1H magnetic resonance spectroscopic imaging of deuterated glucose and of neurotransmitter metabolism at 7 T in the human brain

Abstract

Impaired brain glucose metabolism characterizes most severe brain diseases. Recent studies have proposed deuterium ( 2 H)-Magnetic Resonance Spectroscopic Imaging (MRSI) as a reliable, non-invasive, and safe method to quantify the human metabolism of 2 H-labeled substrates such as glucose and their downstream metabolism (e.g., aerobic/anaerobic glucose utilization and neurotransmitter synthesis) and address the major drawbacks of positron emission tomography (PET) or carbon ( 13 C)-MRS. Here, for the first time, we show an indirect dynamic proton ( 1 H)-MRSI technique in humans, which overcomes four critical 2 H-MRSI limitations. Our innovative approach provides higher sensitivity with improved spatial/temporal resolution and higher chemical specificity to differentiate glutamate (Glu4), glutamine (Gln4), and gamma-aminobutyric acid (GABA2) deuterated at specific molecular positions while allowing simultaneous mapping of both labeled and unlabeled metabolites without the need for specialized hardware. Our novel method demonstrated significant Glu4, Gln4, and GABA2 decreases, with 18% faster Glu4 reduction in the gray matter than white matter after ingestion of deuterated glucose. Thus, robustly detected downstream glucose metabolism utilizing clinically available MR hardware without the need for radioactive tracers and PET.

Over 20% Carbon-13 Polarization of Perdeuterated Pyruvate Using Reversible Exchange with Parahydrogen and Spin-Lock Induced Crossing at 50 μT

“…32 However, the effects are often small. 34,35 Particularly, for pyruvate, no significant deuterium isotope effect on metabolic conversion kinetics has been observed, meaning that, for metabolic HP MRI, pyruvate-d 3 can successfully be utilized instead of the nondeuterated variant. 36 Notably, both isotope-enriched [1-13 C]-and [2-13 C]pyruvate-d 3 are commercially available, and no further chemical modification is needed for SABRE in sharp contrast to hydrogenative pH 2 -based hyperpolarization approaches that require suitable unsaturated molecular precursors.…”

“…Indeed, changes in the conversion rates have been reported for other hyperpolarized molecules, such as [2- 2 H]­alanine . However, the effects are often small. , Particularly, for pyruvate, no significant deuterium isotope effect on metabolic conversion kinetics has been observed, meaning that, for metabolic HP MRI, pyruvate- d 3 can successfully be utilized instead of the non-deuterated variant …”

Magnetic Resonance Water Tracer Imaging Using 17O-Labeled Water

“…In contrast, in 1 H-MRI, proton signals are used, and the proton signals decrease by the H 2 O-D 2 O replacement effect, 71–74 allowing for higher sensitivity than that of the direct method. Recently, this high sensitivity has been exploited in 1 H-magnetic resonance spectroscopic imaging ( 1 H-MRSI) to map metabolites of deuterium-labeled compounds 75,76 . Regarding safety, its isotope effect may cause biological toxicity.…”

“…Recently, this high sensitivity has been exploited in 1 H-magnetic resonance spectroscopic imaging ( 1 H-MRSI) to map metabolites of deuterium-labeled compounds. 75,76 Regarding safety, its isotope effect may cause biological toxicity. Animal experiments have suggested significant adverse effects, particularly when administered in large quantities (the toxicity threshold being approximately 30%-40% concentration), 77 making its application to humans, particularly in high-concentration formulations, challenging.…”

Predicting dynamic, motion‐related changes in B0 field in the brain at a 7T MRI using a subject‐specific fine‐trained U‐net

“…2 In particular, a stable B 0 field is critical for dynamic mapping of metabolites. 3,4 In fast MR imaging, B 0 inhomogeneities cause nonlinear image distortions (e.g., for EPI) or image blurring (e.g., for spiral acquisitions). 5 For CEST, B 0 inhomogeneities induce frequency offsets 6 which cause systematic errors in quantification.…”