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Cited by 318Cerebrospinal fluid and hydrocephalusBarrier Structure and Function StudiesAlzheimer's disease research and treatments

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Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer

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Yang, Lijun, Kress, Benjamin T, Weber, Harris J, Thiyagarajan, Meenakshisundaram, Wang, Baozhi, Deane, Rashid, Benveniste, Helene, Iliff, Jeffrey J, Nedergaard, Maiken·2013·Journal of Translational Medicine
DOI 10.1186/1479-5876-11-107PMC PMC3665671
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Abstract

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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Crossref · 10.1186/1479-5876-11-107

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Figure 1 Defining the effect of intrathecal tracer infusion on intracranial pressure (ICP). Ventricular ICP was monitored continuously during infusion of CSF tracer Texas Red-conjugated dextran (TR-d3, MW 3 kD) in rats. (A) Intracisternal TR-d3 infusion at 1.6 ul/min did not appreciatively alter ICP, whereas increasing the infusion rate to 3.2 and 6.4 ul/min significantly elevated ICP. (B) Intracisternal and lumbar infusion of TR-d3 did at 1.6 μl/min for 60min did not significantly alter ICP (n = 4 per group).
Figure 1 Defining the effect of intrathecal tracer infusion on intracranial pressure (ICP). Ventricular ICP was monitored continuously during infusion of CSF tracer Texas Red-conjugated dextran (TR-d3, MW 3 kD) in rats. (A) Intracisternal TR-d3 infusion at 1.6 ul/min did not appreciatively alter ICP, whereas increasing the infusion rate to 3.2 and 6.4 ul/min significantly elevated ICP. (B) Intracisternal and lumbar infusion of TR-d3 did at 1.6 μl/min for 60min did not significantly alter ICP (n = 4 per group).CC BY · PubMed Central
Figure 2 Evaluating intracisternal CSF tracer influx and clearance in mouse and rat. Representative anterior (A-B) and posterior (D-E) coronal slices from mouse (A, D) and rat (B, E) brains following intracisternal infusion of Texas Red-conjugated dextran (TR-d3, MW 3kD; t = 30min post-infusion) show similar tracer distributions between species. (C, F) Un-infused rat brain slices exhibit little tissue autofluorescence. (G-J) Tissue fluorescence was evaluated in different brain regions: cortex (blue), white matter (grey), hippocampus (magenta), and subcortical structures (red) of the anterior (G-H) and posterior (I-J) brain. (H, J) Quantification of mean fluorescence intensity within each region (*P < 0.05 cortex vs. subcortical structures; ##P < 0.01 cortex vs. white matter structures; 2-way ANOVA; n = 3–4 per time point). Dashed line indicates average gray matter tissue autofluorescence level.
Figure 2 Evaluating intracisternal CSF tracer influx and clearance in mouse and rat. Representative anterior (A-B) and posterior (D-E) coronal slices from mouse (A, D) and rat (B, E) brains following intracisternal infusion of Texas Red-conjugated dextran (TR-d3, MW 3kD; t = 30min post-infusion) show similar tracer distributions between species. (C, F) Un-infused rat brain slices exhibit little tissue autofluorescence. (G-J) Tissue fluorescence was evaluated in different brain regions: cortex (blue), white matter (grey), hippocampus (magenta), and subcortical structures (red) of the anterior (G-H) and posterior (I-J) brain. (H, J) Quantification of mean fluorescence intensity within each region (*P < 0.05 cortex vs. subcortical structures; ##P < 0.01 cortex vs. white matter structures; 2-way ANOVA; n = 3–4 per time point). Dashed line indicates average gray matter tissue autofluorescence level.CC BY · PubMed Central
