2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas

Abstract

Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.

Figures

Figure 1

(a) Quantum-mechanically calculated spectra of the 2HG H4 resonances, at 3T, are displayed vs. TE1 and TE2 of PRESS (subecho times of the first and second slice-selective 180° radio-frequency pulses, respectively). (b) Calculated difference-edited multiplets of the 2HG H2 resonance are plotted vs. subecho times TE1 and TE2 of scalar difference editing. Shown for each TE1-TE2 pair are, top to bottom, E180-on (brown) and E180-off (green) subspectra, and difference between the two subspectra (blue). Here E180 denotes editing 180° pulses tuned to 1.9 p.p.m. PRESS and edited spectra are all broadened to singlet line width of 4 Hz. Spectra in (a) and (b) are scaled equally for direct comparison. Signal reduction due to T2 relaxation effects was not included in the calculations. (c) Calculated and phantom spectra of 2HG for PRESS and difference editing. The echo times were 97 and 106 ms for PRESS and editing. The concentrations of 2HG and glycine in the phantom were both 10 mM (pH = 7.0). Spectra are scaled with respect to the glycine singlet at 3.55 p.p.m..

Figure 2

In vivo single-voxel localized PRESS spectra from normal brain (a) and tumors (b-f), at 3T, are shown together with spectral fits (LCModel) and the components of 2HG, GABA, glutamate, and glutamine, and voxel positioning (2×2×2 cm3). Spectra are scaled with respect to the water signal from the voxel. Vertical lines are drawn at 2.25 p.p.m. to indicate the H4 multiplet of 2HG. Shown in brackets is the estimated metabolite concentration (mM) ± standard deviation. Abbreviations: Cho, choline; Cr, creatine; NAA, N-acetylaspartate; Glu, glutamate; Gln, glutamine; GABA, γ-aminobutyric acid; Gly, glycine; Lac, lactate; Lip, lipids. Scale bars, 1 cm.

Figure 3

(a) LCModel fitting results (fits and residuals) of PRESS spectra obtained with basis set with or without 2HG. Data are displayed in the order of increasing 2HG estimates, top to bottom. (b) PRESS and difference-edited spectra from four subjects are shown in pairs, together with LCModel fits and 2HG signal components. Vertical lines are drawn at 2.25 and 4.02 p.p.m. in the PRESS and edited spectra, respectively.

Figure 4

(a) Multi-voxel imaging spectra from a patient with a WHO Grade 3 oligodendroglioma patient are displayed on top of the T2w-FLAIR image. The grid size is 1×1 cm, with slice thickness 1.5 cm. The spectra are displayed between 4.1 – 1.8 p.p.m. (left to right). (b,c) Two representative spectra (one from the tumor and another from the contralateral normal brain) are shown together with LCModel fits and residuals. (d) The estimated concentrations of 2HG, choline and NAA in individual voxels were color coded for comparison. The NAA level in gray matter in normal brain was assumed to be 12 mM. Scale bars, 1 cm.