Deuterium labeling enables non-invasive 3D proton MR imaging of glucose and neurotransmitter metabolism in the human brain

Impaired brain glucose metabolism characterizes most severe brain diseases. Recent studies have proposed deuterium (2H)-Magnetic Resonance Spectroscopic Imaging (MRSI) as a reliable, non-invasive, and safe method to quantify the human metabolism of 2H-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 (13C)-MRS. Here, for the first time, we show an indirect dynamic proton (1H)-MRSI technique in humans, which overcomes four critical 2H-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.