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The Glymphatic System

Year 2024, Volume: 3 Issue: 3, 102 - 110, 01.10.2024
https://doi.org/10.59518/farabimedj.1420088

Abstract

The glymphatic system was named based on its similarity to the lymphatic system in peripheral tissue and the important role of glial aquaporin-4 channels in fluid transport. Although the lymphatic system in the human body was described towards the end of the eighteenth century, for many years the existence of a lymphatic system in the brain was ignored. Since the second half of the twentieth century, attempts have been made to explain the existence of a functional lymphatic system within the central nervous system. In recent experimental studies, the perivascular exchange movement of cerebrospinal fluid and intercellular fluid within the central nervous system was demonstrated by observing the path of a fluorescent dextrans tracer injected into the cisterna magna of the mouse, and it was suggested that this system should be called the "glymphatic" system. Recently, the mechanisms directing the glymphatic flow have been tried to be explained. The relationship of the glymphatic system with the cardiac and respiratory cycles as well as with vasodynamic changes, sleep and body posture-related changes has been demonstrated by experimental studies. In addition, in recent years, a large number of studies have been conducted on the relationship between the glymphatic system and many pathological conditions, diseases and syndromes such as subarachnoid hemorrhage, aging, small vessel disease and hypertension, Alzheimer's disease, Parkinsonism, depression and obesity and treatment options through the glymphatic system. The aim of this review is to introduce the glymphatic system, its historical development, its role in physiological and pathological mechanisms, the importance of the glymphatic system in medical imaging methods and treatment approaches.

