I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences65208710.31857/S0044467724030024ОБЗОРЫ И ТЕОРЕТИЧЕСКИЕ СТАТЬИResearch ArticleGlymphatic system, sleep, neurodegenerationГлимфатическая система, сон, нейродегенерацияGorbachevskiiA. V.ГорбачевскийА. В.
Russian Federation
gorbachevskyalex@mail.ruKicherovaO. A.КичероваО. А.
Russian Federation
gorbachevskyalex@mail.ruReikhertL. I.РейхертЛ. И.
Russian Federation
gorbachevskyalex@mail.ruFederal State Budgetary Educational Institution of Higher Education “Tyumen State Medical University” of the Ministry of Health of the Russian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования “Тюменский государственный медицинский университет” Министерства здравоохранения Российской Федерации2410202474326928402022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://innoscience.ru/0044-4677/article/view/652087

The prevalence of neurodegenerative diseases and the complexity of their treatment in late stages make it urgent to identify early markers and symptoms of this group of diseases in order to optimize diagnosis, treatment and prevention.

Materials and methods. The PubMed database was analyzed for the following queries: perivascular space, Virchow–Robin space, glymphatic system, sleep disorders, Alzheimer’s disease.

Conclusion: enlargement of perivascular spaces (Virchow–Robin) can be considered an early structural marker of both glymphatic dysfunction and neurodegenerative diseases, while sleep disturbance can be considered as a functional marker (symptom) of these disorders.

Распространенность нейродегенеративных заболеваний и сложность их лечения в поздних стадиях делает актуальным выявление ранних маркеров и симптомов данной группы заболеваний с целью оптимизации диагностики, лечения и профилактики.

Материалы и методы. Был проведен анализ базы данных PubMed по запросам: периваскулярное пространство, пространство Вирхова–Робина, глимфатическая система, нарушения сна, болезнь Альцгеймера.

Заключение: расширение периваскулярных пространств (Вирхова–Робина) можно считать ранним структурным маркером как глимфатической дисфункции, так и нейродегенеративных заболеваний, тогда как нарушение сна можно рассматривать как функциональный маркер (симптом) данных нарушений.

perivascular spaceVirchow–Robin spaceglymphatic systeminsomniaAlzheimer’s diseaseastrocytenorepinephrineMRIpolysomnographyпериваскулярное пространствопространство Вирхова–Робинаглимфатическая системаинсомнияболезнь АльцгеймераастроцитнорадреналинМРТполисомнографияСемячкина-Глушковская О.В., Постнов Д.Э., Хороводов А.П., Наволокин Н.А., Куртц Ю.Г.Г. Лимфодренажная система мозга: новый игрок в нейронауке. Журнал эволюционной биохимии и физиологии. 2023. 59 (1): 3–19. https://doi.org/10.31857/S0044452923010084Николенко В.Н., Оганесян М.В., Яхно Н.Н., Орлов Е.А., Порубаева Е.Е., Попова Е.Ю. Глимфатическая система головного мозга: физиологическая анатомия и клинические перспективы. Неврология, нейропсихиатрия, психосоматика. 2018. 10 (4): 94–100. https://doi.org/10.14412/2074-2711-2018-4-94-100Alcendor D.J. Interactions between Amyloid-Β Proteins and Human Brain Pericytes: Implications for the Pathobiology of Alzheimer’s Disease. J Clin Med. 2020 May 15. 9 (5): 1490. https://doi.org/10.3390/jcm9051490Arcuri C., Mecca C., Bianchi R., Giambanco I., Donato R. The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS. Front Mol Neurosci. 2017 Jun 19; 10: 191. https://doi.org/10.3389/fnmol.2017.00191Banerjee G., Kim H.J., Fox Z., Jäger H., Wilson D., Charidimou A. et al. MRI-visible perivascular space location is associated with Alzheimer’s disease independently of amyloid burden. Brain. 2017 Apr 1; 140 (4): 1107–1116. https://doi.org/10.1093/brain/awx003Barisano G., Sheikh-Bahaei N., Law M., Toga A.W., Sepehrband F. Body mass index, time of day and genetics affect perivascular spaces in the white matter. J Cereb Blood Flow Metab. 