Multi-parametric hyperpolarized 13C/1H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas

Background: Dynamic hyperpolarized (HP)-C-13 MRI has enabled real-time, non-invasive assessment of Warburgrelated metabolic dysregulation in glioma using a [1-C-13]pyruvate tracer that undergoes conversion to [1-C-13] lactate and [C-13]bicarbonate. Using a multi-parametric H-1/HP-C-13 imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor. Methods: Multi-parametric H-1/HP-1(3C) MRI data were acquired from fifteen patients with progressive/treatmentnaive glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4A(IDH+), 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-C-13/spectroscopic) metabolic data were collectively examined at the C-13 resolution. Prog/TN GBM were similarly compared against progressive G4AIDH+ and treatment effects. Results: Regional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in 1H choline-to-N-acetylaspartate index (CNI)max, [1-C-13]lactate, modified [1-C-13]lactate-to-[1-C-13]pyruvate ratio (CELval > NELval > NAWMval); [1-C-13]lactate-to-[C-13]bicarbonate ratio (CELval > NELval/NAWMval); and 1Hlactate (CELval/NELval > NAWMundetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-C-13]pyruvate and [1-C-13]lactate, as well as between CNImax and levels of [1-C-13]pyruvate, [1-C-13]lactate and modified ratio. GBM, by comparison to G4(AIDH+), displayed lower perfusion %-recovery and modeled rate constants for [1-C-13]pyruvate-to-[1-C-13] lactate conversion (kPL), and higher 1H-lactate and [1-C-13]pyruvate levels, while having higher nCBV, %-recovery, kPL, [1-C-13]pyruvate-to-[1-C-13]lactate and modified ratios relative to treatment effects. Conclusions: GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-C-13/H-1 imaging techniques.