Multi-parametric hyperpolarized 13C/1H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas
Adam Autry, Sana Vaziri, Marisa Lafontaine, Jeremy W. Gordon, Hsin‐Yu Chen, Yaewon Kim, Javier Villanueva-Meyer, Annette M. Molinaro, Jennifer Clarke, Nancy Ann Oberheim Bush, Duan Xu, Janine Lupo, Peder E. Z. Larson, Daniel B. Vigneron, Susan M. Chang, Yan Li
Abstract
Dynamic hyperpolarized (HP)-13C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-13C]pyruvate tracer that undergoes conversion to [1-13C]lactate and [13C]bicarbonate. Using a multi-parametric 1H/HP-13C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor. Multi-parametric 1H/HP-13C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n=11)], progressive astrocytoma, IDH-mutant, grade 4 (G4AIDH+, n=2) and GBM manifesting treatment effects (n=2). Voxel-wise regional analysis of the cohort with prog/TN GBM assessed imaging heterogeneity across contrast-enhancing/non-enhancing lesions (CEL/NEL) and normal-appearing white matter (NAWM) using a mixed effects model. To enable cross-nucleus parameter association, normalized perfusion, diffusion, and dynamic/steady-state (HP-13C/spectroscopic) metabolic data were collectively examined at the 13C resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects. Regional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-13C]lactate, modified [1-13C]lactate-to-[1-13C]pyruvate ratio (CELval>NELval>NAWMval); [1-13C]lactate-to-[13C]bicarbonate ratio (CELval>NELval/NAWMval); and 1H-lactate (CELval/NELval>NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-13C]pyruvate and [1-13C]lactate, as well as between CNImax and levels of [1-13C]pyruvate, [1-13C]lactate and modified ratio. GBM, by comparison to G4AIDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-13C]pyruvate-to-[1-13C]lactate conversion (kPL), and higher 1H-lactate and [1-13C]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-13C]pyruvate-to-[1-13C]lactate and modified ratios relative to treatment effects. GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-13C/1H imaging techniques.