Figure 3 Effect of molecular weight on tracer influx into the brain after lumbar intrathecal infusion. (A-B) Coronal brain slices show penetration of large molecular weight FITC-conjugated dextran (FITC-d500, MW 500kD) and small molecular weight Texas Red-conjugated dextran (TR-d3, MW 3kD) 120 min after lumbar intrathecal co-infusion. FITC-d500 is largely confined to perivascular spaces (B, arrows), while TR-d3 moves readily though the brain parenchyma from perivascular spaces (A, arrows) or from the pial surface (arrowheads). (C-F) Quantification of fluorescent tracer influx into anterior (C-D) and posterior (E-F) brain after lumbar intrathecal infusion, anatomically subdivided into cortex, white matter, subcortical structures, and hippocampus.(*P < 0.05, *P < 0.01 cortex vs. subcortical structures; ##P < 0.01 cortex vs. white matter; †P < 0.05, ††P < 0.01 cortex vs. hippocampus; 2-way ANOVA; n = 3-4 per time point).
Figure 3 Effect of molecular weight on tracer influx into the brain after lumbar intrathecal infusion. (A-B) Coronal brain slices show penetration of large molecular weight FITC-conjugated dextran (FITC-d500, MW 500kD) and small molecular weight Texas Red-conjugated dextran (TR-d3, MW 3kD) 120 min after lumbar intrathecal co-infusion. FITC-d500 is largely confined to perivascular spaces (B, arrows), while TR-d3 moves readily though the brain parenchyma from perivascular spaces (A, arrows) or from the pial surface (arrowheads). (C-F) Quantification of fluorescent tracer influx into anterior (C-D) and posterior (E-F) brain after lumbar intrathecal infusion, anatomically subdivided into cortex, white matter, subcortical structures, and hippocampus.(*P < 0.05, *P < 0.01 cortex vs. subcortical structures; ##P < 0.01 cortex vs. white matter; †P < 0.05, ††P < 0.01 cortex vs. hippocampus; 2-way ANOVA; n = 3-4 per time point).CC BY · PubMed Central
Figure 4 CSF tracer localization after intracisternal and lumbar intrathecal infusion. (A-F) Localization of FITC-conjugated dextran (FITC-d500, MW 500kD) and Texas Red-conjugated dextran (TR-d3, MW 3 kD) 30 min after intracisternal infusion. Large molecular weight FITC-d500 remained restricted to perivascular spaces (arrows) surrounding penetrating arteries (A-B) and extending to the level of the terminal capillary beds (C-F, arrows). Small molecular weight TR-d3 moved quickly into the brain interstitium and was taken up by subpopulations of neurons (arrowheads). (G-L) 120 min after lumbar intrathecal infusion of tracers, large molecular weight FITC-d500 accumulated in perivascular spaces (arrows), but not as uniformly as observed after intracisternal infusion. Small molecular weight TR-d3 moved readily throughout the brain parenchyma. Inset (L) depicts IB4 staining and background green and red fluorescence in tissue from animals not injected with CSF tracer. GFAP: glial fibrillary acidic protein (astrocytic marker); IB4: isolectin B4 (vascular endothelial marker).
Figure 4 CSF tracer localization after intracisternal and lumbar intrathecal infusion. (A-F) Localization of FITC-conjugated dextran (FITC-d500, MW 500kD) and Texas Red-conjugated dextran (TR-d3, MW 3 kD) 30 min after intracisternal infusion. Large molecular weight FITC-d500 remained restricted to perivascular spaces (arrows) surrounding penetrating arteries (A-B) and extending to the level of the terminal capillary beds (C-F, arrows). Small molecular weight TR-d3 moved quickly into the brain interstitium and was taken up by subpopulations of neurons (arrowheads). (G-L) 120 min after lumbar intrathecal infusion of tracers, large molecular weight FITC-d500 accumulated in perivascular spaces (arrows), but not as uniformly as observed after intracisternal infusion. Small molecular weight TR-d3 moved readily throughout the brain parenchyma. Inset (L) depicts IB4 staining and background green and red fluorescence in tissue from animals not injected with CSF tracer. GFAP: glial fibrillary acidic protein (astrocytic marker); IB4: isolectin B4 (vascular endothelial marker).CC BY · PubMed Central

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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
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2013-05-01
Volume
11
Issue
1
Pages
107-107
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/1479-5876-11-107
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
FWCI
10.96
Type
journal article
Language
en
Open access
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
  • Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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