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13C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI.

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cam.issuedOnline2018-10-10
dc.contributor.authorMiller, Jack J
dc.contributor.authorGrist, James T
dc.contributor.authorSerres, Sébastien
dc.contributor.authorLarkin, James R
dc.contributor.authorLau, Angus Z
dc.contributor.authorRay, Kevin
dc.contributor.authorFisher, Katherine R
dc.contributor.authorHansen, Esben
dc.contributor.authorTougaard, Rasmus Stilling
dc.contributor.authorNielsen, Per Mose
dc.contributor.authorLindhardt, Jakob
dc.contributor.authorLaustsen, Christoffer
dc.contributor.authorGallagher, Ferdia A
dc.contributor.authorTyler, Damian J
dc.contributor.authorSibson, Nicola
dc.contributor.orcidMiller, Jack J [0000-0002-6258-1299]
dc.contributor.orcidGrist, James T [0000-0001-7223-4031]
dc.contributor.orcidLarkin, James R [0000-0002-4169-8447]
dc.contributor.orcidFisher, Katherine R [0000-0002-2716-561X]
dc.contributor.orcidLaustsen, Christoffer [0000-0002-0317-2911]
dc.date.accessioned2018-11-22T00:30:15Z
dc.date.available2018-11-22T00:30:15Z
dc.date.issued2018-10-10
dc.description.abstractHyperpolarised 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 [1-13C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1-13C]pyruvate and ethyl-[1-13C]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 [1-13C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1-13C]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.
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.32930
dc.identifier.eissn2045-2322
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285575
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41598-018-33363-5
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectBiological Transport
dc.subjectBlood-Brain Barrier
dc.subjectBrain Neoplasms
dc.subjectCarbon Isotopes
dc.subjectCell Line, Tumor
dc.subjectFemale
dc.subjectHumans
dc.subjectKinetics
dc.subjectMagnetic Resonance Imaging
dc.subjectMannitol
dc.subjectPyruvic Acid
dc.subjectRats
dc.subjectSwine
dc.title13C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI.
dc.typeArticle
dcterms.dateAccepted2018-09-26
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameSci Rep
prism.startingPage15082
prism.volume8
pubs.funder-project-idMRC (1508766)
pubs.funder-project-idCancer Research Uk (None)
rioxxterms.licenseref.startdate2018-10-10
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41598-018-33363-5

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