References

  • Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The Glymphatic System: A beginner’s guide. Neurochem Res. 2015;40(12):2583-2599. doi:10.1007/s11064-015-1581-6
  • 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. doi:10.1126/scitranslmed.3003748
  • Di Matteo B, Tarabella V, Filardo G, et al. Art in Science: Giovanni Paolo Mascagni and the Art of Anatomy. Clinical Orthopaedics & Related Research. 2015;473(3):783-788. doi:10.1007/s11999-014-3909-y
  • Sandrone S, Moreno-Zambrano D, Kipnis J, van Gijn J. A (delayed) history of the brain lymphatic system. Nat Med. 2019;25(4):538-540. doi:10.1038/s41591-019-0417-3
  • Prineas JW. Multiple Sclerosis: Presence of Lymphatic Capillaries and Lymphoid Tissue in the Brain and Spinal Cord. Science. 1979;203(4385):1123-1125. doi:10.1126/science.424741
  • Schwalbe G. Der Arachnoidalraum ein Lymphraum und sein Zusammenhang mit dem Perichorioidalraum. Centralbl med Wiss. 1969;7:465-467.
  • Földi M, Gellért A, Kozma M, Poberai M, Zoltán OT, Csanda E. New contributions to the anatomical connections of the brain and the lymphatic system. Acta Anat (Basel). 1966;64(4):498-505. doi:10.1159/000142849
  • 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(1):47-63. doi:10.1016/0006-8993(85)91383-6
  • Louveau A, Harris TH, Kipnis J. Revisiting the Mechanisms of CNS Immune Privilege. Trends in Immunology. 2015;36(10):569-577. doi:10.1016/j.it.2015.08.006
  • Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337-341. doi:10.1038/nature14432
  • Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. Journal of Experimental Medicine. 2015;212(7):991-999. doi:10.1084/jem.20142290
  • Munk AS, Wang W, Bèchet NB, et al. PDGF-B is required for development of the Glymphatic System. Cell Rep. 2019;26(11):2955-2969.e3. doi:10.1016/j.celrep.2019.02.050
  • Antila S, Karaman S, Nurmi H, et al. Development and plasticity of meningeal lymphatic vessels. Journal of Experimental Medicine. 2017;214(12):3645-3667. doi:10.1084/jem.20170391
  • Gómez DG, DiBenedetto AT, Pavese AM, Firpo A, Hershan DB, Potts DG. Development of arachnoid villi and granulations in man. cells tissues organs. 1981;111(3):247-258. doi:10.1159/000145473
  • Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun. 2020;11(1):354. doi:10.1038/s41467-019-14195-x
  • Rasmussen MK, Mestre H, Nedergaard M. Fluid transport in the brain. Physiological Reviews. 2022;102(2):1025-1151. doi:10.1152/physrev.00031.2020
  • Mestre H, Tithof J, Du T, et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018;9(1):4878. doi:10.1038/s41467-018-07318-3
  • Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377. doi:10.1126/science.1241224
  • Hablitz LM, Vinitsky HS, Sun Q, et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv. 2019;5(2):eaav5447. doi:10.1126/sciadv.aav5447
  • Lee H, Xie L, Yu M, et al. The effect of body posture on brain glymphatic transport. J Neurosci. 2015;35(31):11034-11044. doi:10.1523/JNEUROSCI.1625-15.2015
  • Louveau A, Plog BA, 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
  • De Leon MJ, Li Y, Okamura N, et al. Cerebrospinal fluid clearance in alzheimer disease measured with dynamic PET. J Nucl Med. 2017;58(9):1471-1476. doi:10.2967/jnumed.116.187211
  • Johnston M, Zakharov A, Papaiconomou C, Salmasi G, Armstrong D. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res. 2004;1(1):2. doi:10.1186/1743-8454-1-2
  • Löwhagen P, Johansson BB, Nordborg C. The nasal route of cerebrospinal fluid drainage in man. A light–microscope study. Neuropathol Appl Neurobiol. 1994;20(6):543-550. doi:10.1111/j.1365-2990.1994.tb01008.x
  • Brierley JB, Field EJ. The connexions of the spinal sub-arachnoid space with the lymphatic system. J Anat. 1948;82(Pt 3):153-166.
  • Verma A, Hesterman JY, Chazen JL, et al. Intrathecal 99m Tc‐DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2020;12(1). doi:10.1002/dad2.12030
  • Dai Z, Yang Z, Chen X, et al. The aging of glymphatic system in human brain and its correlation with brain charts and neuropsychological functioning. Cerebral Cortex. Published online March 16, 2023:bhad086. doi:10.1093/cercor/bhad086
  • Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299-1309. doi:10.1172/JCI67677
  • Yang L, Kress BT, Weber HJ, et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. Journal of Translational Medicine. 2013;11(1):107. doi:10.1186/1479-5876-11-107
  • Goulay R, Flament J, Gauberti M, et al. Subarachnoid hemorrhage severely impairs brain parenchymal cerebrospinal fluid circulation in nonhuman primate. Stroke. 2017;48(8):2301-2305. doi:10.1161/STROKEAHA.117.017014
  • Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560(7717):185-191. doi:10.1038/s41586-018-0368-8
  • Perivascular (Virchow–Robin) spaces. Kastamonu Med J. Published online September 1, 2021:86-89. doi:10.51271/KMJ-0021
  • Sugai Y, Niino K, Shibata A, et al. Association between visualization of the perivascular space and morphological changes in the brain among the community-dwelling elderly. European Journal of Radiology. 2023;162:110792. doi:10.1016/j.ejrad.2023.110792
  • Venkat P, Chopp M, Zacharek A, et al. White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies. Neurobiology of Aging. 2017;50:96-106. doi:10.1016/j.neurobiolaging.2016.11.002
  • Viggiano D, Wagner CA, Martino G, et al. Mechanisms of cognitive dysfunction in CKD. Nat Rev Nephrol. 2020;16(8):452-469. doi:10.1038/s41581-020-0266-9
  • Gaberel T, Gakuba C, Goulay R, et al. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: A new target for fibrinolysis? Stroke. 2014;45(10):3092-3096. doi:10.1161/STROKEAHA.114.006617
  • Roberts RO, Christianson TJH, Kremers WK, et al. Association between olfactory dysfunction and amnestic mild cognitive impairment and alzheimer disease dementia. JAMA Neurol. 2016;73(1):93. doi:10.1001/jamaneurol.2015.2952
  • Chen HL, Chen PC, Lu CH, et al. Associations among cognitive functions, plasma DNA, and diffusion tensor image along the perivascular space (DTI-ALPS) in patients with parkinson’s disease. Lloret A, ed. Oxidative Medicine and Cellular Longevity. 2021;2021:1-10. doi:10.1155/2021/4034509
  • Ding XB, Wang XX, Xia DH, et al. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease. Nat Med. 2021;27(3):411-418. doi:10.1038/s41591-020-01198-1
  • Rajkowska G, Miguel-Hidalgo JJ. Glial pathology in major depressive disorder: An approach to investigate the coverage of blood vessels by astrocyte endfeet in human postmortem brain. In: Di Benedetto B, ed. Astrocytes. Vol 1938. Methods in Molecular Biology. Springer New York; 2019:247-254. doi:10.1007/978-1-4939-9068-9_17
  • Delle C, Cankar N, Digebjerg Holgersson C, et al. Long-term high-fat diet increases glymphatic activity in the hypothalamus in mice. Sci Rep. 2023;13:4137. doi:10.1038/s41598-023-30630-y
  • Lilius TO, Blomqvist K, Hauglund NL, et al. Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs. Journal of Controlled Release. 2019;304:29-38. doi:10.1016/j.jconrel.2019.05.005
  • Plog BA, Mestre H, Olveda GE, et al. Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI Insight. 2018;3(20):e120922. doi:10.1172/jci.insight.120922