2021 Jul; 41 (7): 1563–1578. https://doi.org/10.1177/0271678X20972856.Barisano G., Law M., Custer R.M., Toga A.W., Sepehrband F. Perivascular Space Imaging at Ultrahigh Field MR Imaging. Magn Reson Imaging Clin N Am. 2021 Feb; 29 (1): 67–75. https://doi.org/10.1016/j.mric.2020.09.005Bateman R.J., Munsell L.Y., Morris J.C., Swarm R., Yarasheski K.E., Holtzman D.M. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul; 12 (7): 856–861. https://doi.org/10.1038/nm1438Berezuk C., Ramirez J., Gao F., Scott C.J., Huroy M., Swartz R.H., Murray B.J., Black S.E., Boulos M.I. Virchow-Robin Spaces: Correlations with Polysomnography-Derived Sleep Parameters. Sleep. 2015 Jun 1; 38 (6): 853–858. https://doi.org/10.5665/sleep.4726Boespflug E.L., Iliff J.J. The Emerging Relationship Between Interstitial Fluid-Cerebrospinal Fluid Exchange, Amyloid-β, and Sleep. Biol Psychiatry. 2018 Feb 15; 83 (4): 328–336. https://doi.org/10.1016/j.biopsych.2017.11.031Boespflug E.L., Schwartz D.L., Lahna D., Pollock J., Iliff J.J., Kaye J.A., et al. MR Imaging-based Multimodal Autoidentification of Perivascular Spaces (mMAPS): Automated Morphologic Segmentation of Enlarged Perivascular Spaces at Clinical Field Strength. Radiology. 2018 Feb; 286 (2): 632–642. https://doi.org/10.1148/radiol.2017170205Boespflug E.L., Simon M.J., Leonard E., Grafe M., Woltjer R., Silbert L.C. et al. Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer’s Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer’s Disease. J Alzheimers Dis. 2018; 66 (4): 1587–1597. https://doi.org/10.3233/JAD-180367Buccellato F.R., D’Anca M., Serpente M., Arighi A., Galimberti D. The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis. Biomedicines. 2022 Sep 13; 10 (9): 2261. https://doi.org/10.3390/biomedicines10092261Cordone S., Scarpelli S., Alfonsi V., De .Gennaro L., Gorgoni M. Sleep-Based Interventions in Alzheimer’s Disease: Promising Approaches from Prevention to Treatment along the Disease Trajectory. Pharmaceuticals (Basel). 2021 Apr 19; 14 (4): 383. https://doi.org/10.3390/ph14040383Cordone S., Annarumma L., Rossini P.M., De .Gennaro L. Sleep and β-Amyloid Deposition in Alzheimer Disease: Insights on Mechanisms and Possible Innovative Treatments. Front Pharmacol. 2019 Jun 20; 10: 695. https://doi.org/10.3389/fphar.2019.00695Del Brutto O.H., Mera R.M., Del Brutto V.J., Castillo P.R. Enlarged basal ganglia perivascular spaces and sleep parameters. A population-based study. Clin Neurol Neurosurg. 2019; 182:53–57. https://doi.org/10.1016/j.clineuro.2019.05.002. Epub 2019 May 6. PMID: 31078956.Dubois B., Hampel H., Feldman H.H., Scheltens P., Aisen P., Andrieu S. et al. Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016Edler M.K., Mhatre-Winters I., Richardson J.R. Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review. Cells. 2021 May 8; 10 (5): 1138. https://doi.org/10.3390/cells10051138.Eide P.K., Vinje V., Pripp A.H., Mardal K.A., Ringstad G. Sleep deprivation impairs molecular clearance from the human brain. Brain. 2021 Apr 12; 144 (3): 863–874. https://doi.org/10.1093/brain/awaa443.Engelhardt B., Coisne C. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS. 2011 Jan 18; 8 (1): 4. https://doi.org/10.1186/2045-8118-8-4.Engelhardt B., Carare R.O., Bechmann I., Flügel A., Laman J.D., Weller R.O. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 2016 Sep; 132 (3): 317–338. https://doi.org/10.1007/s00401-016-1606-5.Frost B., Diamond M.I. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010 Mar; 11 (3): 155–159. https://doi.org/10.1038/nrn2786.Fultz 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. Nov 1; 366 (6465): 628–631. https://doi.org/10.1126/science.aax5440.Chang J.Guo B.Gao Y.Li .W.Tong X.Feng Y.Abumaria N. Characteristic Features of Deep Brain Lymphatic Vessels and Their Regulation by Chronic Stress. Research (Wash D C). 