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  • 1
    Language: English
    In: PloS one, 2015, Vol.10(3), pp.e0121220
    Description: To explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells. For 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST-contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTRasym) at 3.3ppm, B1 = 0.7 μT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTRasym values within both regions of interest were correlated voxelwise yielding the correlation coefficient rSpearman (rSp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTRasym and ADC values of the biopsy site. Eight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16≤rSp≤0.53, p0.05, n = 4) or yielded rSp≈0 (p0.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTRasym values in two of the three patients (rSppatient3 = 0.69 and rSppatient15 = 0.87, p〈0.05), while the correlation of ADC and cellularity was heterogeneous (rSppatient3 = 0.545 (p = 0.067), rSppatient4 = -0.021 (p = 0.948), rSppatient15 = -0.755 (p = 0.005)). NOE-imaging is a new contrast promising insight into pathophysiologic processes in glioblastoma regarding cell density and protein content, setting itself apart from DWI. Future studies might be based on the assumption that NOE-mediated CEST visualizes cellularity more accurately than ADC, especially in the CE-T1 tumor region.
    Keywords: Diffusion Magnetic Resonance Imaging ; Brain Neoplasms -- Diagnosis ; Glioblastoma -- Diagnosis
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PloS one, 2014, Vol.9(8), pp.e104181
    Description: Nuclear 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. Twelve 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 3.3 ppm (B1 = 0.7 µT) to calculate the magnetization transfer ratio asymmetry (MTR(asym)). Contrast enhanced T1 (CE-T1) and T2-weighted images were acquired at 3T and used for data co-registration and comparison. Mean NOE mediated CEST signal based on MTR(asym) 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 MTR(asym) 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. NOE mediated CEST Imaging at 7 T 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.
    Keywords: Glioblastoma -- Diagnosis
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: NeuroImage, 15 May 2015, Vol.112, pp.180-188
    Description: Endogenous chemical exchange saturation transfer (CEST) effects of protons resonating near to water protons are always diluted by competing effects such as direct water saturation and semi-solid magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that contaminate the observed CEST signal. Furthermore, all CEST effects appear to be scaled by the T1 relaxation time of the mediating water pool. As MT, T1 and T2 are also altered in tumor regions, a recently published correction algorithm yielding the apparent exchange-dependent relaxation AREX, is used to evaluate CEST effects. This study focuses on CEST effects of amides (3.5 ppm) and Nuclear-Overhauser-mediated saturation transfer (NOE, − 3.5 ppm) that can be properly isolated at 7 T. These were obtained in 10 glioblastoma patients, and this is the first comprehensive study where AREX is applied in human brain as well as in human glioblastoma. The correction of CEST effects alters the contrast significantly: after correction, the CEST effect of amides does not show significant contrast between contrast enhancing tumor regions and normal tissue, whereas NOE drops significantly in the tumor area. In addition, new features in the AREX contrasts are visible. This suggests that previous CEST approaches might not have shown pure CEST effects, but rather water relaxation shine-through effects. Our insights help to improve understanding of the CEST effect changes in tumors and correlations on a cellular and molecular level.
    Keywords: Arex ; Cest ; Noe ; Relaxation-Compensated Cest ; Comprehensive Cest Study ; Spillover Correction ; Relaxation Compensation ; Glioblastoma ; 7 T High Resolution ; Medicine
    ISSN: 1053-8119
    E-ISSN: 1095-9572
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  • 4
    In: NMR in Biomedicine, May 2015, Vol.28(5), pp.529-537
    Description: Chemical exchange saturation transfer (CEST) imaging of endogenous agents 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 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 ‐correction of CEST contrasts is crucial for the evaluation of data obtained in clinical studies at high field strengths with strong ‐inhomogeneities. Herein two approaches for ‐inhomogeneity correction, based on either CEST contrasts or Z‐spectra, are investigated. Both rely on multiple acquisitions with different ‐values. One volunteer was examined with eight different ‐values to optimize the saturation field strength and the correction algorithm. Histogram evaluation allowed quantification of the quality of the ‐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. Copyright © 2015 John Wiley & Sons, Ltd. We present two methods to correct CEST images with the relaxation‐compensated contrast parameter MTR for strong ‐inhomogeneities that are apparent for MRI at 7 T. In this work, the potential of the two correction methods, the number and distribution of sampling points relevant for correction, and the influence of the correction algorithm were investigated.
