Deuterium Metabolic Imaging of the Healthy and Diseased Brain

Abstract

Altered brain metabolism contributes to pathophysiology in cerebrovascular and neurodegenerative diseases such as stroke and Alzheimer's disease. Current clinical tools to study brain metabolism rely on positron emission tomography (PET) requiring specific hardware and radiotracers, or magnetic resonance spectroscopy (MRS) involving technical complexity. In this review we highlight deuterium metabolic imaging (DMI) as a novel translational technique for assessment of brain metabolism, with examples from brain tumor and stroke studies. DMI is an MRS-based method that enables detection of deuterated substrates, such as glucose, and their metabolic products, such as lactate, glutamate and glutamine. It provides additional detail of downstream metabolites compared to analogous approaches like fluorodeoxyglucose (FDG)-PET, and can be implemented and executed on clinical and preclinical MR systems. We foresee that DMI, with future improvements in spatial and temporal resolutions, holds promise to become a valuable MR imaging (MRI) method for non-invasive mapping of glucose uptake and its downstream metabolites in healthy and diseased brain.

Keywords: MR spectroscopy; MRI; brain metabolism; deuterium; stroke; tumor.

Figure 1.

DMI captures altered glucose metabolism after ischemic stroke in rats. We acquired steady state DMI data at 9.4 T with 3 × 3 × 3 mm³ = 27 μl nominal spatial resolution in approximately 35 min (repetition time = 400 ms; 8 averages). A) A typical single-voxel DMI spectrum from a healthy rat brain acquired at 60–90 minutes after start of intravenous infusion with ²H-labeled glucose (1.95 g/kg in 120 minutes). B) Maps of glucose uptake and metabolic products, i.e. glutamate and glutamine (Glx) and lactate, across the healthy rat brain reveal even distribution of glucose delivery and uptake and oxidative phosphorylation (reflected by the Glx pool), while anaerobic glycolysis (i.e. lactate formation) is minimal. C) A DMI spectrum from a single-voxel placed in a rat’s ischemic brain hemisphere shortly after unilateral middle cerebral artery occlusion shows active lactate formation, indicative of anaerobic glucose metabolism. The infusion of ²H-labeled glucose was started directly after occlusion of the middle cerebral artery. D) Acutely after stroke induction, we observed lactate formation in and around the ischemic lesion coupled with reduction in oxidative phosphorylation indicated by a lowered Glx signal. In B and D, color-coded (Crameri, 2020) glucose and metabolite maps, expressed in millimolar concentrations, are overlaid on T₂-weighted anatomical MR images of the brain. The black arrowheads mark the ischemic hemisphere. Abbreviations: Glc = glucose, Glx = glutamate & glutamine, Lac = lactate.

Figure 2.

DMI depicts the Warburg effect in experimental and clinical glioblastoma multiforme (GBM). A) Contrast-enhanced T₁-weighted MRI shows hyperintense signal from tumor tissue in a rat glioma model. Surface radiofrequency coil position for DMI (yellow circle) and localized ²H MR spectra are overlaid onto the MR image. B) Maps of glucose uptake and downstream metabolites, i.e. glutamate and glutamine (Glx) and lactate, reveal active Warburg effect in and around the brain tumor after intravenous infusion of 1.95 g [6,6′]-²H₂-glucose per kg body weight. C) Standard-of-care T₂-weighted fluid-attenuated inversion recovery MR image from a patient diagnosed with GBM in the right frontal lobe. D) Glucose and metabolite maps overlaid onto T₂-weighted MRI show lower levels of ²H-labeled Glx and higher concentration of ²H-labeled lactate in and around the tumor lesion compared to normal-appearing brain tissue, similar to the metabolite maps from the rat glioma model in (B). Subjects orally ingested 0.60–0.75 g [6,6′]-²H₂-glucose per kg body weight, with a maximum of 60 g. Color-coded glucose, Glx and lactate maps are expressed in millimolar concentrations. Abbreviations: Glc = glucose, Glx = glutamate & glutamine, Lac = lactate. Figure adapted from De Feyter et al. (2018) with authors’ permission.