kpcczКомплексные проблемы сердечно-сосудистых заболеванийComplex Issues of Cardiovascular Diseases2306-12782587-9537Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”10.17802/2306-1278-2020-9-3-81-89kpccz-760Research ArticleАНАЛИТИЧЕСКИЙ ОБЗОРANALYTICAL REVIEWЛимфодренажная система головного мозга: возможности визуализации и современное состояние проблемыBrain lymphatic drainage system – visualization opportunities and current state of the arthttps://orcid.org/0000-0002-0782-1819ЯньковаГ. С.YankovaG. S.

младший научный сотрудник лаборатории дифференциальных уравнений, просп. акад. Лаврентьева, 15, Новосибирск, 630090;

ассистент кафедры высшей математики механико-математического факультета, ул. Пирогова, 2, Новосибирск, 630090

assistant researcher at the Laboratory of Differential Equations, 15, acad. Lavrenteva Ave., Novosibirsk, 630090;

assistant Professor at the Department of Mechanics and Mathematics, Pirogova St., Novosibirsk, 630090

g.iankova@g.nsu.ruhttps://orcid.org/0000-0002-8880-100XБогомяковаО. Б.BogomyakovaO. B.

кандидат медицинских наук, научный сотрудник лаборатории МРТ технологии,

ул. Институтская, 3а, Новосибирск, 630090

PhD., MD, researcher at Laboratory of MRI technologies,

3а, Institutskaya St., Novosibirsk, 630090

Федеральное государственное бюджетное учреждение науки Институт гидродинамики им. М.А. Лаврентьева Сибирского отделения Российской академии наук; Федеральное государственное автономное образовательное учреждение высшего образования «Новосибирский национальный исследовательский государственный университет»РоссияFederal State Budgetary Institution of Science “Lavrentyev Institute of Hydrodynamics”, Siberian Branch of the Russian Academy of Sciences; Federal State Budgetary Educational Institution of Higher Professional Education “Novosibirsk National Research State University”Russian FederationФедеральное государственное бюджетное учреждение науки Институт «Международный томографический центр» Сибирского отделения Российской академии наукРоссияFederal State Budgetary Institution of Science “International Tomographic Center”, Siberian Branch, Russian Academy of SciencesRussian Federation202028092020938189Copyright © Янькова Г.С., Богомякова О.Б., 20202020Янькова Г.С., Богомякова О.Б.Yankova G.S., Bogomyakova O.B.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nii-kpssz.com/jour/article/view/760

Предполагается, что лимфодренажная система головного мозга состоит из глимфатической системы и сети менингеальных лимфатических сосудов. Данная система поддерживает гомеостаз мозга, участвует в иммунном надзоре и представляет собой новую терапевтическую мишень в лечении неврологических дисфункций.

В статье проанализированы и систематизированы данные о лимфодренажной системе головного мозга. Рассматриваются ключевые компоненты данной системы: недавно охарактеризованные менингеальные лимфатические сосуды и их взаимосвязь с глимфатической системой, которая обеспечивает перфузию центральной нервной системы цереброспинальной и интерстициальной жидкостями. Лимфодренажная система помогает поддерживать водный и ионный баланс интерстициальной жидкости, способствует очистке от шлаков метаболитов и продуктов жизнедеятельности клеток, реабсорбции макромолекул, а нарушения в ее работе играют решающую роль в возрастных изменениях головного мозга, патогенезе нейроваскулярных, нейродегенеративных заболеваний, а также при травмах и опухолях головного мозга. Также в обзоре приведены результаты исследований на людях, посвященных изучению наличия, анатомии и структуры менингеальных лимфатических сосудов и глимфатической системы. Открытие лимфодренажной системы не только изменило представление о циркуляции жидкости в головном мозге, но и внесло вклад в понимание патологии центральной нервной системы и механизмов нейродегенеративных заболеваний. 

