Assessment of hypoxia and its dynamic evolution in glioblastoma via qBOLD MRI: a comparative study with metformin treatment

Abstract

Background: To investigate the accuracy of quantitative blood oxygen level-dependent (qBOLD) magnetic resonance imaging (MRI) in identifying hypoxia within glioblastoma and explore dynamic changes in oxygenation status of glioblastoma with and without metformin administration.

Methods: Three healthy and seven C6-bearing rats underwent 7-T qBOLD MRI. Oxygen extraction fraction (OEF) and cerebral metabolism rate of O₂ (CMRO₂) were calculated from qBOLD data. Tumor tissues were stained using hypoxia-inducible factor-1 $\alpha$ (HIF-1 $\alpha$ ) and pimonidazole. The correlation between the hypoxia markers and corresponding qBOLD-based parameters was analyzed. Six C6-bearing rats were divided into metformin-treated and control groups for a longitudinal study of qBOLD imaging changes, with scans conducted on the 12th, 15th, and 18th day post-tumor implantation.

Results: In healthy rats, gray matter showed higher values than white matter in T2, T2*, cerebral blood volume (CBV), and cerebral blood flow (CBF), whereas OEF was lower. Glioblastoma tissues exhibited elevated T2, T2*, CBV, and CBF but decreased OEF and CMRO₂ relative to normal-appearing white matter. No significant correlation was found between staining scores from HIF-1 $\alpha$ and pimonidazole. T2* and T2 values were negatively correlated with pimonidazole scores in tumor regions. As the tumor progressed, OEF values increased with intra-tissue variations, whereas CMRO₂ decreased. Metformin delayed the reduction of T2 and T2* values, with significant differences in OEF and CMRO₂ values compared to controls on day 18.

Conclusion: T2* and T2 values were significantly associated with the hypoxia status in glioma. Metformin could potentially mitigate the progression of hypoxia in glioblastoma, which can be tracked by qBOLD parameters.

Relevance statement: This study demonstrates the potential of qBOLD parameters in assessing glioma dynamic oxygen metabolism and the efficacy of metformin as an anti-hypoxic agent, providing insights into improving glioblastoma treatment strategies.

Key points: The study investigated qBOLD imaging's accuracy in identifying hypoxia status within glioblastoma. qBOLD effectively assesses hypoxia and its dynamic evolution in glioblastoma. qBOLD parameters assist in identifying a suitable patient demographic for metformin treatment.

Keywords: Glioblastoma; Hypoxia; Magnetic resonance imaging; Metformin; Rats.