Absolute Metabolite Quantification in Individuals with Glioma and Healthy Individuals Using Whole-Brain Three-dimensional MR Spectroscopic and Echo-planar Time-resolved Imaging

Abstract

Background: MR spectroscopic imaging (MRSI) can be used to quantify an extended brain metabolic profile but is confounded by changes in tissue water levels due to disease.

Purpose: To develop a fast absolute quantification method for metabolite concentrations combining whole-brain MRSI with echo-planar time-resolved imaging (EPTI) relaxometry in individuals with glioma and healthy individuals.

Materials and methods: In this prospective study performed from August 2022 to August 2023, using internal water as concentration reference, the MRSI-EPTI quantification method was compared with the conventional method using population-average literature relaxation values. Healthy participants and participants with mutant IDH1 gliomas underwent imaging at 3 T with a 32-channel coil. Real-time navigated adiabatic spiral three-dimensional MRSI scans were acquired in approximately 8 minutes and reconstructed with a super-resolution pipeline to obtain brain metabolic images at 2.4-mm isotropic resolution. High-spatial-resolution multiparametric EPTI was performed in 3 minutes, with 1-mm isotropic resolution, to correct the relaxation and proton density of the water reference signal. Bland-Altman analysis and the Wilcoxon signed rank test were used to compare absolute quantifications from the proposed and conventional methods.

Results: Six healthy participants (four male; mean age, 37 years ± 11 [SD]) and nine participants with glioma (six male; mean age, 41 years ± 15; one with wild-type IDH1 and eight with mutant IDH1) were included. In healthy participants, there was good agreement (+4% bias) between metabolic concentrations derived using the two methods, with a CI of plus or minus 26%. In participants with glioma, there was large disagreement between the two methods (+39% bias) and a CI of plus or minus 55%. The proposed quantification method improved tumor contrast-to-noise ratio (median values) for total N-acetyl-aspartate (EPTI: 0.541 [95% CI: 0.217, 0.910]; conventional: 0.484 [95% CI: 0.199, 0.823]), total choline (EPTI: 1.053 [95% CI: 0.681, 1.713]; conventional: 0.940 [95% CI: 0.617, 1.295]), and total creatine (EPTI: 0.745 [95% CI: 0.628, 0.909]; conventional: 0.553 [95% CI: 0.444, 0.828]) (P = .03 for all).

Conclusion: The whole-brain MRSI-EPTI method provided fast absolute quantification of metabolic concentrations with individual-specific corrections at 2.4-mm isotropic resolution, yielding concentrations closer to the true value in disease than the conventional literature-based corrections. © RSNA, 2024 Supplemental material is available for this article.

Graphical abstract

Figure 1:

Flowchart of participant enrollment in the study.

Figure 2:

(A) Flowchart of the pipeline for absolute quantification of metabolic concentrations that combines metabolic MR spectroscopic imaging (MRSI), multiparametric echo-planar time-resolved imaging (EPTI), and anatomic MRI. MRSI maps at the original resolution are checked for spectral quality (signal-to-noise ratio [SNR] > 5, full width at half maximum [FWHM] < 0.1 ppm, Cramer-Rao lower bound [CRLB] < 20%), missing voxels are inpainted, and images undergo denoising. Anatomic MRI is used as a prior to guide super-resolution MRSI upsampling and to segment the brain into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Multiparametric EPTI provides T1, T2, and proton density (PD) maps for relaxation correction of super-resolution MRSI scans to obtain absolute concentration metabolic images. (B) Example axial images of absolute metabolite quantification for creatine show the intermediate image processing steps from the initial low-resolution MRSI scan to the super-resolution image and the final absolute concentration map. The low-resolution creatine map is combined with MRSI quality control maps (signal-to-noise ratio, full width at half maximum, Cramer-Rao lower bound), anatomic imaging (multi-echo magnetization-prepared gradient echo [MEMPRAGE]), and brain segmentation (gray matter, white matter, and cerebrospinal fluid) and multiparametric (T1, T2, PD) maps. A.U. = arbitrary units.