2023 Apr 13; 6:0120. https://doi.org/10.34133/research.0120.Gędek A., Koziorowski D., Szlufik S. Assessment of factors influencing glymphatic activity and implications for clinical medicine. Front Neurol. 2023 Sep 7; 14:1232304. https://doi.org/10.3389/fneur.2023.1232304.Hablitz L.M., Plá V., Giannetto M., Vinitsky H.S., Stæger F.F., Metcalfe T. et al. Circadian control of brain glymphatic and lymphatic fluid flow. Nat Commun. 2020 Sep 2; 11 (1): 4411. https://doi.org/10.1038/s41467-020-18115-2.Harrison I.F., Siow B., Akilo A.B., Evans P.G., Ismail O., Ohene Y. et al. Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with diffusion tensor MRI. Elife. 2018 Jul 31; 7:e34028. https://doi.org/10.7554/eLife.34028.Heneka M.T., Carson M.J., El .Khoury J., Landreth G.E., Brosseron F., Feinstein D.L., et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015 Apr; 14 (4): 388–405. https://doi.org/10.1016/S1474-4422(15)70016-5.Hladky S.B., Barrand M.A. The glymphatic hypothesis: the theory and the evidence. Fluids Barriers CNS. 2022 Feb 3; 19 (1): 9. https://doi.org/10.1186/s12987-021-00282-z.Hughes TM., Kuller L.H., Barinas-Mitchell E.J., Mackey R.H., McDade E.M. et al. Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology. 2013 Nov 5; 81 (19): 1711–1718. https://doi.org/10.1212/01.wnl.0000435301.64776.37.Iliff J.J., Wang M., Liao Y., Plogg B.A., Peng W., Gundersen G.A., 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 Aug 15; 4 (147): 147ra111. https://doi.org/10.1126/scitranslmed.3003748.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 Mar; 123 (3):1299–1309. https://doi.org/10.1172/JCI67677.Insel P.S., Mohlenhoff B.S., Neylan T.C., Krystal A.D., Mackin R.S. Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults. JAMA Netw Open. 2021 Jul 1; 4 (7): e2117573. https://doi.org/10.1001/jamanetworkopen.2021.17573.Jack C.R.Jr., Wiste H.J., Vemuri P., Weigand S.D., Senjem M.L., Zeng G. et al. Alzheimer’s Disease Neuroimaging Initiative. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain. 2010 Nov; 133 (11): 3336–48. https://doi.org/10.1093/brain/awq277.Jack C.R.Jr., Bennett D.A., Blennow K., Carrillo M.C., Feldman H.H., Frisoni G.B. et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2; 87 (5): 539–547. https://doi.org/10.1212/WNL.0000000000002923.Jack CR .Jr., Bennett D.A., Blennow K., Carrillo M.C., Dunn B., Haeberlein S.B. et al. Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018 Apr; 14 (4): 535–562. https://doi.org/10.1016/j.jalz.2018.02.018.Jessen N.A., Munk A.S., Lundgaard I., Nedergaard M. The Glymphatic System: A Beginner’s Guide. Neurochem Res. 2015 Dec; 40 (12): 2583–2599. https://doi.org/10.1007/s11064-015-1581-6.Johanson C.E., Duncan J.A.3rd. Klinge P.M., Brinker T., Stopa E.G. Silverberg GD.Multiplicity of cerebrospinal fluid functions: New challenges in health and disease. Cerebrospinal Fluid Res. 2008 May 14; 5:10. https://doi.org/10.1186/1743-8454-5-10.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 Dec 10; 1 (1): 2. https://doi.org/10.1186/1743-8454-1-2.Ju .Y.E., Lucey B.P., Holtzman D.M. Sleep and Alzheimer disease pathology–a bidirectional relationship. Nat Rev Neurol. 2014 Feb; 10 (2): 115–119. https://doi.org/10.1038/nrneurol.2013.269.Keable A., Fenna K., Yuen H.M., Johnston D.A., Smyth N.R., Smith C. et al. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim Biophys Acta. 2016 May; 1862 (5): 1037–1046. https://doi.org/10.1016/j.bbadis.2015.08.024.Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016 Aug 19; 353 (6301): 766–71. https://doi.org/10.1126/science.aag2638.Kiviniemi V., Wang X., Korhonen V., Keinänen T., Tuovinen T., Autio J., et al. Ultra-fast magnetic resonance encephalography of physiological brain activity – Glymphatic pulsation mechanisms? J Cereb Blood Flow Metab. 2016 Jun; 36 (6): 1033–1045. https://doi.org/10.1177/0271678X15622047.Kwee R.M., Kwee T.C. Virchow-Robin spaces at MR imaging. Radiographics. 2007 Jul-Aug; 27 (4):1071–86. https://doi.org/10.1148/rg.274065722.Lancini E., Haag L., Bartl F., Rühling M., Ashton N.J., Zetterberg H. et al. Cerebrospinal fluid and positron-emission tomography biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis. Brain Commun. 2023 Mar 29; 5 (3): fcad085. https://doi.org/10.1093/braincomms/fcad085.Lee Y.F., Gerashchenko D., Timofeev I., Bacskai B.J., Kastanenka K.V. Slow Wave Sleep Is a Promising Intervention Target for Alzheimer’s Disease. Front Neurosci. 2020 Jun 30; 14: 705. https://doi.org/10.3389/fnins.2020.00705.Liao F., Yoon H., Kim J. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Curr Opin Lipidol. 2017 Feb; 28 (1): 60–67. https://doi.org/10.1097/MOL.0000000000000383.Lynch M.Pham W.Sinclair B.O’Brien TJ.Law M. Vivash L. Perivascular spaces as a potential biomarker of Alzheimer’s disease. Front Neurosci. 2022 Oct 18; 16: 1021131. https://doi.org/10.3389/fnins.2022.1021131.Mander B.A., Marks S.M., Vogel J.W., Rao V., Lu .B., Saletin J.M. et al. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015 Jul; 18 (7): 1051–1057. https://doi.org/10.1038/nn.4035.Mander B.A., Winer J.R., Jagust W.J., Walker M.P. Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer’s Disease? Trends Neurosci. 2016 Aug; 39 (8): 552–566. https://doi.org/10.1016/j.tins.2016.05.002.Mander B.A. Local Sleep and Alzheimer’s Disease Pathophysiology. Front Neurosci. 2020 Sep 23; 14: 525970. https://doi.org/10.3389/fnins.2020.525970.Meraz-Ríos M.A., Toral-Rios D., Franco-Bocanegra D., Villeda-Hernández J., Campos-Peña V. Inflammatory process in Alzheimer’s Disease. Front Integr Neurosci. 2013 Aug 13; 7: 59. https://doi.org/10.3389/fnint.2013.00059.Mestre H., Kostrikov S., Mehta R.I., Nedergaard M. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin Sci (Lond). 2017 Aug 10; 131 (17): 2257–2274. https://doi.org/10.1042/CS20160381.Mezey É., Szalayova I., Hogden C.T., Brady A., Dósa Á., Sótonyi P., Palkovits M. An immunohistochemical study of lymphatic elements in the human brain. Proc Natl Acad Sci U S A. 2021 Jan 19; 118 (3): e2002574118. https://doi.org/10.1073/pnas.2002574118.Naganawa S., Taoka T. The Glymphatic System: A Review of the Challenges in Visualizing its Structure and Function with MR Imaging. Magn Reson Med Sci. 2022 Mar 1; 21 (1): 182–194. https://doi.org/10.2463/mrms.rev.2020-0122.Nedergaard M., Goldman S.A. BRAIN DRAIN. Sci Am. 2016 Mar; 314 (3): 44–49. https://doi.org/10.1038/scientificamerican0316-44.Newman E.A. New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci. 2003 Oct; 26 (10): 536–542. https://doi.org/10.1016/S0166-2236(03)00237-6.O’Donnell J., Zeppenfeld D., McConnell E., Pena S., Nedergaard M. Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem Res. 2012 Nov; 37 (11): 2496–2512. https://doi.org/10.1007/s11064-012-0818-x. Epub 2012 Jun 21.Okar S.V., Hu F., Shinohara R.T., Beck E.S., Reich D.S., Ineichen B.V. The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis. Front Neurosci. 2023 Mar 30; 17:1038011. https://doi.org/10.3389/fnins.2023.1038011.Parnetti L., Chipi E., Salvadori N., D’Andrea K., Eusebi P. Prevalence and risk of progression of preclinical Alzheimer’s disease stages: a systematic review and meta-analysis. Alzheimers Res Ther. 2019 Jan 15; 11 (1): 7. https://doi.org/10.1186/s13195-018-0459-7.Peng W., Achariyar T.M., Li .B., Liao Y., Mestre H., Hitomi E., et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2016 Sep; 93: 215–225. https://doi.org/10.1016/j.nbd.2016.05.015.Plog B.A., Nedergaard M. The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future. Annu Rev Pathol. 