Deuterated water imaging of the rat brain following metabolism of [²H₇]glucose

Abstract

Purpose: To determine whether deuterated water (HDO) generated from the metabolism of [ 2 H 7 ]glucose is a sensitive biomarker of cerebral glycolysis and oxidative flux. Methods: A bolus of [ 2 H 7 ]glucose was injected through the tail vein at 1.95 g/kg into Sprague-Dawley rats. A 2 H surface coil was placed on top of the head to record 2 H spectra of the brain every 1.3 minutes to measure glucose uptake and metabolism to HDO, lactate, and glutamate/glutamine. A two-point Dixon method based on a gradient-echo sequence was used to reconstruct deuterated glucose and water (HDO) images selectively. Results: The background HDO signal could be detected and imaged before glucose injection. The 2 H NMR spectra showed arrival of [ 2 H 7 ]glucose and its metabolism in a time-dependent manner. A ratio of the HDO to glutamate/glutamine resonances demonstrates a pseudo-steady state following injection, in which cerebral metabolism dominates wash-in of HDO generated by peripheral metabolism. Brain spectroscopy reveals that HDO generation is linear with lactate and glutamate/glutamine appearance in the appropriate pseudo-steady state window. Selective imaging of HDO and glucose is easily accomplished using a gradient-echo method. Conclusion: Metabolic imaging of HDO, as a marker of glucose, lactate, and glutamate/glutamine metabolism, has been shown here for the first time. Cerebral glucose metabolism can be assessed efficiently using a standard gradient-echo sequence that provides superior in-plane resolution compared with CSI-based techniques. K E Y W O R D S [ 2 H 7 ]glucose, brain, DMRI, HDO, metabolism 1 | INTRODUCTION Glucose is the principal source of energy in the brain, and its dynamic uptake and use remain a key topic after decades of research. Metabolic imaging using MR-based methods has traditionally been limited to 1 H-based spectroscopic detection of metabolites through CSI or single-voxel spectroscopy. 1,2 Although these methods have been of immense How to cite this article: Mahar R, Zeng H, Giacalone A, Ragavan M, Mareci TH, Merritt ME. Deuterated water imaging of the rat brain following metabolism of [ 2 H 7 ]glucose.

Deuterium Metabolic Imaging—Rediscovery of a Spectroscopic Tool

“…Furthermore, a recent publication compered DMI and HP [1- 13 C] pyruvate in imaging of cerebral metabolism, showing that they are both feasible methods at 4.7 T [ 61 ]. An alternate approach, described recently in Mahar et al, was to assess cerebral glucose metabolism by administering [ 2 H 7 ] glucose by looking at the HDO as the metabolic product, bypassing the need for lower resonance products such as lactate and Glx and showing that HDO can indeed serve as a biomarker of [ 2 H 7 ] glucose, lactate, and Glx metabolism [ 99 ]. Riis-Vestergaard et al reported the effect of temperature on metabolically active brown adipose tissue.…”

Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions

“…A bolus of [6,6′- 2 H 2 ] Glc in mice anesthetized by isoflurane resulted in the transfer of the 2 H labeling to the glutamate–glutamine pool, water pool, and lactate pool as previously reported in the rat brain [ 17 , 18 , 39 ]. Interestingly, when a similar bolus was infused into mice anesthetized by a combination of medetomidine and isoflurane, no labeling in the lactate pool could be detected in the mouse brain ( Figure 1 b,e and Figure 2 a,b).…”

“…Additionally, the sum analysis of the metabolites labeled 1 hour post bolus of [6,6′- 2 H 2 ] Glc showed labeling in the Lac pool only in the ISO group, as well as a significantly higher HDO labeling in this group. After 1 hour from [6,6′- 2 H 2 ] Glc bolus, the metabolites detected by 2 H MRS are not only a product of cerebral utilization of [6,6′- 2 H 2 ] Glc, but also a consequence of the exchange with labeled blood Lac and water resulting from metabolism of Glc in peripheral organs [ 39 ]. Thus, the observed significant differences in 2 H labeling of Lac and water imply a global effect of the anesthesia on the animal’s metabolism.…”

“…A solution of 0.97 ± 0.05 M [6,6′- 2 H 2 ] D Glc in a physiological buffer (PBS, Sigma-Aldrich, Buchs, Switzerland) was loaded into the separator/ infusion pump [ 70 ] before the animal was entered into the magnet leading to similar bolus dose as previously reported [ 39 ]. 2 H MR measurements were performed using a home-built 1 H-quadrature/ 2 H single loop surface coil that was positioned on top of the mouse head.…”

Deuterium Metabolic Imaging of Pancreatic Cancer

“…Typically, the intravenous or intraperitoneal administration of deuterated glucose (such as [6,6′‐ 2 H 2 ] glucose or [ 2 H 7 ] glucose) in animal models or human subjects leads to the production of its downstream metabolites over time which can be captured in dynamic or steady‐state measurements, providing insights into metabolic flux through disease‐related metabolic pathways. Though DMI has served as a promising reporter of glucose metabolism in the normal brain and liver as well as in brain, liver, and lymphatic tumors, 4,6–12 none of the studies explore the possibility of this technique to study pancreatic cancer which remains a major challenge for early detection and treatment 13 . Much effort has been devoted to develop diagnostic methods, such as CT, FDG‐PET, 1 H MRI, for targeting and imaging pancreatic tumors, although imaging contrast is still difficult to achieve.…”