Single-shot frequency offset measurement with HASTE using the selective parity approach.

Measurements of frequency offset are commonly required in MRI. The standard method measures the signal phase as a function of evolution time. Here we use a single shot turbo-spin-echo acquisition method to measure frequency offset at a single evolution time. After excitation the transverse magnetisation evolves during the evolution time, and is then repeatedly refocused. The phase is conjugated between alternate echoes. Using partial parallel acquisition techniques we obtain separate odd- and even- echo images. An iterative procedure ensures self-consistency between them. The difference in phase between the two images yields frequency offset maps. The technique was implemented at 3 Tesla and tested on a healthy human volunteer for a range of evolution times between 6 and 42 ms. A standard method using a similar readout train and multiple evolution times was used as a gold-standard measure. In a statistical comparison with the gold standard no evidence for bias or offset was found. There was no systematic variation in precision or accuracy as a function of evolution time. We conclude that the presented approach represents a viable method for the rapid generation of frequency offset maps with a high image quality and minimal distortion.

In vivo biochemical assessment of cartilage with gagCEST MRI: Correlation with cartilage properties.

To assess articular cartilage in vivo, a noninvasive measurement is proposed to evaluate damage of the cartilage. It is hypothesized that glycosaminoglycan chemical exchange saturation transfer (gagCEST) can be applied as a noninvasive imaging technique as it would relate to electromechanical indentation and GAG content as measured with biochemical assays. This pilot study applies gagCEST MRI in total knee arthroplasty (TKA) patients to assess substantially damaged articular cartilage. The outcome was verified against electromechanical indentation and biochemical assays to assess the potential of gagCEST MRI. Five TKA patients were scanned on a 7.0 T MRI with a gagCEST sequence. Articular resurfacing cuts after TKA were obtained for electromechanical and biochemical analyses. The gagCEST MRI measurements on the medial condyle showed a moderate correlation with the GAG content, although sensitivity on the lateral condyle was lacking. Additionally, a strong negative correlation of gagCEST MRI with the electromechanical measurements was observed in the regression analysis. Correlation of gagCEST MRI with electromechanical measurements was shown, but the correlation of gagCEST MRI with GAG content was not convincing. In conclusion, gagCEST could be a useful tool to assess the GAG content in articular cartilage noninvasively, although the mismatch in heterogeneity requires further investigation.

Contradiction between amide-CEST signal and pH in breast cancer explained with metabolic MRI.

PURPOSE: Metabolic MRI is a noninvasive technique that can give new insights into understanding cancer metabolism and finding biomarkers to evaluate or monitor treatment plans. Using this technique, a previous study has shown an increase in pH during neoadjuvant chemotherapy (NAC) treatment, while recent observation in a different study showed a reduced amide proton transfer (APT) signal during NAC treatment (negative relation). These findings are counterintuitive, given the known intrinsic positive relation of APT signal to pH. METHODS: In this study we combined APT MRI and 31 P-MRSI measurements to unravel the relation between the APT signal and pH in breast cancer. Twenty-two breast cancer patients were scanned with a 7 T MRI before and after the first cycle of NAC treatment. pH was determined by the chemical shift of inorganic phosphate (Pi). RESULTS: While APT signals have a positive relation to pH and amide content, we observed a direct negative linear correlation between APT signals and pH in breast tumors in vivo. CONCLUSIONS: As differentiation of cancer stages was confirmed by observation of a linear correlation between cell proliferation marker PE/Pi (phosphoethanolamine over inorganic phosphate) and pH in the tumor, our data demonstrates that the concentration of mobile proteins likely supersedes the contribution of the exchange rate to the APT signal.

Analysis of chemical exchange saturation transfer contributions from brain metabolites to the Z-spectra at various field strengths and pH.

Chemical exchange saturation transfer (CEST) exploits the chemical exchange of labile protons of an endogenous or exogenous compound with water to image the former indirectly through the water signal. Z-spectra of the brain have traditionally been analyzed for two most common saturation phenomena: downfield amide proton transfer (APT) and upfield nuclear Overhauser enhancement (NOE). However, a great body of brain metabolites, many of interest in neurology and oncology, contributes to the downfield saturation in Z-spectra. The extraction of these "hidden" metabolites from Z-spectra requires careful design of CEST sequences and data processing models, which is only possible by first obtaining CEST signatures of the brain metabolites possessing labile protons. In this work, we measured exchange rates of all major-for-CEST brain metabolites in the physiological pH range at 37 °C. Analysis of their contributions to Z-spectra revealed that regardless of the main magnetic field strength and pH, five main contributors, i.e. myo-inositol, creatine, phosphocreatine, glutamate, and mobile (poly)peptides, account for ca. 90% of downfield CEST effect. The fundamental CEST parameters presented in this study can be exploited in the design of novel CEST sequences and Z-spectra processing models, which will enable simultaneous and quantitative CEST imaging of multiple metabolites: multicolor CEST.

