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A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β
Open accessAbstract
Cerebrospinal fluid flows through channels around brain blood vessels that are bounded by astrocytic endfeet, mediated by water transport through aquaporin-4.
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In the citing paper
“The motion of the brain is locally supplemented by the pulsatility of the penetrating arteries, as they enter the brain from the CSF-filled subarachnoid space, thereby driving CSF into the neuropil along the periarteral spaces (24).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [24]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the glymphatic system, a CSF–interstitial fluid transport pathway, supported by perivascular spaces, astrocytic water channels, vascular pulsatility, and meningeal lymphatic drainage, that contributes to waste clearance and fluid homeostasis in the brain (Iliff et al., 2012).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Iliff et al., 2012
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Deletion of AQP4 channels reduces clearance of exogenous Aβ by 65%”
From Sleep Drives Metabolite Clearance from the Adult Brain (2013) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The glymphatic system uses the perivascular spaces as low-resistance routes for fast influx of CSF into deep brain regions1.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The glymphatic system is a highly organized, brain-wide network for cerebrospinal fluid (CSF) transport that exports protein waste, including amyloid and tau1–3.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [1]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Previous animal studies have shown communication between the subarachnoid cerebrospinal fluid (CSF) space and perivascular compartments of the brain (6-10) and spinal cord (11).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“In 2012, a brain-wide pathway for convective transport of waste solutes from the brain was first described and denoted the glymphatic system (7).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Impaired glymphatic function has been suggested to be instrumental in a range of brain diseases; this has been illustrated most in Alzheimer's dementia (7, 19, 20) but has also been shown to be relevant in posttraumatic encephalopathy (21), ageing (22), sleep (23, 24), depression (20), and exercise (25).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Moreover, animal studies report diverging findings regarding the sites of perivascular brain influx and efflux and direction of perivascular flow (7, 15, 16).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“and may thus be a determining factor for parenchymal tracer enrichment more than clearance, which has rather been proposed to be dependent on convective forces and AQP4 status in the glymphatic system (7).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Clearance of MRI contrast agents, such as gadobutrol, has previously been proposed to potentially resemble clearance of brain macromolecules with similar properties (14), including amyloidβ (7) and tau (21, 66).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“For example, studies using injection of fluorescent tracers into cisterna magna of mice have suggested that paravascular circulation occurs via CSF convective flow through the ECS from the para-arterial to the paravenous spaces, which is regulated by AQP4 water channels on astrocytes, and therefore the system was renamed as the 'glymphatic' system (276, 293).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [276]
The cited source says what the claim attributes to it.
In the citing paper
“cerebrospinal fluid (CSF) recirculates through the brain, interchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ (12, 13).”
From Sleep Drives Metabolite Clearance from the Adult Brain (2013) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Influx of CSF is in part driven by arterial pulse waves that propel the movement of CSF inward along periarterial spaces (12).”
From Sleep Drives Metabolite Clearance from the Adult Brain (2013) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that convective movement of ISF is a substantial contributor to the removal of interstitial waste products and other products of cellular activity (12).”
From Sleep Drives Metabolite Clearance from the Adult Brain (2013) · cites this paper as [12]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“This mechanism is how curbing PCSK9 activity provides protection against the vascular aspects of Alzheimer’s pathology [33,77].”
From The Roles of PCSK9 in Alzheimer’s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence (2025) · cites this paper as [77]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Since it is difficult to control when rodents enter natural sleep, anesthesia is commonly used as a proxy for sleep1,24,99,100.”
From Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep (2025) · cites this paper as [1]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“No statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported in previous publications3,4,12.”
From Brain clearance is reduced during sleep and anesthesia (2024) · cites this paper as [4]
Experimental — accuracy not yet measuredIn the citing paper
“The glymphatic system is a highly organized cerebrospinal fluid transport system that shares several key functions with the lymphatic vessels of peripheral tissues, including the export of excess interstitial fluid and proteins”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [24]
In the citing paper
“fluid transport through the glymphatic system is directionally polarized, with influx along penetrating arteries, fluid entry into the neuropil supported by AQP4, and efflux along the peri-venous spaces, as well as along the cranial and spinal nerves (24, 32–34).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [24]
In the citing paper
“Deletion of AQP4 channels reduces both the influx of CSF tracers and the efflux of solutes from the neuropil (24, 30, 31).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [24]
In the citing paper
“The polarized expression of the water channel, AQP4, in the vascular endfeet of astrocytes facilitates glymphatic fluid transport and amyloid-ß export in rodents (24, 30)(Fig. 1).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [24]
In the citing paper
“The expression of aquaporin-4 (AQP4) in astrocytes significantly influences the transport and clearance functions of the glymphatic system.155”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [155]
In the citing paper
“It has previously been shown that neurotoxic molecules such as amyloid-β and tau are cleared from brain tissue along paravenous pathways (the glymphatic system)20”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [20]
In the citing paper
“Molecules from 0.8 to 70 kDa have been shown to penetrate the glia limitans to varying degrees, whereas molecules from 150 to 2000 kDa are confined within the perivascular space (18, 39, 40).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [40]
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Citations
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BackgroundMethodInfluential
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“Of note, this observation has been made not only in regard to exogenous, drug-like substances as mannitol (138) or dextran (137) but also applied to endogenous substances like tau (139–141), betaamyloid (138, 140, 142, 143) or lipoproteins (144), which are involved in the pathogenesis of degenerative encephalopathies.”
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“Astrocytes are also an essential component of the glymphatic system, a brain-wide fluid transport pathway that supports the clearance of potentially harmful metabolic or protein waste products, such as amyloid-β, through the rapid and circadian rhythm-dependent exchange of cerebrospinal fluid and interstitial fluid al…”
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“The IPAD hypothesis is in direct opposition to the current glymphatic system model, where waste drainage 20 occurs along small cerebral veins that merge into larger neck veins before entering the lymphatic system 21 .”
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“glymphatic clearance.(96) However, the importance of AQP4 in glymphatic clearance is still controversial (Reviewed in(97)).”
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“15 In histological sections, PVS appears as a space between the outer aspect of an artery wall and the brain parenchyma (BP) that can be expanded experimentally by the intracerebral injection of Indian ink particles or fl uorescent polystyrene beads.”
BackgroundInfluentialSelf-citationThe glymphatic system: a new perspective on brain diseases
Ding, Z., Fan, X., Zhang, Y., Yao, M., Wang, G., Dong, Y., Liu, J., & Song, W. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1179988 · Cited by 111
“Then the mixture of CSF and ISF was cleared along the perivenous drainage pathways (Iliff et al., 2012).”
BackgroundInfluentialThe Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep
Voumvourakis, K. I., Sideri, E., Papadimitropoulos, G. N., Tsantzali, I., Hewlett, P., Kitsos, D. K., Stefanou, M., Bonakis, A., Giannopoulos, S., Tsivgoulis, G., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11082092 · Cited by 84
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“ISF bulk flow or CSF/ISF PVS flow [8, 27], and the associated term thus models solute advection.”
BackgroundVenular degeneration leads to vascular dysfunction in a transgenic model of Alzheimer’s disease
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Altered neurovascular coupling as measured by optical imaging: a biomarker for Alzheimer’s disease
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“13 In animal models of blast TBI, the glym-phatic pathway is partially responsible for the clearance of p-tau that accumulates in the PVS immediately after an injury.”
Self-citationBrain pharmacokinetics of two BBB penetrating bispecific antibodies of different size
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“8 Since the initial discovery of the glymphatic system in mouse central nervous systems by Iliff et al 9 using 2-photon microscopy in 2012, numerous detection techniques have been developed to evaluate the glymphatic system over the past decade.”
Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration
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“The glymphatic system, first described in 2012, seems particularly important in this regard [23].”
BackgroundInfluentialAmmonia-induced stress response in liver disease progression and hepatic encephalopathy
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“In rodent studies, perivascular glymphatic function has been implicated in the clearance of soluble Aβ and tau (Iliff et al., 2014; Iliff et al., 2012; Ishida et al., 2022).”
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“Distribution of CSF-interstitial fluid in brain tissue has been demonstrated to be via interstitial flow, with arterial pulsation as the driving force.(1) However, a mathematical model(40) suggested that arterial pulsation would only result in diffusion of molecules to the perivascular space rather than triggering int…”
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“This may support the following re fl ective wave that passes along the vessel wall in the opposite direction to blood fl ow and so drive ISF fl ow in the perivascular drainage pathway (Carare et al, 2013; Morris et al, 2014).”
InfluentialPerez, J. G., Tran, N. L., Rosenblum, M. G., Schneider, C. S., Connolly, N. P., Kim, A. J., Woodworth, G. F., & Winkles, J. A. (2015) · Oncogene · doi:10.1038/onc.2015.310 · Cited by 77
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“conducted experiments comparing clearance from Aqp4 knockout (KO) mice, mice lacking AQP4 channels, to wild-type (WT) mice [27].”
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Pulsatile flow drivers in brain parenchyma and perivascular spaces: a resistance network model study
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Health-Promoting Strategies for the Aging Brain
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Sleep as a Therapeutic Target in the Aging Brain
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Self-citationAquaporin 4 deletion exacerbates brain impairments in a mouse model of chronic sleep disruption
Zhang, R., Liu, Y., Chen, Y., Li, Q., Marshall, C., Wu, T., Hu, G., & Xiao, M. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13194 · Cited by 76
Metadata
- Authors
- Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., Nagelhus, E. A., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- University of Oslo (NO)
- Stony Brook University (US)
- Corresponding author
- Iliff, Jeffrey J.
- Nedergaard, Maiken
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2012-08-15
- Volume
- 4
- Issue
- 147
- Pages
- 147ra111-147ra111
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC3551275
- OpenAlex
- W2167183660
- Cited by
- 5,824
- References
- 56
- Citations by year
- 2026: 871 · 2025: 767 · 2024: 669 · 2023: 605 · 2022: 546 · 2021: 456 · 2020: 400 · 2019: 358 · 2018: 281 · 2017: 279 · 2016: 203 · 2015: 160 · 2014: 128 · 2013: 83 · 2012: 13
- FWCI
- 50.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS078304, R01NS078167, R01NS075177, R01NS075345, R01NS052534)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- cerebrospinal fluid flow, interstitial fluid clearance, amyloid-beta clearance, aquaporin-4, astrocytes, Alzheimer's disease, neurodegeneration
- MeSH terms
- Animals, Astrocytes, Biological Transport, Brain, Cerebral Ventricles, Cerebrospinal Fluid, Male, Mice, Inbred C57BL, Water, Amyloid beta-Peptides, Imaging, Three-Dimensional, Microscopy, Fluorescence, Multiphoton, Extracellular Fluid, Mice, Aquaporin 4
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