Current Understanding of Central Nervous System Drainage Systems: Implications in the Context of Neurodegenerative Diseases

Author(s): Vladimir N. Nikolenko, Marine V. Oganesyan, Angela D. Vovkogon, Arina T. Nikitina, Ekaterina A. Sozonova, Valentina A. Kudryashova, Negoria A. Rizaeva, Ricardo Cabezas, Marco Avila-Rodriguez, Margarita E. Neganova, Liudmila M. Mikhaleva, Sergey O. Bachurin, Siva G. Somasundaram, Cecil E. Kirkland, Vadim V. Tarasov, Gjumrakch Aliev*

Journal Name: Current Neuropharmacology

Volume 18 , Issue 11 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Until recently, it was thought that there were no lymphatic vessels in the central nervous system (CNS). Therefore, all metabolic processes were assumed to take place only in the circulation of the cerebrospinal fluid (CSF) and through the blood-brain barrier’s (BBB), which regulate ion transport and ensure the functioning of the CNS. However, recent findings yield a new perspective: There is an exchange of CSF with interstitial fluid (ISF), which is drained to the paravenous space and reaches lymphatic nodes at the end. This circulation is known as the glymphatic system. The glymphatic system is an extensive network of meningeal lymphatic vessels (MLV) in the basal area of the skull that provides another path for waste products from CNS to reach the bloodstream. MLV develop postnatally, initially appearing around the foramina in the basal part of the skull and the spinal cord, thereafter sprouting along the skull’s blood vessels and spinal nerves in various areas of the meninges. VEGF-C protein (vascular endothelial growth factor), expressed mainly by vascular smooth cells, plays an important role in the development of the MLV. The regenerative potential and plasticity of MLV and the novel discoveries related to CNS drainage offer potential for the treatment of neurodegenerative diseases such as dementia, hydrocephalus, stroke, multiple sclerosis, and Alzheimer disease (AD). Herein, we present an overview of the structure and function of the glymphatic system and MLV, and their potential involvement in the pathology and progression of neurodegenerative diseases.

Keywords: Glymphatic system, meningeal lymphatic vessels (MLV), cerebrospinal fluid (CSF), blood-brain barrier (BBB), functional anatomy, interstitial fluid of the brain, aquaporin-4, clinical perspective, neurodegenerative disorders.

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.
[] [PMID: 26030524]
Bradbury, M.W.B.; Cole, D.F. The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour. J. Physiol., 1980, 299, 353-365.
[] [PMID: 6155466]
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.
[] [PMID: 26077718]
Raper, D.; Louveau, A.; Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci., 2016, 39(9), 581-586.
[] [PMID: 27460561]
Plog, B.A.; Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol., 2018, 13, 379-394.
[] [PMID: 29195051]
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.
[] [PMID: 28862640]
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.
[PMID: 2396537]
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 β. Sci. Transl. Med., 2012, 4(147),147ra111.
[]] [PMID: 22896675]
Sakka, L.; Chazal, J. The meninges, an anatomical point of view. Morphologie, 2005, 89(284), 35-42.
[] [PMID: 15943079]
Antila, S.; Karaman, S.; Nurmi, H.; Airavaara, M.; Voutilainen, M.H.; Mathivet, T.; Chilov, D.; Li, Z.; Koppinen, T.; Park, J-H.; Fang, S.; Aspelund, A.; Saarma, M.; Eichmann, A.; Thomas, J-L.; Alitalo, K. Development and plasticity of meningeal lymphatic vessels. J. Exp. Med., 2017, 214(12), 3645-3667.
[] [PMID: 29141865]
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.
[] [PMID: 26245965]
Limanaqi, F.; Biagioni, F.; Busceti, C.L.; Ryskalin, L.; Soldani, P.; Frati, A.; Fornai, F. Cell clearing systems bridging neuro-immunity and synaptic plasticity. Int. J. Mol. Sci., 2019, 20(9), 2197.
[] [PMID: 31060234]
Bower, N.I.; Hogan, B.M. Brain drains: new insights into brain clearance pathways from lymphatic biology. J. Mol. Med. (Berl.), 2018, 96(5), 383-390.
