Objectives Noninvasive, affordable, and reliable mapping of brain glucose metabolism is of critical interest for clinical research and routine application as metabolic impairment is linked to numerous pathologies, for example, cancer, dementia, and depression. A novel approach to map glucose metabolism noninvasively in the human brain has been presented recently on ultrahigh-field magnetic resonance (MR) scanners (≥7T) using indirect detection of deuterium-labeled glucose and downstream metabolites such as glutamate, glutamine, and lactate. The aim of this study was to demonstrate the feasibility to noninvasively detect deuterium-labeled downstream glucose metabolites indirectly in the human brain via 3-dimensional (3D) proton (1H) MR spectroscopic imaging on a clinical 3T MR scanner without additional hardware. Materials and Methods This prospective, institutional review board–approved study was performed in 7 healthy volunteers (mean age, 31 ± 4 years, 5 men/2 women) after obtaining written informed consent. After overnight fasting and oral deuterium-labeled glucose administration, 3D metabolic maps were acquired every ∼4 minutes with ∼0.24 mL isotropic spatial resolution using real-time motion-, shim-, and frequency-corrected echo-less 3D 1H-MR spectroscopic Imaging on a clinical routine 3T MR system. To test the interscanner reproducibility of the method, subjects were remeasured on a similar 3T MR system. Time courses were analyzed using linear regression and nonparametric statistical tests. Deuterium-labeled glucose and downstream metabolites were detected indirectly via their respective signal decrease in dynamic 1H MR spectra due to exchange of labeled and unlabeled molecules. Results Sixty-five minutes after deuterium-labeled glucose administration, glutamate + glutamine (Glx) signal intensities decreased in gray/white matter (GM/WM) by −1.63 ± 0.3/−1.0 ± 0.3 mM (−13% ± 3%, P = 0.02/−11% ± 3%, P = 0.02), respectively. A moderate to strong negative correlation between Glx and time was observed in GM/WM (r = −0.64, P < 0.001/r = −0.54, P < 0.001), with 60% ± 18% (P = 0.02) steeper slopes in GM versus WM, indicating faster metabolic activity. Other nonlabeled metabolites showed no significant changes. Excellent intrasubject repeatability was observed across scanners for static results at the beginning of the measurement (coefficient of variation 4% ± 4%), whereas differences were observed in individual Glx dynamics, presumably owing to physiological variation of glucose metabolism. Conclusion Our approach translates deuterium metabolic imaging to widely available clinical routine MR scanners without specialized hardware, offering a safe, affordable, and versatile (other substances than glucose can be labeled) approach for noninvasive imaging of glucose and neurotransmitter metabolism in the human brain.
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.
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.
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 and address the major drawbacks of positron emission tomography or carbon (13C)-MRS. Here, we pioneered a dynamic proton 3D (1H)-MRSI for indirect 2H-measurements in humans. In contrast to 2H-MRS(I), the method provides higher sensitivity and chemical specificity to differentiate glutamate, glutamine, and gamma-aminobutyric acid deuterated at specific molecular positions while simultaneously mapping both labeled and unlabeled metabolites without specialized hardware after peroral ingestion of 2H-labeled glucose.
Objectives Non-invasive, affordable, and reliable mapping of brain glucose metabolism is of critical interest for clinical research and routine application as metabolic impairment is linked to numerous pathologies e.g., cancer, dementia and depression. A novel approach to map glucose metabolism non-invasively in the human brain and separate normal oxidative from pathologic anaerobic pathways has been presented recently on experimental MR scanners using direct or indirect detection of deuterium-labeled glucose and downstream metabolites such as glutamate, glutamine and lactate. The aim of this study was to demonstrate the feasibility to non-invasively detect deuterium labeled downstream glucose metabolites indirectly in the human brain via 3D proton (1H) MR spectroscopic imaging on a clinical 3T MR scanner without additional hardware. Materials and Methods This prospective, institutional review board approved study was performed in seven healthy volunteers (mean age, 31+-4 years, 5 m/ 2 f) following written informed consent. After overnight fasting and oral deuterium-labeled glucose administration 3D metabolic maps were acquired every 4 min with 0.24 ml isotropic spatial resolution using real-time motion-, shim- and frequency-corrected echo-less 3D 1H-MR Spectroscopic Imaging. Time courses were analyzed using linear regression and non-parametric statistical tests. Deuterium labeled glucose and downstream metabolites were detected indirectly via their respective signal decrease in dynamic 1H MR spectra due to deuterium to proton exchange in the molecules. Results Sixty-five minutes after deuterium-labeled glucose administration, glutamate+glutamine (Glx) signal intensities decreased in gray/white matter (GM,WM) by -15+-2%,(p=0.02)/-14+-3%,(p=0.02), respectively. Strong negative correlation between Glx and time was observed in GM/WM (r=-0.71 p<0.001)/(r=-0.67,p<0.001) with 38+-18% (p=0.02) steeper slopes, indicating faster metabolic activity in GM compared to WM. Other non-labeled metabolites showed no significant changes. Conclusion Our approach translates deuterium metabolic imaging to widely available clinical routine MR scanners without specialized hardware offering a safe, affordable, and versatile (other substances than glucose can be labeled) approach for non-invasive imaging of glucose and neurotransmitter metabolism in the human brain.
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