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.

Semi-solid MT and APTw CEST-MRI predict clinical outcome of patients with glioma early after radiotherapy.

PURPOSE: The purpose of this study was to compare the potential of asymmetry-based (APTwasym ), Lorentzian-fit-based (PeakAreaAPT and MTconst ), and relaxation-compensated (MTRRex APT and MTRRex MT) CEST contrasts of the amide proton transfer (APT) and semi-solid magnetization transfer (ssMT) for early response assessment and prediction of progression-free survival (PFS) in patients with glioma. METHODS: Seventy-two study participants underwent CEST-MRI at 3T from July 2018 to December 2021 in a prospective clinical trial four to 6 wk after the completion of radiotherapy for diffuse glioma. Tumor segmentations were performed on T2w -FLAIR and contrast-enhanced T1w images. Therapy response assessment and determination of PFS were performed according to response assessment in neuro oncology (RANO) criteria using clinical follow-up data with a median observation time of 9.2 mo (range, 1.6-40.8) and compared to CEST MRI metrics. Statistical testing included receiver operating characteristic analyses, Mann-Whitney-U-test, Kaplan-Meier analyses, and logrank-test. RESULTS: MTconst (AUC = 0.79, p < 0.01) showed a stronger association with RANO response assessment compared to PeakAreaAPT (AUC = 0.71, p = 0.02) and MTRRex MT (AUC = 0.71, p = 0.02), and enabled differentiation of participants with pseudoprogression (n = 8) from those with true progression (AUC = 0.79, p = 0.02). Furthermore, MTconst (HR = 3.04, p = 0.01), PeakAreaAPT (HR = 0.39, p = 0.03), and APTwasym (HR = 2.63, p = 0.02) were associated with PFS. MTRRex APT was not associated with any outcome. CONCLUSION: MTconst , PeakAreaAPT, and APTwasym imaging predict clinical outcome by means of progression-free survival. Furthermore, MTconst enables differentiation of radiation-induced pseudoprogression from disease progression. Therefore, the assessed metrics may have synergistic potential for supporting clinical decision making during follow-up of patients with glioma.

CEST imaging of the APT and ssMT predict the overall survival of patients with glioma at the first follow-up after completion of radiotherapy at 3T.

BACKGROUND AND PURPOSE: Outcome prediction of patients with glioma early after the completion of radiotherapy represents a major clinical challenge. Previously, the prognostic value of chemical exchange saturation transfer (CEST) imaging has been demonstrated in patients with newly diagnosed glioma. The objective of this study was to assess the potential of amide proton transfer (APT)-, relayed nuclear Overhauser effect (rNOE)- and semi-solid magnetization transfer (ssMT)-imaging according to Zhou et al. (APTwasym), Goerke et al. (MTRRexAPT, MTRRexNOE and MTRRexMT) and Mehrabian et al. (PeakAreaAPT, PeakAreaNOE and MTconst) for the prognostication of the overall survival (OS) of patients with glioma at the first follow-up after the completion of radiotherapy. MATERIALS AND METHODS: 49 of 72 participants with diffuse glioma, who underwent CEST MRI at 3T between July 2018 and December 2021 4 to 6 weeks after the completion of radiotherapy, were analyzed. Contrast-enhancing tumor (CE) and whole tumor (WT) volumes were segmented on T2w-FLAIR and contrast-enhanced T1w images. Kaplan-Meier analysis and logrank-test were used for statistical analyses. RESULTS: APTw imaging demonstrated the strongest association with OS (HR = 4.66, p < 0.001). The MTconst (HR = 2.54, p = 0.044) was associated with the OS of participants with residual contrast-enhancing glioma tissue, whilst the MTRRexAPT (HR = 2.44, p = 0.056) showed a trend in this sub-cohort. The MTRRexNOE, MTRRexMT and PeakAreaNOE were not associated with survival. CONCLUSION: Imaging of the APT and ssMT at the first follow-up 4 to 6 weeks after the completion of radiotherapy at 3T were associated with the overall survival of study participants with glioma.

Assessing the influence of the menstrual cycle on APT CEST-MRI in the human breast.

