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(13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI
Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180068/ https://www.ncbi.nlm.nih.gov/pubmed/30305655 http://dx.doi.org/10.1038/s41598-018-33363-5 |
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author | Miller, Jack J. Grist, James T. Serres, Sébastien Larkin, James R. Lau, Angus Z. Ray, Kevin Fisher, Katherine R. Hansen, Esben Tougaard, Rasmus Stilling Nielsen, Per Mose Lindhardt, Jakob Laustsen, Christoffer Gallagher, Ferdia A. Tyler, Damian J. Sibson, Nicola |
author_facet | Miller, Jack J. Grist, James T. Serres, Sébastien Larkin, James R. Lau, Angus Z. Ray, Kevin Fisher, Katherine R. Hansen, Esben Tougaard, Rasmus Stilling Nielsen, Per Mose Lindhardt, Jakob Laustsen, Christoffer Gallagher, Ferdia A. Tyler, Damian J. Sibson, Nicola |
author_sort | Miller, Jack J. |
collection | PubMed |
description | Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1-(13)C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1-(13)C]pyruvate and ethyl-[1-(13)C]pyruvate in naïve brain, a rodent model of metastasis to the brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier of anaesthetised animals is rate-limiting. We show through use of a well-characterised rat model of brain metastasis that the appearance of hyperpolarized [1-(13)C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1-(13)C]pyruvate, we observe pyruvate production endogenously throughout the entire brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain, which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain barrier permeability in future studies. |
format | Online Article Text |
id | pubmed-6180068 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61800682018-10-15 (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI Miller, Jack J. Grist, James T. Serres, Sébastien Larkin, James R. Lau, Angus Z. Ray, Kevin Fisher, Katherine R. Hansen, Esben Tougaard, Rasmus Stilling Nielsen, Per Mose Lindhardt, Jakob Laustsen, Christoffer Gallagher, Ferdia A. Tyler, Damian J. Sibson, Nicola Sci Rep Article Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1-(13)C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1-(13)C]pyruvate and ethyl-[1-(13)C]pyruvate in naïve brain, a rodent model of metastasis to the brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier of anaesthetised animals is rate-limiting. We show through use of a well-characterised rat model of brain metastasis that the appearance of hyperpolarized [1-(13)C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1-(13)C]pyruvate, we observe pyruvate production endogenously throughout the entire brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain, which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain barrier permeability in future studies. Nature Publishing Group UK 2018-10-10 /pmc/articles/PMC6180068/ /pubmed/30305655 http://dx.doi.org/10.1038/s41598-018-33363-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Miller, Jack J. Grist, James T. Serres, Sébastien Larkin, James R. Lau, Angus Z. Ray, Kevin Fisher, Katherine R. Hansen, Esben Tougaard, Rasmus Stilling Nielsen, Per Mose Lindhardt, Jakob Laustsen, Christoffer Gallagher, Ferdia A. Tyler, Damian J. Sibson, Nicola (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI |
title | (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI |
title_full | (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI |
title_fullStr | (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI |
title_full_unstemmed | (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI |
title_short | (13)C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI |
title_sort | (13)c pyruvate transport across the blood-brain barrier in preclinical hyperpolarised mri |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180068/ https://www.ncbi.nlm.nih.gov/pubmed/30305655 http://dx.doi.org/10.1038/s41598-018-33363-5 |
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