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

NeuroImage: Clinical (Jan 2023)

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

Affiliations

Adam W. Autry: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Sana Vaziri: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Marisa LaFontaine: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Jeremy W. Gordon: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Hsin-Yu Chen: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Yaewon Kim: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Javier E. Villanueva-Meyer: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA; Department of Neurological Surgery, University of California, San Francisco, USA
Annette Molinaro: Department of Epidemiology and Biostatistics, University of California, San Francisco, USA; Department of Neurological Surgery, University of California, San Francisco, USA
Jennifer L. Clarke: Department of Neurological Surgery, University of California, San Francisco, USA; Department of Neurology, University of California, San Francisco, USA
Nancy Ann Oberheim Bush: Department of Neurological Surgery, University of California, San Francisco, USA; Department of Neurology, University of California, San Francisco, USA
Duan Xu: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Janine M. Lupo: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Peder E.Z. Larson: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA
Daniel B. Vigneron: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA; Department of Bioengineering and Therapeutic Science, University of California, San Francisco, USA
Susan M. Chang: Department of Neurological Surgery, University of California, San Francisco, USA
Yan Li: Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA; Corresponding author at: Department of Radiology and Biomedical Imaging, University of California, 185 Berry Street, Ste. 350, San Francisco, CA 94107, USA.

Journal volume & issue: Vol. 39
p. 103501

Abstract

Read online

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

Published in NeuroImage: Clinical

ISSN: 2213-1582 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General): Computer applications to medicine. Medical informatics; Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system
Website: http://www.journals.elsevier.com/neuroimage-clinical/

About the journal

Abstract

Keywords