PURPOSE: In fibroglandular breast tissue, conventional dynamic contrast-enhanced MR-mammography is known to be affected by water content changes during the menstrual cycle. Likewise, amide proton transfer (APT) chemical exchange saturation transfer (CEST)-MRI might be inherently prone to the menstrual cycle, as CEST signals are indirectly detected via the water signal. The purpose of this study was to investigate the influence of the menstrual cycle on APT CEST-MRI in fibroglandular breast tissue. METHOD: Ten healthy premenopausal women (19-34 years) were included in this IRB approved prospective study and examined twice during their menstrual cycle. Examination one and two were performed during the first half (day 2-8) and the second half (day 15-21) of the menstrual cycle, respectively. As a reference for the APT signal in malignant breast tumor tissue, previously reported data of nine breast cancer patients were included in this study. CEST-MRI (B1 = 0.7µT) was performed on a 7 T whole-body scanner followed by a multi-Lorentzian fit analysis. The APT signal was corrected for B0/B1-field inhomogeneities, fat signal contribution, and relaxation effects of the water signal and evaluated in the fibroglandular breast tissue. Intra-individual APT signal differences between examination one and two were compared using the Wilcoxon signed-rank test. The level of significance was set at p < 0.05. RESULTS: The APT signal showed no significant difference in the fibroglandular breast tissue of healthy premenopausal volunteers throughout the menstrual cycle (p = 1.00) (examination 1 vs. examination 2: mean and standard deviation = 3.24 ± 0.68%Hz vs. 3.30 ± 0.73%Hz, median and IQR = 3.36%Hz and 0.87%Hz vs. 3.38%Hz and 0.71%Hz). CONCLUSION: The present study provides an important basis for the clinical application of APT CEST-MRI as an additional contrast mechanism in MR-mammography, as menstrual cycle-related APT signal fluctuations seem to be negligible compared to the APT signal increase in breast cancer tissue.

31 P MRSI at 7 T enables high-resolution volumetric mapping of the intracellular magnesium ion content in human lower leg muscles.

PURPOSE: The non-invasive determination of the free magnesium ion concentration ([Mg2+free ]) using 31 P MRSI in vivo is of interest in research on various pathologies, e.g. diabetes. The purpose of this study was to demonstrate the potential of 31 P MRSI at 7 T to enable volumetric, high-resolution mapping of [Mg2+free ]. METHODS: 3D 31 P MRSI datasets from the lower leg of three healthy volunteers were acquired at B0  = 7 T with a nominal spatial resolution of (8 × 8 × 16) mm3 in 56 min. Volumetric [Mg2+free ] maps were calculated based on the quantified local chemical shift difference between the α- and ß-resonance of adenosine triphosphate (ATP) considering also local pH values. Mean [Mg2+free ] values from three different muscle groups were compared. To demonstrate the potential of reducing the measurement time, the analysis was repeated on the acquired MRSI data retrospectively reconstructed with fewer averages. RESULTS: The generated [Mg2+free ] maps revealed local differences, and mean [Mg2+free ] values of (1.08 ± 0.03) mM were found in the tibialis anterior, (0.91 ± 0.04) mM in the soleus and (0.98 ± 0.03) mM in the gastrocnemius medialis. The time-reduced 28-min scan resulted in comparable [Mg2+free ] maps, and mean values being in agreement with the values from the 56-min scan. CONCLUSION: 31 P MRSI at 7 T enables volumetric, high-resolution mapping of free magnesium ion content in human lower leg muscles. The measurement time of the 31 P MRSI acquisition can be reduced to 28 min, opening the potential to apply volumetric [Mg2+free ] mapping for the investigation of pathologies with altered magnesium homeostasis.

Motion correction for three-dimensional chemical exchange saturation transfer imaging without direct water saturation artifacts.