The lymphatic drainage system of the brain is assumed to consist of the lymphatic system and a network of meningeal lymphatic vessels. This system supports brain homeostasis, participates in immune surveillance and presents a new therapeutic target in the treatment of neurological disorders.

The article analyzes and systematizes data on the brain lymphatic drainage system. The key components of this system are considered: recently described meningeal lymphatic vessels and their relationship with the glymphatic system, which provides perfusion of the central nervous system with cerebrospinal and interstitial fluids. The lymphatic drainage system helps to maintain water and ion balances of the interstitial fluid and to remove metabolic waste products, assists in reabsorption of macromolecules. Disorders in its work play a crucial role in age-related changes in the brain, the pathogenesis of neurovascular and neurodegenerative diseases, as well as injuries and brain tumors. The review also presents the results of human studies concerning the presence, anatomy and structure of meningeal lymphatic vessels and the glymphatic system. The discovery of the brain lymphatic drainage system has not only changed our understanding of cerebrospinal fluid circulation, but also contributed to understanding the pathology and mechanisms of neurodegenerative diseases.

глимфатическая системаменингеальные лимфатические сосудыцереброспинальная жидкостьAQP4болезнь Альцгеймераglymphatic systemmeningeal lymphatic vesselscerebrospinal fluidAQP4alzheimer`s diseaseReferencesAspelund 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. doi: 10.1084/jem.20142290Aspelund 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. doi: 10.1084/jem.20142290Louveau 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. doi: 10.1038/nature14432Louveau 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. doi: 10.1038/nature14432Iliff J.J., Wang M., Liao Y., Plogg B., 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 β. Sci Transl Med. 2012;4(147):147ra111- 147ra111. doi: 10.1126/scitranslmed.3003748Iliff J.J., Wang M., Liao Y., Plogg B., 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 β. Sci Transl Med. 2012;4(147):147ra111- 147ra111. doi: 10.1126/scitranslmed.3003748Jessen N.A., Munk A.S.F., Lundgaard I., Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40(12):2583-2599. doi:10.1007/s11064-015-1581-6Jessen N.A., Munk A.S.F., Lundgaard I., Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40(12):2583-2599. doi:10.1007/s11064-015-1581-6Da Mesquita S., Louveau A., Vaccari A., Smirnov I., Cornelison R.C., Kingsmore K.M., Contarino C., OnengutGumuscu S., Farber E., Raper D., Viar K.E., Powell R.D., Baker W., Dabhi N., Bai R., Cao R., Hu S., Rich S.S., Munson J.M., Lopes M.B., Overall C.C., Acton S.T., Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560(7717):185-191. doi: /10.1038/ s41586-018-0368-8Da Mesquita S., Louveau A., Vaccari A., Smirnov I., Cornelison R.C., Kingsmore K.M., Contarino C., OnengutGumuscu S., Farber E., Raper D., Viar K.E., Powell R.D., Baker W., Dabhi N., Bai R., Cao R., Hu S., Rich S.S., Munson J.M., Lopes M.B., Overall C.C., Acton S.T., Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560(7717):185-191. doi: /10.1038/ s41586-018-0368-8Kress 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. Ann Neurol. 2014;76(6):845-861. doi: 10.1002/ana.24271Kress 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. Ann Neurol. 2014;76(6):845-861. doi: 10.1002/ana.24271Xie 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. doi: 10.1126/science.1241224Xie 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. doi: 10.1126/science.1241224Fultz N.E., Bonmassar G., Setsompop K., Stickgold R.A., Rosen B.R., Polimeni J.R., Lewis L.D. