neurosci. 2003 4 12 991 1001 10.1038/nrn1252 14682361
    [Google Scholar]
  76. Igarashi H. Huber V.J. Tsujita M. Nakada T. Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema. Neurol. Sci. 2011 32 1 113 116 10.1007/s10072‑010‑0431‑1 20924629
    [Google Scholar]
  77. Popescu E.S. Pirici I. Ciurea R.N. Bălşeanu, T.A.; Cătălin, B.; Mărgăritescu, C.; Mogoantă L.; Hostiuc, S.; Pirici, D. Threedimensional organ scanning reveals brain edema reduction in a rat model of stroke treated with an aquaporin 4 inhibitor. Rom. J. Morphol. Embryol. 2017 58 1 59 66 28523299
    [Google Scholar]
  78. Zekeridou A. Lennon V.A. Aquaporin-4 autoimmunity. Neurol. Neuroimmunol. Neuroinflamm. 2015 2 4 e110 10.1212/NXI.0000000000000110 26185772
    [Google Scholar]
  79. Misu T. Fujihara K. Kakita A. Konno H. Nakamura M. Watanabe S. Takahashi T. Nakashima I. Takahashi H. Itoyama Y. Loss of aquaporin 4 in lesions of neuromyelitis optica: Distinction from multiple sclerosis. Brain 2007 130 5 1224 1234 10.1093/brain/awm047 17405762
    [Google Scholar]
  80. Emerich D.F. Vasconcellos A.V. Elliott R.B. Skinner S.J.M. Borlongan C.V. The choroid plexus: Function, pathology and therapeutic potential of its transplantation. Expert Opin. Biol. Ther. 2004 4 8 1191 1201 10.1517/14712598.4.8.1191 15268655
    [Google Scholar]
  81. Deng S. Gan L. Liu C. Xu T. Zhou S. Guo, Y roles of ependymal cells in the physiology and pathology of the central nervous system. Aging Dis. 2023 14 2 468 483 10.14336/AD.2022.0826‑1
    [Google Scholar]
  82. Chen L. Elias G. Yostos M.P. Stimec B. Fasel J. Murphy K. Pathways of cerebrospinal fluid outflow: A deeper understanding of resorption. Neuroradiology 2015 57 2 139 147 10.1007/s00234‑014‑1461‑9 25398655
    [Google Scholar]
  83. Albargothy N.J. Johnston D.A. MacGregor-Sharp M. Weller R.O. Verma A. Hawkes C.A. Carare R.O. Convective influx/glymphatic system: Tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol. 2018 136 1 139 152 10.1007/s00401‑018‑1862‑7 29754206
    [Google Scholar]
  84. Jessen N.A. Munk A.S.F. Lundgaard I. Nedergaard M. The glymphatic system: A beginner’s guide. Neurochem. Res. 2015 40 12 2583 2599 10.1007/s11064‑015‑1581‑6 25947369
    [Google Scholar]
  85. Shah T. Leurgans S.E. Mehta R.I. Yang J. Galloway C.A. de Mesy Bentley K.L. Schneider J.A. Mehta R.I. Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma. J. Exp. Med. 2023 220 2 e20220618 10.1084/jem.20220618 36469302
    [Google Scholar]
  86. Radoš M. Živko M. Periša A. Orešković D.; Klarica, M. No arachnoid granulations—no problems: Number, size, and distribution of arachnoid granulations from birth to 80 years of age. Front. Aging Neurosci. 2021 13 698865 10.3389/fnagi.2021.698865 34276348
    [Google Scholar]
  87. Smyth L.C.D. Xu D. Okar S.V. Dykstra T. Rustenhoven J. Papadopoulos Z. Bhasiin K. Kim M.W. Drieu A. Mamuladze T. Blackburn S. Gu X. Gaitán M.I. Nair G. Storck S.E. Du S. White M.A. Bayguinov P. Smirnov I. Dikranian K. Reich D.S. Kipnis J. Identification of direct connections between the dura and the brain. Nature 2024 627 8002 165 173 10.1038/s41586‑023‑06993‑7 38326613
    [Google Scholar]