Glenfatik Sistem

Year 2024, Volume: 3 Issue: 3, 102 - 110, 01.10.2024
https://doi.org/10.59518/farabimedj.1420088

Abstract

Glenfatik sistem, periferik dokudaki lenfatik sisteme benzerliğine ve glial aquaporin-4 kanallarının sıvı taşınmasındaki önemli rolüne dayalı olarak adlandırılmıştır. On sekizinci yüzyılın sonlarına doğru insan vücudundaki lenfatik sistem tanımlanmış olmasına rağmen uzun yıllar boyunca beyinde lenfatik sistem varlığı göz ardı edilmiştir. Yirminci yüzyılın ikinci yarısından itibaren merkezi sinir sistemi içinde fonksiyonel bir lenfatik sistemin olduğu açıklanmaya çalışılmıştır. Yakın dönemde yapılan deneysel çalışmalarda, farenin cisterna magna’sına enjekte edilen floresan desktrandan oluşan izleyicinin takip ettiği yol gözlemlenerek, merkezi sinir sistemi içinde beyin omurilik sıvısı ve hücreler arası sıvının perivasküler değişim hareketi gösterilmiş ve bu sistemin "glymphatic" yol olarak adlandırılmasını önerilmiştir. Son zamanlarda glenfatik akımı yönlendiren mekanizmalar açıklanmaya çalışılmıştır. Glenfatik sistemin kardiyak ve solunum siklus ile ilişkilsinin yanında vazodinamik değişiklikler, uyku ve vücut duruşuna bağlı değişikliklerle olan ilişkisi yapılan deneysel çalışmalarla gösterilmiştir. Bunun yanında son yıllarda subaraknoid kanama, yaşlanma, küçük damar hastalığı ve hipertansiyon, Alzheimer, Parkinsonizm, depresyon ve obezite gibi birçok patolojik durum, hastalık ve sendromlarda glenfatik sistem ile olan ilişkisi ve glenfatik sistem yoluyla tedavi seçenekleri üzerine oldukça fazla sayıda araştırma yapılmıştır. Bu derlememizin amacı, glenfatik sistemi tanıtmak, bu sistemin tarihsel gelişiminden başlayarak günümüze kadar süregelen gelişimini, fizyolojik ve patolojik mekanizmalardaki rolünü, tıbbi görüntüleme yöntemleri ve tedavi yaklaşımlarında glenfatik sistemin önemini belirtmektir.