Figure 3:

Quantification of absolute concentration of metabolites in the brain of a healthy participant (healthy participant 4 in Table). (A) Axial anatomic T1-weighted multi-echo magnetization-prepared gradient-echo (MEMPRAGE) image and quantitative proton density (PD), T1, and T2 maps acquired using three-dimensional echo-planar time-resolved imaging (EPTI) at 1-mm isotropic resolution. (B) Absolute concentration metabolic images for relevant brain metabolites (N-acetyl-aspartate [NAA] and N-acetyl-aspartyl-glutamate [NAAG], glycerophosphocholine [GPC] and phosphocholine [PCh], creatine [Cr] and phosphocreatine [PCr], glutamate [Glu], and myo-inositol [Ins]) with reference water signal corrected using T1, T2, and PD measured with EPTI or standard values from the conventional literature-based method (Conv). The spectra in B (black line, measured spectrum; red line, LCModel fit) are from four brain locations (anterior and posterior in the right and left hemispheres) indicated by the arrows in A. Spectra show good quality throughout the brain, with high signal-to-noise ratio, narrow line width, and no water or fat artifacts, enabling visualization of the complex metabolic pattern for both singlet peaks and spin-coupled multiplets. A.U. = arbitrary units.

Figure 4:

Absolute quantification of metabolites in the brain of a participant with World Health Organization grade 3 mutant IDH1 anaplastic astrocytoma (participant 1 with glioma in Table). (A) Axial anatomic fluid-attenuated inversion recovery (FLAIR) image and proton density (PD), T1, and T2 parametric maps acquired with three-dimensional echo-planar time-resolved imaging (EPTI). (B) Absolute concentration metabolic images for brain metabolites (N-acetyl-aspartate [NAA] and N-acetyl-aspartyl-glutamate [NAAG], glycerophosphocholine [GPC] and phosphocholine [PCh], glutamate [Glu], and myo-inositol [Ins]) and the oncometabolite D-2-hydroxyglutarate (2HG) produced using relaxation parameters measured with EPTI or assuming conventional values from the literature (Conv). The spectra in B (black line, measured spectrum; red line, LCModel fit) are from four brain locations, including the tumor (arrow 1 in A), the infiltrating edge of the tumor (arrows 2 and 3 in A), and normal-appearing brain (arrow 4 in A). The good-quality spectra from the tumor, infiltrative edge, and normal-appearing brain show a gradual transition from the tumor metabolic profile to the normal brain metabolic profile. A.U. = arbitrary units.

Figure 5:

Bland-Altman plots in (A) healthy participants and (B) participants with glioma of the difference in absolute concentration of metabolites using relaxation parameters measured with echo-planar time-resolved imaging (EPTI) or assuming conventional values from the literature. In all plots, the solid line represents the bias between the two methods, and the dashed lines represent the 95% CI of the limits of agreement. Cr = creatine, GPC = glycerophosphocholine, Glu = glutamate, Ins = myo-inositol, NAA = N-acetyl-aspartate, NAAG = N-acetyl-aspartyl-glutamate, PCh = phosphocholine, PCr = phosphocreatine, 2HG = D-2-hydroxyglutarate.

Figure 6:

Absolute concentrations of metabolites and water relaxation parameters with echo-planar time-resolved imaging (EPTI) and the conventional literature-based method (Conv.). (A, B) Box plots show metabolite concentrations in (A) gray matter (GM) and white matter (WM) in healthy participants and (B) tumor and healthy-appearing brain in participants with glioma. (C, D) Box plots show T1, T2, and proton density (PD) of water in (C) gray and white matter in healthy participants and (D) tumor and healthy-appearing brain in participants with glioma. Arrows in C indicate the healthy population-average T1 and T2 literature values (14) for water relaxation correction used in the conventional method. Concentrations are given in millimolars (mM), and relaxation times are given in milliseconds (ms). Cr = creatine, GPC = glycerophosphocholine, Glu = glutamate, Ins = myo-inositol, NAA = N-acetyl-aspartate, NAAG = N-acetyl-aspartyl-glutamate, PCh = phosphocholine, PCr = phosphocreatine.