CC BY-NC-ND 4.0 · Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery 2018; 37(03): 190-195
DOI: 10.1055/s-0038-1667052
Review Article | Artigo de Revisão
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

The Glymphatic System: A Review

O sistema glinfático: revisão
Louise Makarem Oliveira
1   Faculty of Medicine, Universidade Federal do Amazonas, Manaus, AM, Brazil
Eberval Gadelha Figueiredo
2   Department of Neurosurgery, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
Carlos Michel Albuquerque Peres
3   Neurosurgery Service, Hospital Santa Julia, Manaus, AM, Brazil
› Author Affiliations
Further Information

Publication History

28 January 2018

11 June 2018

Publication Date:
27 July 2018 (online)


The brain represents ∼ 2% of the adult body mass; conversely, it is responsible for 20% to 25% of the glucose and 20% of the oxygen consumption, receiving 15% of the cardiac output. This substantial metabolic rate is associated with a significant production of biological debris, which is potentially toxic. Therefore, a complex and efficient clearance system is required to prevent the accumulation of byproducts and ensure optimal function. However, until today, there is little knowledge about this topic. The glymphatic system, also known as perivascular pathway, is a recently described glial-dependent network that is responsible for the clearance of metabolites from the central nervous system (CNS), playing a role equivalent to the one played by the lymphatic vessels present in other organs. Studies have demonstrated that the glymphatic pathway has a paramount role in protein homeostasis, and that the malfunction of this system may be related to the development of neurodegenerative disorders such as Alzheimer disease and normal pressure hydrocephalus. They also showed that body posture, exercise and the state of consciousness influence the glymphatic transport. In this context, the understanding of this clearance system could not only clarify the pathophysiology of several diseases, but also contribute to future therapeutic interventions. In the present article, we will evaluate the glymphatic pathway, focusing on the factors that regulate its flow, as well as on its role in CNS physiology and in disease initiation and progression, including dementia, hydrocephalus, glaucoma and traumatic brain injury. Ultimately, this review also aims to encourage further research on novel therapeutic targets.


O cérebro representa cerca de 2% da massa corporal de um adulto; contrariamente, é responsável por entre 20% e 25% do consumo de glicose, e 20% do consumo de oxigênio, respectivamente. Essa taxa metabólica substancial está associada à produção elevada de detritos biológicos, potencialmente tóxicos. Desse modo, um sistema de depuração complexo e eficiente faz-se necessário para prevenir o acúmulo de subprodutos e assegurar função ideal. No entanto, até os dias atuais, há pouco conhecimento acerca desse tópico. O sistema glinfático, também conhecido como via perivascular, é uma rede dependente de células da glia recentemente descrita, que é responsável pela depuração de metabólitos do sistema nervoso central (SNC), à semelhança dos vasos linfáticos presentes em outros órgãos. Estudos demonstraram que a via glinfática tem um papel fundamental na homeostase proteica, podendo sua disfunção ser associada ao desenvolvimento de transtornos neurodegenerativos, como a doença de Alzheimer e a hidrocefalia de pressão normal. Do mesmo modo, esses estudos demonstraram que a postura corporal, o exercício e o estado de consciência influenciam no transporte glinfático. Nesse contexto, o entendimento do sistema de depuração cerebral pode não só esclarecer a fisiopatologia de diversas doenças, como também contribuir para intervenções futuras. Neste artigo, revisaremos a via glinfática, focando em fatores que regulam o seu fluxo, e em seu papel na fisiologia do SNC e na iniciação e progressão de doenças, incluindo demência, hidrocefalia de pressão normal, glaucoma e traumatismo cranioencefálico. Por fim, esta revisão também visa estimular pesquisas sobre novos alvos terapêuticos.