  88. Rustenhoven J. Pavlou G. Storck S.E. Dykstra T. Du S. Wan Z. Quintero D. Scallan J.P. Smirnov I. Kamm R.D. Kipnis J. Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage. J. Exp. Med. 2023 220 7 e20221929 10.1084/jem.20221929 37027179
    [Google Scholar]
  89. Ma Q. Ries M. Decker Y. Müller A. Riner C. Bücker A. Fassbender K. Detmar M. Proulx S.T. Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. Acta Neuropathol. 2019 137 1 151 165 10.1007/s00401‑018‑1916‑x 30306266
    [Google Scholar]
  90. Mestre H. Mori Y. Nedergaard M. The brain’s glymphatic system: Current controversies. Trends Neurosci. 2020 43 7 458 466 10.1016/j.tins.2020.04.003 32423764
    [Google Scholar]
  91. Furukawa M. Shimoda H. Kajiwara T. Kato S. Yanagisawa S. Topographic study on nerve-associated lymphatic vessels in the murine craniofacial region by immunohistochemistry and electron microscopy. Biomed. Res. 2008 29 6 289 296 10.2220/biomedres.29.289 19129672
    [Google Scholar]
  92. Koh L. Zakharov A. Johnston M. Integration of the subarachnoid space and lymphatics: Is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res. 2005 2 1 6 10.1186/1743‑8454‑2‑6 16174293
    [Google Scholar]
  93. Yağmurlu, K.; Sokolowski, J.D.; Çırak, M.; Urgun, K.; Soldozy, S.; Mut, M.; Shaffrey, M.E.; Tvrdik, P.; Kalani, M.Y.S. Anatomical features of the deep cervical lymphatic system and intrajugular lymphatic vessels in humans. Brain Sci. 2020 10 12 953 10.3390/brainsci10120953 33316930
    [Google Scholar]
  94. Benveniste H. Elkin R. Heerdt P.M. Koundal S. Xue Y. Lee H. Wardlaw J. Tannenbaum A. The glymphatic system and its role in cerebral homeostasis. J. Appl. Physiol. 2020 129 6 1330 1340
    [Google Scholar]
  95. Aspelund A. Tammela T. Antila S. Nurmi H. Leppänen V.M. Zarkada G. Stanczuk L. Francois M. Mäkinen T. Saharinen P. Immonen I. Alitalo K. The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J. Clin. Invest. 2014 124 9 3975 3986 10.1172/JCI75395 25061878
    [Google Scholar]
  96. Weller R.O. Subash M. Preston S.D. Mazanti I. Carare R.O. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol. 2008 18 2 253 266 10.1111/j.1750‑3639.2008.00133.x 18363936
    [Google Scholar]
  97. Proulx S.T. Cerebrospinal fluid outflow: A review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics. Cell. Mol. Life Sci. 2021 78 6 2429 2457 10.1007/s00018‑020‑03706‑5 33427948
    [Google Scholar]
  98. Benveniste H. Heerdt P.M. Fontes M. Rothman D.L. Volkow N.D. Glymphatic system function in relation to anesthesia and sleep states. Anesth. Analg. 2019 128 4 747 758 10.1213/ANE.0000000000004069 30883420
    [Google Scholar]
  99. Hertz L. Rothman D. Glutamine-glutamate cycle flux is similar in cultured astrocytes and brain and both glutamate production and oxidation are mainly catalyzed by aspartate aminotransferase. Biology (Basel) 2017 6 1 17 10.3390/biology6010017 28245547
    [Google Scholar]
  100. Hertz L. Rothman D.L. Glucose, lactate, β-hydroxybutyrate, acetate, gaba, and succinate as substrates for synthesis of glutamate and GABA in the glutamine-glutamate/gaba cycle. Adv. Neurobiol. 2016 13 9 42 10.1007/978‑3‑319‑45096‑4_2 27885625
    [Google Scholar]
