Highly specific determination of IDH status using edited in vivo magnetic resonance spectroscopy

Abstract

Background: Mutations in the isocitrate dehydrogenase (IDH) enzyme affect 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG) and to compare performance of these methods with DNA sequencing and tissue 2HG analysis.

Methods: Twenty-four subjects with suspected diagnosis of low-grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3T using 2 MRS methods, edited MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by a combination of automated immunohistochemical analysis and Sanger sequencing. Levels of 2HG in tissue samples measured by gas chromatography-mass spectrometry were compared with those estimated by MRS.

Results: Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings.

Conclusions: Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning.

Fig. 1

In vivo ¹H MEGA-PRESS and optimized PRESS spectra and volumes of interest. The location and size of the VOIs are shown on FLAIR images in (A) IDH1-mutated glioma, (B) IDH wild-type glioma, and (C) healthy tissue. In vivo MEGA-PRESS and optimized PRESS spectra (black lines) acquired at 3T in (D, G) IDH1-mutated glioma, (E, H) IDH wild-type glioma, and (F, I) healthy tissue are shown together with LCModel fits (red lines), the 2HG contribution (green lines), and residuals (blue lines). Spectra are shown scaled to the NAA signal. No line broadening was applied. In the MEGA-PRESS and optimized PRESS spectra acquired in the IDH1-mutated glioma, the 2HG resonances can be observed at 4.02 ppm and at 2.25 ppm, respectively. NAA = N-acetylaspartate, GABA+ = GABA + macromolecules, Glx = glutamate + glutamine, tCr = creatine + phosphocreatine, tCho = choline containing compounds.

Fig. 2

Correlation between 2HG quantified by MRS and GC-MS. Regression plots of 2HG concentrations measured in tumor tissue by GC-MS with concentrations derived from (A) MEGA-PRESS and (B) optimized PRESS in the subgroup of subjects harboring IDH mutation. 2HG concentrations estimated from MEGA-PRESS show a significant correlation with concentrations derived by GC-MS (r = 0.68; P = 0.0009), while for optimized PRESS data the correlation was not significant (r = 0.36; P = 0.14).