    Keywords: Chemical Exchange Saturation Transfer ; Cest ; Noe ; B 1 ‐Correction ; Arex ; Lorentzian Fit
    ISSN: 0952-3480
    E-ISSN: 1099-1492
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  • 5
    Language: English
    In: NMR in Biomedicine, 2015, Vol.28(5), p.529(9)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/nbm.3283/abstract Byline: Johannes Windschuh, Moritz Zaiss, Jan-Eric Meissner, Daniel Paech, Alexander Radbruch, Mark E. Ladd, Peter Bachert 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 B.sub.1 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 3.5ppm or -3.5ppm from water protons, respectively. A B.sub.1-correction of CEST contrasts is crucial for the evaluation of data obtained in clinical studies at high field strengths with strong B.sub.1-inhomogeneities. Herein two approaches for B.sub.1-inhomogeneity correction, based on either CEST contrasts or Z-spectra, are investigated. Both rely on multiple acquisitions with different B.sub.1-values. One volunteer was examined with eight different B.sub.1-values to optimize the saturation field strength and the correction algorithm. Histogram evaluation allowed quantification of the quality of the B.sub.1-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. Copyright [c] 2015 John Wiley & Sons, Ltd. CAPTION(S): Supporting info item
    ISSN: 0952-3480
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  • 6
    In: NMR in Biomedicine, October 2015, Vol.28(10), pp.1196-1208
    Description: 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 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 ‐spectrum calculations and permits deeper insight into pulsed CEST. Furthermore, it extends Dixon's ‐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 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. Copyright © 2015 John Wiley & Sons, Ltd. We propose a new analytical description of pulsed saturation transfer experiments feasible with clinical MR scanners. Analytical integration of the continuous wave eigenvalue as a function of the RF pulse shape leads to two form factors, which are determined by the pulse shape. Using the AREX signal then allows extension of the ‐plot method, and thus enables the simultaneous determination of exchange rate and relative concentration for pulsed CEST experiments. The theory is proven by simulations and experiments.
    Keywords: Cest ; Ω ‐Plot ; Pulsed Pre‐Saturation ; Creatine ; Mri
    ISSN: 0952-3480
    E-ISSN: 1099-1492
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  • 7
    In: Magnetic Resonance in Medicine, January 2017, Vol.77(1), pp.196-208
    Description: 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...
    Keywords: Arex ; Cest ; Aromatic Rnoe ; Aliphatic Rnoe ; Relaxation‐Compensated Cest ; Spillover Correction ; Relaxation Compensation ; Brain Tumor ; Glioblastoma ; 7t ; Ultra‐High Field
    ISSN: 0740-3194
    E-ISSN: 1522-2594
    Source: John Wiley & Sons, Inc.
