<sup>13</sup>C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI.
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Authors
Serres, Sébastien
Lau, Angus Z
Ray, Kevin
Nielsen, Per Mose
Lindhardt, Jakob
Sibson, Nicola
Publication Date
2018-10-10Journal Title
Scientific reports
ISSN
2045-2322
Volume
8
Issue
1
Pages
15082
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Miller, J. J., Grist, J., Serres, S., Larkin, J. R., Lau, A. Z., Ray, K., Fisher, K. R., et al. (2018). <sup>13</sup>C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI.. Scientific reports, 8 (1), 15082. https://doi.org/10.1038/s41598-018-33363-5
Abstract
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 [1-13C]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 na¨ıve 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.
Keywords
Blood-Brain Barrier, Cell Line, Tumor, Animals, Swine, Humans, Rats, Brain Neoplasms, Carbon Isotopes, Mannitol, Pyruvic Acid, Magnetic Resonance Imaging, Biological Transport, Kinetics, Female
Sponsorship
MRC (1508766)
Identifiers
External DOI: https://doi.org/10.1038/s41598-018-33363-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285575