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628-631. doi: 10.1126/science.aax5440Fultz N.E., Bonmassar G., Setsompop K., Stickgold R.A., Rosen B.R., Polimeni J.R., Lewis L.D. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628-631. doi: 10.1126/science.aax5440Lee 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. doi: 10.1523/JNEUROSCI.1625-15.2015Lee 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. doi: 10.1523/JNEUROSCI.1625-15.2015Davson H., Segal M.B. Physiology of the CSF and blood-brain barriers.: CRC press.; 1996.Davson H., Segal M.B. Physiology of the CSF and blood-brain barriers.: CRC press.; 1996.Ma Q., Ineichen B.V., Detmar M., Proulx S.T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun. 2017;8(1):1- 13. doi: 10.1038/s41467-017-01484-6Ma Q., Ineichen B.V., Detmar M., Proulx S.T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun. 2017;8(1):1- 13. doi: 10.1038/s41467-017-01484-6Jackson R.T., Tigges J., Arnold W. Subarachnoid space of the CNS, nasal mucosa, and lymphatic system. Arch Otolaryngol. 1979;105(4):180-184. doi:10.1001/archotol.1979.00790160014003Jackson R.T., Tigges J., Arnold W. Subarachnoid space of the CNS, nasal mucosa, and lymphatic system. Arch Otolaryngol. 1979;105(4):180-184. doi:10.1001/archotol.1979.00790160014003Gomez D.G., Manzo R.P., Fenstermacher J.D., Potts D.G. Cerebrospinal fluid absorption in the rabbit. Graefes Arch Clin Exp Ophthalmol. 1988;226(1):1-7. doi: 10.1007/BF02172707Gomez D.G., Manzo R.P., Fenstermacher J.D., Potts D.G. Cerebrospinal fluid absorption in the rabbit. Graefes Arch Clin Exp Ophthalmol. 1988;226(1):1-7. doi: 10.1007/BF02172707Orešković D., Klarica M. The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations. Brain Res Brain Res Rev. 2010;64(2):241- 262. doi: 10.1016/j.brainresrev.2010.04.006Orešković D., Klarica M. The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations. Brain Res Brain Res Rev. 2010;64(2):241- 262. doi: 10.1016/j.brainresrev.2010.04.006Hannocks 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. doi: 10.1177/0271678X17749689Hannocks 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. doi: 10.1177/0271678X17749689Rennels 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. doi: 10.1016/0006-8993(85)91383-6Rennels 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. doi: 10.1016/0006-8993(85)91383-6Rennels M.L., Blaumanis O.R., Grady P.A. Rapid solute transport throughout the brain via paravascular fluid pathways. Adv Neurol. 1990;52:431-439.Rennels M.L., Blaumanis O.R., Grady P.A. Rapid solute transport throughout the brain via paravascular fluid pathways. Adv Neurol. 1990;52:431-439.Brightman M.W. The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. II. Parenchymal distribution. Am J Anat. 1965;117(2):193-219.Brightman M.W. The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. II. Parenchymal distribution. Am J Anat. 1965;117(2):193-219.Brightman M.W., Reese T.S. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol. 1969;40(3):648-677.Brightman M.W., Reese T.S. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol. 1969;40(3):648-677.Ichimura T., Fraser P.A., Cserr H.F. Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res. 1991;545((1-2)):103-113. doi: 10.1016/0006-8993(91)91275-6Ichimura T., Fraser P.A., Cserr H.F. Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res. 1991;545((1-2)):103-113. doi: 10.1016/0006-8993(91)91275-6Carare R.O., Bernardes-Silva M., Newman T.A., Page A.M., Nicoll J.A.R., Perry V.H., Weller R.O. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008;34(2):131-144. doi: 10.1111/j.1365-2990.2007.00926.xCarare R.O., Bernardes-Silva M., Newman T.A., Page A.M., Nicoll J.A.R., Perry V.H., Weller R.O. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008;34(2):131-144. doi: 10.1111/j.1365-2990.2007.00926.xMorris A.W., Sharp M.M., Albargothy N.J., Fernandes R., Hawkes C.A., Verma A., Weller R.O., Carare R.O. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 2016;131(5):725-736. doi: 10.1007/s00401-016-1555-zMorris A.W., Sharp M.M., Albargothy N.J., Fernandes R., Hawkes C.A., Verma A., Weller R.O., Carare R.O. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 2016;131(5):725-736. doi: 10.1007/s00401-016-1555-zAbbott N.J. Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437-449. doi: 10.1007/s10545-013-9608-0Abbott N.J. Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437-449. doi: 10.1007/s10545-013-9608-0Bakker E.N., 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. doi: 10.1007/s10571-015-0273-8Bakker E.N., 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. doi: 10.1007/s10571-015-0273-8Hladky S.B., Barrand M.A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS. 2014;11(1):1-32. doi: 10.1186/2045-8118-11-26Hladky S.B., Barrand M.A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS. 2014;11(1):1-32. doi: 10.1186/2045-8118-11-26Sharp M.K., Diem A.K., Weller R.O., Carare R.O. Peristalsis with oscillating flow resistance: a mechanism for periarterial clearance of amyloid beta from the brain. Ann Biomed Eng. 2016;44(5):1553-1565. doi: 10.1007/s10439-015-1457-6Sharp M.K., Diem A.K., Weller R.O., Carare R.O. Peristalsis with oscillating flow resistance: a mechanism for periarterial clearance of amyloid beta from the brain. Ann Biomed Eng. 2016;44(5):1553-1565. doi: 10.1007/s10439-015-1457-6Coloma M., Schaffer J.D., Carare R.O., Chiarot P.R., Huang P. Pulsations with reflected boundary waves: a hydrodynamic reverse transport mechanism for perivascular drainage in the brain. J Math Biol. 2016;73(2):469-490. doi: 10.1007/s00285-015-0960-6Coloma M., Schaffer J.D., Carare R.O., Chiarot P.R., Huang P. Pulsations with reflected boundary waves: a hydrodynamic reverse transport mechanism for perivascular drainage in the brain. J Math Biol. 2016;73(2):469-490. doi: 10.1007/s00285-015-0960-6Iliff 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. doi: 10.1523/JNEUROSCI.3020-14.2014Iliff 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. doi: 10.1523/JNEUROSCI.3020-14.2014Mathiisen 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. doi: 10.1002/glia.20990Mathiisen 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. doi: 10.1002/glia.20990Korogod N., Petersen C.C., Knott G.W. Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife. 2015;4:e05793. doi: 10.7554/eLife.05793Korogod N., Petersen C.C., Knott G.W. Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife. 2015;4:e05793. doi: 10.7554/eLife.05793Jin B.J., Smith A.J., Verkman A.S.. Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism. J Gen Physiol. 2016;148(6):489-501. doi: 10.1085/jgp.201611684Jin B.J., Smith A.J., Verkman A.S.. Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism. J Gen Physiol. 2016;148(6):489-501. doi: 10.1085/jgp.201611684Iliff J.J., Lee H., Yu M., Feng T., Logan J., Nedergaard M., Benveniste H. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299- 1309. doi: 10.1172/JCI67677.Iliff J.J., Lee H., Yu M., Feng T., Logan J., Nedergaard M., Benveniste H. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299- 1309. doi: 10.1172/JCI67677.Taoka T., Jost G., Frenzel T., Naganawa S., Pietsch H. Impact of the glymphatic system on the kinetic and distribution of gadodiamide in the rat brain: observations by dynamic MRI and effect of circadian rhythm on tissue gadolinium concentrations. Invest Radiol. 2018;53(9):529-534. doi: 10.1097/RLI.0000000000000473Taoka T., Jost G., Frenzel T., Naganawa S., Pietsch H. Impact of the glymphatic system on the kinetic and distribution of gadodiamide in the rat brain: observations by dynamic MRI and effect of circadian rhythm on tissue gadolinium concentrations. Invest Radiol. 