  101. Xie L. Kang H. Xu Q. Chen M.J. Liao Y. Thiyagarajan M. O’Donnell J. Christensen D.J. Nicholson C. Iliff J.J. Takano T. Deane R. Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science 2013 342 6156 373 377 10.1126/science.1241224 24136970
    [Google Scholar]
  102. Kang J.E. Lim M.M. Bateman R.J. Lee J.J. Smyth L.P. Cirrito J.R. Fujiki N. Nishino S. Holtzman D.M. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 2009 326 5955 1005 1007 10.1126/science.1180962 19779148
    [Google Scholar]
  103. Spira A.P. Gamaldo A.A. An Y. Wu M.N. Simonsick E.M. Bilgel M. Zhou Y. Wong D.F. Ferrucci L. Resnick S.M. Selfreported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013 70 12 1537 1543 10.1001/jamaneurol.2013.4258 24145859
    [Google Scholar]
  104. Sundaram S. Hughes R.L. Peterson E. Müller-Oehring E.M. Brontë-Stewart H.M. Poston K.L. Faerman A. Bhowmick C. Schulte T. Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson’s disease. Neurosci. Biobehav. Rev. 2019 103 305 315 10.1016/j.neubiorev.2019.05.016 31132378
    [Google Scholar]
  105. Bolte A.C. Dutta A.B. Hurt M.E. Smirnov I. Kovacs M.A. McKee C.A. Ennerfelt H.E. Shapiro D. Nguyen B.H. Frost E.L. Lammert C.R. Kipnis J. Lukens J.R. Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis. Nat. Commun. 2020 11 1 4524 10.1038/s41467‑020‑18113‑4 32913280
    [Google Scholar]
  106. Hertz L. Gibbs M.E. Dienel G.A. Fluxes of lactate into, from, and among gap junction-coupled astrocytes and their interaction with noradrenaline. Front. Neurosci. 2014 8 261 10.3389/fnins.2014.00261 25249930
    [Google Scholar]
  107. Tavares G.A. Louveau, A Meningeal lymphatics: An immune gateway for the central nervous system. Cells 2021 10 12 3385
    [Google Scholar]
  108. Bauer J. Bradl M. Hickey W.F. Forss-Petter S. Breitschopf H. Linington C. Wekerle H. Lassmann H. T-cell apoptosis in inflammatory brain lesions: Destruction of T cells does not depend on antigen recognition. Am. J. Pathol. 1998 153 3 715 724 10.1016/S0002‑9440(10)65615‑5 9736022
    [Google Scholar]
  109. Engelhardt B. Vajkoczy P. Weller R.O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 2017 18 2 123 131 10.1038/ni.3666 28092374
    [Google Scholar]
  110. Bartholomäus I. Kawakami N. Odoardi F. Schläger C. Miljkovic D. Ellwart J.W. Klinkert W.E.F. Flügel-Koch C. Issekutz T.B. Wekerle H. Flügel A. Effector T. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 2009 462 7269 94 98 10.1038/nature08478 19829296
    [Google Scholar]
  111. Flügel A. Odoardi F. Nosov M. Kawakami N. lomyelitis visualized in the light of two-photon microscopy. J. Neuroimmunol. 2007 191 1-2 86 97 10.1016/j.jneuroim.2007.09.017 17976745
    [Google Scholar]
  112. Louveau A. Smirnov I. Keyes T.J. Eccles J.D. Rouhani S.J. Peske J.D. Derecki N.C. Castle D. Mandell J.W. Lee K.S. Harris T.H. Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature 2015 523 7560 337 341 10.1038/nature14432 26030524
    [Google Scholar]
  113. Louveau A. Herz J. Alme M.N. Salvador A.F. Dong M.Q. Viar K.E. Herod S.G. Knopp J. Setliff J.C. Lupi A.L. Da Mesquita S. Frost E.L. Gaultier A. Harris T.H. Cao R. Hu S. Lukens J.R. Smirnov I. Overall C.C. Oliver G. Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci. 2018 21 10 1380 1391 10.1038/s41593‑018‑0227‑9 30224810
