Chemical exchange saturation transfer (CEST) imaging of endogenous agents in vivo is influenced by direct water proton saturation (spillover) and semi-solid macromolecular magnetization transfer (MT). Lorentzian fit isolation and application of the inverse metric yields the pure CEST contrast AREX, which is less affected by these processes, but still depends on the measurement technique, in particular on the irradiation amplitude B1 of the saturation pulses. This study focuses on two well-known CEST effects in the slow exchange regime originating from amide and aliphatic protons resonating at 3.5 ppm or -3.5 ppm from water protons, respectively. A B1-correction of CEST contrasts is crucial for the evaluation of data obtained in clinical studies at high field strengths with strong B1-inhomogeneities. Herein two approaches for B1-inhomogeneity correction, based on either CEST contrasts or Z-spectra, are investigated. Both rely on multiple acquisitions with different B1-values. One volunteer was examined with eight different B1-values to optimize the saturation field strength and the correction algorithm. Histogram evaluation allowed quantification of the quality of the B1-correction. Finally, the correction was applied to CEST images of a patient with oligodendroglioma WHO grade 2, and showed improvement of the image quality compared with the non-corrected CEST images, especially in the tumor region.

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Purpose: The chemical exchange saturation transfer (CEST) effect observed in brain tissue in vivo at the frequency offset 3.5 ppm downfield of water was assigned to amide protons of the protein backbone. Obeying a base-catalyzed exchange process such an amide-CEST effect would correlate with intracellular pH and protein concentration, correlations that are highly interesting for cancer diagnosis. However, recent experiments suggested that, besides the known aliphatic relayednuclear Overhauser effect (rNOE) upfield of water, an additional downfield rNOE is apparent in vivo resonating as well around þ3.5 ppm. In this study, we present further evidence for the underlying downfield-rNOE signal, and we propose a first method that suppresses the downfield-rNOE contribution to the amide-CEST contrast. Thus, an isolated amide-CEST effect depending mainly on amide proton concentration and pH is generated. Methods: The isolation of the exchange mediated amide proton effect was investigated in protein model-solutions and tissue lysates and successfully applied to in vivo CEST images of 11 glioblastoma patients. Results: Comparison with gadolinium contrast enhancing longitudinal relaxation time-weighted images revealed that the downfield-rNOE-suppressed amide-CEST contrast forms a unique contrast that delineates tumor regions and show remarkable overlap with the gadolinium contrast enhancement. Conclusion: Thus, suppression of the downfield rNOE contribution might be the important step to yield the amide proton CEST contrast originally aimed at.

Relaxation-compensated multipool CEST MRI, particularly dns-APT imaging, enabled prediction of IDH mutation status and differentiation of LGG versus HGG and should therefore be considered as a non-invasive MR biomarker in the diagnostic workup.

Chemical exchange saturation transfer (CEST) allows the indirect detection of dilute metabolites in living tissue via MRI of the tissue water signal. Selective radio frequency (RF) with amplitude B1 is used to saturate the magnetization of protons of exchanging groups, which transfer the saturation to the abundant water pool. In a clinical setup, the saturation scheme is limited to a series of short pulses to follow regulation of the specific absorption rate (SAR). Pulsed saturation is difficult to describe theoretically, thus rendering quantitative CEST a challenging task. In this study, we propose a new analytical treatment of pulsed CEST by extending a former interleaved saturation-relaxation approach. Analytical integration of the continuous wave (cw) eigenvalue as a function of the RF pulse shape leads to a formula for pulsed CEST that has the same structure as that for cw CEST, but incorporates two form factors that are determined by the pulse shape. This enables analytical Z-spectrum calculations and permits deeper insight into pulsed CEST. Furthermore, it extends Dixon's Ω-plot method to the case of pulsed saturation, yielding separately, and independently, the exchange rate and the relative proton concentration. Consequently, knowledge of the form factors allows a direct comparison of the effect of the strength and B1 dispersion of pulsed CEST experiments with the ideal case of cw saturation. The extended pulsed CEST quantification approach was verified using creatine phantoms measured on a 7 T whole-body MR tomograph, and its range of validity was assessed by simulations.

