Deuterium Magnetic Resonance Spectroscopy Quantifies Tumor Fraction in a Mouse Model of a Mixed Radiation Necrosis / GL261-Glioblastoma Lesion

Purpose: Distinguishing recurrent brain tumor from treatment effects, including late time-to-onset radiation necrosis (RN), presents an on-going challenge in post-treatment imaging of neuro-oncology patients. Experiments were performed in a novel mouse model that recapitulates the relevant clinical histologic features of recurrent glioblastoma growing in a RN environment, the mixed tumor/RN model. The goal of this work was to apply single-voxel deuterium (²H) magnetic resonance spectroscopy (MRS), in concert with administration of deuterated glucose, to determine if the metabolic signature of aerobic glycolysis (Warburg effect: glucose → lactate in the presence of O₂), a distinguishing characteristic of proliferating tumor, provides a quantitative readout of the tumor fraction (percent) in a mixed tumor/RN lesion. Procedures: ²H MRS employed the SPin-ECho full-Intensity Acquired Localized (SPECIAL) MRS pulse sequence and outer volume suppression at 11.74 T. For each subject, a single ²H MRS voxel was placed over the mixed lesion as defined by contrast enhanced (CE) ¹H T1-weighted MRI. Following intravenous administration of [6,6-²H₂]glucose (Glc), ²H MRS monitored the glycolytic conversion to [3,3-²H₂]lactate (Lac) and glutamate + glutamine (Glu + Gln = Glx). Results: Based on previous work, the tumor fraction of the mixed lesion was quantified as the ratio of tumor volume, defined by ¹H magnetization transfer experiments, vs. the total mixed-lesion volume. Metabolite ²H MR spectral-amplitude values were converted to metabolite concentrations using the natural-abundance semi-heavy water (¹HO²H) resonance as an internal concentration standard. The ²H MR-determined [Lac] / [Glx] ratio was strongly linearly correlated with tumor fraction in the mixed lesion (n = 9), Pearson’s r = 0.87, and 77% of the variation in the [Lac] / [Glx] ratio was due to tumor percent r² = 0.77. Conclusions: This preclinical study supports the proposal that ²H MR could occupy a well-defined secondary role when standard-of-care ¹H imaging is non-diagnostic regarding tumor presence and/or response to therapy.