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

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. A method that quantifies signal reductions in proton magnetic resonance spectroscopy resulting from the replacement of 1H with 2H after the administration of a deuterated substrate can be used to monitor the turnover of cellular metabolites in vivo.

[1]  J. Haxby,et al.  Positron emission tomography in Alzheimer's disease , 1986, Neurology.

[2]  Arvind Caprihan,et al.  Comparative reliability of proton spectroscopy techniques designed to improve detection of J‐coupled metabolites , 2008, Magnetic resonance in medicine.

[3]  L. Ko,et al.  Morphological characterization of nitrosourea-induced glioma cell lines and clones , 2004, Acta Neuropathologica.

[4]  Anke Henning,et al.  Methodological consensus on clinical proton MRS of the brain: Review and recommendations , 2019, Magnetic resonance in medicine.

[5]  P. Sundgren,et al.  Magnetic resonance spectroscopy. , 2005, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[6]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[7]  R G Shulman,et al.  The Flux from Glucose to Glutamate in the Rat Brain in vivo as Determined by 1-Observed, 13C-Edited NMR Spectroscopy , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  O. Snead,et al.  GABA, γ‐hydroxybutyric acid, and neurological disease , 2003 .

[9]  Wei Min,et al.  Spectral tracing of deuterium for imaging glucose metabolism , 2019, Nature Biomedical Engineering.

[10]  A. Schousboe,et al.  The glutamate/GABA‐glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer , 2006, Journal of neurochemistry.

[11]  F. Hyder,et al.  In vivo 13C and 1H‐[13C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer , 2019, NMR in biomedicine.

[12]  J. Tonn,et al.  Molecular imaging of gliomas with PET: opportunities and limitations. , 2011, Neuro-oncology.

[13]  P. Bottomley Spatial Localization in NMR Spectroscopy in Vivo , 1987, Annals of the New York Academy of Sciences.

[14]  R. Gruetter,et al.  Glutamatergic and GABAergic energy metabolism measured in the rat brain by 13C NMR spectroscopy at 14.1 T , 2013, Journal of neurochemistry.

[15]  K. Behar,et al.  In vivo 1H‐[13C]‐NMR spectroscopy of cerebral metabolism , 2003, NMR in biomedicine.

[16]  P. G. Morris,et al.  Nuclear Magnetic Resonance Imaging in Medicine and Biology , 1986 .

[17]  R. Kreis Issues of spectral quality in clinical 1H‐magnetic resonance spectroscopy and a gallery of artifacts , 2004, NMR in biomedicine.

[18]  Rolf Gruetter,et al.  In vivo 13C NMR spectroscopy and metabolic modeling in the brain: a practical perspective. , 2006, Magnetic resonance imaging.

[19]  R. de Beer,et al.  Java-based graphical user interface for MRUI, a software package for quantitation of in vivo/medical magnetic resonance spectroscopy signals , 2001, Comput. Biol. Medicine.

[20]  C. Thompson,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[21]  K. Behar,et al.  State of the art direct 13C and indirect 1H‐[13C] NMR spectroscopy in vivo. A practical guide , 2011, NMR in biomedicine.

[22]  Wei Chen,et al.  Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  C S Patlak,et al.  A method to obtain infusion schedules for prescribed blood concentration time courses. , 1976, Journal of applied physiology.

[24]  K. Behar,et al.  In vivo neurochemical profiling of rat brain by 1H‐[13C] NMR spectroscopy: cerebral energetics and glutamatergic/GABAergic neurotransmission , 2010, Journal of neurochemistry.

[25]  Hellmut Merkle,et al.  Dynamic Imaging of Glucose and Lactate Metabolism by 13C-MRS without Hyperpolarization , 2019, Scientific Reports.

[26]  Nirbhay N. Yadav,et al.  Chemical exchange saturation transfer (CEST): What is in a name and what isn't? , 2011, Magnetic resonance in medicine.

[27]  U. Keller,et al.  13C NMR for the assessment of human brain glucose metabolism in vivo. , 1991, Biochemistry.

[28]  R G Shulman,et al.  13C NMR of intermediary metabolism: implications for systemic physiology. , 2001, Annual review of physiology.

[29]  J. Jeudy,et al.  Cardiac Applications of PET-MR , 2017, Current Cardiology Reports.

[30]  Leo L. Cheng,et al.  Metabolic Imaging in Humans , 2016, Topics in magnetic resonance imaging : TMRI.

[31]  I. Johnstone,et al.  Needles and straw in haystacks: Empirical Bayes estimates of possibly sparse sequences , 2004, math/0410088.

[32]  Bruce D Cheson,et al.  Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development , 2005, Clinical Cancer Research.

[33]  Craig R. Malloy,et al.  Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR , 2007, Proceedings of the National Academy of Sciences.

[34]  R. Fulbright,et al.  Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo , 2018, Science Advances.

[35]  John A. Detre,et al.  Magnetic Resonance Imaging of Glutamate , 2011, Nature Medicine.

[36]  K. Brindle Imaging metabolism with hyperpolarized (13)C-labeled cell substrates. , 2015, Journal of the American Chemical Society.

[37]  Stephen Pickup,et al.  Diffusion tensor MRI in rat models of invasive and well‐demarcated brain tumors , 2008, NMR in biomedicine.

[38]  R. Gruetter,et al.  Simultaneous Determination of the Rates of the TCA Cycle, Glucose Utilization, α-Ketoglutarate/Glutamate Exchange, and Glutamine Synthesis in Human Brain by NMR , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[39]  Victor C. Strasburger,et al.  Review and Recommendations , 1983 .

[40]  R. Gruetter,et al.  In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time , 1999, Magnetic resonance in medicine.

[41]  Morris H. Baslow,et al.  N-Acetylaspartate in the Vertebrate Brain: Metabolism and Function , 2003, Neurochemical Research.

[42]  P Boesiger,et al.  Detection of glutathione in the human brain in vivo by means of double quantum coherence filtering , 1999, Magnetic resonance in medicine.

[43]  R. Deberardinis,et al.  Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? , 2012, Cell.

[44]  David Nachmansohn,et al.  Metabolism and function , 1950 .

[45]  S. Provencher Estimation of metabolite concentrations from localized in vivo proton NMR spectra , 1993, Magnetic resonance in medicine.

[46]  David L. Donoho,et al.  De-noising by soft-thresholding , 1995, IEEE Trans. Inf. Theory.

[47]  B D Ross,et al.  Hyperpolarized MR Imaging: Neurologic Applications of Hyperpolarized Metabolism , 2010, American Journal of Neuroradiology.

[48]  V. Tiwari,et al.  Glutamatergic and GABAergic TCA Cycle and Neurotransmitter Cycling Fluxes in Different Regions of Mouse Brain , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.