Diffusion pore imaging in the presence of extraporal water.

Diffusion-weighted imaging (DWI) is a powerful, non-invasive tool which is widely used in clinical routine. Mostly, apparent diffusion coefficient maps are acquired, which cannot be related directly to cellular structure. More recently it was shown that DWI is able to reconstruct pore shapes using a specialized magnetic field gradient scheme so that cell size distributions may be obtained. So far, artificial systems have been used for experimental demonstration without extraporal signal components and relatively low gradient amplitudes. The aim of this study was to investigate the feasibility of diffusion pore imaging in the presence of extraporal fluids and to develop correction methods for the effects arising from extraporal signal contributions. Monte Carlo simulations and validation experiments on a 14.1 T NMR spectrometer equipped with a dedicated diffusion probe head were performed. Both by using a filter gradient approach suppressing extraporal signal components as well as by using post-processing methods relying on the Gaussian phase approximation, it was possible to reconstruct pore space functions in the presence of extraporal fluids with little to no deviations from the expectations. These results may be a significant step towards application of diffusion pore imaging to biological samples.

Apparent exchange rate imaging: On its applicability and the connection to the real exchange rate.

PURPOSE: Water exchange between the intracellular and extracellular space can be measured using apparent exchange rate (AXR) imaging. The aim of this study was to investigate the relationship between the measured AXR and the geometry of diffusion restrictions, membrane permeability, and the real exchange rate, as well as to explore the applicability of AXR for typical human measurement settings. METHODS: The AXR measurements and the underlying exchange rates were simulated using the Monte Carlo method with different geometries, size distributions, packing densities, and a broad range of membrane permeabilities. Furthermore, the influence of SNR and sequence parameters was analyzed. RESULTS: The estimated AXR values correspond to the simulated values and show the expected proportionality to membrane permeability, except for fast exchange (ie, AXR>20-30s-1 ) and small packing densities. Moreover, it was found that the duration of the filter gradient must be shorter than 2·AXR-1 . In cell size and permeability distributions, AXR depends on the average surface-to-volume ratio, permeability, and the packing density. Finally, AXR can be reliably determined in the presence of orientation dispersion in axon-like structures with sufficient gradient sampling (ie, 30 gradient directions). CONCLUSION: Currently used experimental settings for in vivo human measurements are well suited for determining AXR, with the exception of single-voxel analysis, due to limited SNR. The detection of changes in membrane permeability in diseased tissue is nonetheless challenging because of the AXR dependence on further factors, such as packing density and geometry, which cannot be disentangled without further knowledge of the underlying cell structure.

Influence of residual fat signal on diffusion kurtosis MRI of suspicious mammography findings.

Recent studies showed the potential of diffusion kurtosis imaging (DKI) as a tool for improved classification of suspicious breast lesions. However, in diffusion-weighted imaging of the female breast, sufficient fat suppression is one of the main factors determining the success. In this study, the data of 198 patients examined in two study centres was analysed using standard diffusion and kurtosis evaluation methods and three DKI fitting approaches accounting phenomenologically for fat-related signal contamination of the lesions. Receiver operating characteristic curve analysis showed the highest area under the curve (AUC) for the method including fat correction terms (AUC = 0.85, p < 0.015) in comparison to the values obtained with the standard diffusion (AUC = 0.77) and kurtosis approach (AUC = 0.79). Comparing the two study centres, the AUC value improved from 0.77 to 0.86 (p = 0.036) using a fat correction term for the first centre, while no significant difference with no adverse effects was observed for the second centre (AUC 0.89 vs. 0.90, p = 0.95). Contamination of the signal in breast lesions with unsuppressed fat causing a reduction of diagnostic performance of diffusion kurtosis imaging may potentially be counteracted by proposed adapted evaluation methods.

Relaxation-compensated CEST (chemical exchange saturation transfer) imaging in breast cancer diagnostics at 7T.