In chemical exchange saturation transfer (CEST) MRI, motion correction is compromised by the drastically changing image contrast at different frequency offsets, particularly at the direct water saturation. In this study, a simple extension for conventional image registration algorithms is proposed, enabling robust and accurate motion correction of CEST-MRI data. The proposed method uses weighted averaging of motion parameters from a conventional rigid image registration to identify and mitigate erroneously misaligned images. Functionality of the proposed method was verified by ground truth datasets generated from 10 three-dimensional in vivo measurements at 3 T with simulated realistic random rigid motion patterns and noise. Performance was assessed using two different criteria: the maximum image misalignment as a measure for the robustness against direct water saturation artifacts, and the spectral error as a measure of the overall accuracy. For both criteria, the proposed method achieved the best scores compared with two motion-correction algorithms specifically developed to handle the varying contrasts in CEST-MRI. Compared with a straightforward linear interpolation of the motion parameters at frequency offsets close to the direct water saturation, the proposed method offers better performance in the absence of artifacts. The proposed method for motion correction in CEST-MRI allows identification and mitigation of direct water saturation artifacts that occur with conventional image registration algorithms. The resulting improved robustness and accuracy enable reliable motion correction, which is particularly crucial for an automated and carefree evaluation of spectral CEST-MRI data, e.g., for large patient cohorts or in clinical routines.

Mapping intracellular pH in tumors using amide and guanidyl CEST-MRI at 9.4 T.

PURPOSE: In principle, non-invasive mapping of the intracellular pH (pHi ) in vivo is possible using endogenous chemical exchange saturation transfer (CEST)-MRI of the amide and guanidyl signals. However, the application for cancer imaging is still impeded, as current state-of-the-art approaches do not allow for simultaneous compensation of concomitant effects that vary within tumors. In this study, we present a novel method for absolute pHi mapping using endogenous CEST-MRI, which simultaneously compensates for concentration changes, superimposing CEST signals, magnetization transfer contrast, and spillover dilution. THEORY AND METHODS: Compensation of the concomitant effects was achieved by a ratiometric approach (i.e. the ratio of one CEST signal at different B1 ) in combination with the relaxation-compensated inverse magnetization transfer ratio MTRRex and a separate first-order polynomial-Lorentzian fit of the amide and guanidyl signals at 9.4 T. Calibration of pH values was accomplished using in vivo-like model suspensions from porcine brain lysates. Applicability of the presented method in vivo was demonstrated in n = 19 tumor-bearing mice. RESULTS: In porcine brain lysates, measurement of pH was feasible over a broad range of physiologically relevant pH values of 6.2 to 8.0, while being independent of changes in concentration. A median pHi of approximately 7.2 was found in the lesions of 19 tumor-bearing mice. CONCLUSION: The presented method enables non-invasive mapping of absolute pHi values in tumors using CEST-MRI, which was so far prevented by concomitant effects. Consequently, pre-clinical studies on pHi changes in tumors are possible allowing the assessment of pHi in vivo as a biomarker for cancer diagnosis or treatment monitoring.

Clinical routine acquisition protocol for 3D relaxation-compensated APT and rNOE CEST-MRI of the human brain at 3T.

PURPOSE: The value of relaxation-compensated amide proton transfer (APT) and relayed nuclear Overhauser effect (rNOE) chemical exchange saturation transfer (CEST)-MRI has already been demonstrated in various neuro-oncological clinical applications. Recently, we translated the approach from 7T to a clinically relevant magnetic field strength of 3T. However, the overall acquisition time was still too long for a broad application in the clinical setting. The aim of this study was to establish a shorter acquisition protocol whilst maintaining the contrast behavior and reproducibility. METHODS: Ten patients with glioblastoma were examined using the previous state-of-the-art acquisition protocol at 3T. The acquired spectral data were retrospectively reduced to find the minimal amount of required information that allows obtaining the same contrast behavior. To further reduce the acquisition time, also the image readout was accelerated and the pre-saturation parameters were further optimized. RESULTS: In total, the overall acquisition time could be reduced from 19 min to under 7 min. One key finding was that, when evaluated by the relaxation-compensated inverse metric, a contrast correction for B1 -field inhomogeneities at 3T can also be achieved reliably with CEST data at only one B1 value. In contrast, a 1-point B1 -correction was not sufficient for the common linear difference evaluation. The reproducibility of the new clinical routine acquisition protocol was similar to the previous state-of-the-art protocol with limits of agreement below 20%. CONCLUSIONS: The substantial reduction in acquisition time by about 64% now allows the application of 3D relaxation-compensated APT and rNOE CEST-MRI for examinations of the human brain at 3T in clinical routine.

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.

Volumetric mapping of intra- and extracellular pH in the human brain using 31 P MRSI at 7T.