    [Google Scholar]
  114. Song E. Mao T. Dong H. Boisserand L.S.B. Antila S. Bosenberg M. Alitalo K. Thomas J.L. Iwasaki A. VEGF-Cdriven lymphatic drainage enables immunosurveillance of brain tumours. Nature 2020 577 7792 689 694 10.1038/s41586‑019‑1912‑x 31942068
    [Google Scholar]
  115. Hu X. Deng Q. Ma L. Li Q. Chen Y. Liao Y. Zhou F. Zhang C. Shao L. Feng J. He T. Ning W. Kong Y. Huo Y. He A. Liu B. Zhang J. Adams R. He Y. Tang F. Bian X. Luo J. Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res. 2020 30 3 229 243 10.1038/s41422‑020‑0287‑8 32094452
    [Google Scholar]
  116. Mapunda J.A. Tibar H. Regragui W. Engelhardt B. How does the immune system enter the brain? Front. Immunol. 2022 13 805657 10.3389/fimmu.2022.805657 35273596
    [Google Scholar]
  117. Lun M. Lok E. Gautam S. Wu E. Wong E.T. The natural history of extracranial metastasis from glioblastoma multiforme. J. Neurooncol. 2011 105 2 261 273 10.1007/s11060‑011‑0575‑8 21512826
    [Google Scholar]
  118. Pizzo M.E. Wolak D.J. Kumar N.N. Brunette E. Brunnquell C.L. Hannocks M.J. Abbott N.J. Meyerand M.E. Sorokin L. Stanimirovic D.B. Thorne R.G. Intrathecal antibody distribution in the rat brain: Surface diffusion, perivascular transport and osmotic enhancement of delivery. J. Physiol. 2018 596 3 445 475 10.1113/JP275105 29023798
    [Google Scholar]
  119. Abbott N.J. Evidence for bulk flow of brain interstitial fluid: Significance for physiology and pathology. Neurochem. Int. 2004 45 4 545 552 10.1016/j.neuint.2003.11.006 15186921
    [Google Scholar]
  120. Hannocks M.J. Pizzo M.E. Huppert J. Deshpande T. Abbott N.J. Thorne R.G. Sorokin L. Molecular characterization of perivascular drainage pathways in the murine brain. J. Cereb. Blood Flow Metab. 2018 38 4 669 686 10.1177/0271678X17749689 29283289
    [Google Scholar]
  121. Cserr H.F. Ostrach L.H. Bulk flow of interstitial fluid after intracranial injection of Blue Dextran 2000. Exp. Neurol. 1974 45 1 50 60 10.1016/0014‑4886(74)90099‑5 4137563
    [Google Scholar]
  122. Nicholson C. Tao L. Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys. J. 1993 65 6 2277 2290 10.1016/S0006‑3495(93)81324‑9 7508761
    [Google Scholar]
  123. Cserr H.F. Cooper D.N. Milhorat T.H. Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp. Eye Res. 1977 25 Suppl. 461 473 10.1016/S0014‑4835(77)80041‑9 590401
    [Google Scholar]
  124. Rosenberg G.A. Kyner W.T. Estrada E. Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am. J. Physiol. 1980 238 1 F42 F49 7356021
    [Google Scholar]
  125. Asgari M. de Zélicourt D. Kurtcuoglu V. Glymphatic solute transport does not require bulk flow. Sci. Rep. 2016 6 1 38635 10.1038/srep38635 27929105
    [Google Scholar]
  126. Lun M.P. Monuki E.S. Lehtinen M.K. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat. Rev. Neurosci. 2015 16 8 445 457 10.1038/nrn3921 26174708
    [Google Scholar]
  127. Durand-Fardel M. Treatise on the softening of the brain: Work coauthored by the Royal Academy of Medicine. Baillières 1843
    [Google Scholar]
