What is Deuterium Metabolic Imaging (DMI)?

Deuterium metabolic imaging or DMI is a recently described, innovative MR-based method to map metabolism non-invasively in 3D. DMI allows imaging of substrates and their metabolic products enriched with the non-radioactive and biocompatible deuterium (or ²H) isotope. Common ²H-enriched substrates include [6,6-²H₂]-glucose and ²H₃-acetate to study pathways involved in energy metabolism such as glycolysis and the tricarboxylic acid (TCA) or citric acid cycle.

A typical DMI study is composed of three main steps (Fig. 1). As a first step, the ²H-enriched substrate must be administered to the subject. Ideally the substrate is administered via intravenous infusion in order to achieve and maintain a high and stabile level of ²H-enriched substrate in the blood. Sometimes an intravenous infusion is impractical to implement, in which case, an oral administration can be a practical alternative when glucose is used. Human and animal substrate administration protocols can be downloaded under Resources.

Figure 1 – Workflow of a typical DMI study. (A) Administration of a deuterated substrate. For deuterated glucose (or water) the substrate can be taken orally, whereas for other substrates (e.g. acetate) an intravenous infusion may be required. For steady-state DMI scans, the subject can relax outside the magnet for 30-45 min while the deuterated substrate is metabolized into a number of downstream products. For dynamic DMI scans, the substrate administration takes place inside the magnet whereby the formation of metabolic products is followed over time. (B) The acquisition of DMI data is performed as a 3D MR spectroscopic imaging (MRSI) study, whereby each spatial location is characterized by a deuterium spectral signature. (C) Quantification of the deuterium spectra at each spatial location by spectral fitting leads the metabolic maps for individual metabolic substrates (glucose) and downstream products (lactate).

Over time the ²H-enriched substrate will be broken down and converted into a range of metabolic products, for example glutamate and lactate in the case of glucose. In the brain these metabolic processes can take between 45 and 90 min to reach steady-state. The build-up of metabolic products can be dynamically followed over time or detected when steady-state has been reached. The dynamic option allows the calculation of absolute rates through metabolic pathways, whereas the steady-state option only allows one to detect the presence of an active metabolic pathway.

DMI is a MR-based method and as such the ²H-enriched substrate and products are detected with ²H MR acquisition methods. A standard DMI acquisition is executed as MR spectroscopic imaging (MRSI) with a simple pulse-acquire sequence extended with phase-encoding gradients to obtain spatial information. DMI acquisition methods for a number of MR vendor platforms can be downloaded under Resources.

Finally, the ²H-MR-based data is quantified by integration or spectral fitting and displayed as color-coded metabolic maps overlaying anatomical MR images. For dynamic acquisitions, the DMI data can be converted into absolute metabolic flux maps. A complete processing platform for DMI data, DMIWizard, is available for download under Resources.

Bigger is better for DMI sensitivity!

The sensitivity of ²H NMR and thus DMI was recently shown to increase supralinear with the magnetic field strength (Fig. 2A). For small animal surface coils (Ø 30 mm) the sensitivity between 4.0 T and 11.7 T scaled at the theoretical maximum (SNR ~ B₀^1.75), whereas for larger human surface coils (Ø 80 mm) the sensitivity between 4.0 T and 7.0 T scaled as B₀^1.65. In addition to the higher sensitivity, DMI at higher magnetic fields also displayed the anticipated increased spectral dispersion (Fig. 2B).

More information of the magnetic field dependence of DMI sensitivity and resolution can be found in R. A. de Graaf et al, NMR Biomed e4235 (2019)

Figure 2 – Magnetic field dependence of DMI. (A) For small surface coils (30 mm diameter, single turn) the relative 2H SNR as measured at 4 T, 9.4 T and 11.7 T is well approximated by the theoretical maximum magnetic field dependence (solid black line). (B) For larger human surface coils (80 mm diameter, single turn), the SNR improves circa 2.5 times between 4 T and 7 T. In addition to the improved SNR, the 7 T 2H MR data is also characterized by a greatly increased spectral dispersion.

These results underline the expectation that the performance of DMI increases dramatically at higher magnetic fields. Nominal resolution of circa 1 mL for human steady-state DMI are anticipated for 7 T and beyond.

DMI – Deuterium Mouse Imaging? ... Yes!

DMI has previously been demonstrated to provide 3D metabolic images in rats and humans. The availability of transgenic mouse models and the need for in vivo metabolic phenotyping tools provides incentive to extend DMI to mice. Using a small (8 x 12 mm), arched DMI coil and uniformly deuterated glucose, high-resolution (5µL) DMI maps could be generated on mouse brain at 11.7 T (Fig. 3). Fig. 3B shows a Lac/Glx ratio map in a mouse model of glioblastoma, highlighting the Warburg effect in the brain tumor.

Figure 3 – DMI on mouse brain following intravenous infusion of [6,6’-2H2]-glucose. (A, B) 2H MR spectra extracted from a 5 uL resolution DMI dataset (11 x 11 x 11, spherical k-space encoding, 8 averages, 35 min) from the positions indicated in (C). The 2H MR spectrum from tumor (A) is characterized by elevated lactate and decreased glutamate/glutamine (Glx), whereas the 2H MR spectrum from normal-appearing brain (B) contains high glutamate/glutamine and low lactate. (D) Lactate-over-Glx ratio or Warburg map.

This spatial resolution opens up the possibility of studying a wide range of pathologies in mouse models in vivo and reveal regional differences in metabolism.