The glymphatic system: Current understanding and modeling

Tomas Bohr; Poul G Hjorth; Sebastian C Holst; Sabina Hrabětová; Vesa Kiviniemi; Tuomas Lilius; Iben Lundgaard; Kent-Andre Mardal; Erik A Martens; Yuki Mori; U Valentin Nägerl; Charles Nicholson; Allen Tannenbaum; John H Thomas; Jeffrey Tithof; Helene Benveniste; Jeffrey J Iliff; Douglas H Kelley; Maiken Nedergaard

doi:10.1016/j.isci.2022.104987

The glymphatic system: Current understanding and modeling

iScience. 2022 Aug 20;25(9):104987. doi: 10.1016/j.isci.2022.104987. eCollection 2022 Sep 16.

Authors

Tomas Bohr¹, Poul G Hjorth², Sebastian C Holst³, Sabina Hrabětová⁴, Vesa Kiviniemi^{5

6}, Tuomas Lilius^{7

8

9

10}, Iben Lundgaard^{11

12}, Kent-Andre Mardal^{13

14}, Erik A Martens¹⁵, Yuki Mori⁹, U Valentin Nägerl¹⁶, Charles Nicholson^{17

18}, Allen Tannenbaum¹⁹, John H Thomas²⁰, Jeffrey Tithof²¹, Helene Benveniste^{22

23}, Jeffrey J Iliff^{24

25

26}, Douglas H Kelley²⁰, Maiken Nedergaard^{9

27}

Affiliations

¹ Department of Physics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
² Department of Applied Mathematics and Computer Science, Technical University of Denmark, Richard Petersens Plads, 2800 Kgs. Lyngby, Denmark.
³ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland.
⁴ Department of Cell Biology and The Robert Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
⁵ Oulu Functional NeuroImaging, Department of Diagnostic Radiology, MRC, Oulu University Hospital, Oulu, Finland.
⁶ Medical Imaging, Physics and Technology, the Faculty of Medicine, University of Oulu, Oulu, Finland.
⁷ Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁸ Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Department of Emergency Medicine and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
¹¹ Department of Experimental Medical Science, Lund University, Lund, Sweden.
¹² Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
¹³ Department of Mathematics, University of Oslo, Oslo, Norway.
¹⁴ Simula Research Laboratory, Department of Numerical Analysis and Scientific Computing, Oslo, Norway.
¹⁵ Centre for Mathematical Sciences, Lund University, Sweden.
¹⁶ Instítut Interdisciplinaire de Neurosciences, Université de Bordeaux / CNRS UMR 5297, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, CS 61292 Case 130, 33076 Bordeaux Cedex France.
¹⁷ Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USA.
¹⁸ Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
¹⁹ Departments of Computer Science/ Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.
²⁰ Department of Mechanical Engineering, University of Rochester, Rochester, 14627 NY, USA.
²¹ Department of Mechanical Engineering, University of Minnesota, Minneapolis, USA.
²² Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
²³ Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA.
²⁴ VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
²⁶ Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
²⁷ Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, 14642 NY, USA.

Abstract

We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid and interstitial fluid around the brain, facilitating solute transport. Models enable hypothesis development and predictions of transport, with clinical applications including drug delivery, stroke, cardiac arrest, and neurodegenerative disorders like Alzheimer's disease. We sort existing models into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, and links to neuronal activity. Needs and opportunities for future work are highlighted wherever possible; new models, expanded models, and novel experiments to inform models could all have tremendous value for advancing the field.

Keywords: Neuroanatomy; Neuroscience; Systems biology.

Publication types

Review

Grants and funding

R01 AG054456/AG/NIA NIH HHS/United States