Lower Lactate Levels and Lower Intracellular pH in Patients with IDH-Mutant versus Wild-Type Gliomas.

Abstract

Preclinical evidence points toward a metabolic reprogramming in isocitrate dehydrogenase (IDH) mutated tumor cells with down-regulation of the expression of genes that encode for glycolytic metabolism. We noninvasively investigated lactate and Cr concentrations, as well as intracellular pH using 1H/phosphorus 31 (31P) MR spectroscopy in a cohort of patients with gliomas. Thirty prospectively enrolled, mostly untreated patients with gliomas met the spectral quality criteria (World Health Organization II [n = 7], III [n = 16], IV [n = 7]; IDH-mutant [n = 23]; IDH wild-type [n = 7]; 1p/19q codeletion [n = 9]). MR imaging protocol included 3D 31P chemical shift imaging and 1H single-voxel spectroscopy (point-resolved spectroscopy sequence at TE = 30 ms and TE = 97 ms with optimized echo spacing for detection of 2-hydroxyglutarate) from the tumor area. Values for absolute metabolite concentrations were calculated (phantom replacement method). Intracellular pH was determined from 31P chemical shift imaging. At TE = 97 ms, lactate peaks can be fitted with little impact of lipid/macromolecule contamination. We found a significant difference in lactate concentrations, lactate/Cr ratios, and intracellular pH when comparing tumor voxels of patients with IDH-mutant with those of patients with IDH wild-type gliomas, with reduced lactate levels and near-normal intracellular pH in patients with IDH-mutant gliomas. We additionally found evidence for codependent effects of 1p/19q codeletion and IDH mutations with regard to lactate concentrations for World Health Organization tumor grades II and III, with lower lactate levels in patients exhibiting the codeletion. There was no statistical significance when comparing lactate concentrations between IDH-mutant World Health Organization II and III gliomas. We found indirect evidence for metabolic reprogramming in IDH-mutant tumors with significantly lower lactate concentrations compared with IDH wild-type tumors and a near-normal intracellular pH.