MRS detection of 2HG in vivo in patient-derived xenograft (PDX) mouse models of IDH-mutant gliomas may help unravel the alterations in metabolic profile in IDH-mutant gliomas. However, precise evaluation in vivo remains challenging when 2HG elevation is moderate, so we have developed a new PRESS method for 2HG detection at 9.4T in PDX mice with brain glioma.
Fig. 1. Volume-localized density matrix simulation for PRESS subecho time optimization. Volume-localized density-matrix simulations were performed to optimize the PRESS subecho times for 2HG detection. The simulations indicated that the 2HG C4-proton resonance at 2.25 ppm depends on the subecho times, TE1 and TE2. The 2HG signal was temporally maximized at TE = 96 ms (TE1 = 19 ms and TE2 = 77 ms). While the 2HG signal was masked by the glutamate (Glu) and GABA signals at a short TE (TE1 = 8 ms, TE2 = 6.7 ms) (Figure 2, top), the 2HG signal became narrow with negative polarity at TE = 96 ms (Figure 2, bottom), well separated from the neighboring resonances.
Fig. 2. Calculated PRESS spectra of 2HG, GABA, GLu, and Gly at TE= 14.7 ms (top) and TE = 96 ms (bottom). In vivo spectra obtained with the PRESS TE = 96ms from IDH-mutant mouse glioma showed a large inverted peak at 2.25 ppm, which was well reproduced by the LCModel fit. 2HG was estimated to be 26.1 mM (SD = 1%) (Figure 4). IDH-mutation was confirmed with IDH-immunohistochemistry (Figure 5).
Currently, we are studying the effect of IDH inhibitors using the 2HG optimized PRESS method in mouse glioma models.
Figure 4. In vivo PRESS TE = 96ms data from IDH mutant glioma 
Figure 5. IDH-mutation confirmed by IDH-immunohistochemistry. (Left) IDH-IHC. (Right) H&E staining.