Measurement of glycine in the human brain in vivo by 1H-MRS at 3 T: application in brain tumors

Abstract

Glycine is a key metabolic intermediate required for the synthesis of proteins, nucleic acids, and other molecules, and its detection in cancer could, therefore, provide biologically relevant information about the growth of the tumor. Here, we report measurement of glycine in human brain and gliomas by an optimized point-resolved spectroscopy sequence at 3 T. Echo time dependence of the major obstacle, myo-inositol (mI) multiplet, was investigated with numerical simulations, incorporating the 3D volume localization. The simulations indicated that a subecho pair (TE(1) , TE(2) ) = (60, 100) ms permits detection of both glycine and mI with optimum selectivity. In vivo validation of the optimized point-resolved spectroscopy was conducted on the right parietal cortex of five healthy volunteers. Metabolite signals estimated from LC Model were normalized with respect to the brain water signal, and the concentrations were evaluated assuming the total creatine concentration at 8 mM. The glycine concentration was estimated as 0.6 ± 0.1 mM (mean ± SD, n = 5), with a mean Cramér-Rao lower bound of 9 ± 1%. The point-resolved spectroscopy sequence was applied to measure the glycine levels in patients with glioblastoma multiforme. Metabolite concentrations were obtained using the water signal from the tumor mass. The study revealed that a subset of human gliomas contains glycine levels elevated 1.5-8 fold relative to normal.

FIG. 1

Calculated PRESS spectra of mI+Gly (thick/blue) and mI (thin/brown), at 3T, are displayed vs. subecho times TE₁ and TE₂ for 50 – 110 ms with 10 ms increments. The spectra are scaled with a concentration ratio of [Gly]:[mI] = 1:5. The spectral range is 3.75 – 3.35 ppm (left to right). Spectra, calculated without T₂ relaxation effects , were broadened to singlet linewidth of 3 Hz (Lorentzian).

FIG. 2

In vitro spectra at PRESS (TE₁, TE₂) = (60, 100) ms, obtained from Phantom-1 with mI (25 mM) and Cr (40 mM), and Phantom-2 with Gly, mI, Cr, NAA and Glu at a concentration ratio of 1:5:8:10:10, at 3T, are shown together with short-TE STEAM spectra. Singlet linewidth is 3 Hz. TR was 15 s (> 5T₁). Vertical dotted lined are drawn at 3.55 and 3.62 ppm.

FIG. 3

(a) In vivo brain spectra are presented vs. number of signal averages (NSA). Vertical dotted lines are drawn at 3.55 and 3.62 ppm. (b) Voxel (2×2×2 mm³) positioning in the occipital cortex. (c) Concentration estimates and (d) LCModel spectral fit errors (CRLB) are plotted vs. NSA for Gly, mI, tCr, NAA, and GPCPC. Data were acquired using PRESS (TE₁, TE₂) = (60, 100) ms and TR = 2 s. Shown in (e) and (f) are LCModel fitting results from basis sets with or without Gly, respectively (NSA = 128).

FIG. 4

In vivo brain spectra from (a) a healthy volunteer and (b, c) a multi-focal GBM patient are shown together with the LCModel fits and individual signals of Gly, mI, Lac, Ala, Glu and Gln. Voxel positioning (2×2×2 cm³) is shown in the images. Spectra were acquired using PRESS (TE₁, TE₂) = (60, 100) ms, TR = 2 s, and NSA = 128. Spectra are normalized with respect to the brain water signal (TR = 20 s; TE = 18 ms). A vertical dotted line is drawn at the 3.55 ppm Gly resonance.

FIG. 5

In vivo brain spectra from a normal subject (a) and 7 patients with GBM are shown on top of LCModel fits, together with voxel positioning (size 2×2×2 cm³). Spectra were all acquired with PRESS (TE₁, TE₂) = (60, 100) ms, TR = 2 s, and NSA = 128. Spectra are normalized with respect to the brain water signal (TR = 20 s; TE = 18 ms). A vertical dotted line is drawn at the 3.55 ppm Gly resonance.