References

  • Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The Glymphatic System: A beginner’s guide. Neurochem Res. 2015;40(12):2583-2599. doi:10.1007/s11064-015-1581-6
  • 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. doi:10.1126/scitranslmed.3003748
  • Di Matteo B, Tarabella V, Filardo G, et al. Art in Science: Giovanni Paolo Mascagni and the Art of Anatomy. Clinical Orthopaedics & Related Research. 2015;473(3):783-788. doi:10.1007/s11999-014-3909-y
  • Sandrone S, Moreno-Zambrano D, Kipnis J, van Gijn J. A (delayed) history of the brain lymphatic system. Nat Med. 2019;25(4):538-540. doi:10.1038/s41591-019-0417-3
  • Prineas JW. Multiple Sclerosis: Presence of Lymphatic Capillaries and Lymphoid Tissue in the Brain and Spinal Cord. Science. 1979;203(4385):1123-1125. doi:10.1126/science.424741
  • Schwalbe G. Der Arachnoidalraum ein Lymphraum und sein Zusammenhang mit dem Perichorioidalraum. Centralbl med Wiss. 1969;7:465-467.
  • Földi M, Gellért A, Kozma M, Poberai M, Zoltán OT, Csanda E. New contributions to the anatomical connections of the brain and the lymphatic system. Acta Anat (Basel). 1966;64(4):498-505. doi:10.1159/000142849
  • 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(1):47-63. doi:10.1016/0006-8993(85)91383-6
  • Louveau A, Harris TH, Kipnis J. Revisiting the Mechanisms of CNS Immune Privilege. Trends in Immunology. 2015;36(10):569-577. doi:10.1016/j.it.2015.08.006
  • Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337-341. doi:10.1038/nature14432
  • Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. Journal of Experimental Medicine. 2015;212(7):991-999. doi:10.1084/jem.20142290
  • Munk AS, Wang W, Bèchet NB, et al. PDGF-B is required for development of the Glymphatic System. Cell Rep. 2019;26(11):2955-2969.e3. doi:10.1016/j.celrep.2019.02.050
  • Antila S, Karaman S, Nurmi H, et al. Development and plasticity of meningeal lymphatic vessels. Journal of Experimental Medicine. 2017;214(12):3645-3667. doi:10.1084/jem.20170391
  • Gómez DG, DiBenedetto AT, Pavese AM, Firpo A, Hershan DB, Potts DG. Development of arachnoid villi and granulations in man. cells tissues organs. 1981;111(3):247-258. doi:10.1159/000145473
  • Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun. 2020;11(1):354. doi:10.1038/s41467-019-14195-x
  • Rasmussen MK, Mestre H, Nedergaard M. Fluid transport in the brain. Physiological Reviews. 2022;102(2):1025-1151. doi:10.1152/physrev.00031.2020
  • Mestre H, Tithof J, Du T, et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018;9(1):4878. doi:10.1038/s41467-018-07318-3
  • Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377. doi:10.1126/science.1241224
  • Hablitz LM, Vinitsky HS, Sun Q, et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv. 2019;5(2):eaav5447. doi:10.1126/sciadv.aav5447
  • Lee H, Xie L, Yu M, et al. The effect of body posture on brain glymphatic transport. J Neurosci. 2015;35(31):11034-11044. doi:10.1523/JNEUROSCI.1625-15.2015
  • Louveau A, Plog BA, 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
  • De Leon MJ, Li Y, Okamura N, et al. Cerebrospinal fluid clearance in alzheimer disease measured with dynamic PET. J Nucl Med. 2017;58(9):1471-1476. doi:10.2967/jnumed.116.187211
  • Johnston M, Zakharov A, Papaiconomou C, Salmasi G, Armstrong D. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res. 2004;1(1):2. doi:10.1186/1743-8454-1-2
  • Löwhagen P, Johansson BB, Nordborg C. The nasal route of cerebrospinal fluid drainage in man. A light–microscope study. Neuropathol Appl Neurobiol. 1994;20(6):543-550. doi:10.1111/j.1365-2990.1994.tb01008.x
  • Brierley JB, Field EJ. The connexions of the spinal sub-arachnoid space with the lymphatic system. J Anat. 1948;82(Pt 3):153-166.
  • Verma A, Hesterman JY, Chazen JL, et al. Intrathecal 99m Tc‐DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2020;12(1). doi:10.1002/dad2.12030