[] [PMID: 29610928]
Da Mesquita, S.; Louveau, A.; Vaccari, A.; Smirnov, I.; Cornelison, R.C.; Kingsmore, K.M.; Contarino, C.; Onengut-Gumuscu, 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.
[] [PMID: 30046111]
Verheggen, I.C.M.; Van Boxtel, M.P.J.; Verhey, F.R.J.; Jansen, J.F.A.; Backes, W.H. Interaction between blood-brain barrier and glymphatic system in solute clearance. Neurosci. Biobehav. Rev., 2018, 90, 26-33.
[] [PMID: 29608988]
Ramanan, V.K.; Risacher, S.L.; Nho, K.; Kim, S.; Shen, L.; McDonald, B.C.; Yoder, K.K.; Hutchins, G.D.; West, J.D.; Tallman, E.F.; Gao, S.; Foroud, T.M.; Farlow, M.R.; De Jager, P.L.; Bennett, D.A.; Aisen, P.S.; Petersen, R.C.; Jack, C.R., Jr; Toga, A.W.; Green, R.C.; Jagust, W.J.; Weiner, M.W.; Saykin, A.J. Alzheimer’s disease neuroimaging initiative (adni). gwas of longitudinal amyloid accumulation on 18f-florbetapir pet in alzheimer’s disease implicates microglial activation gene IL1RAP. Brain, 2015, 138(Pt 10), 3076-3088.
[] [PMID: 26268530]
Ehsan, Shokri-Kojori Gene-Jack, W.; Corinde, E. W., Sukru, B, Demiral.; Min, G.; Sung, W. K.; Elsa, L.; Veronica, R.; Amna, Zehra.; Clara, F.; Gregg, M.; Peter, M.; Tansha, S.; Susan, De Santi.; Dardo, T.; Helene, B.; and Nora, D. V. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl. Acad. Sci. USA, 2018, 115, 4483-4488.
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. J., 1985, 326, 47-63.
Benveniste, H.; Lee, H.; Volkow, N.D. The glymphatic pathway: waste removal from the cns via cerebrospinal fluid transport. Neuroscientist, 2017, 23(5), 454-465.
[] [PMID: 28466758]
Bucchieri, F.; Farina, F.; Zummo, G.; Cappello, F. Lymphatic vessels of the dura mater: a new discovery? J. Anat., 2015, 227(5), 702-703.
[] [PMID: 26383824]
Zou, W.; Pu, T.; Feng, W.; Lu, M.; Zheng, Y.; Du, R.; Xiao, M.; Hu, G. Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein. Transl. Neurodegener., 2019, 8, 7.
[] [PMID: 30867902]
Cao, X.; Xu, H.; Feng, W.; Su, D.; Xiao, M. Deletion of aquaporin-4 aggravates brain pathology after blocking of the meningeal lymphatic drainage. Brain Res. Bull., 2018, 143, 83-96.
[] [PMID: 30347264]
Kerjaschki, D. The lymphatic vasculature revisited. J. Clin. Invest., 2014, 124(3), 874-877.
[] [PMID: 24590271]
Mader, S.; Brimberg, L. Aquaporin-4 Water channel in the brain and its implication for health and disease. Cells, 2019, 8(2), 90.
[] [PMID: 30691235]
Hui, F.K. Clearing your mind: a glymphatic system? World Neurosurg., 2015, 83(5), 715-717.
[] [PMID: 25818892]
Roth, C.; Stitz, H.; Roth, C.; Ferbert, A.; Deinsberger, W.; Pahl, R.; Engel, H.; Kleffmann, J. Craniocervical manual lymphatic drainage and its impact on intracranial pressure - a pilot study. Eur. J. Neurol., 2016, 23(9), 1441-1446.
[] [PMID: 27238738]
Brightman, M. Ultrastructure of brain endothelium. Physiology and Pharmacology of the Blood-Brain Barrier; Bradbury, M.W.B., Ed.; Springer-Verlag: Berlin, Heidelberg, 1992, pp. 1-22.
