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Cited by 353Cerebrospinal fluid and hydrocephalusBarrier Structure and Function StudiesAlzheimer's disease research and treatments

Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases

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Bakker, Erik N. T. P., Bacskai, Brian J., Arbel-Ornath, Michal, Aldea, Roxana, Bedussi, Beatrice, Morris, Alan W. J., Weller, Roy O., Carare, Roxana O.·2016·Cellular and Molecular Neurobiology
DOI 10.1007/s10571-015-0273-8PMC PMC4844641
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Abstract

The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (Aβ). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer's disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that Aβ is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of Aβ in the glia limitans in Alzheimer's disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of Aβ. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance.

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  • Solutes diffuse across brain extracellular spaces and are cleared along the basement membranes of arterial vessel walls by perivascular interstitial fluid flow, which travels in the reverse direction of blood flow.

    “Besides the major role of transvascular transport in clearance of solutes across the BBB by CMT, RMT, major facilitators, and active efflux transporters (514, 682, 693), solutes diffuse across brain ECS and are cleared along the basement membranes of the arterial vessel walls by the perivascular ISF flow, which travels in the reverse direction of the blood flow (37, 514, 581) (FIGURE 4) .”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [37]

    The Introduction’s Interstitial Fluid section says solutes diffuse through the extracellular space and ISF drains along arterial basement membranes. The Perivascular and Paravascular Clearance Pathways section describes drainage opposite to blood flow as a suggested route and notes controversy over flow direction. The claim presents that direction as established rather than proposed; page numbers are not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Under physiological conditions, brain-derived molecules secreted into interstitial fluid are present at higher concentrations in the interstitial fluid than in the cerebrospinal fluid.

    “This concept is supported by recent findings showing that under physiological conditions brain-derived molecules secreted into ISF are present at higher concentrations in the ISF than in the CSF (32, 37, 160, 162, 514, 581).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [37]

    The Introduction’s “Interstitial Fluid (ISF)” section says ISF contains tissue metabolites and secreted proteins, including Aβ. Neither that section nor the “Cerebrospinal Fluid (CSF)” section establishes that brain-derived molecules have higher concentrations in ISF than in CSF under physiological conditions; the CSF concentration comparison given is with plasma. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The centripetal pattern of brain enhancement seems to contradict studies in which intraparenchymal tracers were injected and described as leaving the brain centrifugally along the walls of arteries.

    “The centripetal pattern of brain enhancement seems to contradict studies in which intraparenchymal tracers have been injected and described as leaving the brain centrifugally along the walls of arteries (15, 46).”

    From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [46]

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Cited by

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Authors
Bakker, E. N. T. P., Bacskai, B. J., Arbel-Ornath, M., Aldea, R., Bedussi, B., Morris, A. W. J., Weller, R. O., & Carare, R. O.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Massachusetts General Hospital (US)
  • University of Southampton (GB)
  • Southampton General Hospital (GB)
Corresponding author
Carare, Roxana O.
ORCID
Venue
Cellular and Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2016-03
Volume
36
Issue
2
Pages
181-194
ISSN
  • 0272-4340 (ISSN-L)
  • 1573-6830
DOI
10.1007/s10571-015-0273-8
PMC
PMC4844641
OpenAlex
W2298163613
Cited by
353
References
19
Citations by year
2026: 12 · 2025: 19 · 2024: 22 · 2023: 31 · 2022: 43 · 2021: 45 · 2020: 54 · 2019: 39 · 2018: 35 · 2017: 38 · 2016: 15
FWCI
4.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Neurobiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Biotechnology and Biological Sciences Research Council
  • Kirby Laing Foundation
  • Rosetrees Trust
  • Alzheimer’s Research UK
  • Engineering and Physical Sciences Research Council (EP/G03690X/1)
  • National Institutes of Health (EB000768)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
perivascular spaces, cerebrospinal fluid, interstitial fluid, amyloid-beta clearance, Alzheimer's disease, cerebral amyloid angiopathy, glia limitans, subarachnoid space, neurodegenerative diseases, vascular pathology
MeSH terms
Animals, Brain, Cerebrovascular Circulation, Humans, Lymph, Models, Biological, Neurodegenerative Diseases

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