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

Abstract

The quantitative mapping of the in vivo dynamics of cellular metabolism via non-invasive imaging contributes to the understanding of the initiation and progression of diseases associated with dysregulated metabolic processes. Current methods for imaging cellular metabolism are limited by low sensitivities, by costs, or by 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 1 H with 2 H. The method, which we termed quantitative exchanged-label turnover MRS, only requires deuterium-labelled glucose and standard MRI scanners, and with a single acquisition provides steady-state information and metabolic rates for several metabolites. We used the method to monitor glutamate, glutamine, γaminobutyric acid and lactate in the brains of normal and glioma-bearing rats following the administration of 2 H 2-labelled glucose and 2 H 3-labelled acetate. Quantitative exchanged-label turnover MRS should broaden the applications of routine 1 H MRS. Cellular metabolism is maintained by a network of biochemical reactions essential for normal tissue function 1. These reactions form larger metabolic pathways which exist under tight regulatory control to help balance metabolic fluctuations experienced by the cell. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Deuterium Metabolic Imaging—Rediscovery of a Spectroscopic Tool

“…Brain and liver studies in animals used a dual-tuned 2 H/ 1 H coil design whereby the 2 H coil was mounted inside of the 1 H coil. Human studies also used a dedicated 2 H coil, with other recent work highlighting the way standard 1 H RF coils could also be used to detect 2 H metabolites indirectly via the reduction of normal signals [ 71 ]. For a full description of the techniques used for human 2 H DMI, please refer reference [ 1 ].…”

“…Recent work has also highlighted that spectral editing and 2-dimensional 1 H MRS [ 68 ] techniques can be used to “uncover” steady-state metabolites of high interest, for example, 2-HG, an oncometabolite present at high concentrations in patients with isocitrate dehydrogenase mutant (IDHm) tumors [ 69 , 70 ]. Furthermore, a recent study found that spectral changes after administration of deuterated compounds, such as [6,6′- 2 H 2 ] glucose and [2,2,2′- 2 H 3 ] acetate, could be detected by 1 H MRS, showing the potential synergy between 1 H MRS and deuterium-enriched methods [ 71 ].…”

“…Kreis et al [ 3 ] took the use of D-[6,6′- 2 H 2 ] glucose even further and presented a method to quantitate the tumor glucose flux while using 3D accelerated chemical shift images of the tumor before and after chemotherapy in a murine lymphoma model. Later, Rich et al [ 71 ] applied a novel approach called quantitative exchanged-label turnover MRS (qMRS), in which they infused healthy and glioblastoma bearing rats with deuterated compounds of glucose and acetate, and imaged them with 1 H MRS. This allowed detection of changes in the 1 H MRS spectra, following 2 H incorporation.…”

“…This allowed detection of changes in the 1 H MRS spectra, following 2 H incorporation. This method thus provides improved spectral resolution and enables not only the tracking of metabolite production but also their quantification without the need for specialized 2 H coils [ 71 ]. Recently, Markovic et al used DMI to demonstrate the increased anaerobic glycolysis in preeclamptic rodents compared to control.…”

Effect of Ketamine on Human Neurochemistry in Posterior Cingulate Cortex: A Pilot Magnetic Resonance Spectroscopy Study at 3 Tesla

“…In contrast to 1 H-MRS, the speed of metabolite turnover and Glu/Gln cycling can be assessed by technically challenging and clinically less accessible 13 C-MRS ( Abdallah et al, 2018 ). Emerging non-invasive approaches, which benefit from direct and indirect detection of deuterium-labeled tracers with 2 H and 1 H-MRS, respectively, promise to provide clinically available quantitative markers of energetic glucose metabolism and synaptic processes that are relevant to ketamine action ( Lu et al, 2017 ; De Feyter et al, 2018 ; Rich et al, 2020 ). Also, methods of chemical exchange saturation transfer (CEST) can potentially gain from more sensitive molecular detection of Glc and Glu and can verify our findings in the future ( Cai et al, 2012 ; Roalf et al, 2017 ; Poblador Rodriguez et al, 2019 ).…”