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Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with diffusion tensor MRI
Open accessAbstract
The glymphatics system describes a CSF-mediated clearance pathway for the removal of potentially harmful molecules, such as amyloid beta, from the brain. As such, its components may represent new therapeutic targets to alleviate aberrant protein accumulation that defines the most prevalent neurodegenerative conditions. Currently, however, the absence of any non-invasive measurement technique prohibits detailed understanding of glymphatic function in the human brain and in turn, it’s role in pathology. Here, we present the first non-invasive technique for the assessment of glymphatic inflow by using an ultra-long echo time, low b -value, multi-direction diffusion weighted MRI sequence to assess perivascular fluid movement (which represents a critical component of the glymphatic pathway) in the rat brain. This novel, quantitative and non-invasive approach may represent a valuable biomarker of CSF-mediated brain clearance, working towards the clinical need for reliable and early diagnostic indicators of neurodegenerative conditions such as Alzheimer’s disease.
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Previous studies have proposed microscopic arterial pulsation, corresponding to the ~1 Hz cardiac cycle, as a mechanism for driving interstitial fluid flow.
“Previous studies have proposed microscopic arterial pulsation, corresponding to the ~1 Hz cardiac cycle, as a mechanism for driving interstitial fluid flow (20-23).”
From Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep (2019) · cites this paper as [23]
The Results and Discussion (page not available) identify cerebral arterial pulsation as a driver of perivascular fluid movement. They do not establish interstitial fluid flow or a ~1 Hz cardiac cycle; the rat heart rate reported in the Results was 354 bpm before treatment. (LLM, conf=0.88)
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Impairment of paravascular clearance pathways in the aging brain
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“This, in turn, may help fully characterise impairment of CSF-mediated clearance pathways with age (Kress et al., 2014), as well as the contribution to Ab accumulation in AD.”
BackgroundCerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain
Iliff, J. J., Wang, M., Zeppenfeld, D. M., Venkataraman, A., Plog, B. A., Liao, Y., Deane, R., & Nedergaard, M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1592-13.2013 · Cited by 1,319 · cited 2×
“In addition, given evidence that cerebral arterial pulsation is a key mechanism that drives PVS fluid movement (Rennels et al., 1985; Iliff et al., 2013b), we investigate the dependence of the technique on vascular pulsatility through cardiac gating and modulation by the adrenoceptor agonist, dobutamine.”
BackgroundA new look at cerebrospinal fluid circulation
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Cited by
Sorted by citations
Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019) · Science · doi:10.1126/science.aax5440 · Cited by 1,197
Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension.
Mestre, H., Tithof, J., Du, T., Song, W., Peng, W., Sweeney, A. M., Olveda, G., Thomas, J. H., Nedergaard, M., & Kelley, D. H. (2018) · Nature Communications · doi:10.1038/s41467-018-07318-3 · Cited by 1,110
The Brain’s Glymphatic System: Current Controversies
Mestre, H., Mori, Y., & Nedergaard, M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.04.003 · Cited by 609
Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice
Deng, S., Hu, Y., Chen, S., Xue, Y., Yao, D., Sun, Q., Nedergaard, M., Wang, W., & Ding, F. (2024) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241230188 · Cited by 52
The brain washing system in sepsis-associated encephalopathy
Chen, T., Hu, J., Liao, Y., Xie, S., & Zhang, L. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03602-4 · Cited by 8
40 Years of diffusion MRI in the brain: From history to emerging frontiers
Le Bihan, D. (2026) · Imaging Neuroscience · doi:10.1162/imag.a.1365
“…transport in the same way that tracer studies do, but can probe free-water, CSF flow ( Le Bihan et al., 1987), and perivascular fluid movement ( Harrison et al., 2018), perivascular spaces and adjacent tissue anisotropy, as illustrated by DTI-ALPS ( Naganawa & Taoka, 2022), although this…”
Metadata
- Authors
- Harrison, I. F., Siow, B., Akilo, A. B., Evans, P. G., Ismail, O., Ohene, Y., Nahavandi, P., Thomas, D. L., Lythgoe, M. F., & Wells, J. A.
- Affiliations
- University College London (GB)
- The Francis Crick Institute (GB)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Wells, Jack A
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-07-31
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6117153
- OpenAlex
- W2885225461
- Cited by
- 170
- References
- 10
- Citations by year
- 2026: 21 · 2025: 24 · 2024: 25 · 2023: 26 · 2022: 18 · 2021: 24 · 2020: 14 · 2019: 12 · 2018: 6
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome (Sir Henry Dale Fellowship 204624/Z/16/Z)
- Royal Society (Sir Henry Dale Fellowship 204624/Z/16/Z)
- Engineering and Physical Sciences Research Council (EP/N034864/1, UCL Centre for Doctoral Training in Medical Imaging (EP/L016478/1)
- National Institute for Health Research
- Medical Research Council (MR/K026739/1)
- Department of Health
- Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- glymphatic system, cerebrospinal fluid clearance, diffusion tensor imaging, amyloid-beta clearance, neurodegenerative disease biomarkers, Alzheimer's disease, rat brain
- MeSH terms
- Animals, Brain, Cerebrospinal Fluid, Male, Rheology, Rats, Sprague-Dawley, Imaging, Three-Dimensional, Diffusion Tensor Imaging
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