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.
Highlights
IntroductionThere are numerous distinct properties that an injectable hyperpolarised probe must possess in order to be of biomedical utility: a long nuclear T1, glassing ability, and miscibility with commonly-used electronic free radicals are required from a technical perspective, whereas minimal toxicity, rapid vascular transportation, uptake across the plasma membrane, and subsequent cellular metabolism on the timescale of T1 are required for the probe to be of subsequent biomedical utility[4,5,6]
We initially performed slice-selective hyperpolarised [1-13C]pyruvate MRS weekly on female BD-IX rats following the induction of a well-characterised intracerebral model of breast carcinoma brain metastases using ENU-1564 cells over a four-week period, with visible disruption of the blood-brain barrier (BBB) present at approximately week three
We initially wished to use longitudinal hyperpolarised [1-13C]pyruvate imaging to detect a rodent model of cancer metastasis to the brain by its metabolic phenotype before its direct detection via gadolinium enhanced MRI mediated by disruption of the BBB
Summary
There are numerous distinct properties that an injectable hyperpolarised probe must possess in order to be of biomedical utility: a long nuclear T1, glassing ability, and miscibility with commonly-used electronic free radicals are required from a technical perspective, whereas minimal toxicity, rapid vascular transportation, uptake across the plasma membrane, and subsequent cellular metabolism on the timescale of T1 are required for the probe to be of subsequent biomedical utility[4,5,6]
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