Advanced Hyperpolarized 13C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach

Abstract

This study aimed to implement a multimodal ¹H/HP-¹³C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-¹³C metabolic data. A total of 100 ¹H/HP [1-¹³C]-pyruvate MR examinations (104 HP-¹³C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-¹³C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-¹³C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [¹³C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-¹³C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal ¹H/HP-¹³C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.

Keywords: Warburg; atlas-based prescription; glioma; hyperpolarized carbon-13; kinetics; metabolism; serial imaging.

Figure 1

HP-¹³C/¹H imaging overview. A procedural and illustrative summary of the multimodal HP-¹³C/¹H imaging protocol that was developed around a dual-tuned 8/24-channel ¹H/¹³C receiver coil. Key features include: tracer polarization begun before patient imaging; RF power calibration on an ethylene glycol (EG) phantom to determine the transmit gain for ¹³C imaging; atlas-based lactate-edited ¹H MRSI; and atlas-based dynamic HP-¹³C EPI. Any secondary HP-¹³C EPI acquisition was acquired 15 min after the first injection to minimize the effects of residual metabolism and dose response. QC, quality control; EPA, electron paramagnetic agent; asset calibration sequences were used to determine coil element weighting; IR-SPGR, inversion recovery spoiled gradient echo; FLAIR, fluid-attenuated inversion recovery; IDEAL, iterative decomposition of water and fat with echo asymmetry and least-squares estimation; ASL, arterial spin labeling; SWAN, susceptibility-weighted angiography; TOF, time-of-flight angiography; DTI, diffusion tensor imaging; DSC, dynamic susceptibility contrast-enhanced perfusion; CF, correction factor; CNI, choline-to-N-acetylaspartate (NAA) index (z-score); Cho, total choline; Cr, total creatine; AUC, area under the curve (signal); Rx, prescription.

Figure 2

Atlas-based HP-¹³C EPI. Automatic prescription schema for HP-¹³C EPI, which leveraged the 3-plane oblique orientation of atlas-based ¹H MRSI (A). Atlas-based HP-¹³C EPI of a patient (P-01) diagnosed with GBM demonstrated consistent volumetric coverage from dice coefficients ranging 0.965–0.978 over 4 scans spanning 159 days, enabling inter-exam voxel-wise correspondence (B). Serial maps of k_PL reflected the consistency in volumetric coverage and regional k_PL values. Largely resected tumor location highlighted at baseline with a red arrow. Rx, prescription; dy, days.

Figure 3

Hemispheric k_PL asymmetry. Brain-wide comparison of hemispheric asymmetry (S) in k_PL from normal-appearing tissue for manually prescribed axial (n = 78) versus atlas-based (n = 26) HP-¹³C EPI acquisitions. Rx, prescription; *, statistically significant difference.

Figure 4

Manual vs. atlas-based prescription. Representative patient (P-01) data from contemporaneous acquisitions of manually prescribed and atlas-based HP-¹³C EPI demonstrating reduced hemispheric asymmetry in atlas-based kinetics, particularly for regions with non-pathologic elevations of k_PL (red arrows); global asymmetry (S) calculated on a per-slice basis provided reference values for this finding. The atlas-based EPI acquisition further helped to highlight the tumor region (yellow arrow) relative to surrounding parenchyma on asymmetry maps. Rx, prescription.

Figure 5

HP-¹³C EPI methodologies. Example non-selective FID-CSI spectra following EPI that display the f_offset,Pyr; alanine is extra-parenchymal (A). Histogram of the |f_offset,Pyr| obtained using a coil-embedded [¹³C]-urea phantom versus water reference is shown alongside the corresponding EPI excitation spectral response that indicates relative signal loss due to off-resonance; the maximum f_offset,Pyr resulting from the water reference technique still retained ~0.96 M_xy (B). Definition of pyruvate inflow for NAWM (C) and histogram of pyruvate inflow percentages captured by 5 s versus 2 s EPI acquisition delays after tracer injection and saline flush (D). *, statistically significant difference.

Figure 6

Effects of acquisition delay. Interpolated HP-¹³C traces are shown for an EPI acquisition with a 2 s post-injection delay (A). These data from NAWM thresholded by 30–60% of ¹³C voxel volume were temporally shifted and resampled back to 3 s resolution to simulate the effects of delay on capturing pyruvate inflow (results recapitulated the empirical median inflow of 69% for the data acquired with a 5 s delay) (B). Values of k_PL,NAWM are plotted relative to complete capture of pyruvate rise at the 30% NAWM threshold (C); and alongside relative k_PL,error (D). Analogous plots of relative k_PB,NAWM (E) and k_PB,error (F) are also displayed. Ref, reference.