Background and PurposeNuclear Overhauser Enhancement (NOE) mediated chemical exchange saturation transfer (CEST) is a novel magnetic resonance imaging (MRI) technique on the basis of saturation transfer between exchanging protons of tissue proteins and bulk water. The purpose of this study was to evaluate and compare the information provided by three dimensional NOE mediated CEST at 7 Tesla (7T) and standard MRI in glioblastoma patients.Patients and MethodsTwelve patients with newly diagnosed histologically proven glioblastoma were enrolled in this prospective ethics committee–approved study. NOE mediated CEST contrast was acquired with a modified three-dimensional gradient-echo sequence and asymmetry analysis was conducted at 3.3ppm (B1 = 0.7 µT) to calculate the magnetization transfer ratio asymmetry (MTRasym). Contrast enhanced T1 (CE-T1) and T2-weighted images were acquired at 3T and used for data co-registration and comparison.ResultsMean NOE mediated CEST signal based on MTRasym values over all patients was significantly increased (p<0.001) in CE-T1 tumor (−1.99±1.22%), tumor necrosis (−1.36±1.30%) and peritumoral CEST hyperintensities (PTCH) within T2 edema margins (−3.56±1.24%) compared to contralateral normal appearing white matter (−8.38±1.19%). In CE-T1 tumor (p = 0.015) and tumor necrosis (p<0.001) mean MTRasym values were significantly higher than in PTCH. Extent of the surrounding tumor hyperintensity was smaller in eight out of 12 patients on CEST than on T2-weighted images, while four displayed at equal size. In all patients, isolated high intensity regions (0.40±2.21%) displayed on CEST within the CE-T1 tumor that were not discernible on CE-T1 or T2-weighted images.ConclusionNOE mediated CEST Imaging at 7T provides additional information on the structure of peritumoral hyperintensities in glioblastoma and displays isolated high intensity regions within the CE-T1 tumor that cannot be acquired on CE-T1 or T2-weighted images. Further research is needed to determine the origin of NOE mediated CEST and possible clinical applications such as therapy assessment or biopsy planning.

PurposeTo prospectively investigate chemical exchange saturation transfer (CEST) MRI in glioblastoma patients as predictor of early tumor progression after first-line treatment.Experimental DesignTwenty previously untreated glioblastoma patients underwent CEST MRI employing a 7T whole-body scanner. Nuclear Overhauser effect (NOE) as well as amide proton transfer (APT) CEST signals were isolated using Lorentzian difference (LD) analysis and relaxation compensated by the apparent exchange-dependent relaxation rate (AREX) evaluation. Additionally, NOE-weighted asymmetric magnetic transfer ratio (MTRasym) and downfield-NOE-suppressed APT (dns-APT) were calculated. Patient response to consecutive treatment was determined according to the RANO criteria. Mean signal intensities of each contrast in the whole tumor area were compared between early-progressive and stable disease.ResultsPre-treatment tumor signal intensity differed significantly regarding responsiveness to first-line therapy in NOE-LD (p = 0.0001), NOE-weighted MTRasym (p = 0.0186) and dns-APT (p = 0.0328) contrasts. Hence, significant prediction of early progression was possible employing NOE-LD (AUC = 0.98, p = 0.0005), NOE-weighted MTRasym (AUC = 0.83, p = 0.0166) and dns-APT (AUC = 0.80, p = 0.0318). The NOE-LD provided the highest sensitivity (91%) and specificity (100%).ConclusionsCEST derived contrasts, particularly NOE-weighted imaging and dns-APT, yielded significant predictors of early progression after fist-line therapy in glioblastoma. Therefore, CEST MRI might be considered as non-invasive tool for customization of treatment in the future.

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, T2w and diffusion‐weighted imaging) at 3T and T2w 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 1H‐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 1H‐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.