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  • 8
    In: Journal of Magnetic Resonance Imaging, March 2019, Vol.49(3), pp.777-785
    Description: Byline: Constantin Dreher, Johanna Oberhollenzer, Jan-Eric Meissner, Johannes Windschuh, Patrick Schuenke, Sebastian Regnery, Felix Sahm, Sebastian Bickelhaupt, Martin Bendszus, Wolfgang Wick, Andreas Unterberg,Moritz Zaiss, Peter Bachert, Mark E. Ladd, Heinz-Peter Schlemmer, Alexander Radbruch,Daniel Paech Keywords: magnetic resonance imaging; neuroimaging; biomarkers; glioma; glioblastoma; CEST Background Chemical exchange saturation transfer (CEST) is a novel MRI technique applied to brain tumor patients. Purpose To investigate the anatomic location dependence of CEST MRI obtained at 7T and histopathological/molecular parameters in WHO IV[degrees] glioma patients. Study Type Analytic prospective study. Population Twenty-one patients with newly diagnosed WHO IV[degrees] gliomas were studied prior to surgery; 11 healthy volunteers were investigated. Field Strength/Sequence Conventional MRI (contrast-enhanced, T.sub.2w and diffusion-weighted imaging) at 3T and T.sub.2w and CEST MRI at 7T was performed for patients and both patients and volunteers. Assessment Mean CEST signal intensities (nuclear-Overhauser-enhancement [NOE], amide-proton-transfer [APT], downfield NOE-suppressed APT [dns-APT]), ADC values, and histopathological/molecular parameters were evaluated with regard to hemisphere location and contact with the subventricular zone. CEST signal intensities of cerebral tissue of healthy volunteers were evaluated with regard to hemisphere discrimination. Statistical Tests Spearman correlation, Mann-Whitney U-test, Wilcoxon signed-rank-test, Fisher's exact test, and area under the receiver operating curve. Results Maximum APT and dns-APT signal intensities were significantly different in right vs. left hemisphere gliomas (P=0.037 and P=0.007), but not in right vs. left hemisphere cerebral tissue of healthy subjects (P=0.062-0.859). Mean ADC values were significantly decreased in right vs. left hemisphere gliomas (P=0.044). Mean NOE signal intensity did not differ significantly between gliomas of either hemisphere (P=0.820), but in case of subventricular zone contact (P=0.047). A significant correlation was observed between APT and dns-APT and ADC signal intensities (r.sub.s=-0.627, P=0.004 and r.sub.s=-0.534, P=0.019), but not between NOE and ADC (r.sub.s=-0.341, P=0.154). Histopathological/molecular parameters were not significantly different concerning the tumor location (P=0.104-1.000, P=0.286-0.696). Data Conclusion APT, dns-APT, and ADC were inversely correlated and depended on the gliomas' hemisphere location. NOE showed significant dependence on subventricular zone contact. Location dependency of APT- and NOE-mediated CEST effects should be considered in clinical investigations of CEST MRI. Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:777-785.
    Keywords: Magnetic Resonance Imaging ; Neuroimaging ; Biomarkers ; Glioma ; Glioblastoma ; Cest
    ISSN: 1053-1807
    E-ISSN: 1522-2586
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  • 9
    Language: English
    In: Magnetic resonance in medicine, January 2017, Vol.77(1), pp.196-208
    Description: 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 relayed-nuclear Overhauser effect (rNOE) upfield of water, an additional downfield rNOE is apparent in vivo resonating as well around +3.5 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. 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. 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. Thus, suppression of the downfield rNOE contribution might be the important step to yield the amide proton CEST contrast originally aimed at. Magn Reson Med 77:196-208, 2017. © 2016 Wiley Periodicals, Inc.
    Keywords: 7t ; Arex ; Cest ; Aliphatic Rnoe ; Aromatic Rnoe ; Brain Tumor ; Glioblastoma ; Relaxation Compensation ; Relaxation-Compensated Cest ; Spillover Correction ; Ultra-High Field ; Brain Neoplasms -- Diagnostic Imaging ; Glioblastoma -- Diagnostic Imaging ; Image Processing, Computer-Assisted -- Methods ; Magnetic Resonance Imaging -- Methods
    ISSN: 07403194
    E-ISSN: 1522-2594
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  • 10
    Language: English
    In: Oncotarget, 19 June 2018, Vol.9(47), pp.28772-28783
    Description: To prospectively investigate chemical exchange saturation transfer (CEST) MRI in glioblastoma patients as predictor of early tumor progression after first-line treatment. Twenty 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. Pre-treatment tumor signal intensity differed significantly regarding responsiveness to first-line therapy in NOE-LD ( = 0.0001), NOE-weighted MTRasym ( = 0.0186) and dns-APT ( = 0.0328) contrasts. Hence, significant prediction of early progression was possible employing NOE-LD (AUC = 0.98, = 0.0005), NOE-weighted MTRasym (AUC = 0.83, = 0.0166) and dns-APT (AUC = 0.80, = 0.0318). The NOE-LD provided the highest sensitivity (91%) and specificity (100%). CEST 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.
    Keywords: Amide-Proton-Transfer-Imaging ; Glioblastoma ; Magnetic Resonance Imaging ; Nuclear Overhauser Imaging ; Predictive Biomarker
    E-ISSN: 1949-2553
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