Dynamic ¹³C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans

Abstract

This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-13 C]pyruvate in the human brain.Methods: Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/ 1 H dualfrequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO − 3 . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval.Results: [1-13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [ 13 C] HCO − 3 /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO − 3 were calculated as 0.

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1‐13C]pyruvate

“…Each participant underwent a 1 H/ 13 C‐integrated MR protocol (45–60 min), which includes proton ( 1 H) BOLD fMRI, 1 H MPRAGE, and two dynamic 13 C MRS with separate injections of hyperpolarized [1‐ 13 C]pyruvate (pyruvate concentration = 250 mM, dose = 0.1 mmol/kg body weight, volume = 0.43 mL/kg, injection rate = 5 mL/s) with a 30‐min interval between the injections (Figure 2A). A 13 C/ 1 H dual‐frequency head coil (Clinical MR Solutions, LLC, Brookfield, WI) that consists of 1 H quadrature transmit and receive, 13 C quadrature transmit, and eight‐channel 13 C receive arrays was used for the study 9 (Figure 2B ) .…”

“…Dynamic MRS in combination with RF receive arrays has demonstrated robust regional detection of time-resolved hyperpolarized [ 13 C]bicarbonate in human brains. 9 However, dynamic 13 C MRS of hyperpolarized signals using a constant flip angle limits the RF sampling of product peaks at each timepoint and carries over the remaining "unsampled" signals to the next timepoint, making the sectional quantification of the products complicated. Moreover, lactate may play a significant role in the production of bicarbonate because the interconversion of pyruvate and lactate, catalyzed by the enzyme lactate dehydrogenase, is rapid and can occur before and after reaching brain tissues.…”

“…The advent of dissolution dynamic nuclear polarization of carbon‐13 ( 13 C)‐labeled pyruvate enabled in vivo assessment of oxidative phosphorylation in the mitochondria as the production of [ 13 C]bicarbonate from administered hyperpolarized [1‐ 13 C]pyruvate is a biomarker of PDH flux 5 . High‐resolution 13 C imaging of cerebral metabolism in rodents using hyperpolarized [1‐ 13 C]pyruvate 6 and its recent translation to human studies 7–9 have reported that [ 13 C]bicarbonate is primarily produced in the cerebral cortex where the majority of neuron cell bodies are located. The absence or miniscule amounts of labeled metabolic products specific to pyruvate carboxylase in astrocytes supports that the detected [ 13 C]bicarbonate is predominantly produced from neurons 9–11 .…”

“…High‐resolution 13 C imaging of cerebral metabolism in rodents using hyperpolarized [1‐ 13 C]pyruvate 6 and its recent translation to human studies 7–9 have reported that [ 13 C]bicarbonate is primarily produced in the cerebral cortex where the majority of neuron cell bodies are located. The absence or miniscule amounts of labeled metabolic products specific to pyruvate carboxylase in astrocytes supports that the detected [ 13 C]bicarbonate is predominantly produced from neurons 9–11 . Coupling neuronal metabolism with hyperpolarized bicarbonate has not been actively explored in preclinical models because the pyruvate metabolism is heavily impacted by the anesthetic condition 12–14 ; therefore, detection of in vivo [ 13 C]bicarbonate production in humans presents exciting opportunities to assess the activation of neuronal metabolism directly.…”

“…However, it is also possible that the large variation is attributed to the difficulty of reliably imaging [ 13 C]bicarbonate in the human brain. Dynamic MRS in combination with RF receive arrays has demonstrated robust regional detection of time‐resolved hyperpolarized [ 13 C]bicarbonate in human brains 9 . However, dynamic 13 C MRS of hyperpolarized signals using a constant flip angle limits the RF sampling of product peaks at each timepoint and carries over the remaining “unsampled” signals to the next timepoint, making the sectional quantification of the products complicated.…”