Nagelhus, E.A.; Ottersen, O.P. Physiological roles of aquaporin-4 in brain. Physiol. Rev., 2013, 93(4), 1543-1562.
[] [PMID: 24137016]
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.
[] [PMID: 25471560]
Louveau, A.; Da Mesquita, S.; Kipnis, J. Lymphatics in neurological disorders: A neuro-lymphovascular component of multiple sclerosis and Alzheimer’s disease? Neuron, 2016, 91(5), 957-973.
[] [PMID: 27608759]
Papadopoulos, M.C.; Verkman, A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci., 2013, 14(4), 265-277.
[] [PMID: 23481483]
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.
[] [PMID: 24227727]
Thomas, J-L.; Jacob, L.; Boisserand, L. [Lymphatic system in central nervous system] Med. Sci. (Paris), 2019, 35(1), 55-61.
[] [PMID: 30672459]
Herz, J.; Louveau, A.; Da Mesquita, S.; Kipnis, J. Morphological and functional analysis of cns-associated lymphatics. Methods Mol. Biol., 2018, 1846, 141-151.
[] [PMID: 30242757]
Hägerling, R.; Pollmann, C.; Andreas, M.; Schmidt, C.; Nurmi, H.; Adams, R.H.; Alitalo, K.; Andresen, V.; Schulte-Merker, S.; Kiefer, F. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J., 2013, 32(5), 629-644.
[] [PMID: 23299940]
Dimana, O. M.; Joseph, M.; Rutkowski, J.; Brandon, D.; Witold, K.; Jacqueline, D. S.; Melody, A. S. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res., 2010, 106, 920-931.
Jordan, N. N.; Qingguang, Z.; David, C.; Amanda, C.; Timothy, M.R.; Patrick, J. D. Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate. eLife, 2019, 8,e44278.
Maloveska, 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.
[] [PMID: 29619904]
Morfoisse, F.; Noel, A. Lymphatic and blood systems: Identical or fraternal twins? Int. J. Biochem. Cell Biol., 2019, 114105562
[] [PMID: 31278994]
Oliver, G. Lymphatic vasculature development. Nat. Rev. Immunol., 2004, 4(1), 35-45.
[] [PMID: 14704766]
Detry, B.; Erpicum, C.; Paupert, J.; Blacher, S.; Maillard, C.; Bruyère, F.; Pendeville, H.; Remacle, T.; Lambert, V.; Balsat, C.; Ormenese, S.; Lamaye, F.; Janssens, E.; Moons, L.; Cataldo, D.; Kridelka, F.; Carmeliet, P.; Thiry, M.; Foidart, J-M.; Struman, I.; Noël, A. Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase. Blood, 2012, 119(21), 5048-5056.
[] [PMID: 22490679]
Rezaei, M.; Hashemi, M.; Sanaei, S.; Mashhadi, M.A.; Taheri, M. Association between vascular endothelial growth factor gene polymorphisms with breast cancer risk in an iranian population. Breast Cancer (Auckl.), 2016, 10, 85-91.
[] [PMID: 27398026]
Castro Dias, M.; Mapunda, J.A.; Vladymyrov, M.; Engelhardt, B. Structure and junctional complexes of endothelial, epithelial and glial brain barriers. Int. J. Mol. Sci., 2019, 20(21),E5372.
[]] [PMID: 31671721]
Ikeshima-Kataoka, H. Neuroimmunological implications of AQP4 in astrocytes. Int. J. Mol. Sci., 2016, 17(8), 1306.
[] [PMID: 27517922]
Wong, H.L.; Jin, G.; Cao, R.; Zhang, S.; Cao, Y.; Zhou, Z. MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. Nat. Commun., 2016, 7, 10824.
[] [PMID: 26926389]
Levet, S.; Ciais, D.; Merdzhanova, G.; Mallet, C.; Zimmers, T.A.; Lee, S.J.; Navarro, F.P.; Texier, I.; Feige, J.J.; Bailly, S.; Vittet, D. Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood, 2013, 122(4), 598-607.
