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.

First implementation of dynamic oxygen-17 (17O) magnetic resonance imaging at 7 Tesla during neuronal stimulation in the human brain.

OBJECTIVE: First implementation of dynamic oxygen-17 (17O) MRI at 7 Tesla (T) during neuronal stimulation in the human brain. METHODS: Five healthy volunteers underwent a three-phase 17O gas (17O2) inhalation experiment. Combined right-side visual stimulus and right-hand finger tapping were used to achieve neuronal stimulation in the left cerebral hemisphere. Data analysis included the evaluation of the relative partial volume (PV)-corrected time evolution of absolute 17O water (H217O) concentration and of the relative signal evolution without PV correction. Statistical analysis was performed using a one-tailed paired t test. Blood oxygen level-dependent (BOLD) experiments were performed to validate the stimulation paradigm. RESULTS: The BOLD maps showed significant activity in the stimulated left visual and sensorimotor cortex compared to the non-stimulated right side. PV correction of 17O MR data resulted in high signal fluctuations with a noise level of 10% due to small regions of interest (ROI), impeding further quantitative analysis. Statistical evaluation of the relative H217O signal with PV correction (p = 0.168) and without (p = 0.382) did not show significant difference between the stimulated left and non-stimulated right sensorimotor ROI. DISCUSSION: The change of cerebral oxygen metabolism induced by sensorimotor and visual stimulation is not large enough to be reliably detected with the current setup and methodology of dynamic 17O MRI at 7 T.

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.

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.

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.

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.

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.

Double-tuned 31 P/1 H human head array with high performance at both frequencies for spectroscopic imaging at 9.4T.

PURPOSE: To develop a robust design of a human head double-tuned 31 P/1 H array, which provides good performance at both 31 P and 1 H frequencies for MR spectroscopic imaging at 9.4T. METHODS: Increasing the number of surface loops in a human head array improves the peripheral signal-to-noise ratio (SNR), while the central SNR doesn't substantially change. High peripheral SNR can contaminate MR spectroscopic imaging data at both 1 H and 31 P frequency. To minimize this effect, we limited the number of elements in the 31 P array to 10, i.e., 8 transceiver surface loops circumscribing the head and 2 receive "vertical" loops placed at the superior location. The 1 H-portion of the array also consists of 10 elements, i.e., 8 transceiver surface loops circumscribing the head and 2 transceiver "vertical" loops at the superior location of the head. Both the 31 P array and 1 H array are placed in a single layer at the same distance to the head, which provides high loading and, thus, a good performance for both arrays. RESULTS: Transmit efficiency of the 1 H-portion of the double-tuned array was very similar to that of the single-tuned arrays of similar size. Also, addition of the cross-loops substantially improved the brain coverage. CONCLUSION: We developed a novel 31 P/1 H double-tuned array for MR spectroscopic imaging of a human brain at 9.4T. Placing both 31 P and 1 H loops in a single layer provides for high transmit efficiency at both frequencies without compromising SNR near the brain center at the 31 P-frequency. Addition of the cross-loops at the superior location improves the brain coverage.

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.

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.

High-resolution 31 P echo-planar spectroscopic imaging in vivo at 7T.

PURPOSE: Conventional 31 P chemical shift imaging is time-consuming and yields only limited spatial resolution. The purpose of this study was to demonstrate feasibility of 31 P echo-planar spectroscopic imaging (EPSI) in vivo at 7T. METHODS: A 3D 31 P EPSI sequence with trapezoidal-shaped gradient pulses was implemented on a 7T MR scanner. To increase spectral width with reduced demand on gradient performance, a multishot approach was chosen. Acquisition weighting and 31 P-{1 H} double resonance for nuclear Overhauser signal enhancement were applied to increase sensitivity. RESULTS: 3D 31 P-{1 H} EPSI data from model solution and from human calf muscle and brain were obtained from voxels with effective sizes of 4.1 to 16.2 cm3 in measurement times of approximately 10 min. Individual spectra showed well-resolved resonances of endogenous 31 P-metabolites without artifacts. Volumetric high-resolution 31 P-metabolite maps in vivo showed metabolic heterogeneity of different tissues. CONCLUSION: In vivo 31 P EPSI at 7T yields high-quality metabolic images. The proposed multishot EPSI technique reduces the measurement times for acquisition of volumetric high-resolution maps of 31 P-metabolites or intracellular pH in human studies. Magn Reson Med 79:1251-1259, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Adiabatically prepared spin-lock approach for T1ρ-based dynamic glucose enhanced MRI at ultrahigh fields.

