Simultaneous Determination of the Rates of the TCA Cycle, Glucose Utilization, α-Ketoglutarate/Glutamate Exchange, and Glutamine Synthesis in Human Brain by NMR

Abstract

Summary: 13C isotopic tracer data previously obtained by 13C nuclear magnetic resonance in the human brain in vivo were analyzed using a mathematical model to deter mine metabolic rates in a region of the human neocortex. The tricarboxylic acid (TCA) cycle rate was 0.73 ± 0.19 fLmol min -I g-I (mean ± SD; n = 4). The standard deviation reflects primarily intersubject variation, since individual uncertainties were low. The rate of a-ketoglu tarate/glutamate exchange was 57 ± 26 fLmol min -1 g -1 (n = 3), which is much greater than the TCA cycle rate; the high rate indicates that a-ketoglutarate and glutamate are in rapid exchange and can be treated as a single com bined kinetic pool. The rate of synthesis of glutamine from glutamate was 0.47 fLmol min -I g-I (n = 4), withThe stable isotope 13C combined with nuclear magnetic resonance (NMR) spectroscopy allows

Advances in the treatment of anxiety: Targeting glutamate

“…181 13C MRS is an even more powerful technique to measure glutamate activity in the brain and offers a means of capturing dynamic metabolite flux rates of glutamate. 182,183 This technique offers the possibility of monitoring dynamic changes in the glutamate/glutamine shuttle between astrocytes and neurons in discrete brain regions, and it could be an excellent method for monitoring the effects of glutamatergic modulating drugs for mood and anxiety disorders.…”

Clinical experience with 13C MRS in vivo

“…Although the ground work for all 13 C MRS was established by chemists, physical chemists and physicists over many years, we owe almost all of the translational research which made it possible to perform simpler 13 C NMR experiments in whole-body NMR instruments at relatively low magnetic fields (1.5, 2.1, 4.1 T) to a small number of laboratories, [4][5][6][7][8][9] particularly at the University of Zurich, Switzerland and Yale University, USA. The move to higher fields has also proceeded only slowly, and has so far largely been confined to normal volunteers.…”

“…Lactate, readily detected by 1 H MRS but at a concentration of only 2-3 mM in this patient, was not observed with natural abundance 13 C MRS patient positioning needed for accurate spectral subtractions. 10 Others have experimented with localization and the consequent narrower 13 C-excitation range, 6,7,9 thereby avoiding difference-spectroscopy. However, the localization scheme itself (ISIS) is a difference method and shares some of the disadvantages.…”

Studies of metabolic compartmentation and glucose transport using in vivo MRS

“…The time course of label incorporation into 4-13 C glutamate yields (with appropriate corrections for the delays in labeling introduced by the small intervening lactate and glycolytic intermediate pools) the rate of the neuronal TCA cycle. 27 After formation in the neuron 4-13 C glutamate may be released from the nerve terminal and taken up by surrounding glial cells, which are often referred to as astrocytes based upon their morphology. In the glia the glutamate will be converted by glutamine synthetase into 4-13 C glutamine.…”

“…[17][18][19]28,33 In 1994 it was first demonstrated that in vivo 13 C NMR may be used to measure the rate of glutamine labeling from 1-13 C glucose in human occipital/parietal cortex. 18,27 However the rate of the glutamate/glutamine cycle was not uniquely determined from these first experiments due to the inability to distinguish the glutamate/glutamine cycle from other sources of glutamine labeling in the glia. The studies in rats by Sibson and coworkers 29,30 allowed a constraint to be placed on the maximum flow of label from glial pyruvate dehydrogenase into glutamine as the rate of anaplerosis.…”