Glutamate and glutamine: a review of in vivo MRS in the human brain

Abstract

Our understanding of the roles that the amino acids glutamate (Glu) and glutamine (Gln) play in the mammalian central nervous system has increased rapidly in recent times. Many conditions are known to exhibit a disturbance in Glu-Gln equilibrium, and the exact relationships between these changed conditions and these amino acids are not fully understood. This has led to increased interest in Glu/Gln quantitation in the human brain in an array of conditions (e.g. mental illness, tumor, neuro-degeneration) as well as in normal brain function. Accordingly, this review has been undertaken to describe the increasing number of in vivo techniques available to study Glu and Gln separately, or pooled as 'Glx'. The present MRS methods used to assess Glu and Gln vary in approach, complexity, and outcome, thus the focus of this review is on a description of MRS acquisition approaches, and an indication of relative utility of each technique rather than brain pathologies associated with Glu and/or Gln perturbation. Consequently, this review focuses particularly on (1) one-dimensional (1)H MRS, (2) two-dimensional (1)H MRS, and (3) one-dimensional (13)C MRS techniques.

Keywords: 13C; MRS; glutamate; glutamine; human; in vivo; one dimensional; two dimensional.

Copyright © 2013 John Wiley & Sons, Ltd.

Figures

Figure 1

Simulated 1D proton spectra of Glu and Gln with 5% Cr (peaks with *) at 3 Tesla. Notice the striking similarity of Glu and Gln structure and as a consequence, the spectral profile. A line broadening of 10 Hz was applied to spectra. Chemical shifts and scalar J-coupling were obtained from (1).

Figure 2

Simulated 2D COSY proton spectra of Glu and Gln with 5% Cr (peaks with *, at 3.02 and 3.92ppm) at 3 Tesla. Notice the striking similarity of Glu and Gln spectral profiles. Spectra were simulated with 512 points in F2 and 200 points in F1 using a non-localized gradient COSY sequence (90° t1 G 90° G Acquire, G: gradient pulse), with 1.62ms increment, spectral width of 5ppm in both dimensions. Processing was performed by zero filling to 1024 points in both dimensions and weighting F2 and F1 dimensions by skewed sin2 (0,0.3) and sin2(0), respectively. Chemical shift and scalar J-couplings were obtained from (1).

Figure 3

Simulated J-resolved spectroscopy proton spectra of Glu and Gln with 5% Cr (at F1=0, F2=3.02 and 3.92ppm) at 3 Tesla. Notice the striking similarity of Glu and Gln structure and as a consequence, the spectral profiles. Spectra were simulated with 512 points in F2 and 200 points in F1 using a non-localized gradient JPRESS sequence (90° t1/2 G 180° t1/2 G Acquire, G: gradient pulse), with t1=20ms, F1 spectral width=50Hz, 128 F1 increments, F2 spectral width=7ppm. Processing was performed by zero filling to 2048 points in F2 and 512 points in F1, with skewed sin2 (0,0) and sin2(0) weighting along F2 and F1, respectively. Chemical shift and scalar J-couplings were obtained from (1).

Figure 4

Diagram of the TCA cycle and the Glu /Gln cycle in the neuron and glial cells as [1-13C] glucose is metabolized. The filled circle indicates the carbon-13 label as it is metabolized through each turn of the cycle. The inner circle indicates the second turn of the TCA cycle and subsequent labeling of Glu and Gln.

Figure 5

Representative 13C spectra obtained in healthy controls at 60-100 minutes after infusion (top), baseline (middle), and the difference spectra (bottom) that allows for the visualization of C2-Glu, Gln, and aspartate as well as C3-Asp and C4-glutamate which co-resonates with the natural abundance lipid signal and therefore only visualized upon subtraction.