Impaired Glymphatic Transport in Spontaneously Hypertensive Rats
Open accessAbstract
The glymphatic system is a brainwide CSF transport system that uses the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna during dynamic contrast-enhanced MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared with WKY rats, regardless of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the coexistence of hypertension and concomitant vascular pathologies in Alzheimer9s disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system. SIGNIFICANCE STATEMENT The glymphatic system contributes to the removal of amyloid β from the brain and is disrupted in Alzheimer9s disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer9s disease.
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SVD is linked to glymphatic dysfunction in experimental models.
“SVD is linked glymphatic dysfunction in experimental models (91)”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [91]
Glymphatic function is suppressed in hypertensive rats.
“It has been shown that glymphatic function is suppressed in hypertensive rats (91, 92).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [91]
SVD may potentiate progression of neurodegenerative dementias in patients at risk for SVD-associated vascular dementia.
“SVD is linked glymphatic dysfunction in experimental models (91), and may potentiate the progression of neurodegenerative dementias in precisely the same patients at risk for SVD-associated vascular dementia.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [91]
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Glymphatic failure as a final common pathway to dementia
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- Authors
- Mortensen, K. N., Sanggaard, S., Mestre, H., Lee, H., Kostrikov, S., Xavier, A. L. R., Gjedde, A., Benveniste, H., & Nedergaard, M.
- Affiliations
- University of Copenhagen (DK)
- University of Rochester Medicine (US)
- Yale University (US)
- Montreal Neurological Institute and Hospital (CA)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2019-06-17
- Volume
- 39
- Issue
- 32
- Pages
- 6365-6377
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6687896
- OpenAlex
- W2952584877
- Cited by
- 266
- References
- 72
- Citations by year
- 2026: 34 · 2025: 44 · 2024: 55 · 2023: 45 · 2022: 28 · 2021: 40 · 2020: 20
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
- Funders
- European Commission (666881)
- Fondation Leducq (16CVD05)
- Lundbeckfonden (R249-2017-1511, R155-2016–552)
- Novo Nordisk
- Novo Nordisk Fonden (NNF13OC0004258)
- H. Lundbeck A/S
- National Institutes of Health (UL1TR001863)
- National Institute on Aging (RF1AG057575, R01AG048769)
- National Institute of Neurological Disorders and Stroke (RF1NS110049, R01NS100366)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, spontaneously hypertensive rats, hypertension, cerebrospinal fluid flow, perivascular spaces, arterial pulsation, hydrocephalus, dynamic contrast-enhanced MRI, Gd-DOTA, Alzheimer's disease, vascular pathology, amyloid-beta clearance
- MeSH terms
- Glymphatic System, Age Factors, Alzheimer Disease, Animals, Cerebral Ventricles, Cerebrospinal Fluid, Contrast Media, Heterocyclic Compounds, Hypertension, Magnetic Resonance Imaging, Male, Organ Size, Organometallic Compounds, Rats, Inbred SHR, Rats, Inbred WKY, Rheology, Disease Progression, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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