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

Adam W Autry; Sana Vaziri; Marisa LaFontaine; Jeremy W Gordon; Hsin-Yu Chen; Yaewon Kim; Javier E Villanueva-Meyer; Annette Molinaro; Jennifer L Clarke; Nancy Ann Oberheim Bush; Duan Xu; Janine M Lupo; Peder E Z Larson; Daniel B Vigneron; Susan M Chang; Yan Li

doi:10.1016/j.nicl.2023.103501

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

Neuroimage Clin. 2023:39:103501. doi: 10.1016/j.nicl.2023.103501. Epub 2023 Aug 18.

Authors

Adam W Autry¹, Sana Vaziri¹, Marisa LaFontaine¹, Jeremy W Gordon¹, Hsin-Yu Chen¹, Yaewon Kim¹, Javier E Villanueva-Meyer², Annette Molinaro³, Jennifer L Clarke⁴, Nancy Ann Oberheim Bush⁴, Duan Xu¹, Janine M Lupo¹, Peder E Z Larson¹, Daniel B Vigneron⁵, Susan M Chang⁶, Yan Li⁷

Affiliations

¹ Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA.
² Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA; Department of Neurological Surgery, University of California, San Francisco, USA.
³ Department of Neurological Surgery, University of California, San Francisco, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.
⁴ Department of Neurological Surgery, University of California, San Francisco, USA; Department of Neurology, University of California, San Francisco, USA.
⁵ Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA; Department of Bioengineering and Therapeutic Science, University of California, San Francisco, USA.
⁶ Department of Neurological Surgery, University of California, San Francisco, USA.
⁷ Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA. Electronic address: yan.li@ucsf.edu.

Abstract

Background: 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.

Methods: 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 (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-¹³C/spectroscopic) metabolic data were collectively examined at the ¹³C 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 ¹H choline-to-N-acetylaspartate index (CNI)_max, [1-¹³C]lactate, modified [1-¹³C]lactate-to-[1-¹³C]pyruvate ratio (CEL_val > NEL_val > NAWM_val); [1-¹³C]lactate-to-[¹³C]bicarbonate ratio (CEL_val > NEL_val/NAWM_val); and ¹H-lactate (CEL_val/NEL_val > NAWM_undetected). Significant associations were found between normalized perfusion (cerebral blood volume, nCBV; peak height, nPH) and levels of [1-¹³C]pyruvate and [1-¹³C]lactate, as well as between CNI_max and levels of [1-¹³C]pyruvate, [1-¹³C]lactate and modified ratio. GBM, by comparison to G4A^IDH+, displayed lower perfusion %-recovery and modeled rate constants for [1-¹³C]pyruvate-to-[1-¹³C]lactate conversion (k_PL), and higher ¹H-lactate and [1-¹³C]pyruvate levels, while having higher nCBV, %-recovery, k_PL, [1-¹³C]pyruvate-to-[1-¹³C]lactate and modified ratios relative to treatment effects.

Conclusions: GBM consistently displayed aberrant, Warburg-related metabolism and regional heterogeneity detectable by novel HP-¹³C/¹H imaging techniques.

Keywords: GBM; Hyperpolarized carbon-13; IDH; Metabolism; Treatment effects.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bicarbonates
Glioblastoma* / diagnostic imaging
Glioma* / diagnostic imaging
Humans
Lactic Acid
Pyruvic Acid

Substances

Bicarbonates
Lactic Acid
Pyruvic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding