Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer
Open accessAbstract
Background: Neurodegenerative diseases such as Alzheimer’s are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Methods: Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30–180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Results: Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Conclusion: Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.
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Clearance of MRI contrast agents such as gadobutrol has previously been proposed to potentially resemble clearance of brain macromolecules with similar properties, including amyloidβ and tau.
“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 [66]
The Background (page unavailable) links glymphatic clearance of interstitial solutes, including amyloid β, to measuring pathway function with gadolinium-enhanced MRI. The Methods (page unavailable) compares tracers by molecular weight. The paper does not specifically discuss gadobutrol or propose that contrast-agent clearance resembles clearance of similarly characterized brain macromolecules; the separate citations attached to amyloid β and tau are not judged here. (LLM, conf=0.82)
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- Authors
- Yang, L., Kress, B. T., Weber, H. J., Thiyagarajan, M., Wang, B., Deane, R., Benveniste, H., Iliff, J. J., & Nedergaard, M.
- Affiliations
- Hebei Medical University (CN)
- University of Rochester Medicine (US)
- Stony Brook University (US)
- Oregon Health & Science University (US)
- Corresponding author
- Iliff, Jeffrey J
- Nedergaard, Maiken
- Venue
- Journal of Translational Medicine
- Published
- 2013-05-01
- Volume
- 11
- Issue
- 1
- Pages
- 107-107
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC3665671
- OpenAlex
- W2166233935
- Cited by
- 317
- References
- 40
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 13 · 2023: 23 · 2022: 39 · 2021: 24 · 2020: 26 · 2019: 27 · 2018: 26 · 2017: 38 · 2016: 24 · 2015: 25 · 2014: 14 · 2013: 4 · 2012: 1
- FWCI
- 10.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- American Heart Association
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS078304, R01NS078167, R01NS075177)
- 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
- glymphatic system, intrathecal infusion, interstitial fluid exchange, amyloid-beta clearance, Alzheimer's disease, neurodegenerative diseases, dynamic contrast-enhanced MRI
- MeSH terms
- Animals, Brain, Cerebrospinal Fluid, Female, Injections, Spinal, Intracranial Pressure, Lumbar Vertebrae, Male, Mice, Inbred C57BL, Molecular Weight, Molecular Probes, Rats, Sprague-Dawley, Extracellular Fluid
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