Pitfalls in 2HG detection with TE-optimized MRS at 3T

Background and PurposeIn-vivo magnetic resonance spectroscopy (MRS) of 2-hydroxyglutarate (2HG) may provide diagnostic and monitoring biomarkers in isocitrate dehydrogenase (IDH)-mutated glioma. A previous meta-analysis has shown good diagnostic accuracy of TE-optimized PRESS for IDH-mutated glioma, but most studies feature IDH-wildtype glioma as a comparison. However, when considering newly identified brain lesions that may mimic glioma, full characterization of its diagnostic utility should also consider the accuracy of 2HG measurement in non-tumor tissue. Therefore, we tested how well TE-optimized 2HG levels distinguish between IDH-mutated glioma and non-tumor tissue, in this case, normal-appearing brain. We further examined the impact of different spectral modeling strategies (baseline stiffness, macromolecule inclusion, and basis set composition). Materials and Methods48 patients with diagnosed/suspected IDH-mutated glioma were enrolled. 3T MRS data were acquired from tumor and contralateral non-tumor tissue with PRESS localization (TE = 97 ms, optimized for 2HG detection) and analyzed with LCModel software. Receiver operating characteristic analysis evaluated 2HG estimates ability to distinguish IDH-mutated glioma from non-tumor brain tissue. Modeling interactions between 2HG and other metabolites were evaluated to identify reasons for potential false-positive 2HG detection. ResultsTE-optimized PRESS distinguished IDH-mutated glioma from non-tumor tissue with lower sensitivity (range 0.76-0.62) and specificity (0.85-0.78) than literature suggests for IDH-mutated vs. IDH-wildtype glioma. Strong negative correlations between gamma-aminobutyric acid (GABA) and 2HG persisted across all modeling strategies and may lead to false-positive 2HG detection in non-tumor tissue. We further present a cautionary example from a patient on a ketogenic diet, showing that the ketone body acetone can interfere with 2HG detection. ConclusionsSpectral overlap with GABA and acetone can lead to false-positive 2HG detection in non-tumor tissue. Clinicians need to be mindful of these pitfalls when interpreting 2HG estimates.