Synopsis

An introduction to the use of 13C and 1H-13C MRS to measure metabolic fluxes in pre clinical models and clinical research studies will be presented. The presentation will have the following sections: 1. introduction to 13C MRS 2. use of 13C MRS to measure metabolite labeling 3. calculations of metabolic fluxes from metabolite labeling curves 4. applications to study metabolism in health and disease 5. application to study therapy. The main goals are to provide the audience with basic knowledge of how to perform and interpret 13C MRS measurements of metabolic fluxes and their potential for use in clinical research.

¹³C Measurements of Metabolic Fluxes, not Hyperpolarized

Douglas L. Rothman

Yale University School of Medicine

Target Audience

This talk is directed at scientists with a basic background in MRS and metabolism who are interested in using ¹³C MRS to measure metabolic fluxes and/or interpret studies using these methods.

Outcome/Objectives

• Understand the basic principles of the ¹³C MRS measurement and its spatial and temporal resolution

• Understand the basics of how in combination with ¹³C isotopes metabolic fluxes are measured.

• Understand the difference between dynamic and steady state ¹³C MRS flux measurements.

• Understand the difference between hyperpolarized and natural polarization ¹³C MRS.

• Understand the strategy of how ¹³C MRS can be used to study disease or follow treatment.

Purpose

• Introduce the basics of ¹³C MRS and ¹H ¹³C MRS

• Introduce the basics of how ¹³C MRS time course data during infusion of 13C labeled substrates is used to measure key metabolic fluxes

• Give examples of how metabolic fluxes are altered in disease

• Give examples of how ¹³C MRS can be used to track treatment.

Methods

• ¹³C and ¹H-¹³C MRS.

• ¹³C isotope labeling of metabolic pathways

• Metabolic modeling of ¹³C kinetic data

Results

• ¹³C and ¹H -¹³C MRS spectra obtained from preclinical and clinical research studies.

• ¹³C isotopic time courses of metabolite labeling from these studies.

• Metabolic fluxes calculated from ¹³C isotopic the time courses.

• Altered metabolic fluxes in disease measured by ¹³C MRS.

Conclusions

¹³C MRS is the only method available for non invasively measuring metabolic fluxes in animal models and humans.

¹³C MRS (and the more sensitive ¹H- ¹³C MRS) have made significant contributions to understanding basic brain, muscle, liver, and heart metabolism and the metabolic basis of disease in these organs including cancer, diabetes, epilepsy, and psychiatric disorders.

Recent studies suggest that ¹³C MRS will be a valuable method for both developing new treatments and potentially assessing treatment effectiveness in patients.

Acknowledgements

References

References

Review papers:

Krssak M C-13 MRS in human tissue. EMAGRES 5(1),. 1027-1037 2016.

Malloy CR, Sherry AD, Jeffery FMH. Heart by ¹³C NMR. Chaper 10. In Cardiovascular Magnetic Resonance Spectroscopy. Springer Science 2012.

Rothman DL, de Feyter HM, de Graaf RA, Mason GF, Behar KL. ¹³C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR in Biomed. Volume: 24 Issue: 8 Special Issue: SI Pages: 943-957, 2011.

de Graaf RA, Rothman,DL , Behar, KL. State of the art ¹³C and indirect ¹H-¹³C NMR Spectroscopy in Vivo: A Practical Guide. NMR in Biomed. Volume: 24 Issue: 8 Special Issue: SI Pages: 958-972, 2011 Oct

Henry PG, Adriany G, Deelchand D, Gruetter R, Marjanska M, Oz G, Seaquest RE , Shestov A, Ugurbil K. In vivo 13C NMR spectroscopy and metabolic modeling in the brain: a practical perspective. Magnetic Resonance Imaging. 24(4), 527-539 (2007).

Ross B, Lin A, harris K, Bhattacharya P, Schweinsburg B. Clinical experience with 13C MRS in vivo. NMR Biomed 16:358-369, 2003.

Some of the studies referred to in the presentation

Li S, An L, Yu S, Ferraris AM, Johnson CS, Wang S. 13C MRS of human brain at 7T using 2-13C glucose infusion and low power broadband stochastic proton decoupling. Magn Reson Med. 75(3) 954-61 2016.

De Feyter HMD, Behar KL, Rao JU, Kriby MH, Ip KL, Hyder F, Drewes LR, Geschwind J, de Graaf RA, Rothman DL. A ketogenic diet increase transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth. Neurooncology. 18(8), 1079-1087, 2016.

Petersen KF, Befroy DE, Dufour S, Rothman DL, Shulman GI. Direct assessment of hepatic mitochondrial oxidation and pyruvate cycling in nonalcoholic fatty liver disease by ¹³C magnetic resonance spectroscopy. Cell metabolism. 24(1), 157-171, 2016.

Abdallah CG, Jiang J, De Feyter HM, Fasula M, Krystal JH, Rothman DL, Mason GF, Sanacora G. Reduced glutamate metabolism in major depressive disorder. American Journal of Psychiatry (USA). 171 (12), 1320-1327, 2014