On the Utility of Short Echo Time (TE) Single Voxel 1H–MRS in Non–Invasive Detection of 2–Hydroxyglutarate (2HG); Challenges and Potential Improvement Illustrated with Animal Models Using MRUI and LCModel

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are frequently found in brain tumors, and the resulting onco-metabolite, 2-hydroxyglutarate (2HG), has been suggested to be a potential diagnostic and prognostic biomarker of the diseases. Indeed, recent studies have demonstrated the feasibility of non-invasively detecting 2HG by using proton magnetic resonance spectroscopy (1H-MRS). Due to severe spectral overlaps of 2HG with its background metabolites and spectral baselines, however, the majority of those previous studies employed spectral editing methods with long echo times (TEs) instead of the most commonly used short TE approach with spectral fitting. Consequently, the results obtained with spectral editing methods may potentially be prone to errors resulting from substantial signal loss due to relaxation. Given that the spectral region where the main signal of 2HG resides is particularly sensitive to spectral baseline in metabolite quantification, we have investigated the impact of incorporating voxel-specifically measured baselines into the spectral basis set on the performance of the conventional short TE approach in 2HG detection in rodent models (Fisher 344 rats; n = 19) of IDH1/2 mutant-overexpressing F98 glioma at 9.4T. Metabolite spectra were acquired (SPECIAL sequence) for a tumor region and the contralateral normal region of the brain for each animal. For the estimation of spectral baselines metabolite-nulled spectra were obtained (double-inversion-recovery SPECIAL sequence) for each individual voxels. Data were post-processed with and without the measured baselines using MRUI and LCModel-the two most widely used data post-processing packages. Our results demonstrate that in-vivo detection of 2HG using the conventional short TE approach is challenging even at 9.4T. However, incorporation of voxel-specifically measured spectral baselines may potentially improve its performance. Upon more thorough validation in a larger number of animals and more importantly in human patients, the potential utility of the proposed short TE acquisition with voxel-specific baseline measurement approach in 2HG detection may need to be considered in the study design.