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glymphatic clearance; glymphatic flow (glymphatic system)

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] - 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] 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

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MRI brain perivascular spaces

General

clearance

References

  1. 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. Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996
  3. 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: 27836940
  4. 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: 27126509
  5. 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: 26975356 Free PMC Article
  6. 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: 26448331 Free PMC Article
  7. 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: 26195256 Free PMC Article
  8. 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: 26077718 Free PMC Article
  9. 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: 25947369 Free PMC Article
  10. 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: 31672896 - Grubb S, Lauritzen M Deep sleep drives brain fluid oscillations. Science 2019 Nov 1;366(6465) PMID: 31672882
  11. Fultz NE et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 2019 Nov 1; 366:628 PMID: 31672896 https://science.sciencemag.org/content/366/6465/628
  12. 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: 33911285 https://www.nature.com/articles/s41586-021-03489-0
  13. Kamaroff AL Does Sleep Flush Wastes From the Brain? JAMA. Published online May 17, 2021. PMID: 33999096 https://jamanetwork.com/journals/jama/fullarticle/2780296
  14. Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The Glymphatic System: A Beginner's Guide Neurochem Res. 2015 Dec;40(12):2583-99 PMID: 25947369 PMCID: PMC4636982 Free PMC article
  15. 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. Murdock MH, Yanng CY, Sun N et al Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature 2024. 627:149-156 PMID: 38418876 PMCID: PMC10917684 Free PMC article https://www.nature.com/articles/s41586-024-07132-6
  17. 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: 39374384