Abstract
BACKGROUND: Dynamic hyperpolarized (HP)-(13)C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-(13)C]pyruvate tracer that undergoes conversion to [1-(13)C]lactate and [(13)C]bicarbonate. Using a multi-parametric (1)H/HP-(13)C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor. METHODS: Multi-parametric (1)H/HP-(13)C 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 (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-(13)C/spectroscopic) metabolic data were collectively examined at the (13)C resolution. Prog/TN GBM were similarly compared against progressive G4A(IDH+) and treatment effects. RESULTS: Regional analysis of Prog/TN GBM metabolism revealed statistically significant heterogeneity in (1)H choline-to-N-acetylaspartate index (CNI)(max), [1-(13)C]lactate, modified [1-(13)C]lactate-to-[1-(13)C]pyruvate ratio (CEL(val) > NEL(val) > NAWM(val)); [1-(13)C]lactate-to-[(13)C]bicarbonate ratio (CEL(val) > NEL(val)/NAWM(val)); and (1)H-lactate (CEL(val)/NEL(val) > NAWM(undetected)). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-(13)C]pyruvate and [1-(13)C]lactate, as well as between CNI(max) and levels of [1-(13)C]pyruvate, [1-(13)C]lactate and modified ratio. GBM, by comparison to G4A(IDH+), displayed lower perfusion %-recovery and modeled rate constants for [1-(13)C]pyruvate-to-[1-(13)C]lactate conversion (k(PL)), and higher (1)H-lactate and [1-(13)C]pyruvate levels, while having higher nCBV, %-recovery, k(PL), [1-(13)C]pyruvate-to-[1-(13)C]lactate and modified ratios relative to treatment effects. CONCLUSIONS: GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-(13)C/(1)H imaging techniques.