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Sleep and Biotransformation

Paravascular Clearance Pathways

Though for many Americans sleep can seem elusive,1 it is essential to many physiological functions. One of those essential functions may be the clearance of toxins from the brain. The theory of the glymphatic system (first documented in rodents) has highlighted the role of sleep in the clearance of many toxins.2

The word glymphatic is a portmanteau of “glial” and “lymphatic,” highlighting the role that glial cells are theorized to play in helping rid the brain of waste, in a manner similar to the lymphatic system. The theory suggests that active transport of cerebrospinal fluid (CSF) through brain spaces pushes CSF into glia lining the paravascular space, and at night, that space expands and harmful proteins and waste are transported out of the brain.3 A full understanding of the fluid dynamics has not yet been reached.3

The glymphatic system was named by the lead researcher who discovered this paravascular pathway: Maiken Nedergaard, MD, DMSc, professor and co-director at the Center for Translational Neuromedicine, University of Rochester, as well as professor in the Division of Glial Disease and Therapeutics at the University of Copenhagen. She received the 2018 Nordic Fernström Prize in recognition of her achievement.

Controversy

Importantly, not all researchers agree with the mechanisms proposed in the glymphatic system theory. Specifically, some researchers have questioned whether passive diffusion could account for the same results.4,5 In fact, some have suggested that the glymphatic system theory “appears to contradict a large body of experimental evidence.”4

Yet these researchers also agree that clearance of toxins from the brain does occur via interstitial spaces, even if the glymphatic theory is not accurate with respect to mechanisms.4 Some have also suggested that the human brain may be more complex than the rodent brain with respect to toxin clearance.6

Whether or not the flow is active or passive remains a question,7-9 but paravascular spaces do seem to play a role in toxin clearance from the brain.

The Role of Sleep in Paravascular Toxin Clearance

During sleep, the extracellular space of the brain expands, and toxins are exchanged from cerebrospinal fluid into interstitial fluid.2 Amyloid beta, buildup of which is heavily implicated in Alzheimer’s, is transported out of the brain via this pathway in rodents,2 and PET studies have confirmed similar findings of amyloid beta accumulation during sleep deprivation in humans.3 Clearance of both amyloid beta and tau has been shown to be reduced in human patients with Alzheimer’s when compared to healthy controls.3 This paravascular system may also be impaired in patients with metabolic syndrome and hyperglycemia, which may contribute to diabetes-induced dementia.10

Further study of the glymphatic system in humans relies on newer imaging technologies, as animal studies use invasive procedures.3 As fluid dynamics are increasingly understood, specific mechanisms for these observational findings will be uncovered.

At least in rodents, the glymphatic system is primarily active during sleep, with reduced or no flow during wakefulness; this is due to the increase in interstitial space during sleep.11 In addition, increasing age is correlated with decreased cerebrospinal fluid pressure12 and volume13 in humans, which likely also decreases glymphatic flow.

Furthermore, many adults struggle with sleep as they age. Poor quality sleep and frequent napping have both been correlated with lower amyloid beta levels in cerebrospinal fluid and increased amyloid deposits in the brain—even in healthy volunteers—although the poor sleepers may have had preclinical Alzheimer’s.14

Non-Paravascular Mechanisms for Brain Toxin Clearance

The glymphatic system is not the only toxin clearance system in the brain. Another route by which metabolic byproducts and toxins are expelled from the brain is through the olfactory nerve to the cervical lymphatic vessels.3 Post-mortem tests have shown that nasal lymphatic vessels play a role in cerebrospinal fluid transport in many mammalian species (sheep, pigs, rabbits, rats, mice, monkeys, and one human).15

Meningeal lymphatic vessels also play a role in the drainage of interstitial fluid, cerebrospinal fluid, molecules, and immune cells.16

Clinical Consequences of Reduced Sleep

Research points to a decades-long decrease in sleep duration across the population, particularly on workdays, and along with this sleep deprivation, obesity continues to increase.17 Emerging research also suggests that increased levels of certain toxins, like BPA, may also contribute to sleep disorders like obstructive sleep apnea.18-19 Increased levels of toxins including urinary arsenic, phthalates, and polyfluoroalkyl compounds have been correlated with more waking episodes during the night.20

Better self-reported sleep has also been correlated with improved health outcomes—strongly for mental health and moderately for physical and cognitive health.21 Sleep plays a role in a huge range of illnesses. Regarding biotransformation, the liver plays a large role. In patients with non-alcoholic fatty liver disease (NAFLD), sleep disturbances and quality have been found to predict 20% of the variability in liver stiffness,22 suggesting that at least in a compromised liver, sleep is vital. A meta-analysis also found a small but significant increase in the risk of NAFLD in patients with shorter sleep duration.21

Sleep plays an important role not only in overall health, but in biotransformation. For many patients, supporting strong sleep habits may not only increase overall health, but also help them to eliminate toxins that can contribute to their symptoms.