PURPOSE: Chemical exchange sensitive spin-lock and related techniques allow to observe the uptake of administered D-glucose in vivo. The exchange-weighting increases with the magnetic field strength, but inhomogeneities in the radiofrequency (RF) field at ultrahigh field whole-body scanners lead to artifacts in conventional spin-lock experiments. Thus, our aim was the development of an adiabatically prepared T1ρ -based imaging sequence applicable to studies of glucose metabolism in tumor patients at ultrahigh field strengths. METHODS: An adiabatically prepared on-resonant spin-lock approach was realized at a 7 Tesla whole-body scanner and compared with conventional spin-lock. The insensitivity to RF field inhomogeneities as well as the chemical exchange sensitivity of the approach was investigated in simulations, model solutions and in the human brain. RESULTS: The suggested spin-lock approach was shown to be feasible for in vivo application at ultrahigh field whole-body scanners and showed substantially improved image quality compared with conventional spin-lock. The sensitivity of the presented method to glucose was verified in model solutions and a glucose contrast was observed in a glioblastoma patient after intravenous administration of glucose solution. CONCLUSION: An adiabatically prepared spin-lock preparation was presented that enables a homogeneous and chemical exchange sensitive T1ρ -based imaging at ultra-high field whole-body scanners, e.g., for T1ρ -based dynamic glucose enhanced MRI. Magn Reson Med 78:215-225, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Relaxation-compensated CEST-MRI at 7 T for mapping of creatine content and pH--preliminary application in human muscle tissue in vivo.

The small biomolecule creatine is involved in energy metabolism. Mapping of the total creatine (mostly PCr and Cr) in vivo has been done with chemical shift imaging. Chemical exchange saturation transfer (CEST) allows an alternative detection of creatine via water MRI. Living tissue exhibits CEST effects from different small metabolites, including creatine, with four exchanging protons of its guanidinium group resonating about 2 ppm from the water peak and hence contributing to the amine proton CEST peak. The intermediate exchange rate (≈ 1000 Hz) of the guanidinium protons requires high RF saturation amplitude B1. However, strong B1 fields also label semi-solid magnetization transfer (MT) effects originating from immobile protons with broad linewidths (~kHz) in the tissue. Recently, it was shown that endogenous CEST contrasts are strongly affected by the MT background as well as by T1 relaxation of the water protons. We show that this influence can be corrected in the acquired CEST data by an inverse metric that yields the apparent exchange-dependent relaxation (AREX). AREX has some useful linearity features that enable preparation of both concentration, and--by using the AREX-ratio of two RF irradiation amplitudes B1--purely exchange-rate-weighted CEST contrasts. These two methods could be verified in phantom experiments with different concentration and pH values, but also varying water relaxation properties. Finally, results from a preliminary application to in vivo CEST imaging data of the human calf muscle before and after exercise are presented. The creatine concentration increases during exercise as expected and as confirmed by (31)P NMR spectroscopic imaging. However, the estimated concentrations obtained by our method were higher than the literature values: cCr,rest=24.5±3.74mM to cCr,ex=38.32±13.05mM. The CEST-based pH method shows a pH decrease during exercise, whereas a slight increase was observed by (31)P NMR spectroscopy.

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.

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.

Post-Surgical Depositions of Blood Products Are No Major Confounder for the Diagnostic and Prognostic Performance of CEST MRI in Patients with Glioma.

Amide proton transfer (APT) and semi-solid magnetization transfer (ssMT) imaging can predict clinical outcomes in patients with glioma. However, the treatment of brain tumors is accompanied by the deposition of blood products within the tumor area in most cases. For this reason, the objective was to assess whether the diagnostic interpretation of the APT and ssMT is affected by methemoglobin (mHb) and hemosiderin (Hs) depositions at the first follow-up MRI 4 to 6 weeks after the completion of radiotherapy. A total of 34 participants underwent APT and ssMT imaging by applying reconstruction methods described by Zhou et al. (APTwasym), Goerke et al. (MTRRexAPT and MTRRexMT) and Mehrabian et al. (MTconst). Contrast-enhancing tumor (CE), whole tumor (WT), mHb and Hs were segmented on contrast-enhanced T1wCE, T2w-FLAIR, T1w and T2*w images. ROC-analysis, Kaplan-Meier analysis and the log rank test were used to test for the association of mean contrast values with therapy response and overall survival (OS) before (WT and CE) and after correcting tumor volumes for mHb and Hs (CEC and WTC). CEC showed higher associations of the MTRRexMT with therapy response (CE: AUC = 0.677, p = 0.081; CEC: AUC = 0.705, p = 0.044) and of the APTwasym with OS (CE: HR = 2.634, p = 0.040; CEC: HR = 2.240, p = 0.095). In contrast, WTC showed a lower association of the APTwasym with survival (WT: HR = 2.304, p = 0.0849; WTC: HR = 2.990, p = 0.020). Overall, a sophisticated correction for blood products did not substantially influence the clinical performance of APT and ssMT imaging in patients with glioma early after radiotherapy.

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.