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

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.

Autonomous cryogenic RF receive coil for 13C imaging of rodents at 3 T

“…experience, which is a particularly challenging modality due to the reported low level of permeability of the blood-brain barrier in anesthetized animals. 18 The initial results show clear metabolic maps, consistent with the brain anatomy.…”

“…We successfully demonstrated the suitability of the proposed cryogenic coil setup with in vivo experimental conditions, and reported on 2 different experiments of 13 C hyperpolarized metabolic imaging (performed in healthy rats). Rat brain metabolic imaging was chosen for this initial experience, which is a particularly challenging modality due to the reported low level of permeability of the blood–brain barrier in anesthetized animals . The initial results show clear metabolic maps, consistent with the brain anatomy.…”

“…The theoretically predicted SNR enhancement was confirmed with MR experiments, compared to an identical setup at room temperature (with a similar coil‐to‐sample distance), and a more fair comparison to a similar coil placed as close as possible to the sample, where a nearly 2‐fold SNR gain was obtained. Additionally, the setup has been used successfully to obtain 13 C metabolic images of the healthy rat brain in vivo with hyperpolarized [1‐ 13 C]pyruvate, a particularly low SNR case …”

“…Additionally, the setup has been used successfully to obtain 13 C metabolic images of the healthy rat brain in vivo with hyperpolarized [1-13 C]pyruvate, a particularly low SNR case. 17,18…”

Detection of acute kidney injury with hyperpolarized [13C, 15N]Urea and multiexponential relaxation modeling

“…Hyperpolarized 13 C MRI, recently translated in to clinical studies and offers the exciting possibility to noninvasively map biochemical processes and enzymatic activity. [1][2][3][4] Several novel imaging biomarkers have been demonstrated using a variety of hyperpolarized imaging probes beyond hyperpolarized [1-13 C]pyruvate, such as tissue necrosis using [1,[4][5][6][7][8][9][10][11][12][13] C]fumarate, pH with 13 C-bicarbonate and perfusion with urea. 5-7 13 C, 14 N 2 -urea and the longer lived 13 C, 15 N 2 -urea has shown great promise for renal examinations for assessing the perfusion and renal functional dependent urea distribution, in several renal physiological and pathophysiological models.…”