1H magnetic resonance spectroscopy of 2H-to-1H exchange quantifies the dynamics of cellular metabolism in vivo

Abstract

Quantitative mapping of the in vivo dynamics of cellular metabolism via non-invasive imaging contributes to our understanding of the initiation and progression of diseases associated with dysregulated metabolic processes. Current methods for imaging cellular metabolism are limited by low sensitivities, costs or the use of specialized hardware. Here, we introduce a method that captures the turnover of cellular metabolites by quantifying signal reductions in proton magnetic resonance spectroscopy (MRS) resulting from the replacement of 1H with 2H. The method, which we termed quantitative exchanged-label turnover MRS, only requires deuterium-labelled glucose and standard magnetic resonance imaging scanners, and with a single acquisition provides steady-state information and metabolic rates for several metabolites. We used the method to monitor glutamate, glutamine, γ-aminobutyric acid and lactate in the brains of unaffected and glioma-bearing rats following the administration of 2H2-labelled glucose and 2H3-labelled acetate. Quantitative exchanged-label turnover MRS should broaden the applications of routine 1H MRS.

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Fig. 1: Fundamentals of qMRS.
Fig. 2: Simultaneous qMRS and DMRS acquisition in normal rat brain.
Fig. 3: Comparison of qMRS and DMRS metabolite quantification.
Fig. 4: Kinetics of deuterium labelling of neural metabolites.
Fig. 5: Detection of glycolysis in rat glioblastoma.
Fig. 6: Metabolic imaging of neural metabolism.

Data availability

The main data supporting the results of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too big to be shared publicly, but they are available for research purposes from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank D. Reddy for help with the animal model preparation, M. Elliot for expertise in MRS acquisition and processing and S. Pickup and W. Liu for technical assistance with using the 9.4 T horizontal bore animal magnetic resonance scanner. The authors also thank G. Mizsei for constructing the deuterium coil, H. Poptani for providing insight into CSI acquisition and processing on the 9.4 T preclinical scanner and R. de Graaf for providing guidance during interfacing of the deuterium coil to the scanner console. This work was carried out at a US National Institutes of Health-supported resource, with funding from the NIBIB (under grant no. P41 EB015893), the National Institute of Neurological Disorders and Stroke (award no. R01NS087516) and training grant no. T32EB020087-02.

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R.R. conceived of and designed the study and contributed to data analyses, manuscript writing and editing. L.J.R. and P.B. contributed to the conception and design of the study, performed the experiments, analysed the data and wrote the manuscript. N.E.W. provided insights on the data analyses and contributed to spectral denoising of the datasets. M.D.S., J.A.D. and M.H. contributed to manuscript writing and editing.

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Correspondence to Ravinder Reddy.

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Supplementary Figs. 1–6 and references.

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Rich, L.J., Bagga, P., Wilson, N.E. et al. 1H magnetic resonance spectroscopy of 2H-to-1H exchange quantifies the dynamics of cellular metabolism in vivo. Nat Biomed Eng 4, 335–342 (2020). https://doi.org/10.1038/s41551-019-0499-8

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