Regional distributions of brain glutamate and glutamine in normal subjects

Abstract

Glutamate (Glu) and glutamine (Gln) play an important role in neuronal regulation and are of value as MRS-observable diagnostic biomarkers. In this study the relative concentrations of these metabolites have been measured in multiple regions in the normal brain using a short-TE whole-brain MRSI measurement at 3 T combined with a modified data analysis approach that used spatial averaging to obtain high-SNR spectra from atlas-registered anatomic regions or interest. By spectral fitting of high-SNR spectra this approach yielded reliable measurements across a wide volume of the brain. Spectral averaging also demonstrated increased SNR and improved fitting accuracy for the sum of Glu and Gln (Glx) compared with individual voxel fitting. Results in 26 healthy controls showed relatively constant Glu/Cr and Gln/Cr throughout the cerebrum, although with increased values in the anterior cingulum and paracentral lobule, and increased Gln/Cr in the superior motor area. The deep gray-matter regions of thalamus, putamen, and pallidum show lower Glu/Cr compared with cortical white-matter regions. Lobar measurements demonstrated reduced Glu/Cr and Gln/Cr in the cerebellum as compared with the cerebrum, where white-matter regions show significantly lower Glu/Cr and Gln/Cr as compared with gray-matter regions across multiple brain lobes. Regression analysis showed no significant effect of gender on Glu/Cr or Gln/Cr measurement; however, Glx/Cr ratio was found to be significantly negatively correlated with age in some lobar brain regions. In summary, this methodology provides the spectral quality necessary for reliable separation of Glu and Gln at 3 T from a single MRSI acquisition enabling generation of regional distributions of metabolites over a large volume of the brain, including cortical regions. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: MRSI; aging; glutamate; glutamine; spectroscopy.

Figure 1

Example spectrum for a single voxel in the central white-matter (a) and summed spectra for the left putamen (b), left calcarine (c), and left frontal white-matter (d). With each spectrum is given the corresponding number of voxels summed (N_Voxels), Cramer-Rao bounds of fitting of Glx (CRLB_Glx), linewidth (LW), and signal-to-noise ratio (SNR). The corresponding regions are indicated on the MRI shown to the left of each spectrum.

Figure 2

Relationship between CRLBs for spectral fitting of Glx, Glu, and Gln and number of voxels in a region. Trend lines are generated using a 50-point moving average filter to illustrate the approximate relationship between CRLB and number of voxels. Results indicate that the average CRLBs produced by the spectral averaging technique reduce as the size of the region is increased.

Figure 3

Mean lobar Glu/Cr (a), Gln/Cr (b), and Glx/Cr (c) measurements for gray- and white-matter regions with error bars denoting standard deviation in measurements. Significance of difference between gray- and white-matter ratios are shown by asterisks (* p<0.05, ** p < 0.01, *** p<0.001). (d) Glu/Gln ratio for gray- and white-matter lobar brain regions with error bars denoting confidence interval (CI) calculated using the Fieller method.

Figure 4

Maps showing the AAL anatomic regions (a), and mean regional values for Glu/Cr (b), Gln/Cr (c), Glx/Cr (d), Glu Cramer-Rao (e) and Gln Cramer-Rao (f), for each of the atlas regions.