PURPOSE: In vivo 31 P MRSI enables noninvasive mapping of absolute pH values via the pH-dependent chemical shifts of inorganic phosphates (Pi ). A particular challenge is the quantification of extracellular Pi with low SNR in vivo. The purpose of this study was to demonstrate feasibility of assessing both intra- and extracellular pH across the whole human brain via volumetric 31 P MRSI at 7T. METHODS: 3D 31 P MRSI data sets of the brain were acquired from three healthy volunteers and three glioma patients. Low-rank denoising was applied to enhance the SNR of 31 P MRSI data sets that enables detection of extracellular Pi at high spatial resolutions. A robust two-compartment quantification model for intra- and extracellular Pi signals was implemented. RESULTS: In particular low-rank denoising enabled volumetric mapping of intra- and extracellular pH in the human brain with voxel sizes of 5.7 mL. The average intra- and extracellular pH measured in white matter of healthy volunteers were 7.00 ± 0.00 and 7.33 ± 0.03, respectively. In tumor tissue of glioma patients, both the average intra- and extracellular pH increased to 7.12 ± 0.01 and 7.44 ± 0.01, respectively, compared to normal appearing tissue. CONCLUSION: Mapping of pH values via 31 P MRSI at 7T using the proposed two-compartment quantification model improves reliability of pH values obtained in vivo, and has the potential to provide novel insights into the pH heterogeneity of various tissues.

Optimized dualCEST-MRI for imaging of endogenous bulk mobile proteins in the human brain.

Dual-frequency irradiation chemical exchange saturation transfer (dualCEST) allows imaging of endogenous bulk mobile proteins by selectively measuring the intramolecular spin diffusion. The resulting specificity to changes in the concentration, molecular size, and folding state of mobile proteins is of particular interest as a marker for neurodegenerative diseases and cancer. Until now, application of dualCEST in clinical trials was prevented by the inherently small signal-to-noise ratio and the resulting comparatively long examination time. In this study, we present an optimized acquisition protocol allowing 3D dualCEST-MRI examinations in a clinically relevant time frame. The optimization comprised the extension of the image readout to 3D, allowing a retrospective co-registration and application of denoising strategies. In addition, cosine-modulated dual-frequency presaturation pulses were implemented with a weighted acquisition scheme of the necessary frequency offsets. The optimization resulted in a signal-to-noise ratio gain by a factor of approximately 8. In particular, the application of denoising and the motion correction were the most crucial improvement steps. In vitro experiments verified the preservation of specificity of the dualCEST signal to proteins. Good-to-excellent intra-session and good inter-session repeatability was achieved, allowing reliable detection of relative signal differences of about 16% or higher. Applicability in a clinical setting was demonstrated by examining a patient with glioblastoma. The optimized acquisition protocol for dualCEST-MRI at 3 T enables selective imaging of endogenous bulk mobile proteins under clinically relevant conditions.

A novel normalization for amide proton transfer CEST MRI to correct for fat signal-induced artifacts: application to human breast cancer imaging.

PURPOSE: The application of amide proton transfer (APT) CEST MRI for diagnosis of breast cancer is of emerging interest. However, APT imaging in the human breast is affected by the ubiquitous fat signal preventing a straightforward application of existing acquisition protocols. Although the spectral region of the APT signal does not coincide with fat resonances, the fat signal leads to an incorrect normalization of the Z-spectrum, and therefore to distorted APT effects. In this study, we propose a novel normalization for APT-CEST MRI that corrects for fat signal-induced artifacts in the postprocessing without the need for application of fat saturation schemes or water-fat separation approaches. METHODS: The novel normalization uses the residual signal at the spectral position of the direct water saturation to estimate the fat contribution. A comprehensive theoretical description of the normalization for an arbitrary phase relation of the water and fat signal is provided. Functionality and applicability of the proposed normalization was demonstrated by in vitro and in vivo experiments. RESULTS: In vitro, an underestimation of the conventional APT contrast of approximately -1.2% per 1% fat fraction was observed. The novel normalization yielded an APT contrast independent of the fat contribution, which was also independent of the water-fat phase relation. This allowed APT imaging in patients with mamma carcinoma corrected for fat signal contribution, field inhomogeneities, spillover dilution, and water relaxation effects. CONCLUSION: The proposed normalization increases the specificity of APT imaging in tissues with varying fat content and represents a time-efficient and specific absorption rate-efficient alternative to fat saturation and water-fat separation approaches.