  • References

  • 1 Nedergaard M. Neuroscience. Garbage truck of the brain. Science 2013; 340 (6140): 1529-1530
  • 2 Benveniste H, Lee H, Volkow ND. The Glymphatic Pathway. Neuroscientist 2017; •••: 1073858417691030
  • 3 Nedergaard M, Goldman SA. Brain Drain. Sci Am 2016; 314 (03) 44-49
  • 4 Cserr HF, Cooper DN, Milhorat TH. 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
  • 5 Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA. 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 (01) 47-63
  • 6 Iliff JJ, Chen MJ, Plog BA. , et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 2014; 34 (49) 16180-16193
  • 7 Iliff JJ, Wang M, Liao Y. , et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 2012; 4 (147) 147ra111
  • 8 Murlidharan G, Crowther A, Reardon RA, Song J, Asokan A. Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain. JCI Insight 2016; 1 (14) e88034
  • 9 Bradley Jr WG. CSF Flow in the Brain in the Context of Normal Pressure Hydrocephalus. AJNR Am J Neuroradiol 2015; 36 (05) 831-838
  • 10 Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014; 69 (Suppl. 01) S4-S9
  • 11 Di Benedetto S, Müller L, Wenger E, Düzel S, Pawelec G. Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehav Rev 2017; 75: 114-128
  • 12 Barrientos RM, Kitt MM, Watkins LR, Maier SF. Neuroinflammation in the normal aging hippocampus. Neuroscience 2015; 309: 84-99
  • 13 Ren H, Luo C, Feng Y. , et al. Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system. FASEB J 2017; 31 (01) 282-293
  • 14 Raha AA, Henderson JW, Stott SR. , et al. Neuroprotective Effect of TREM-2 in Aging and Alzheimer's Disease Model. J Alzheimers Dis 2017; 55 (01) 199-217
  • 15 Eckert A, Hauptmann S, Scherping I. , et al. Oligomeric and fibrillar species of beta-amyloid (A beta 42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med (Berl) 2008; 86 (11) 1255-1267
  • 16 Rijal Upadhaya A, Capetillo-Zarate E, Kosterin I. , et al. Dispersible amyloid β-protein oligomers, protofibrils, and fibrils represent diffusible but not soluble aggregates: their role in neurodegeneration in amyloid precursor protein (APP) transgenic mice. Neurobiol Aging 2012; 33 (11) 2641-2660
  • 17 Iliff JJ, Wang M, Zeppenfeld DM. , et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 2013; 33 (46) 18190-18199
  • 18 Kress BT, Iliff JJ, Xia M. , et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 2014; 76 (06) 845-861
  • 19 Xie L, Kang H, Xu Q. , et al. Sleep drives metabolite clearance from the adult brain. Science 2013; 342 (6156): 373-377
  • 20 Malow BA. Sleep deprivation and epilepsy. Epilepsy Curr 2004; 4 (05) 193-195
  • 21 Stickgold R. Neuroscience: a memory boost while you sleep. Nature 2006; 444 (7119): 559-560
  • 22 Schneider GH, von Helden GH, Franke R, Lanksch WR, Unterberg A. Influence of body position on jugular venous oxygen saturation, intracranial pressure and cerebral perfusion pressure. Acta Neurochir Suppl (Wien) 1993; 59: 107-112
  • 23 Brosnan RJ, Steffey EP, LeCouteur RA, Imai A, Farver TB, Kortz GD. Effects of body position on intracranial and cerebral perfusion pressures in isoflurane-anesthetized horses. J Appl Physiol (1985) 2002; 92 (06) 2542-2546
  • 24 Lee H, Xie L, Yu M. , et al. The Effect of Body Posture on Brain Glymphatic Transport. J Neurosci 2015; 35 (31) 11034-11044
  • 25 He XF, Liu DX, Zhang Q. , et al. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice. Front Mol Neurosci 2017; 10: 144
  • 26 Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011; 7 (03) 137-152
  • 27 Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014; 71 (04) 505-508
  • 28 Honig LS, Vellas B, Woodward M. , et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med 2018; 378 (04) 321-330
  • 29 Eide PK, Sorteberg W. Diagnostic intracranial pressure monitoring and surgical management in idiopathic normal pressure hydrocephalus: a 6-year review of 214 patients. Neurosurgery 2010; 66 (01) 80-91
  • 30 Cabral D, Beach TG, Vedders L. , et al. Frequency of Alzheimer's disease pathology at autopsy in patients with clinical normal pressure hydrocephalus. Alzheimers Dement 2011; 7 (05) 509-513
  • 31 Williams MA. Comment: the trouble with “n” in normal-pressure hydrocephalus. Neurology 2014; 82 (15) 1350
  • 32 Williams MA, Malm J. Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus. Continuum (Minneap Minn) 2016; 22 (2 Dementia): 579-599
  • 33 Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 2017; 140 (10) 2691-2705
  • 34 Iliff JJ, Lee H, Yu M. , et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 2013; 123 (03) 1299-1309
  • 35 Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open 2015; 4 (11) 2058460115609635
  • 36 Wostyn P, De Groot V, Van Dam D, Audenaert K, De Deyn PP. Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma. Am J Ophthalmol 2013; 156 (01) 5-14.e2
  • 37 Wostyn P, Van Dam D, Audenaert K, Killer HE, De Deyn PP, De Groot V. A new glaucoma hypothesis: a role of glymphatic system dysfunction. Fluids Barriers CNS 2015; 12: 16
  • 38 Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci 2008; 49 (12) 5412-5418
  • 39 Ren R, Jonas JB, Tian G. , et al. Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology 2010; 117 (02) 259-266
  • 40 Killer HE, Miller NR, Flammer J. , et al. Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol 2012; 96 (04) 544-548
  • 41 McKinnon SJ, Lehman DM, Kerrigan-Baumrind LA. , et al. Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci 2002; 43 (04) 1077-1087
  • 42 McKinnon SJ. Glaucoma: ocular Alzheimer's disease?. Front Biosci 2003; 8: s1140-s1156
  • 43 Guo L, Salt TE, Luong V. , et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci U S A 2007; 104 (33) 13444-13449
  • 44 Yoneda S, Hara H, Hirata A, Fukushima M, Inomata Y, Tanihara H. Vitreous fluid levels of beta-amyloid((1-42)) and tau in patients with retinal diseases. Jpn J Ophthalmol 2005; 49 (02) 106-108
  • 45 McCaa CS. The eye and visual nervous system: anatomy, physiology and toxicology. Environ Health Perspect 1982; 44: 1-8
  • 46 Wostyn P, De Groot V, Van Dam D, Audenaert K, Killer HE, De Deyn PP. The Glymphatic Hypothesis of Glaucoma: A Unifying Concept Incorporating Vascular, Biomechanical, and Biochemical Aspects of the Disease. BioMed Res Int 2017; 2017: 5123148
  • 47 Guo Z, Cupples LA, Kurz A. , et al. Head injury and the risk of AD in the MIRAGE study. Neurology 2000; 54 (06) 1316-1323
  • 48 Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron 2011; 70 (03) 410-426
  • 49 Magnoni S, Esparza TJ, Conte V. , et al. Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain 2012; 135 (Pt 4): 1268-1280
  • 50 Tsitsopoulos PP, Marklund N. Amyloid-β Peptides and Tau Protein as Biomarkers in Cerebrospinal and Interstitial Fluid Following Traumatic Brain Injury: A Review of Experimental and Clinical Studies. Front Neurol 2013; 4: 79