[] [PMID: 23741013]
Baluk, P.; Fuxe, J.; Hashizume, H.; Romano, T.; Lashnits, E.; Butz, S.; Vestweber, D.; Corada, M.; Molendini, C.; Dejana, E.; McDonald, D.M. Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med., 2007, 204(10), 2349-2362.
[] [PMID: 17846148]
Johanson, C.; Flaherty, S.; Duncan, J. Aging rat brain: A model for analyzing interactions among CSF dynamics, ventriculomegaly and the beta-amyloid retention of Alzheimer’s disease. Cerebrospinal Fluid Res., 2005, 2, S6.
Demiral, Ş.B.; Tomasi, D.; Sarlls, J.; Lee, H.; Wiers, C.E.; Zehra, A.; Srivastava, T.; Ke, K.; Shokri-Kojori, E.; Freeman, C.R.; Lindgren, E.; Ramirez, V.; Miller, G.; Bandettini, P.; Horovitz, S.; Wang, G-J.; Benveniste, H.; Volkow, N.D. Apparent diffusion coefficient changes in human brain during sleep - Does it inform on the existence of a glymphatic system? Neuroimage, 2019, 185, 263-273.
[] [PMID: 30342236]
Elvsåshagen, T.; Mutsaerts, H.J.; Zak, N.; Norbom, L.B.; Quraishi, S.H.; Pedersen, P.Ø.; Malt, U.F.; Westlye, L.T.; van Someren, E.J.; Bjørnerud, A.; Groote, I.R. Cerebral blood flow changes after a day of wake, sleep, and sleep deprivation. Neuroimage, 2019, 186, 497-509.
[] [PMID: 30471387]
Bernardi, G.; Cecchetti, L.; Siclari, F.; Buchmann, A.; Yu, X.; Handjaras, G.; Bellesi, M.; Ricciardi, E.; Kecskemeti, S.R.; Riedner, B.A.; Alexander, A.L.; Benca, R.M.; Ghilardi, M.F.; Pietrini, P.; Cirelli, C.; Tononi, G. Sleep reverts changes in human gray and white matter caused by wake-dependent training. Neuroimage, 2016, 129, 367-377.
[] [PMID: 26812659]
Kim, Y-K.; Nam, K.I.; Song, J. The Glymphatic System in Diabetes-Induced Dementia. Front. Neurol., 2018, 9, 867.
[] [PMID: 30429819]
Veening, J.G.; Barendregt, H.P. The regulation of brain states by neuroactive substances distributed via the cerebrospinal fluid; a review. Cerebrospinal Fluid Res., 2010, 7, 1.
[] [PMID: 20157443]
Goldmann, J.; Kwidzinski, E.; Brandt, C.; Mahlo, J.; Richter, D.; Bechmann, I. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J. Leukoc. Biol., 2006, 80(4), 797-801.
[] [PMID: 16885505]
Fitzner, D.; Schnaars, M.; van Rossum, D.; Krishnamoorthy, G.; Dibaj, P.; Bakhti, M.; Regen, T.; Hanisch, U-K.; Simons, M. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J. Cell Sci., 2011, 124(Pt 3), 447-458.
[] [PMID: 21242314]
Struckhoff, G Coculture of meningeal and astrocytic cells – a model for the formation of the glial limiting membrane Int J Devl Neurosci, 1995, 13, 595-606.
Karman, J.; Ling, C.; Sandor, M.; Fabry, Z. Initiation of immune responses in brain is promoted by local dendritic cells. J. Immunol., 2004, 173(4), 2353-2361.
[] [PMID: 15294948]
Noé, F.M.; Marchi, N. Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link? Epilepsia Open, 2019, 4(1), 30-39.
[] [PMID: 30868113]
Peng, W.; Achariyar, T.M.; Li, B.; Liao, Y.; Mestre, H.; Hitomi, E.; Regan, S.; Kasper, T.; Peng, S.; Ding, F.; Benveniste, H.; Nedergaard, M.; Deane, R. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol. Dis., 2016, 93, 215-225.
