A versatile look-up algorithm for mapping pH values and magnesium ion content using 31P MRSI.

31P MRSI allows for the non-invasive mapping of pH and magnesium ion content (Mg) in vivo, by translating the chemical shifts of inorganic phosphate and adenosine-5'-triphosphate (ATP) to pH and Mg via suitable calibration equations, such as the modified Henderson-Hasselbalch equation. However, the required constants in these calibration equations are typically only determined for physiological conditions, posing a particular challenge for their application to diseased tissue, where the biochemical conditions might change manyfold. In this article, we propose a multi-parametric look-up algorithm aiming at the condition-independent determination of pH and Mg by employing multiple quantifiable 31P spectral properties simultaneously. To generate entries for an initial look-up table, measurements from 114 model solutions prepared with varying chemical properties were made at 9.4 T. The number of look-up table entries was increased by inter- and extrapolation using a multi-dimensional function developed based on the Hill equation. The assignment of biochemical parameters, that is, pH and Mg, is realized using probability distributions incorporating specific measurement uncertainties on the quantified spectral parameters, allowing for an estimation of most plausible output values. As proof of concept, we applied a version of the look-up algorithm employing only the chemical shifts of γ- and ß-ATP for the determination of pH and Mg to in vivo 3D 31P MRSI data acquired at 7 T from (i) the lower leg muscles of healthy volunteers and (ii) the brains of patients with glioblastoma. The resulting volumetric maps showed plausible values for pH and Mg, partly revealing differences from maps generated using the conventional calibration equations.

Whole-Brain Intracellular pH Mapping of Gliomas Using High-Resolution 31P MR Spectroscopic Imaging at 7.0 T.

Malignant tumors commonly exhibit a reversed pH gradient compared with normal tissue, with a more acidic extracellular pH and an alkaline intracellular pH (pHi). In this prospective study, pHi values in gliomas were quantified using high-resolution phosphorous 31 (31P) spectroscopic MRI at 7.0 T and were used to correlate pHi alterations with histopathologic findings. A total of 12 participants (mean age, 58 years ± 18 [SD]; seven male, five female) with histopathologically proven, newly diagnosed glioma were included between September 2018 and November 2019. The 31P spectroscopic MRI scans were acquired using a double-resonant 31P/1H phased-array head coil together with a three-dimensional (3D) 31P chemical shift imaging sequence (5.7-mL voxel volume) performed with a 7.0-T whole-body system. The 3D volumetric segmentations were performed for the whole-tumor volumes (WTVs); tumor subcompartments of necrosis, gadolinium enhancement, and nonenhancing T2 (NCE T2) hyperintensity; and normal-appearing white matter (NAWM), and pHi values were compared. Spearman correlation was used to assess association between pHi and the proliferation index Ki-67. For all study participants, mean pHi values were higher in the WTV (7.057 ± 0.024) compared with NAWM (7.006 ± 0.012; P < .001). In eight participants with high-grade gliomas, pHi was increased in all tumor subcompartments (necrosis, 7.075 ± 0.033; gadolinium enhancement, 7.075 ± 0.024; NCE T2 hyperintensity, 7.043 ± 0.015) compared with NAWM (7.004 ± 0.014; all P < .01). The pHi values of WTV positively correlated with Ki-67 (R2 = 0.74, r = 0.78, P = .001). In conclusion, 31P spectroscopic MRI at 7.0 T enabled high-resolution quantification of pHi in gliomas, with pHi alteration associated with the Ki-67 proliferation index, and may aid in diagnosis and treatment monitoring. Keywords: 31P MRSI, pH, Glioma, Glioblastoma, Ultra-High-Field MRI, Imaging Biomarker, 7 Tesla Supplemental material is available for this article. © RSNA, 2023.

Assessment of Sodium MRI at 7 Tesla as Predictor of Therapy Response and Survival in Glioblastoma Patients.