2018;53(9):529-534. doi: 10.1097/RLI.0000000000000473Akbar J.J., Luetmer P.H., Schwartz K.M., Hunt C.H., Diehn F.E., Eckel L.J. The role of MR myelography with intrathecal gadolinium in localization of spinal CSF leaks in patients with spontaneous intracranial hypotension. AJNR Am J Neuroradiol. 2012;33(3):535-540. doi: 10.3174/ajnr.A2815Akbar J.J., Luetmer P.H., Schwartz K.M., Hunt C.H., Diehn F.E., Eckel L.J. The role of MR myelography with intrathecal gadolinium in localization of spinal CSF leaks in patients with spontaneous intracranial hypotension. AJNR Am J Neuroradiol. 2012;33(3):535-540. doi: 10.3174/ajnr.A2815Ringstad G., Vatnehol S.A.S., Eide P.K. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain. 2017;140(10):2691-2705. doi: 10.1093/brain/awx191Ringstad G., Vatnehol S.A.S., Eide P.K. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain. 2017;140(10):2691-2705. doi: 10.1093/brain/awx191Ringstad 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. doi: 10.1172/jci.insight.121537Ringstad 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. doi: 10.1172/jci.insight.121537Van De Haar H.J., Burgmans S., Jansen J.F., Van Osch M.J.P., Van Buchem M.A., Muller M., Hofman P.A.M., Verhey F.R.J., Backes W.H. Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology. 2016;281(2):527-535. doi: 10.1148/radiol.2016152244Van De Haar H.J., Burgmans S., Jansen J.F., Van Osch M.J.P., Van Buchem M.A., Muller M., Hofman P.A.M., Verhey F.R.J., Backes W.H. Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology. 2016;281(2):527-535. doi: 10.1148/radiol.2016152244Jiang Q., Zhang L., Ding G., Davoodi-Bojd E., Li Q., Li L., Sadry N., Nedergaard M., Chopp M., Zhang Z. Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab. 2017;37(4):1326-1337. doi: 10.1177/0271678X16654702Jiang Q., Zhang L., Ding G., Davoodi-Bojd E., Li Q., Li L., Sadry N., Nedergaard M., Chopp M., Zhang Z. Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab. 2017;37(4):1326-1337. doi: 10.1177/0271678X16654702Mascagni P. Vasorum lymphaticorum corporis humani historia et ichnographia. Siena: Ex typographia Pazzini Carli; 1787. Available at: https://anatomia.library.utoronto.ca/islandora/object/anatomia%3ARBAI052 (accessed 09.07.2020)Mascagni P. Vasorum lymphaticorum corporis humani historia et ichnographia. Siena: Ex typographia Pazzini Carli; 1787. Available at: https://anatomia.library.utoronto.ca/islandora/object/anatomia%3ARBAI052 (accessed 09.07.2020)Lüdemann W., von Rautenfeld D.B., Samii M., Brinker T. Ultrastructure of the cerebrospinal fluid outflow along the optic nerve into the lymphatic system. Childs Nerv Syst. 2005;21(2):96-103. doi: 10.1007/s00381-004-1040-1Lüdemann W., von Rautenfeld D.B., Samii M., Brinker T. Ultrastructure of the cerebrospinal fluid outflow along the optic nerve into the lymphatic system. Childs Nerv Syst. 2005;21(2):96-103. doi: 10.1007/s00381-004-1040-1Furukawa 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. doi: 10.2220/biomedres.29.289Furukawa 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. doi: 10.2220/biomedres.29.289Cserr H.F., Harling‐Berg C.J., Knopf P.M. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992;2(4):269- 276. doi: 10.1111/j.1750-3639.1992.tb00703.xCserr H.F., Harling‐Berg C.J., Knopf P.M. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992;2(4):269- 276. doi: 10.1111/j.1750-3639.1992.tb00703.xAbbott 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. DOI: 10.1007/s00401-018-1812-4Abbott 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. DOI: 10.1007/s00401-018-1812-4Medawar P.B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. British Journal of Experimental Pathology. 