[] [PMID: 27234656]
Ludewig, P.; Winneberger, J.; Magnus, T. The cerebral endothelial cell as a key regulator of inflammatory processes in sterile inflammation. J. Neuroimmunol., 2019, 326, 38-44.
[] [PMID: 30472304]
Kim, J.H.; Kang, D.S.; Kim, J.H.; Kong, M.H.; Song, K.Y. Chronic subdural hematoma treated by small or large craniotomy with membranectomy as the initial treatment. J. Korean Neurosurg. Soc., 2011, 50(2), 103-108.
[] [PMID: 22053228]
Sharon, L.Y.; Wai Hoe, N.G. ‘Subarachnoid cyst’ after evacuation of chronic subdural hematoma: Case report of an unusual postoperative morbidity. Asian J. Neurosurg., 2016, 11(3), 316.
[] [PMID: 27366276]
Modesti, L.M.; Hodge, C.J.; Barnwell, M.L. Intracerebral hematoma after evacuation of chronic extracerebral fluid collections. Neurosurgery, 1982, 10(6 Pt 1), 689-693.
[] [PMID: 7110541]
Iliff, J.J.; Goldman, S.A.; Nedergaard, M. Implications of the discovery of brain lymphatic pathways. Lancet Neurol., 2015, 14(10), 977-979.
[] [PMID: 26376966]
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.
[] [PMID: 25947369]
Molly, J. Sullan, Breton M. Asken, Michael S. Jaffee, Steven T. De Kosky, Russell M. Bauer. Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy. Neurosci. Biobehav. Rev., 2018, 84, 316-324.
Chomicki, A.; Sakka, L.; Avan, P.; Khalil, T.; Lemaire, J.J.; Chazal, J. Derivation of cerebrospinal fluid: consequences on inner ear biomechanics in adult patients with chronic hydrocephalus. Neurochirurgie, 2007, 53(4), 265-271.
[] [PMID: 17559890]
Mestre, H.; Kostrikov, S.; Mehta, R.I.; Nedergaard, M. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin. Sci. , 2017, 131(17), 2257-2274.
Giammattei, L.; Messerer, M.; Daniel, R.T. Contribution of glymphatic system in pathogenesis of secondary brain injury and its modulation. World Neurosurg., 2018, 117, 473-474.
[] [PMID: 30149434]
Catala, M. Embryonic and fetal development of structures associated with the cerebro-spinal fluid in man and other species. Part I: The ventricular system, meninges and choroid plexuses. Arch. Anat. Cytol. Pathol., 1998, 46(3), 153-169.
[PMID: 9754371]
Silver, I.; Li, B.; Szalai, J.; Johnston, M. Relationship between intracranial pressure and cervical lymphatic pressure and flow rates in sheep. Am. J. Physiol., 1999, 277(6), R1712-R1717.
[PMID: 10600918]
Pollay, M. The function and structure of the cerebrospinal fluid outflow system. Cerebrospinal Fluid Res., 2010, 7, 9.
[] [PMID: 20565964]
Hsu, M.; Rayasam, A.; Kijak, J.A.; Choi, Y.H.; Harding, J.S.; Marcus, S.A.; Karpus, W.J.; Sandor, M.; Fabry, Z. Neuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells. Nat. Commun., 2019, 10(1), 229.
[] [PMID: 30651548]
Bordon, Y. Neuroimmunology: A brain drain. Nat. Rev. Immunol., 2015, 15(7), 404.
[] [PMID: 26089284]
Cserr, H.F. Physiology of the choroid plexus. Physiol. Rev., 1971, 51(2), 273-311.
[] [PMID: 4930496]
Hladky, 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), 26.
[] [PMID: 25678956]
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. Ann. Neurol., 2014, 76(6), 845-861.
[] [PMID: 25204284]
Benjamin, A. Plo. The glymphatic system in CNS health and disease: past, present and future. Annu. Rev. Pathol., 2018, 13, 379-394.
[] [PMID: 29195051]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 12 November, 2019
Page: [1054 - 1063]
Pages: 10
DOI: 10.2174/1570159X17666191113103850
Price: $65

Article Metrics

PDF: 55