Simultaneous noninvasive quantification of redox and downstream glycolytic fluxes reveals compartmentalized brain metabolism.

Abstract

Brain metabolism across anatomic regions and cellular compartments plays an integral role in many aspects of neuronal function. Changes in key metabolic pathway fluxes, including oxidative and reductive energy metabolism, have been implicated in a wide range of brain diseases. Given the complex nature of the brain and the need for understanding compartmentalized metabolism noninvasively in vivo, new tools are required. Herein, using hyperpolarized (HP) magnetic resonance imaging coupled with in vivo isotope tracing, we develop a platform to simultaneously probe redox and energy metabolism in the murine brain. By combining HP dehydroascorbate and pyruvate, we are able to visualize increased lactate production in the white matter and increased redox capacity in the deep gray matter. Leveraging positional labeling, we show differences in compartmentalized tricarboxylic acid cycle entry versus downstream flux to glutamate. These findings lay the foundation for clinical translation of the proposed approach to probe brain metabolism.