  128. Ringstad G. Valnes L.M. Dale A.M. Pripp A.H. Vatnehol S.A.S. Emblem K.E. Mardal K.A. Eide P.K. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 2018 3 13 e121537 10.1172/jci.insight.121537 29997300
    [Google Scholar]
  129. Absinta M. Ha S.K. Nair G. Sati P. Luciano N.J. Palisoc M. Louveau A. Zaghloul K.A. Pittaluga S. Kipnis J. Reich D.S. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 2017 6 e29738 10.7554/eLife.29738 28971799
    [Google Scholar]
  130. Visanji N.P. Lang A.E. Munoz D.G. Lymphatic vasculature in human dural superior sagittal sinus: Implications for neurodegenerative proteinopathies. Neurosci. Lett. 2018 665 18 21 10.1016/j.neulet.2017.11.001 29133178
    [Google Scholar]
  131. Goodman J.R. Adham Z.O. Woltjer R.L. Lund A.W. Iliff J.J. Characterization of dural sinus-associated lymphatic vasculature in human Alzheimer’s dementia subjects. Brain Behav. Immun. 2018 73 34 40 10.1016/j.bbi.2018.07.020 30055243
    [Google Scholar]
  132. Eide P.K. Vatnehol S.A.S. Emblem K.E. Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci. Rep. 2018 8 1 7194 10.1038/s41598‑018‑25666‑4 29740121
    [Google Scholar]
  133. Kuo P.H. Stuehm C. Squire S. Johnson K. Meningeal lymphatic vessel flow runs countercurrent to venous flow in the superior sagittal sinus of the human brain. Tomography 2018 4 3 99 104 10.18383/j.tom.2018.00013 30320209
    [Google Scholar]
  134. Plog B.A. Nedergaard M. The glymphatic system in central nervous system health and disease: Past, present, and future. Annu. Rev. Pathol. 2018 13 1 379 394 10.1146/annurev‑pathol‑051217‑111018 29195051
    [Google Scholar]
  135. Nauen D.W. Troncoso J.C. Amyloid-beta is present in human lymph nodes and greatly enriched in those of the cervical region. Alzheimers Dement. 2022 18 2 205 210 10.1002/alz.12385 34057798
    [Google Scholar]
  136. Tarasoff-Conway J.M. Carare R.O. Osorio R.S. Glodzik L. Butler T. Fieremans E. Axel L. Rusinek H. Nicholson C. Zlokovic B.V. Frangione B. Blennow K. Ménard J. Zetterberg H. Wisniewski T. de Leon M.J. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 2015 11 8 457 470 10.1038/nrneurol.2015.119 26195256
    [Google Scholar]
  137. Schubert J.J. Veronese M. Marchitelli L. Bodini B. Tonietto M. Stankoff B. Brooks D.J. Bertoldo A. Edison P. Turkheimer F.E. Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer disease and multiple sclerosis. J. Nucl. Med. 2019 60 10 1452 1460 10.2967/jnumed.118.223834 30850505
    [Google Scholar]
  138. Xu Z. Xiao N. Chen Y. Huang H. Marshall C. Gao J. Cai Z. Wu T. Hu G. Xiao M. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol. Neurodegener. 2015 10 1 58 10.1186/s13024‑015‑0056‑1 26526066
    [Google Scholar]
  139. Hughes T.M. Kuller L.H. Barinas-Mitchell E.J.M. Mackey R.H. McDade E.M. Klunk W.E. Aizenstein H.J. Cohen A.D. Snitz B.E. Mathis C.A. DeKosky S.T. Lopez O.L. Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology 2013 81 19 1711 1718 10.1212/01.wnl.0000435301.64776.37 24132374
    [Google Scholar]
  140. Zeppenfeld D.M. Simon M. Haswell J.D. D’Abreo D. Murchison C. Quinn J.F. Grafe M.R. Woltjer R.L. Kaye J. Iliff J.J. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol. 2017 74 1 91 99 10.1001/jamaneurol.2016.4370 27893874
    [Google Scholar]
