glymphatic clearance; glymphatic flow (glymphatic system)
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Introduction
The term glymphatic derives from its resemblance to the peripheral lymphatic system & the participation of perivascular glial cells (glial-lymphatic -> glymphatic)
Function
- term used in reference to glia-assisted disposal of waste products into the CSF through perivascular spaces for distribution to the systemic circulation (see CSF)
- glymphatic clearance peaks in mice when they sleep
- aquaporin receptors are more highly expressed in sleep
- interstitial spaces themselves expand
- glymphatic clearance is active in humans[17]
- in humans, slow-wave sleep leads to reductions in cerebral blood volume, increases in interstitial fluid, & increased flow of CSF into the ventricles[11]
- pulsatility of the brain's arteries creates a convective force that draws CSF into the brain from the space around its arterial walls & back out again along its veins, facilitating penetration of CSF into the brain parenchyma[1]
- norepinephrine release from the locus coeruleus drives slow vasomotion (rhythmic contraction) in non-REM sleep[19]
- infraslow norepinephrine oscillations control opposing changes in blood & CSF volumes[19]
- vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility[16]
- aquaporins (aquaporin-4) line outer wall of glymphatic vessels along with flat end feet of specialized astrocytes[13]
- the inner wall of glymphatic vessels are the outer walls of brain arteries & veins
- the aquaporins (aquaporin-4) allow passage of CSF (arterioles) & interstitial fluid (venules) across the outer glymphatic walls[13]
- large oscillations of CSF inflow into the brain appear ~ every 20 seconds tightly coupled to fMRI signals of blood flow & EEG slow waves[10]
- CSF exchanges with brain parenchymal interstitial fluid, percolating through & around astroglial end-feet toward nearby venules, along which it then exits the brain thus taking with it neuronal waste products[2]
- the veins must propel the waste CSF-interstitial fluid toward the arachnoid villi where it is absorbed into the systemic circulation
- the process is termed glymphatic clearance[1]
- waste products such as beta-amyloid & other aggregation-prone proteins are cleared not only alongside veins but also across the blood-brain barrier into the systemic circulation
- besides waste elimination, the glymphatic system also facilitates brain-wide distribution of glucose, lipids, amino acids, growth factors, & neuromodulators[14]
Pathology
- impaired glymphatic clearance may exacerbate microglial inflammatory response in Alzheimer's disease[12]
- glymphatic dysfunction may be associated with progression of Creutzfeldt-Jakob disease[18]
- zolpidem suppresses norepinephrine oscillations & glymphatic clearance[19]
- difficulty sleeping associated with reduced glymphatic clearance in patients with multiple sclerosis[20]
Comparative biology
- 40 Hz (gamma) stimulation promotes influx of CSF & efflux of interstitial fluid in the cortex of a mouse model of Alzheimer's disease[16]
- influx of CSF was associated with increased aquaporin-4 polarization along astrocytic endfeet & dilation of meningeal lymphatic vessels
- removal of beta-amyloid by glymphatic clearance was enhanced by gamma stimulation
More general terms
Additional terms
References
- ↑ 1.0 1.1 1.2 Glymphatic Flow, Sleep, microRNA Are Frontiers in Alzheimer's Research. Zilkha Symposium on Alzheimer's Disease and Related Disorders May 6, 2014 http://www.alzforum.org/news/conference-coverage/glymphatic-flow-sleep-microrna-are-frontiers-alzheimers-research
- ↑ 2.0 2.1 Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996
- ↑ Jin BJ, Smith AJ, Verkman AS. Spatial model of convective solute transport in brain extracellular space does not support a "glymphatic" mechanism. J Gen Physiol. 2016 Dec;148(6):489-501. PMID: https://pubmed.ncbi.nlm.nih.gov/27836940
- ↑ Wostyn P, De Groot V, Van Dam D et al Alzheimer's disease and glaucoma: can glymphatic system dysfunction underlie their comorbidity? Acta Ophthalmol. 2016 Apr 29. PMID: https://pubmed.ncbi.nlm.nih.gov/27126509
