13C 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

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 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.

Citation

Miller, J. J., Grist, J. T., Serres, S., Larkin, J. R., Lau, A. Z., Ray, K., Fisher, K. R., Hansen, E., Tougaard, R. S., Nielsen, P. M., Lindhardt, J., Laustsen, C., Gallagher, F. A., Tyler, D. J., & Sibson, N. (2018). 13C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI. Scientific Reports, 8(1), Article 15082. https://doi.org/10.1038/s41598-018-33363-5

• Journal Article Type: Article
• Acceptance Date: Sep 26, 2018
• Online Publication Date: Oct 10, 2018
• Publication Date: 2018-12
• Deposit Date: Nov 23, 2018
• Publicly Available Date: Nov 26, 2018
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 1
• Article Number: 15082
• DOI: https://doi.org/10.1038/s41598-018-33363-5
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/1304920
• Publisher URL: https://www.nature.com/articles/s41598-018-33363-5
• Contract Date: Nov 26, 2018