  141. Chung S.J. Yoo H.S. Shin N.Y. Park Y.W. Lee H.S. Hong J.M. Kim Y.J. Lee S.K. Lee P.H. Sohn Y.H. Perivascular spaces in the basal ganglia and long-term motor prognosis in newly Crosstalk between the Glymphatic System and the Lymphatic System diagnosed parkinson disease. Neurology 2021 96 16 e2121 e2131 10.1212/WNL.0000000000011797 33653906
    [Google Scholar]
  142. Park Y.W. Shin N.Y. Chung S.J. Kim J. Lim S.M. Lee P.H. Lee S.K. Ahn K.J. Magnetic resonance imaging-visible perivascular spaces in basal ganglia predict cognitive decline in parkinson’s disease. Mov. Disord. 2019 34 11 1672 1679 10.1002/mds.27798 31322758
    [Google Scholar]
  143. Li Y. Zhu Z. Chen J. Zhang M. Yang Y. Huang P. Dilated perivascular space in the midbrain may reflect dopamine neuronal degeneration in Parkinson’s disease. Front. Aging Neurosci. 2020 12 161 10.3389/fnagi.2020.00161 32581771
    [Google Scholar]
  144. Zhang J. Liu S. Wu Y. Tang Z. Wu Y. Qi Y. Dong F. Wang Y. Enlarged perivascular space and index for diffusivity along the perivascular space as emerging neuroimaging biomarkers of neurological diseases. Cell. Mol. Neurobiol. 2024 44 1 14 10.1007/s10571‑023‑01440‑7 38158515
    [Google Scholar]
  145. Donahue E.K. Murdos A. Jakowec M.W. Sheikh-Bahaei N. Toga A.W. Petzinger G.M. Sepehrband F. Global and regional changes in perivascular space in idiopathic and familial Parkinson’s disease. Mov. Disord. 2021 36 5 1126 1136 10.1002/mds.28473 33470460
    [Google Scholar]
  146. Hoshi A. Tsunoda A. Tada M. Nishizawa M. Ugawa Y. Kakita A. Expression of aquaporin 1 and aquaporin 4 in the temporal neocortex of patients with Parkinson’s disease. Brain Pathol. 2017 27 2 160 168 10.1111/bpa.12369 26919570
    [Google Scholar]
  147. Zhou Y. Huang X. Zhao T. Qiao M. Zhao X. Zhao M. Xu L. Zhao Y. Wu L. Wu K. Chen R. Fan M. Zhu L. Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice. Brain Behav. Immun. 2017 64 266 275 10.1016/j.bbi.2017.04.013 28433745
    [Google Scholar]
  148. Louveau A. Harris T.H. Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015 36 10 569 577 10.1016/j.it.2015.08.006 26431936
    [Google Scholar]
  149. Willis C.L. Camire R.B. Brule S.A. Ray D.E. Partial recovery of the damaged rat blood-brain barrier is mediated by adherens junction complexes, extracellular matrix remodeling and macrophage infiltration following focal astrocyte loss. Neuroscience 2013 250 773 785 10.1016/j.neuroscience.2013.06.061 23845748
    [Google Scholar]
  150. Gaberel T. Gakuba C. Goulay R. De Lizarrondo S.M. Hanouz J.L. Emery E. Touze E. Vivien D. Gauberti M. Impaired glymphatic perfusion after strokes revealed by contrastenhanced MRI: A new target for fibrinolysis? Stroke 2014 45 10 3092 3096 10.1161/STROKEAHA.114.006617 25190438
    [Google Scholar]
  151. Calias P. Banks W.A. Begley D. Scarpa M. Dickson P. Intrathecal delivery of protein therapeutics to the brain: A critical reassessment. Pharmacol. Ther. 2014 144 2 114 122 10.1016/j.pharmthera.2014.05.009 24854599
    [Google Scholar]
  152. Bellettato C.M. Scarpa M. Possible strategies to cross the bloodbrain barrier. Ital. J. Pediatr. 2018 44 S2 Suppl. 2 131 10.1186/s13052‑018‑0563‑0 30442184