- ↑ Morris AW, Sharp MM, Albargothy NJ et al Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 2016 May;131(5):725-36. PMID: https://pubmed.ncbi.nlm.nih.gov/26975356 Free PMC Article
- ↑ Kyrtsos CR, Baras JS. Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer's Disease Pathogenesis. PLoS One. 2015 Oct 8;10(10):e0139574. PMID: https://pubmed.ncbi.nlm.nih.gov/26448331 Free PMC Article
- ↑ Tarasoff-Conway JM, Carare RO, Osorio RS et al Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015 Aug;11(8):457-70. Review. Erratum in: Nat Rev Neurol. 2016 Apr;12(4):248. PMID: https://pubmed.ncbi.nlm.nih.gov/26195256 Free PMC Article
- ↑ Aspelund A, Antila S, Proulx ST et al A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991-9. PMID: https://pubmed.ncbi.nlm.nih.gov/26077718 Free PMC Article
- ↑ Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The Glymphatic System: A Beginner's Guide. Neurochem Res. 2015 Dec;40(12):2583-99. Review. PMID: https://pubmed.ncbi.nlm.nih.gov/25947369 Free PMC Article
- ↑ 10.0 10.1 George J Waves of CSF Flow Into the Brain During Sleep - Findings may have implications for Alzheimer's and dementia. MedPage Today. Nov 1, 2019 https://www.medpagetoday.com/neurology/sleepdisorders/83097
Fultz N, et al Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019 Nov 1;366(6465):628-631. PMID: https://pubmed.ncbi.nlm.nih.gov/31672896
Grubb S, Lauritzen M Deep sleep drives brain fluid oscillations. Science 2019 Nov 1;366(6465) PMID: https://pubmed.ncbi.nlm.nih.gov/31672882 - ↑ 11.0 11.1 Fultz NE et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 2019 Nov 1; 366:628 PMID: https://pubmed.ncbi.nlm.nih.gov/31672896 https://science.sciencemag.org/content/366/6465/628
- ↑ 12.0 12.1 Da Mesquita S, Papadopoulos Z, Dykstra T et al. Meningeal lymphatics affect microglia responses and anti-Abeta immunotherapy. Nature 2021 Apr 28; [e-pub]. PMID: https://pubmed.ncbi.nlm.nih.gov/33911285 https://www.nature.com/articles/s41586-021-03489-0
- ↑ 13.0 13.1 13.2 Kamaroff AL Does Sleep Flush Wastes From the Brain? JAMA. Published online May 17, 2021. PMID: https://pubmed.ncbi.nlm.nih.gov/33999096 https://jamanetwork.com/journals/jama/fullarticle/2780296
- ↑ 14.0 14.1 Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The Glymphatic System: A Beginner's Guide Neurochem Res. 2015 Dec;40(12):2583-99 PMID: https://pubmed.ncbi.nlm.nih.gov/25947369 PMCID: PMC4636982 Free PMC article
- ↑ Natale G et al Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front. Neurosci. 2021. Feb 9. https://www.frontiersin.org/articles/10.3389/fnins.2021.639140/full
- ↑ 16.0 16.1 16.2 Murdock MH, Yanng CY, Sun N et al Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature 2024. 627:149-156 PMID: https://pubmed.ncbi.nlm.nih.gov/38418876 PMCID: PMC10917684 Free PMC article https://www.nature.com/articles/s41586-024-07132-6
- ↑ 17.0 17.1 Yamamoto EA, Bagley JH, Geltzeiler M et al The perivascular space is a conduit for cerebrospinal fluid flow in humans: A proof-of-principle report. Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2407246121. Epub 2024 Oct 7. PMID: https://pubmed.ncbi.nlm.nih.gov/39374384
- ↑ 18.0 18.1 Chen Z, Jian D, Kong Y et al Association of Glymphatic Function With Clinical Characteristics in Patients With Clinical and Asymptomatic Creutzfeldt-Jakob Disease. Neurology. 2025 Jan 14. PMID: https://pubmed.ncbi.nlm.nih.gov/39671544 https://www.neurology.org/doi/10.1212/WNL.0000000000210055
- ↑ 19.0 19.1 19.2 19.3 Leslie M Scientists uncover how the brain washes itself during sleep Pulsating blood vessels push fluid into and out of the brains of slumbering mice. Science News. 2025. Jan 8 https://www.science.org/content/article/scientists-uncover-how-brain-washes-itself-during-sleep
Hauglund NL, Andersen M, Tokarska K et al Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep. Cell. 2025 Feb 6;188(3):606-622.e17.. PMID: https://pubmed.ncbi.nlm.nih.gov/39788123 PMCID: PMC12340670 https://www.cell.com/cell/abstract/S0092-8674(24)01343-6 - ↑ 20.0 20.1 Jiang M, Rubin M, Storelli L, et al Subjective sleep disturbances are associated with reduced MRI-derived perivascular-space diffusivity in multiple sclerosis. J Neurol. 2026 Aug 22;273(9):538. PMID: https://pubmed.ncbi.nlm.nih.gov/42631758