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

Abstract

Purpose: Pyruvate, produced from either glucose, glycogen, or lactate, is the dominant precursor of cerebral oxidative metabolism. Pyruvate dehydrogenase (PDH) flux is a direct measure of cerebral mitochondrial function and metabolism. Detection of [¹³ C]bicarbonate in the brain from hyperpolarized [1-¹³ C]pyruvate using carbon-13 (¹³ C) MRI provides a unique opportunity for assessing PDH flux in vivo. This study is to assess changes in cerebral PDH flux in response to visual stimuli using in vivo ¹³ C MRS with hyperpolarized [1-¹³ C]pyruvate.

Methods: From seven sedentary adults in good general health, time-resolved [¹³ C]bicarbonate production was measured in the brain using 90° flip angles with minimal perturbation of its precursors, [1-¹³ C]pyruvate and [1-¹³ C]lactate, to test the hypothesis that the appearance of [¹³ C]bicarbonate signals in the brain reflects the metabolic changes associated with neuronal activation. With a separate group of healthy participants (n = 3), the likelihood of the bolus-injected [1-¹³ C]pyruvate being converted to [1-¹³ C]lactate prior to decarboxylation was investigated by measuring [¹³ C]bicarbonate production with and without [1-¹³ C]lactate saturation.

Results: In the course of visual stimulation, the measured [¹³ C]bicarbonate signal normalized to the total ¹³ C signal in the visual cortex increased by 17.1% ± 15.9% (p = 0.017), whereas no significant change was detected in [1-¹³ C]lactate. Proton BOLD fMRI confirmed the regional activation in the visual cortex with the stimuli. Lactate saturation decreased bicarbonate-to-pyruvate ratio by 44.4% ± 9.3% (p < 0.01).

Conclusion: We demonstrated the utility of ¹³ C MRS with hyperpolarized [1-¹³ C]pyruvate for assessing the activation of cerebral PDH flux via the detection of [¹³ C]bicarbonate production.

Keywords: bicarbonate; brain activation; dissolution dynamic nuclear polarization; fMRS; hyperpolarized pyruvate; pyruvate dehydrogenase.