    [Google Scholar]
  153. Soderquist R.G. Mahoney M.J. Central nervous system delivery of large molecules: Challenges and new frontiers for intrathecally administered therapeutics. Expert Opin. Drug Deliv. 2010 7 3 285 293 10.1517/17425240903540205 20201735
    [Google Scholar]
  154. Zhou Y. Cai J. Zhang W. Gong X. Yan S. Zhang K. Luo Z. Sun J. Jiang Q. Lou M. Impairment of the glymphatic pathway and putative meningeal lymphatic vessels in the aging human. Ann. Neurol. 2020 87 3 357 369 10.1002/ana.25670 31916277
    [Google Scholar]
  155. Rustenhoven J. Drieu A. Mamuladze T. de Lima K.A. Dykstra T. Wall M. Papadopoulos Z. Kanamori M. Salvador A.F. Baker W. Lemieux M. Da Mesquita S. Cugurra A. Fitzpatrick J. Sviben S. Kossina R. Bayguinov P. Townsend R.R. Zhang Q. Erdmann-Gilmore P. Smirnov I. Lopes M.B. Herz J. Kipnis J. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 2021 184 4 1000 1016.e27 10.1016/j.cell.2020.12.040 33508229
    [Google Scholar]
  156. Jin P. Munson J.M. Fluids and flows in brain cancer and neurological disorders. WIREs Mech. Dis. 2023 15 1 e1582 10.1002/wsbm.1582 36000149
    [Google Scholar]
  157. Saadoun S. Papadopoulos M.C. Davies D.C. Krishna S. Bell B.A. Aquaporin-4 expression is increased in oedematous human brain tumours. J. Neurol. Neurosurg. Psychiatry 2002 72 2 262 265 10.1136/jnnp.72.2.262 11796780
    [Google Scholar]
  158. Xu D. Zhou J. Mei H. Li H. Sun W. Xu H. Impediment of cerebrospinal fluid drainage through glymphatic system in glioma. Front. Oncol. 2022 11 790821 10.3389/fonc.2021.790821 35083148
    [Google Scholar]
  159. Toh C.H. Siow T.Y. Factors associated with dysfunction of glymphatic system in patients with glioma. Front. Oncol. 2021 11 744318 10.3389/fonc.2021.744318 34631582
    [Google Scholar]
  160. Ma Q. Schlegel F. Bachmann S.B. Schneider H. Decker Y. Rudin M. Weller M. Proulx S.T. Detmar M. Lymphatic outflow of cerebrospinal fluid is reduced in glioma. Sci. Rep. 2019 9 1 14815 10.1038/s41598‑019‑51373‑9 31616011
    [Google Scholar]
  161. Frederico S.C. Hancock J.C. Brettschneider E.E.S. Ratnam N.M. Gilbert M.R. Terabe M. Making a cold tumor hot: The role of vaccines in the treatment of glioblastoma. Front. Oncol. 2021 11 672508 10.3389/fonc.2021.672508 34041034
    [Google Scholar]
  162. Mogensen F.L.H. Delle C. Nedergaard M. The Glymphatic System (En)during Inflammation. Int. J. Mol. Sci. 2021 22 14 7491 10.3390/ijms22147491 34299111
    [Google Scholar]
  163. Iliff J.J. Chen M.J. Plog B.A. Zeppenfeld D.M. Soltero M. Yang L. Singh I. Deane R. Nedergaard M. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 2014 34 49 16180 16193 10.1523/JNEUROSCI.3020‑14.2014 25471560
    [Google Scholar]
  164. Hershenhouse K.S. Shauly O. Gould D.J. Patel K.M. Meningeal lymphatics: A review and future directions from a clinical perspective. Neuroscience Insights 2019 14 1179069519889027 10.1177/1179069519889027 32363346
    [Google Scholar]
  165. Hsu M. Laaker C. Sandor M. Fabry Z. Neuroinflammationdriven lymphangiogenesis in CNS diseases. Front. Cell. Neurosci. 2021 15 683676 10.3389/fncel.2021.683676
    [Google Scholar]
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