A new method based on 1H magnetic resonance spectroscopy to assess cellular metabolism

In summary, in this work we developed qMRS, a method that increases the sensitivity and versatility of 1H MRS for measuring metabolic dynamics without the need for specialized hardware or use of radioactive tracers.

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Cellular metabolism has been an area of significant research interest over the past 100 years. Early research focused on understanding the fundamentals of metabolism involving nutrient utilization and energy production, and defined the central metabolic pathways known today. Not only did this work establish expected patterns in healthy tissues, but it also discovered that significant metabolic changes occur in several human diseases including cancer, neurodegeneration and muscular dystrophies. 

With the advent of medical imaging technologies, efforts were made to develop techniques able to monitor metabolism within living organisms. To date, the only metabolic imaging technique used routinely in the clinic is positron emission tomography (PET) which provides information on tissue glucose uptake after infusion of the glucose analog 2-18F-fluoro-2-deoxy-d-glucose (18FDG). This technique is utilized frequently in cancer as tumor cells tend to take up high levels of glucose. However, PET is also limited because it only provides information on the first step of glucose metabolism and requires radioactive tracers. Given this, a preferred method would be non-ionizing and able to provide information both on glucose uptake and downstream metabolism.

Recognizing this gap in the field, we developed a method that provides quantitative measurements of both upstream and downstream metabolism in vivo without the need for radioactive tracers. This technique takes advantage of the widespread availability of clinical magnetic resonance imaging (MRI) scanners and proton (1H) MR spectroscopy (1H MRS) to detect the metabolic turnover of several key metabolites including glutamate, glutamine, lactate, and gamma-aminobutyric acid. Importantly, our approach does not need specialized MRI hardware and only requires administration of non-toxic and non-radioactive deuterium (2H) labeled glucose, which can be given as a drink. As this glucose is taken up and metabolized by cells, the deuterium label is transferred to downstream metabolites which can be detected using standard MRS protocols. We therefore named this technique quantitative exchanged label turnover (QELT) MRS, or simply qMRS.

Figure 1. Overview of qMRS. In qMRS, deuterium labelled glucose can be given intravenously or as an oral drink to subjects. The subjects are then placed into an MRI and magnetic resonance spectroscopy (MRS) performed to measure levels of metabolites in the tissue of interest. As the deuterium labelled glucose is metabolized, the deuterium label is transferred to downstream metabolites. Since deuterium is invisible on 1H MRS, the signal for these metabolite will go down, enabling us to detect this change. By subtracting the difference between MRS spectra acquired before and after drinking, it is possible to visualize and quantify the labelling of these metabolites over time. 

In the current publication, we performed proof-of-principle studies to test the feasibility of qMRS in both normal and tumor bearing rodents. In normal rats, infusion of deuterium labelled glucose allowed us to track the labelling of several important neurometabolites over time. Furthermore, in a rat model of glioblastoma, we showed that our method could also detect altered lactate metabolism associated with tumorigenesis. Finally, we extended our observation to MRS imaging, allowing us to spatially resolve labelling of metabolites in the rat brain after administration of deuterium labelled glucose. These promising findings thus provided the foundation for clinical studies which are now ongoing in our group.

In summary, in this work we developed qMRS, a method that increases the sensitivity and versatility of 1H MRS for measuring metabolic dynamics without the need for specialized hardware or use of radioactive tracers. Since deuterium labelled glucose is non-toxic and can be given as a drink, this approach is safe and relatively straightforward. Furthermore, as 1H MRS is universally available on most clinical MRI scanners, we expect the translational potential of this technique for to be high. Hence, qMRS is expected to open up new opportunities to probe metabolic derangements in a variety of human diseases, including cancer and neurological disorders. We encourage those who are interested to learn more to read our full article through the link below.

https://www.nature.com/articles/s41551-019-0499-8

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Rich et al.

Post-doctoral Fellow, University of Pennsylvania

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