Carbon-13 NMR for the assessment of human brain glucose metabolism in vivo

Abstract

Proton-decoupled 13C NMR spectra of the human head were obtained during hyperglycemic glucose clamping using intravenous infusions of [1-13C]glucose in normal volunteers. In addition to 13C signals of mobile lipids, a variety of new metabolite resonances could be resolved for the first time in the human brain. At an enrichment level of 20% [1-13C]glucose, the signals of alpha- and beta-glucose at 92.7 and 96.6 ppm, respectively, could be detected in the human brain after only an infusion period of 15 min. The spatial localization of the different regions of interest was confirmed by 13C NMR spectroscopic imaging with a time resolution of 9 min. Increasing the enrichment level to 99% [1-13C]glucose not only improved the time resolution but allowed the detection of metabolic breakdown products of [1-13C]glucose. The time course of 13C label incorporation into the C2, C3, and C4 resonances of glutamate/glutamine and into lactate could be recorded in the human brain. These results suggest the possibility of obtaining time-resolved, spatially selective, and chemically specific information on the human body.

NMR measurement of brain oxidative metabolism in monkeys using 13C‐labeled glucose without a 13C radiofrequency channel

“…On human NMR systems, direct detection allows one to measure 13 C incorporation into glutamate and glutamine C4 and C3 under 13 C-glucose or 13 C-acetate infusions (20,22,(25)(26)(27)(28)(29) leading to absolute metabolic fluxes, such as neuronal and astroglial TCA cycle fluxes and the glutamate/glutamine cycle flux (20,22,25,28). Because of the low sensitivity of 13 C detection, direct detection is either nonlocalized (27)(28)(29) or localized over large brain volumes (20,22,25,26), even at field strengths as high as 4 Tesla.…”

Alternative 1‐13C glucose infusion protocols for clinical 13C MRS examinations of the brain

“…Human brain glutamate/glutamine metabolism can be directly visualized by 13 C MRS, and it has been possible to determine the rates of glucose uptake, glycolysis, tricarboxylic acid (TCA), and glutamate/glutamine cycles after 1- 13 C glucose infusion (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). However, widespread use of the technique to study pathologic states has been prevented by technical limitations of clinical MR scanners, which generally lack the second RF channel necessary for proton decoupling during 13 C observation, and by the cost of 13 C-labeled glucose.…”

“…Although it has been well validated in animal and human studies of normal subjects, such a rigorous procedure has several drawbacks which prevent its routine clinical use. The cost of [1][2][3][4][5][6][7][8][9][10][11][12][13] C glucose can exceed $10,000 per patient. Additional MRI and 1 H MRS procedures may also be needed, and the extra examination times of 1-2 h required to ensure steady-state 1-13 C brain glucose concentrations are not well tolerated by the patient or by clinical MRI schedules.…”

Progress towards in vivo brain 13C-MRS in mice: Metabolic flux analysis in small tissue volumes

“…infusion of labelled glucose in euglycemic and hyperglycemic conditions allowed to detect dynamic data from glutamate enrichment through TCA cycle at sufficient FE [3,70,71,124]. Finally, the introduction of automated shimming [57,58] and 3D localization allowed a great improvement in spectral resolution: for the first time, 13 C localized MRS identified lipid resonances as a contribution from subcutaneous fat rather than intracranial mobile lipids [71].…”