1948;29(1):58-69Medawar P.B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. British Journal of Experimental Pathology. 1948;29(1):58-69Murphy J.B., Sturm E. Conditions determining the transplantability of tissues in the brain. The Journal of experimental medicine. 1923;38(2).Murphy J.B., Sturm E. Conditions determining the transplantability of tissues in the brain. The Journal of experimental medicine. 1923;38(2).Galea I., Bechmann I., Perry V.H. What is immune privilege (not)? Trends Immunol. 2007;28(1):12-18. doi: 10.1016/j.it.2006.11.004Galea I., Bechmann I., Perry V.H. What is immune privilege (not)? Trends Immunol. 2007;28(1):12-18. doi: 10.1016/j.it.2006.11.004Louveau A., Harris T.H., Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015;36(10):569-577. doi: 10.1016/j.it.2015.08.006Louveau A., Harris T.H., Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015;36(10):569-577. doi: 10.1016/j.it.2015.08.006Louveau A., Plog B.A., Antila S., Alitalo K., Nedergaard M., Kipnis J. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017;127(9):3210-3219. doi: 10.1172/JCI90603.Louveau A., Plog B.A., Antila S., Alitalo K., Nedergaard M., Kipnis J. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017;127(9):3210-3219. doi: 10.1172/JCI90603.Antila S., Karaman S., Nurmi H., Airavaara M., Voutilainen M.H., Mathivet T., Chilov D., Li Z., Koppinen T, Park JH, Fang S, Aspelund A, Saarma M, Eichmann A,Thomas JL, Alitalo K. Development and plasticity of meningeal lymphatic vessels. J Exp Med. 2017;214(12):3645-3667. doi: 10.1084/jem.20170391Antila S., Karaman S., Nurmi H., Airavaara M., Voutilainen M.H., Mathivet T., Chilov D., Li Z., Koppinen T, Park JH, Fang S, Aspelund A, Saarma M, Eichmann A,Thomas JL, Alitalo K. Development and plasticity of meningeal lymphatic vessels. J Exp Med. 2017;214(12):3645-3667. doi: 10.1084/jem.20170391Maloveska M., Danko J., Petrovova E., Kresakova L., Vdoviakova K., Michalicova A., Kovac A., Cubinkova V., Cizkova D. Dynamics of Evans blue clearance from cerebrospinal fluid into meningeal lymphatic vessels and deep cervical lymph nodes. Neurol Res. 2018;40(5):372-380. doi: 10.1080/01616412.2018.1446282Maloveska M., Danko J., Petrovova E., Kresakova L., Vdoviakova K., Michalicova A., Kovac A., Cubinkova V., Cizkova D. Dynamics of Evans blue clearance from cerebrospinal fluid into meningeal lymphatic vessels and deep cervical lymph nodes. Neurol Res. 2018;40(5):372-380. doi: 10.1080/01616412.2018.1446282Louveau 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 K.C., Oliver G., Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nature neuroscience. 2018;21(10):1380-1391. doi: 10.1038/s41593-018-0227-9Louveau 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 K.C., Oliver G., Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nature neuroscience. 2018;21(10):1380-1391. doi: 10.1038/s41593-018-0227-9Absinta 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. doi: 10.7554/eLife.29738Absinta 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. doi: 10.7554/eLife.29738Kuo 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):99-103. doi: 10.18383/j.tom.2018.00013Kuo 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):99-103. doi: 10.18383/j.tom.2018.00013Goodman 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. doi: 10.1016/j.bbi.2018.07.020Goodman 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. doi: 10.1016/j.bbi.2018.07.020Raper D., Louveau A., Kipnis J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 2016;39(9):581-586. doi: 10.1016/j.tins.2016.07.001Raper D., Louveau A., Kipnis J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 2016;39(9):581-586. doi: 10.1016/j.tins.2016.07.001

The authors declare that there are no conflicts of interest present.