Dynamic glucose-enhanced (DGE) MRI in the human brain at 7 T with reduced motion-induced artifacts based on quantitative R1ρ mapping.

PURPOSE: Dynamic glucose-enhanced (DGE)-MRI based on chemical exchange-sensitive MRI, that is, glucoCEST and gluco-chemical exchange-sensitive spin-lock (glucoCESL), is intrinsically prone to motion-induced artifacts because the final DGE contrast relies on the difference of images, which were acquired with a time gap of several mins. In this study, identification of different types of motion-induced artifacts led to the development of a 3D acquisition protocol for DGE examinations in the human brain at 7 T with improved robustness in the presence of subject motion. METHODS: DGE-MRI was realized by the chemical exchange-sensitive spin-lock approach based either on relaxation rate in the rotating frame (R1ρ )-weighted or quantitative R1ρ imaging. A 3D image readout was implemented at 7 T, enabling retrospective volumetric coregistration of the image series and quantification of subject motion. An examination of a healthy volunteer without administration of glucose allowed for the identification of isolated motion-induced artifacts. RESULTS: Even after coregistration, significant motion-induced artifacts remained in the DGE contrast based on R1ρ -weighted images. This is due to the spatially varying sensitivity of the coil and was found to be compensated by a quantitative R1ρ approach. The coregistered quantitative approach allowed the observation of a clear increase of the DGE contrast in a patient with glioblastoma, which did not correlate with subject motion. CONCLUSION: The presented 3D acquisition protocol enables DGE-MRI examinations in the human brain with improved robustness against motion-induced artifacts. Correction of motion-induced artifacts is of high importance for DGE-MRI in clinical studies where an unambiguous assignment of contrast changes due to an actual change in local glucose concentration is a prerequisite.

Adaptive denoising for chemical exchange saturation transfer MR imaging.

High image signal-to-noise ratio (SNR) is required to reliably detect the inherently small chemical exchange saturation transfer (CEST) effects in vivo. In this study, it was demonstrated that identifying spectral redundancies of CEST data by principal component analysis (PCA) in combination with an appropriate data-driven extraction of relevant information can be used for an effective and robust denoising of CEST spectra. The relationship between the number of relevant principal components and SNR was studied on fitted in vivo Z-spectra with artificially introduced noise. Three different data-driven criteria to automatically determine the optimal number of necessary components were investigated. In addition, these criteria facilitate straightforward assessment of data quality that could provide guidance for CEST MR protocols in terms of SNR. Insights were applied to achieve a robust denoising of highly sampled low power Z-spectra of the human brain at 3 and 7 T. The median criterion provided the best estimation for the optimal number of components consistently for all three investigated artificial noise levels. Application of the denoising technique to in vivo data revealed a considerable increase in image quality for the amide and rNOE contrast with a considerable SNR gain. At 7 T the denoising capability was quantified to be comparable or even superior to an averaging of six measurements. The proposed denoising algorithm enables an efficient and robust denoising of CEST data by combining PCA with appropriate data-driven truncation criteria. With this generally applicable technique at hand, small CEST effects can be reliably detected without the need for repeated measurements.

Early response assessment of glioma patients to definitive chemoradiotherapy using chemical exchange saturation transfer imaging at 7 T.