Learn More About Biotransformation Pathways and Toxic Exposures

References

  1. Jones JM. In U.S., 40% get less than recommended amount of sleep. Gallup Well-Being. Published December 19, 2013. Accessed August 2, 2019. https://news.gallup.com/poll/166553/less-recommended-amount-sleep.aspx
  2. 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 ?. Sci Transl Med. 2012;4(147):147ra111. doi:1126/scitranslmed.3003748
  3. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018;17(11):1016-1024. doi:1016/S1474-4422(18)30318-1
  4. Smith AJ, Verkman AS. The “glymphatic” mechanism for solute clearance in Alzheimer’s disease: game changer or unproven speculation? FASEB J. 2018;32(2):543-551. doi:1096/fj.201700999
  5. Hladky SB, Barrand MA. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS. 2014;11(1):26. doi:1186/2045-8118-11-26
  6. Demiral ?B, Tomasi D, Sarlls J, et al. Apparent diffusion coefficient changes in human brain during sleep – does it inform on the existence of a glymphatic system? 2019;185:263-273. doi:10.1016/j.neuroimage.2018.10.043
  7. Semyachkina-Glushkovskaya O, Postnov D, Kurths J. Blood-brain barrier, lymphatic clearance, and recovery: Ariadne’s thread in labyrinths of hypotheses. Int J Mol Sci. 2018;19(12):E3818. doi:3390/ijms19123818
  8. Bakker ENTP, Naessens DMP, VanBavel E. Paravascular spaces: entry to or exit from the brain? Exp Physiol. 2019;104(7):1013-1017. doi:1113/EP087424
  9. Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol. 2018;135(3):387-407. doi:1007/s00401-018-1812-4
  10. Kim YK, Nam KI, Song J. The glymphatic system in diabetes-induced dementia. Front Neurol. 2018;9:867. doi:3389/fneur.2018.00867
  11. Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40(12):2583-2599. doi:1007/s11064-015-1581-6
  12. Fleischman D, Berdahl JP, Zaydlarova J, Stinnett S, Fautsch MP, Allingham RR. Cerebrospinal fluid pressure decreases with older age. PLoS One. 2012;7(12):e52664. doi:1371/journal.pone.0052664
  13. Bothwell SW, Janigro D, Patabendige A. Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases. Fluids Barriers CNS. 2019;16(1):9. doi:1186/s12987-019-0129-6
  14. Ju YE, McLeland JS, Toedebusch CD, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013;70(5):587-593. doi:1001/jamaneurol.2013.2334
  15. 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:1186/1743-8454-1-2
  16. 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:1172/JCI90603
  17. Roenneberg T, Allebrandt KV, Merrow M, Vetter C. Social jetlag and obesity. Curr Biol. 2012;22(10):939-943. doi:1016/j.cub.2012.03.038
  18. Beydoun HA, Beydoun MA, Jeng HA, Zonderman AB, Eid SM. Bisphenol-A and sleep adequacy among adults in the National Health and Nutrition Examination Surveys. Sleep. 2016;39(2):467-476. doi:5665/sleep.5466
  19. Erden ES, Genc S, Motor S, et al. Investigation of serum bisphenol A, vitamin D, and parathyroid hormone levels in patients with obstructive sleep apnea syndrome. 2014;45(2):311-318. doi:10.1007/s12020-013-0022-z
  20. Shiue I. Urinary arsenic, pesticides, heavy metals, phthalates, polyaromatic hydrocarbons, and polyfluoroalkyl compounds are associated with sleep troubles in adults: USA NHANES, 2005-2006. Environ Sci Pollut Res Int. 2017;24(3):3108-3116. doi:1007/s11356-016-8054-6
  21. Gadie A, Shafto M, Leng Y, Kievit RA; Cam-CAN. How are age-related differences in sleep quality associated with health outcomes? An epidemiological investigation in a UK cohort of 2406 adults. BMJ Open. 2017;7(7):e014920. doi:1136/bmjopen-2016-014920
  22. Marin-Alejandre BA, Abete I, Cantero I, et al. Association between sleep disturbances and liver status in obese subjects with nonalcoholic fatty liver disease: a comparison with healthy controls. Nutrients. 2019;11(2):E322. doi:3390/nu11020322
  23. Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Ungprasert P. Short sleep duration and risk of nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31(11):1802-1807. doi:1111/jgh.13391

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