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Cited by 690Cerebrospinal fluid and hydrocephalusLymphatic System and DiseasesBarrier Structure and Function Studies

Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice

Open access
Ma, Qiaoli, Ineichen, Benjamin V., Detmar, Michael, Proulx, Steven T.·2017·Nature Communications
DOI 10.1038/s41467-017-01484-6PMC PMC5681558
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Abstract

Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions.

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Crossref · 10.1038/s41467-017-01484-6

Cites

67 of 67 references verified0 citation errors · 0 not checkable

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  • Albumin-binding dyes have reduced clearance to the periphery after ICV infusion in mice and accumulate in perivascular compartments after ICV injection in rats.

    “Prior studies have shown that albumin-binding dyes have reduced clearance to the periphery after intracerebroventricular (ICV) infusion in mice28 and accumulate in perivascular compartments after ICV injection in rats.15,29”

    From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [28]

    The Results section, “CSF outflow of small molecules through the lymphatic system” (page unavailable), reports that less Evans blue reached the bloodstream than two other tracers after ventricular infusion in mice. Our copy does not identify Evans blue as albumin-binding, so that characterization is not verified here. The rat finding is attached to different citations in the citing sentence, not to this paper. (LLM, conf=0.82)

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  • Prior studies have shown that albumin-binding dyes have reduced clearance to the periphery after ICV infusion in mice and accumulate in perivascular compartments after ICV injection in rats.

    “because prior studies have shown that albumin-binding dyes have reduced clearance to the periphery after ICV infusion in mice [23] and accumulate in perivascular compartments after ICV injection in rats [24, 25].”

    From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [23]

  • A recent animal study was unable to reproduce passage of CSF tracer into dural lymphatic vessels.

    “A recent animal study was, however, unable to reproduce passage of CSF tracer into dural lymphatic vessels7”

    From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [7]

  • The present findings stand in contradistinction to a recent CSF tracer study of mice reporting no signs of tracer propagation outside the arachnoid layer and concluding CSF outflow occurred predominantly along cranial nerves through skull neuroforamina.

    “The present findings also stand in contradistinction to a recent CSF tracer study of mice reporting no signs of tracer propagation through outside the arachnoid layer, and concluding that CSF outflow occurred predominately along cranial nerves through skull neuroforamina7.”

    From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [7]

  • Lymphatics have been discovered in the dura mater and just outside holes in the skull bone.

    “Although the CNS parenchyma does not have a conventional lymphatic drainage system (3), lymphatics have been discovered in the dura mater and just outside holes in the skull bone (4-9).”

    From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [9]

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Research works printed but not linked: 4

  1. [16]Bradbury, M. W. B. & Cserr, H. F. in Experimental Biology of the Lymphatic Circulation (ed. Johnston, M. G.) 355–394 (Elsevier, Amsterdam, 1985).
  2. [50]Butler, A. B., van Landingham, K. & McComb, J. G. in Intracranial Pressure V (eds Ishii, S., Nagai, H. & Brock, M.) 598–604 (Springer Berlin, Heidelberg, 1983).
  3. [57]Wagshul, M. E. & Johnston, M. in Immunology of the Lymphatic System (ed. Santambrogio, L.) 143–164 (Springer, New York, NY, 2013).
  4. [67]McComb, J. G., Hyman, S. & Weiss, M. H. in Pathophysiology of the Blood-Brain Barrier (eds Johansson, B. B., Owman, C. & Widner, H.) 421–438 (Elsevier, Amsterdam, 1990).

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Authors
Ma, Q., Ineichen, B. V., Detmar, M., & Proulx, S. T.
Affiliations
  • ETH Zurich (CH)
  • University of Zurich (CH)
Corresponding author
Proulx, Steven T.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-11-10
Volume
8
Issue
1
Pages
1434-1434
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-01484-6
PMC
PMC5681558
OpenAlex
W2768030986
Cited by
690
References
67
Citations by year
2026: 59 · 2025: 91 · 2024: 106 · 2023: 85 · 2022: 107 · 2021: 83 · 2020: 80 · 2019: 44 · 2018: 33 · 2017: 1
FWCI
21.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection (cc-by)
Funders
  • National Science Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A, 130627, 108207, 3100A0)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
cerebrospinal fluid drainage, lymphatic vessels, aging, perivascular spaces, lymph nodes
MeSH terms
Aging, Animals, Arachnoid, Brain, Cerebrospinal Fluid, Coloring Agents, Female, Lymphatic System, Mice, Inbred C57BL, Mice, Transgenic, Lymphatic Vessels, Mice

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