Amide chemical exchange saturation transfer at 7 T: a possible biomarker for detecting early response to neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: The purpose of this work was to investigate noninvasive early detection of treatment response of breast cancer patients to neoadjuvant chemotherapy (NAC) using chemical exchange saturation transfer (CEST) measurements sensitive to amide proton transfer (APT) at 7 T. METHODS: CEST images were acquired in 10 tumors of nine breast cancer patients treated with NAC. APT signals in the tumor, before and after the first cycle of NAC, were quantified using a three-pool Lorentzian fit of the z-spectra in the region of interest. The changes in APT were subsequently related to pathological response after surgery defined by the Miller-Payne system. RESULTS: Significant differences (P <  0.05, unpaired Mann-Whitney test) were found in the APT signal before and after the first cycle of NAC in six out of 10 lesions, of which two showed a pathological complete response. Of the remaining four lesions, one showed a pathological complete response. No significant difference in changes of APT signal were found between the different pathological responses to NAC treatment (P > 0.05, Kruskal-Wallis test). CONCLUSIONS: This preliminary study shows the feasibility of using APT CEST magnetic resonance imaging as a noninvasive biomarker to assess the effect of NAC in an early stage of NAC treatment of breast cancer patients. TRIAL REGISTRATION: Registration number, NL49333.041.14/ NTR4980 . Registered on 16 October 2014.

Detection of early cartilage damage: feasibility and potential of gagCEST imaging at 7T.

OBJECTIVES: The purpose was to implement a fast 3D glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) sequence at 7 T, test stability and reproducibility in cartilage in the knee in healthy volunteers, and evaluate clinical applicability in cartilage repair patients. METHODS: Experiments were carried out on a 7-T scanner using a volume transmit coil and a 32-channel receiver wrap-around knee coil. The 3D gagCEST measurement had an acquisition time of 7 min. Signal stability and reproducibility of the GAG effect were assessed in eight healthy volunteers. Clinical applicability of the method was demonstrated in five patients before cartilage repair surgery. RESULTS: Coefficient of variation of the gagCEST signal was 1.9%. The reproducibility of the GAG effect measurements was good in the medial condyle (ICC = 0.87) and excellent in the lateral condyle (ICC = 0.97). GAG effect measurements in healthy cartilage ranged from 2.6%-12.4% compared with 1.3%-5.1% in damaged cartilage. Difference in GAG measurement between healthy cartilage and damaged cartilage was significant (p < 0.05). CONCLUSIONS: A fast 3D gagCEST sequence was applied at 7 T for use in cartilage in the knee, acquired within a clinically feasible scan time of 7 min. We demonstrated that the method has high stability, reproducibility and clinical applicability. KEY POINTS: • gagCEST measurements are stable and reproducible • A non-invasive GAG measurement with gagCEST can be acquired in 7 min • gagCEST is able to discriminate between healthy and damaged cartilage.

Establishing upper limits on neuronal activity-evoked pH changes with APT-CEST MRI at 7 T.

PURPOSE: To detect neuronal activity-evoked pH changes by amide proton transfer-chemical exchange saturation transfer (APT-CEST) MRI at 7 T. METHODS: Three healthy subjects participated in the study. A low-power 3-dimensional APT-CEST sequence was optimized through the Bloch-McConnell equations. pH sensitivity of the sequence was estimated both in phantoms and in vivo. The feasibility of pH-functional MRI was tested in Bloch-McConnell-simulated data using the optimized sequence. In healthy subjects, the visual stimuli were used to evoke transient pH changes in the visual cortex, and a 3-dimensional APT-CEST volume was acquired at the pH-sensitive frequency offset of 3.5 ppm every 12.6 s. RESULTS: In theory, a three-component general linear model was capable of separating the effects of blood oxygenation level-dependent contrast and pH. The Bloch-McConnell equations indicated that a change in pH of 0.03 should be measurable at the experimentally determined temporal signal-to-noise ratio of 108. However, only a blood oxygenation level-dependent effect in the visual cortex could be discerned during the visual stimuli experiments performed in the healthy subjects. CONCLUSIONS: The results of this study suggest that if indeed there are any transient brain pH changes in response to visual stimuli, those are under 0.03 units pH change, which is extremely difficult to detect using the existent techniques. Magn Reson Med 80:126-136, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

On the transmit field inhomogeneity correction of relaxation-compensated amide and NOE CEST effects at 7 T.