  • Dai Z, Yang Z, Chen X, et al. The aging of glymphatic system in human brain and its correlation with brain charts and neuropsychological functioning. Cerebral Cortex. Published online March 16, 2023:bhad086. doi:10.1093/cercor/bhad086
  • Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299-1309. doi:10.1172/JCI67677
  • Yang L, Kress BT, Weber HJ, et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. Journal of Translational Medicine. 2013;11(1):107. doi:10.1186/1479-5876-11-107
  • Goulay R, Flament J, Gauberti M, et al. Subarachnoid hemorrhage severely impairs brain parenchymal cerebrospinal fluid circulation in nonhuman primate. Stroke. 2017;48(8):2301-2305. doi:10.1161/STROKEAHA.117.017014
  • Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560(7717):185-191. doi:10.1038/s41586-018-0368-8
  • Perivascular (Virchow–Robin) spaces. Kastamonu Med J. Published online September 1, 2021:86-89. doi:10.51271/KMJ-0021
  • Sugai Y, Niino K, Shibata A, et al. Association between visualization of the perivascular space and morphological changes in the brain among the community-dwelling elderly. European Journal of Radiology. 2023;162:110792. doi:10.1016/j.ejrad.2023.110792
  • Venkat P, Chopp M, Zacharek A, et al. White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies. Neurobiology of Aging. 2017;50:96-106. doi:10.1016/j.neurobiolaging.2016.11.002
  • Viggiano D, Wagner CA, Martino G, et al. Mechanisms of cognitive dysfunction in CKD. Nat Rev Nephrol. 2020;16(8):452-469. doi:10.1038/s41581-020-0266-9
  • Gaberel T, Gakuba C, Goulay R, et al. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: A new target for fibrinolysis? Stroke. 2014;45(10):3092-3096. doi:10.1161/STROKEAHA.114.006617
  • Roberts RO, Christianson TJH, Kremers WK, et al. Association between olfactory dysfunction and amnestic mild cognitive impairment and alzheimer disease dementia. JAMA Neurol. 2016;73(1):93. doi:10.1001/jamaneurol.2015.2952
  • Chen HL, Chen PC, Lu CH, et al. Associations among cognitive functions, plasma DNA, and diffusion tensor image along the perivascular space (DTI-ALPS) in patients with parkinson’s disease. Lloret A, ed. Oxidative Medicine and Cellular Longevity. 2021;2021:1-10. doi:10.1155/2021/4034509
  • Ding XB, Wang XX, Xia DH, et al. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease. Nat Med. 2021;27(3):411-418. doi:10.1038/s41591-020-01198-1
  • Rajkowska G, Miguel-Hidalgo JJ. Glial pathology in major depressive disorder: An approach to investigate the coverage of blood vessels by astrocyte endfeet in human postmortem brain. In: Di Benedetto B, ed. Astrocytes. Vol 1938. Methods in Molecular Biology. Springer New York; 2019:247-254. doi:10.1007/978-1-4939-9068-9_17
  • Delle C, Cankar N, Digebjerg Holgersson C, et al. Long-term high-fat diet increases glymphatic activity in the hypothalamus in mice. Sci Rep. 2023;13:4137. doi:10.1038/s41598-023-30630-y
  • Lilius TO, Blomqvist K, Hauglund NL, et al. Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs. Journal of Controlled Release. 2019;304:29-38. doi:10.1016/j.jconrel.2019.05.005
  • Plog BA, Mestre H, Olveda GE, et al. Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI Insight. 2018;3(20):e120922. doi:10.1172/jci.insight.120922
There are 43 citations in total.

Details

Primary Language Turkish
Subjects Health Services and Systems (Other)
Journal Section Reviews
Authors

İlknur Çöllü 0000-0003-1605-6327

Ozan Turamanlar 0000-0002-0785-483X

Publication Date October 1, 2024
Submission Date January 17, 2024
Acceptance Date May 17, 2024
Published in Issue Year 2024 Volume: 3 Issue: 3

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AMA Çöllü İ, Turamanlar O. Glenfatik Sistem. Farabi Med J. October 2024;3(3):102-110. doi:10.59518/farabimedj.1420088

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