2018 Jan 24; 13: 379–394. https://doi.org/10.1146/annurev-pathol-051217-111018.Postnov D., Semyachkina-Glushkovskaya O., Litvinenko E., Kurths J., Penzel T. Mechanisms of Activation of Brain’s Drainage during Sleep: The Nightlife of Astrocytes. Cells. 2023 Nov 20; 12 (22): 2667. https://doi.org/10.3390/cells12222667.Provenzano DA., Pellis Z., DeRiggi L. Fatal gadolinium-induced encephalopathy following accidental intrathecal administration: a case report and a comprehensive evidence-based review. Reg Anesth Pain Med. 2019 Apr 25: rapm-2019–100422. https://doi.org/10.1136/rapm-2019-100422.Rainey-Smith S.R., Mazzucchelli G.N., Villemagne V.L., Brown B.M., Porter T., Weinborn M. et al. AIBL Research Group. Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden. Transl Psychiatry. 2018 Feb 26; 8 (1): 47. https://doi.org/10.1038/s41398-018-0094-x.Rasmussen M.K., Mestre H., Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018 Nov; 17 (11): 1016–1024. https://doi.org/10.1016/S1474-4422(18)30318-1.Reddy O.C., van der Werf Y.D. The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices. Brain Sci. 2020 Nov 17; 10 (11): 868. https://doi.org/10.3390/brainsci10110868.Robin C. Recherches sur quelques particularites de la structure des capillaires de l’encephale. J. Physiol. Homme. Anim. 1859. 2: 537–548.Rodríguez-Giraldo M., González-Reyes R.E., Ramírez-Guerrero S., Bonilla-Trilleras C.E., Guardo-Maya S., Nava-Mesa M.O. Astrocytes as a Therapeutic Target in Alzheimer’s Disease-Comprehensive Review and Recent Developments. Int J Mol Sci. 2022 Nov 7; 23 (21): 13630. https://doi.org/10.3390/ijms232113630.Rowsthorn E., Pham W., Nazem-Zadeh M.R., Law M., Pase M.P., Harding I.H. Imaging the neurovascular unit in health and neurodegeneration: a scoping review of interdependencies between MRI measures. Fluids Barriers CNS. 2023 Dec 21; 20 (1): 97. https://doi.org/10.1186/s12987-023-00499-0.Semyachkina-Glushkovskaya O., Postnov D., Penzel T.. Kurths J. Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer’s Disease and the Blood-Brain Barrier. Int J Mol Sci. 2020 Aug 31; 21 (17): 6293. https://doi.org/10.3390/ijms21176293.Semyachkina-Glushkovskaya O.V., Karavaev A.S., Prokhorov M.D., Runnova A.E., Borovkova E.I., Yu M.I. et al. EEG biomarkers of activation of the lymphatic drainage system of the brain during sleep and opening of the blood-brain barrier. Comput Struct Biotechnol J. 2022 Dec 15; 21: 758–768. https://doi.org/10.1016/j.csbj.2022.12.019.Semyachkina-Glushkovskaya O., Fedosov I., Penzel T., Li .D., Yu .T., Telnova V. et al. Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases. Int J Mol Sci. 2023 Feb 6; 24 (4): 3221. https://doi.org/10.3390/ijms24043221.Shabir O., Berwick J., Francis S.E. Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis. BMC Neurosci. 2018 Oct 17; 19 (1): 62. https://doi.org/10.1186/s12868-018-0465-5.Shokri-Kojori E., Wang G.J., Wiers C.E., Demiral S.B., Guo M., Kim S.W. et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018 Apr 24; 115 (17): 4483–4488. https://doi.org/10.1073/pnas.1721694115.Silva I., Silva J., Ferreira R., Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer’s disease. Neurol Res Pract. 2021 Jan 19; 3 (1):5. https://doi.org/10.1186/s42466-021-00102-7.Soto-Rojas L.O., Pacheco-Herrero M., Martínez-Gómez P.A., Campa-Córdoba B.B., Apátiga-Pérez R., Villegas-Rojas M.M., et al. The Neurovascular Unit Dysfunction in Alzheimer’s Disease. Int J Mol Sci. 2021 Feb 18; 22 (4): 2022. https://doi.org/10.3390/ijms22042022.Sugama S., Kakinuma Y. Noradrenaline as a key neurotransmitter in modulating microglial activation in stress response. Neurochem Int. 2021 Feb; 143: 104943. https://doi.org/10.1016/j.neuint.2020.104943.Taoka T., Masutani Y., Kawai H., Nakane T., Matsuoka K., Yasuno F. et al. Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer’s disease cases. Jpn J Radiol. 2017 Apr; 35 (4): 172–178. https://doi.org/10.1007/s11604-017-0617-z.Tarasoff-Conway J.M., Carare R.O., Osorio R.S., Glodzik L., Butler T., Fieremans E. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015 Aug; 11 (8): 457–70. https://doi.org/10.1038/nrneurol.2015.119.Troili F., Cipollini V., Moci M., Morena E., Palotai M., Rinaldi V. et al. Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System. Front Neuroanat. 2020 Apr 16;14:17. https://doi.org/10.3389/fnana.2020.00017. Erratum in: Front Neuroanat. 2020 Sep 15;14:51.van der Thiel M.M., Backes W.H., Ramakers I.H.G.B., Jansen J.F.A. Novel developments in non-contrast enhanced MRI of the perivascular clearance system: What are the possibilities for Alzheimer’s disease research? Neurosci Biobehav Rev. 2023 Jan; 144: 104999. https://doi.org/10.1016/j.neubiorev.2022.104999.Verghese J.P., Terry A., de Natale E.R., Politis M. Research Evidence of the Role of the Glymphatic System and Its Potential Pharmacological Modulation in Neurodegenerative Diseases. J Clin Med. 2022 Nov 25; 11 (23): 6964. https://doi.org/10.3390/jcm11236964.Virchow R. Ueber die erweiterung kleinerer gefässe. Virchows Archiv. 1851. 3: 427–462.Voumvourakis K.I., Sideri E., Papadimitropoulos G.N., Tsantzali I., Hewlett P., Kitsos D. et al. The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep. Biomedicines. 2023 Jul 25; 11 (8): 2092. https://doi.org/0.3390/biomedicines11082092.Xie L., Kang H., Xu .Q., Chen M.J., Liao Y., Thiyagarajan M., et al. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18; 342 (6156): 373–377. https://doi.org/10.1126/science.1241224.Xu .Z., Xiao N., Chen Y., Huang H., Marshall C.. Gao J. et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener. 2015 Nov 2; 10: 58. https://doi.org/10.1186/s13024-015-0056-1.Yu X., Ji C., Shao A. Neurovascular Unit Dysfunction and Neurodegenerative Disorders. Front Neurosci. 2020 Apr 29; 14: 334. https://doi.org/10.3389/fnins.2020.00334.Wang C., Holtzman D.M. Bidirectional relationship between sleep and Alzheimer’s disease: role of amyloid, tau, and other factors. Neuropsychopharmacology. 2020 Jan; 45 (1): 104–120. https://doi.org/10.1038/s41386-019-0478-5.Wardlaw J.M., Smith E.E., Biessels G.J., Cordonnier C., Fazekas F., Frayne R. et al. Standards for reporting vascular changes on neuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013 Aug; 12 (8): 822–838. https://doi.org/10.1016/S1474-4422(13)70124-8.Weed L.H. Studies on Cerebro-Spinal Fluid. No. II: The Theories of Drainage of Cerebro-Spinal Fluid with an Analysis of the Methods of Investigation. J Med Res. 1914a Sep; 31 (1): 21–49.Weed L.H.Studies on Cerebro-Spinal Fluid. No. IV: The dual Source of Cerebro-Spinal Fluid. J Med Res. 1914b Sep; 31 (1): 93–118.11.Winer J.R., Morehouse A., Fenton L., Harrison TM., Ayangma L., Reed M. et al. Tau and β-Amyloid Burden Predict Actigraphy-Measured and Self-Reported Impairment and Misperception of Human Sleep. J Neurosci. 2021 Sep 8; 41 (36): 7687–7696. https://doi.org/10.1523/JNEUROSCI.0353-21.2021.Yamada S., Miyazaki M., Yamashita Y., Ouyang C., Yui M., Nakahashi M. et al. Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling. Fluids Barriers CNS. 2013 Dec 27; 10 (1): 36. https://doi.org/10.1186/2045-8118-10-36.Zhang Y., Ren R., Yang L., Zhang H., Shi Y., Okhravi H.R. et al. Sleep in Alzheimer’s disease: a systematic review and meta-analysis of polysomnographic findings. Transl Psychiatry. 2022 Apr 1; 12 (1): 136. https://doi.org/10.1038/s41398-022-01897-y.