High field MRI is beneficial for chemical exchange saturation transfer (CEST) in terms of high SNR, CNR, and chemical shift dispersion. These advantages may, however, be counter-balanced by the increased transmit field inhomogeneity normally associated with high field MRI. The relatively high sensitivity of the CEST contrast to B1 inhomogeneity necessitates the development of correction methods, which is essential for the clinical translation of CEST. In this work, two B1 correction algorithms for the most studied CEST effects, amide-CEST and nuclear Overhauser enhancement (NOE), were analyzed. Both methods rely on fitting the multi-pool Bloch-McConnell equations to the densely sampled CEST spectra. In the first method, the correction is achieved by using a linear B1 correction of the calculated amide and NOE CEST effects. The second method uses the Bloch-McConnell fit parameters and the desired B1 amplitude to recalculate the CEST spectra, followed by the calculation of B1 -corrected amide and NOE CEST effects. Both algorithms were systematically studied in Bloch-McConnell equations and in human data, and compared with the earlier proposed ideal interpolation-based B1 correction method. In the low B1 regime of 0.15-0.50 µT (average power), a simple linear model was sufficient to mitigate B1 inhomogeneity effects on a par with the interpolation B1 correction, as demonstrated by a reduced correlation of the CEST contrast with B1 in both the simulations and the experiments.

Amide proton transfer (APT) imaging of brain tumors at 7 T: The role of tissue water T1 -Relaxation properties.

PURPOSE: To provide insight into the effect of water T1 relaxation (T1wat ) on amide proton transfer (APT) contrast in tumors. Three different metrics of APT contrast-magnetization transfer ratio (MTRRex ), relaxation-compensated MTRRex (AREX), and traditional asymmetry (MTRasym )-were compared in normal and tumor tissues in a variety of intracranial tumors at 7 Tesla (T). METHODS: Six consented intracranial tumor patients were scanned using a low-power, three-dimensional (3D) APT imaging sequence. MTRRex and MTRasym were calculated in the region of 3 to 4 ppm. AREX was calculated by T1wat correction of MTRRex . Tumor tissue masks, which classify different tumor tissues, were drawn by an experienced neuroradiologist. ROI-averaged tumor tissue analysis was done for MTRRex , AREX, and MTRasym . RESULTS: MTRRex and MTRasym were slightly elevated in tumor-associated structures. Both metrics were positively correlated to T1wat . The correlation coefficient (R) was determined to be 0.88 (P < 0.05) and 0.92 (P << 0.05) for MTRRex and MTRasym , respectively. After T1wat correction (R = -0.21, P = 0.69), no difference between normal and tumor tissues was found for AREX. CONCLUSIONS: The strong correlation of MTRRex and MTRasym with T1wat and the absence thereof in AREX suggests that much of APT contrast in tumors for the low-power, 3D-acquisition scheme at 7 T originates from the inherent tissue water T1 -relaxation properties. Magn Reson Med 77:1525-1532, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Comparison of pulsed three-dimensional CEST acquisition schemes at 7 tesla: steady state versus pseudosteady state.

PURPOSE: To compare two pulsed, volumetric chemical exchange saturation transfer (CEST) acquisition schemes: steady state (SS) and pseudosteady state (PS) for the same brain coverage, spatial/spectral resolution and scan time. METHODS: Both schemes were optimized for maximum sensitivity to amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects through Bloch-McConnell simulations, and compared in terms of sensitivity to APT and NOE effects, and to transmit field inhomogeneity. Five consented healthy volunteers were scanned on a 7 Tesla Philips MR-system using the optimized protocols at three nominal B1 amplitudes: 1 µT, 2 µT, and 3 µT. RESULTS: Region of interest based analysis revealed that PS is more sensitive (P < 0.05) to APT and NOE effects compared with SS at low B1 amplitudes (0.7-1.0 µT). Also, both sequences have similar dependence on the transmit field inhomogeneity. For the optimum CEST presaturation parameters (1 µT and 2 µT for APT and NOE, respectively), NOE is less sensitive to the inhomogeneity effects (15% signal to noise ratio [SNR] change for a B1 dropout of 40%) compared with APT (35% SNR change for a B1 dropout of 40%). CONCLUSION: For the same brain coverage, spatial/spectral resolution and scan time, at low power levels PS is more sensitive to the slow chemical exchange-mediated processes compared with SS. Magn Reson Med 77:2280-2287, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Is there any difference in Amide and NOE CEST effects between white and gray matter at 7T?

Measurement of Chemical Exchange Saturation Transfer (CEST) is providing tissue physiology dependent contrast, e.g. by looking at Amide and NOE (Nuclear Overhauser Enhancement) effects. CEST is unique in providing quantitative metabolite information at high imaging resolution. However, direct comparison of Amide and NOE effects between different tissues may result in wrong conclusions on the metabolite concentration due to the additional contributors to the observed CEST contrast, such as water content (WC) and water T1 relaxation (T1w). For instance, there are multiple contradictory reports in the literature on Amide and NOE effects in white matter (WM) and gray matter (GM) at 7T. This study shows that at 7T, tissue water T1 relaxation is a stronger contributor to CEST contrasts than WC. After water T1 correction, there was no difference in Amide effects between WM and GM, whereas WM/GM contrast was enhanced for NOE effects.