Target Audience

Imaging scientists/radiologists, physiologists, neuroscientists, neurologists

Learning Objectives

1. We will provide an overview of recent developments in glymphatic system (GS), which is a perivascular pathway that is dedicated to the metabolic waste drainage in the brain.
2. We will discuss our current understanding we know about the relationship between sleep and glymphatics in healthy individuals.
3. We will discuss current imaging modalities that can assess both the glymphatic systems and CSF transport in sleep.
4. We will examine the recent progress made in our understanding of how changes in sleep affect the glymphatic system with sleep disorders and neurodegenerative diseases that have sleep pathologies.

Glymphatics and Sleep relationship

There is a relationship between sleep and the glymphatic system, with increased solute clearance and cerebrospinal fluid flow during sleep. This coupling was originally observed in rodent models, showing a 60% increase in the interstitial space in both sleep and anesthesia (Xie et al., 2013). Recent studies in humans have also shown increases in both CSF volume and circulation in sleep states (Demiral et al., 2019) (Fultz et al., 2019).

Imaging Modalities

Although there have been recent advances in our understanding of the relationship between sleep and glymphatics, it is important to note we are still limited in our tools to measure these systems non-invasively in humans. As of now, the primary MR-based tools that assess aspects of changes in cerebrospinal fluid flow are tracer studies, phase-contrast MRI, BOLD fMRI, diffusion-weighted imaging (DWI), and magnetic resonance encephalography (Chong et al., 2022).

Glymphatics, Sleep, and Sleep Pathologies

Understanding completely how these dynamics work in sleep disordered individuals is difficult because we cannot directly measure glymphatics in humans and there are variabilities in pathologies. Often the waste products that are moved through the glymphatic system have been associated with neurodegenerative diseases that have sleep pathologies (Taoka et al., 2017)(Ringstad et al., 2018). This association between waste product movement, the glymphatic system, and sleep has led recent studies to attempt parse apart how these systems are related to sleep disorders and related pathologies. The relationship between sleep disorders and the glymphatic system is at many points still being examined in animal models and thus still needs to be examined in humans. Here, we will discuss disorders that have relationships with sleep disruption and their glymphatic system, focusing primarily on Alzheimer’s disease, neurodegeneration, obstructive sleep apnea, and narcolepsy.

Conclusion

Although there have been major advances in our understanding of the relationship between sleep, the glymphatic system, and sleep disorders, the literature still presents an incomplete picture. Recent work suggests that these systems may be impacted in clinical conditions. Moving forward, non-invasive imaging methods allow researchers to examine components of these systems and their relationship with sleep in humans, and as these tools progress, they will allow for insight into the relationship between sleep-related disorders and glymphatics.

Acknowledgements

We thank Stephanie Williams and Dr. Daniel Gomez for their comments.

References

Chong, P. L. H., Garic, D., Shen, M. D., Lundgaard, I., & Schwichtenberg, A. J. (2022). Sleep, cerebrospinal fluid, and the glymphatic system: A systematic review. Sleep Medicine Reviews, 61, 101572. https://doi.org/10.1016/j.smrv.2021.101572

Demiral, Ş. B., Tomasi, D., Sarlls, J., Lee, H., Wiers, C. E., Zehra, A., Srivastava, T., Ke, K., Shokri-Kojori, E., Freeman, C. R., Lindgren, E., Ramirez, V., Miller, G., Bandettini, P., Horovitz, S., Wang, G.-J., Benveniste, H., & Volkow, N. D. (2019). Apparent diffusion coefficient changes in human brain during sleep – Does it inform on the existence of a glymphatic system? NeuroImage, 185, 263–273. https://doi.org/10.1016/j.neuroimage.2018.10.043

Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019). Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science, 366(6465), 628–631. https://doi.org/10.1126/science.aax5440

Ringstad, G., Valnes, L. M., Dale, A. M., Pripp, A. H., Vatnehol, S.-A. S., Emblem, K. E., Mardal, K.-A., & Eide, P. K. (n.d.). Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight, 3(13), e121537. https://doi.org/10.1172/jci.insight.121537

Taoka, T., Masutani, Y., Kawai, H., Nakane, T., Matsuoka, K., Yasuno, F., Kishimoto, T., & Naganawa, S. (2017). 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. Japanese Journal of Radiology, 35(4), 172–178. https://doi.org/10.1007/s11604-017-0617-z

Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., Takano, T., Deane, R., & Nedergaard, M. (2013). Sleep Drives Metabolite Clearance from the Adult Brain. Science, 342(6156), 373–377. https://doi.org/10.1126/science.1241224