BACKGROUND: Patients with newly diagnosed inoperable glioma receive chemoradiotherapy (CRT). Standard Response Assessment in Neuro-Oncology (RANO) takes a minimum of 4 weeks after the end of treatment. PURPOSE/HYPOTHESIS: To investigate whether chemical exchange saturation transfer (CEST) MRI enables earlier assessment of response to CRT in glioma patients. STUDY TYPE: Longitudinal prospective study. POPULATION: Twelve brain tumor patients who underwent definitive CRT were included in this study. Three longitudinal CEST MRI measurements were performed for each patient at 7T: first before, second immediately after completion of CRT, and a third measurement as a 6-week follow-up. FIELD STRENGTH/SEQUENCE: Conventional MRI (contrast-enhanced, T2 w and diffusion-weighted imaging) at 3T and T2 w and CEST MRI at 7T was performed for all patients. ASSESSMENT: The mean relaxation-compensated relayed nuclear-Overhauser-effect CEST signal (rNOE) and the mean downfield-rNOE-suppressed amide proton transfer (dns-APT) CEST signal were investigated. Additionally, choline-to-N-acetyl-aspartate ratios (Cho/NAA) were evaluated using single-voxel 1 H-MRS in six of these patients. Performance of obtained contrasts was analyzed in assessing treatment response as classified according to the updated RANO criteria. STATISTICAL TEST: Unpaired Student's t-test. RESULTS: The rNOE signal significantly separated stable and progressive disease directly after the end of therapy (post-treatment normalized to pre-treatment mean ± SD: rNOEresponder = 1.090 ± 0.110, rNOEnon-responder = 0.808 ± 0.155, P = 0.015). In contrast, no significant difference was observed between either group when assessing the normalized dns-APT (dns-APTresponder = 0.953 ± 0.384, dns-APTnon-responder = 0.972 ± 0.477, P = 0.95). In the smaller MRS subcohort, normalized Cho/NAA decreased in therapy responders (Cho/NAAresponder = 0.632 ± 0.007, Cho/NAAnon-responder = 0.946 ± 0.124, P = 0.070). DATA CONCLUSION: rNOE mediated CEST imaging at 7T allowed for discrimination of responders and non-responders immediately after the end of CRT, additionally supported by 1 H-MRS data. This is at least 4 weeks earlier than the standard clinical evaluation according to RANO. Therefore, CEST MRI may enable early response assessment in glioma patients. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:1268-1277.

Relaxation-compensated APT and rNOE CEST-MRI of human brain tumors at 3 T.

PURPOSE: Relaxation-compensated CEST-MRI (i.e., the inverse metrics magnetization transfer ratio and apparent exchange-dependent relaxation) has already been shown to provide valuable information for brain tumor diagnosis at ultrahigh magnetic field strengths. This study aims at translating the established acquisition protocol at 7 T to a clinically relevant magnetic field strength of 3 T. METHODS: Protein model solutions were analyzed at multiple magnetic field strengths to assess the spectral widths of the amide proton transfer and relayed nuclear Overhauser effect (rNOE) signals at 3 T. This prior knowledge of the spectral range of CEST signals enabled a reliable and stable Lorentzian-fitting also at 3 T where distinct peaks are no longer resolved in the Z-spectrum. In comparison to the established acquisition protocol at 7 T, also the image readout was extended to three dimensions. RESULTS: The observed spectral range of CEST signals at 3 T was approximately ±15 ppm. Final relaxation-compensated amide proton transfer and relayed nuclear Overhauser effect contrasts were in line with previous results at 7 T. Examination of a patient with glioblastoma demonstrated the applicability of this acquisition protocol in a clinical setting. CONCLUSION: The presented acquisition protocol allows relaxation-compensated CEST-MRI at 3 T with a 3D coverage of the human brain. Translation to a clinically relevant magnetic field strength of 3 T opens the door to trials with a large number of participants, thus enabling a comprehensive assessment of the clinical relevance of relaxation compensation in CEST-MRI.

Dual-frequency irradiation CEST-MRI of endogenous bulk mobile proteins.

A novel MRI contrast is proposed which enables the selective detection of endogenous bulk mobile proteins in vivo. Such a non-invasive imaging technique may be of particular interest for many diseases associated with pathological alterations of protein expression, such as cancer and neurodegenerative disorders. Specificity to mobile proteins was achieved by the selective measurement of intramolecular spin diffusion and the removal of semi-solid macromolecular signal components by a correction procedure. For this purpose, the approach of chemical exchange saturation transfer (CEST) was extended to a radiofrequency (RF) irradiation scheme at two different frequency offsets (dualCEST). Using protein model solutions, it was demonstrated that the dualCEST technique allows the calculation of an image contrast which is exclusively sensitive to changes in concentration, molecular size and the folding state of mobile proteins. With respect to application in humans, dualCEST overcomes the selectivity limitations at relatively low magnetic field strengths, and thus enables examinations on clinical MR scanners. The feasibility of dualCEST examinations in humans was verified by a proof-of-principle examination of a brain tumor patient at 3 T. With its specificity for the mobile fraction of the proteome, its comparable sensitivity to conventional water proton MRI and its applicability to clinical MR scanners, this technique represents a further step towards the non-invasive imaging of proteomic changes in humans.