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A curious concept of CNS clearance

Nature Neuroscience (2025)Cite this article

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Matters Arising to this article was published on 11 March 2025

The Original Article was published on 13 May 2024

arising from A. Miao et al. Nature Neuroscience https://doi.org/10.1038/s41593-024-01638-y (2024)

Over the past decade, multiple lines of research have shown that sleep decreases amyloid-β and tau burden compared with wakefulness, and glymphatic clearance is increased during sleep in both human and mouse brains1,2,3,4,5,6. A recent study by Miao et al.7 has questioned these findings. We here raise concerns regarding experimental methodology, analytical rigor, and theoretical and mathematical assumptions in the Miao et al.7 study. The conclusion of that study—brain clearance is reduced during sleep and anesthesia—is not supported by the data presented.

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Fig. 1: Discrepancy between flow velocity model and actual velocity.
Fig. 2: Data visualization, unequal sampling and improper statistical analysis may cause interpretation errors in diurnal variation of diffusion.

References

  1. Kang, J. E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep–wake cycle. Science 326, 1005–1007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Holth, J. K. et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880–884 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shokri-Kojori, E. et al. beta-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl Acad. Sci. USA 115, 4483–4488 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Eide, P. K., Vinje, V., Pripp, A. H., Mardal, K. A. & Ringstad, G. Sleep deprivation impairs molecular clearance from the human brain. Brain 144, 863–874 (2021).

    Article  PubMed  Google Scholar 

  6. Fultz, N. E. et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 366, 628–631 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miao, A. et al. Brain clearance is reduced during sleep and anesthesia. Nat. Neurosci. 27, 1046–1050 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Plá, V. et al. A real-time in vivo clearance assay for quantification of glymphatic efflux. Cell Rep 40, 111320 (2022).

    Article  PubMed  Google Scholar 

  9. Bennett, T. D. Transport by advection and diffusion: momentum, heat, and mass transfer (Wiley, 2013).

    Google Scholar 

  10. Oh, S. S. & Narver, H. L. Mouse and rat anesthesia and analgesia. Curr. Protoc. 4, e995 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, K. et al. Anesthesia-induced hippocampal-cortical hyperactivity and tau hyperphosphorylation impair remote memory retrieval in Alzheimer’s disease. Alzheimers Dement. 20, 494–510 (2024).

    Article  CAS  PubMed  Google Scholar 

  12. Reichenberger, D. A. et al. Recovery sleep after sleep restriction is insufficient to return elevated daytime heart rate and systolic blood pressure to baseline levels. Psychosom. Med. 85, 744–751 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kroesbergen, E. et al. Glymphatic clearance is enhanced during sleep. Preprint at bioRxiv https://doi.org/10.1101/2024.08.24.609514 (2024).

  14. Kutuzov, N., Flyvbjerg, H. & Lauritzen, M. Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood–brain barrier. Proc. Natl Acad. Sci. USA 115, E9429–E9438 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Qvist, P. et al. Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1+/− mice. Sci. Rep. 8, 16486 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grant R01AT012312 (to M.N.); NINDS R01AT011439 (to M.N.); U19 NS128613 (to M.N.); the Simons Foundation (to M.N.); Novo Nordisk Foundation NNF20OC0066419 (to M.N.); the Lundbeck Foundation R386-2021-165 (M.N.); The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to M.N.); JPND/HBCI 1098-00030B (to M.N.); JPND/Good Vibes 2092-00006B (to M.N.); DOD W911NF2110006 (to M.N.); Independent Research Fund Denmark 3101-00282B (to M.N.); US Army Research Office grants MURI W911NF1910280 (to M.N.); and American Heart Association Career Development Award 941177 (L.M.H.).

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Author notes

  1. These authors contributed equally: Virginia Plá, Erik Kroesbergen.

Authors and Affiliations

  1. Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark

    Virginia Plá, Erik Kroesbergen, Saiyue Deng, Tina Esmail, Ryszard Stefan Gomolka, Yuki Mori, Steven A. Goldman & Maiken Nedergaard

  2. Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA

    Michael J. Giannetto, Lauren M. Hablitz, Evan Newbold, Antonio Ladrón-de-Guevara, Steven A. Goldman & Maiken Nedergaard

  3. Department of Mechanical Engineering, University of Rochester, Rochester, NY, USA

    Douglas H. Kelley & John H. Thomas

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  1. Virginia Plá
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  11. Steven A. Goldman
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Contributions

M.N., V.P. and E.K.: Writing—original draft preparation. V.P., E.K., S.D., M.J.G., L.M.H., E.N., A.L.G., T.E., R.S.G., D.H.K., J.H.T. and M.N.: Writing—reviewing and editing.

Corresponding author

Correspondence to Maiken Nedergaard.

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The authors declare no competing interests. M.N. is a paid consultant for CNS2 for unrelated work.

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Nature Neuroscience thanks the anonymous reviewers for their contribution to the peer review of this work.

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Plá, V., Kroesbergen, E., Deng, S. et al. A curious concept of CNS clearance. Nat Neurosci (2025). https://doi.org/10.1038/s41593-025-01897-3

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