The purpose of this work was to prospectively investigate sodium (23Na) MRI at 7 Tesla (T) as predictor of therapy response and survival in patients with glioblastoma (GBM). Thus, 20 GBM patients underwent 23Na MRI at 7T before, immediately after and 6 weeks after chemoradiotherapy (CRT). The median tissue sodium concentration (TSC) inside the whole tumor excluding necrosis was determined. Initial response to CRT was assessed employing the updated response assessment in neuro-oncology working group (RANO) criteria. Clinical parameters, baseline TSC and longitudinal TSC differences were compared between patients with initial progressive disease (PD) and patients with initial stable disease (SD) using Fisher's exact tests and Mann-Whitney-U-tests. Univariate proportional hazard models for progression free survival (PFS) and overall survival (OS) were calculated using clinical parameters and TSC metrics as predictor variables. The analyses demonstrated that TSC developed heterogeneously over all patients following CRT. None of the TSC metrics differed significantly between cases of initial SD and initial PD. Furthermore, TSC metrics did not yield a significant association with PFS or OS. Conversely, the initial response according to the RANO criteria could significantly predict PFS [univariate HR (95%CI) = 0.02 (0.0001-0.21), p < 0.001] and OS [univariate HR = 0.17 (0.04-0.65), p = 0.005]. In conclusion, TSC showed treatment-related changes in GBM following CRT, but did not significantly correlate with the initial response according to the RANO criteria, PFS or OS. In contrast, the initial response according to the RANO criteria was a significant predictor of PFS and OS. Future investigations need to elucidate the reasons for treatment-related changes in TSC and their clinical value for response prediction in glioblastoma patients receiving CRT.

Mapping an Extended Metabolic Profile of Gliomas Using High-Resolution 31P MRSI at 7T.

Phosphorus magnetic resonance spectroscopic imaging (31P MRSI) is of particular interest for investigations of patients with brain tumors as it enables to non-invasively assess altered energy and phospholipid metabolism in vivo. However, the limited sensitivity of 31P MRSI hampers its broader application at clinical field strengths. This study aimed to identify the additional value of 31P MRSI in patients with glioma at ultra-high B 0 = 7T, where the increase in signal-to-noise ratio may foster its applicability for clinical research. High-quality, 3D 31P MRSI datasets with an effective voxel size of 5.7 ml were acquired from the brains of seven patients with newly diagnosed glioma. An optimized quantification model was implemented to reliably extract an extended metabolic profile, including low-concentrated metabolites such as extracellular inorganic phosphate, nicotinamide adenine dinucleotide [NAD(H)], and uridine diphosphoglucose (UDPG), which may act as novel tumor markers; a background signal was extracted as well, which affected measures of phosphomonoesters beneficially. Application of this model to the MRSI datasets yielded high-resolution maps of 12 different 31P metabolites, showing clear metabolic differences between white matter (WM) and gray matter, and between healthy and tumor tissues. Moreover, differences between tumor compartments in patients with high-grade glioma (HGG), i.e., gadolinium contrast-enhancing/necrotic regions (C+N) and peritumoral edema, could also be suggested from these maps. In the group of patients with HGG, the most significant changes in metabolite intensities were observed in C+N compared to WM, i.e., for phosphocholine +340%, UDPG +54%, glycerophosphoethanolamine -45%, and adenosine-5'-triphosphate -29%. Furthermore, a prominent signal from mobile phospholipids appeared in C+N. In the group of patients with low-grade glioma, only the NAD(H) intensity changed significantly by -28% in the tumor compared to WM. Besides the potential of 31P MRSI at 7T to provide novel insights into the biochemistry of gliomas in vivo, the attainable spatial resolutions improve the interpretability of 31P metabolite intensities obtained from malignant tissues, particularly when only subtle differences compared to healthy tissues are expected. In conclusion, this pilot study demonstrates that 31P MRSI at 7T has potential value for the clinical research of glioma.