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

Abstract

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.

Non-invasive three-dimensional 1H-MR Spectroscopic Imaging of human brain glucose and neurotransmitter metabolism using deuterium labeling at 3T

“…In contrast to a direct detection of labeled substrates using DMI ( 2 H-MRS/MRSI), 13 C-MRS, or [ 18 F]FDG-PET the indirect 1 H-based QELT approach allows for simultaneous detection of labeled and unlabeled metabolites to quantify an extended neurochemical profile and requires no additional hardware or radioactive tracers (8)(9)(10). In comparison to recent publications presenting QELT MRSI results in animals (9) and humans (7,8,10) at ultra-high field(≥7T) research systems, our approach provides motion-corrected 3D metabolite maps with high temporal stability (26), which were acquired with high spatial and temporal resolution on widely available clinical 3T MR scanners. Further improvements in spatial and temporal stability can be anticipated considering the wide range of stateof-the-art undersampling or super-resolution techniques in MRSI (27)(28)(29).…”

“…Intravenous tracer injection would allow additional blood sampling to estimate isotopic enrichment time courses as an input function to overcome those challenges in future studies (20). A previous study using DMI showed that the increase of deuterium labeled Glx features an approximately linear behavior in the first 60 min (7), therefore, our study used linear fitting as an approximation to estimate the dynamics of Glx, but this approach does not reflect real quantitative turnover rates. Other models, such as exponential fitting has been applied previously, but require longer scan times (e.g., 2-3 hours) and the assessment of a true baseline.…”

“…A proof, that the decrease of Glx 4 is not an artifact or systematic error of the method and indeed reflects physiological incorporation of deuterium into downstream metabolites, has been performed in a previous study by assessing the test-retest repeatability and control measurements using regular glucose (dextrose), employing a similar MR sequence (without motion correction) at 7T (7). Additionally, results were compared to DMI data acquired from the same cohort of subjects and on the same MR scanner.…”

“…Deuterium metabolic imaging (DMI) (5,6) and quantitative exchanged label turnover (QELT) (7)(8)(9)(10) are novel magnetic resonance techniques to non-invasively image Glc metabolism in animals and the human brain using deuterium-labeled Glc as tracer, which are able to separate healthy oxidative from pathologic anaerobic pathways, by simultaneously detecting the respective metabolic products glutamate+glutamine and lactate (4). DMI detects deuterium enrichment in the brain tissue directly via 2 H-MRS, while, indirectly, QELT detects a decrease of signal intensities in conventional 1 H-MR spectra due to deuterium-to-proton exchange in the respective molecule.…”

“…Recently, DMI has been translated to clinical field strength of 3T (11) with a nominal isotropic resolution of 33 ml and an acquisition time of 10 min for each 3D dataset. QELT features higher SNR and spatial resolution (0.12 ml) with shorter acquisition times (~3 min( 7)) compared to DMI, while additionally detecting non- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) labeled metabolites, but so far has been applied in humans only at non-clinical field strength of 7T (7,8).…”