PURPOSE: To investigate whether fat-corrected and relaxation-compensated amide proton transfer (APT) and guanidyl CEST-MRI enables the detection of signal intensity differences between breast tumors and normal-appearing fibroglandular tissue in patients with newly-diagnosed breast cancer. METHOD: Ten patients with newly-diagnosed breast cancer and seven healthy volunteers were included in this prospective IRB-approved study. CEST-MRI was performed on a 7 T-whole-body scanner followed by a multi-Lorentzian fit analysis. APT and guanidyl CEST signal intensities were quantified in the tumor and in healthy fibroglandular tissue after correction of B0/B1-field inhomogeneities, fat signal contribution, T1- and T2-relaxation; signal intensity differences of APT and guanidyl resonances were compared using Mann-Whitney-U-tests. Pearson correlations between tumor CEST signal intensities and the proliferation index Ki-67 were performed. RESULTS: APT CEST signal in tumor tissue (6.70 ±â€¯1.38%Hz) was increased compared to normal-appearing fibroglandular tissue of patients (3.56 ±â€¯0.54%Hz, p = 0.001) and healthy volunteers (3.70 ±â€¯0.68%Hz, p = 0.001). Further, a moderate positive correlation was found between the APT signal and the proliferation index Ki-67 (R2 = 0.367, r = 0.606, p = 0.11). Guanidyl CEST signal was also increased in tumor tissue (5.24 ±â€¯1.85%Hz) compared to patients' (2.42 ±â€¯0.45%Hz, p = 0.006) and volunteers' (2.36 ±â€¯0.54%Hz, p < 0.001) normal-appearing fibroglandular tissue and a positive correlation with the Ki-67 level was observed (R2 = 0.365, r = 0.604, p = 0.11). APT and guanidyl CEST signal in normal-appearing fibroglandular tissue was not different between patients and healthy volunteers (p = 0.88; p = 0.93). CONCLUSION: Relaxation-compensated and fat-corrected CEST-MRI allowed a non-invasive differentiation of breast cancer and normal-appearing breast tissue. Thus, this approach represents a contrast agent-free method that may help to increase diagnostic accuracy in MR-mammography.

Stimulated echo double diffusion encoded imaging of closed pores: Influence and removal of unbalanced terms.

Nuclear magnetic resonance (NMR) diffusion pore imaging has been proposed to study the shape of arbitrary closed pores filled with an NMR-detectable medium by use of nonclassical diffusion encoding schemes. Potential applications can be found in biomedical imaging and porous media research. When studying non-point-symmetric pores, NMR signals with nonvanishing imaginary parts arise containing the pore shape information, which is lost for classical diffusion encoding schemes. Key limitations are the required high magnetic field gradient amplitudes and T2 relaxation while approaching the diffusion long-time limit. To benefit from the slower T1 decay, we demonstrate the feasibility of diffusion pore imaging with stimulated echoes using Monte Carlo simulations and experiments with hyperpolarized xenon-129 gas in well-defined geometries and show that the necessary complex-valued signals can be acquired. Analytical derivation of the stimulated echo double diffusion encoded signal was performed to investigate the effect of the additionally arising undesired terms on the complex phase information. These terms correspond to signals arising for spin-echo sequences with unbalanced gradients. For most possible applications, the unbalanced terms can be neglected. If non-negligible, selection of the appropriate signal component using a phase cycling scheme was demonstrated experimentally. Using stimulated echoes may be a step towards application of diffusion pore imaging to larger pores with gradient amplitudes available today in preclinical systems.

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.

Assessing the predictability of IDH mutation and MGMT methylation status in glioma patients using relaxation-compensated multipool CEST MRI at 7.0 T.

Background: Early identification of prognostic superior characteristics in glioma patients such as isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is of great clinical importance. The study purpose was to investigate the non-invasive predictability of IDH mutation status, MGMT promoter methylation, and differentiation of low-grade versus high-grade glioma (LGG vs HGG) in newly diagnosed patients employing relaxation-compensated multipool chemical exchange saturation transfer (CEST) MRI at 7.0 Tesla. Methods: Thirty-one patients with newly diagnosed glioma were included in this prospective study. CEST MRI was performed at a 7T whole-body scanner. Nuclear Overhauser effect (NOE) and isolated amide proton transfer (APT; downfield NOE-suppressed APT = dns-APT) CEST signals (mean value and 90th signal percentile) were quantitatively investigated in the whole tumor area with regard to predictability of IDH mutation, MGMT promoter methylation status, and differentiation of LGG versus HGG. Statistics were performed using receiver operating characteristic (ROC) and area under the curve (AUC) analysis. Results were compared with advanced MRI methods (apparent diffusion coefficient and relative cerebral blood volume ROC/AUC analysis) obtained at 3T. Results: dns-APT CEST yielded highest AUCs in IDH mutation status prediction (dns-APTmean = 91.84%, P < 0.01; dns-APT90 = 97.96%, P < 0.001). Furthermore, dns-APT metrics enabled significant differentiation of LGG versus HGG (AUC: dns-APTmean = 0.78, P < 0.05; dns-APT90 = 0.83, P < 0.05). There was no significant difference regarding MGMT promoter methylation status at any contrast (P > 0.05). Conclusions: 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.

Nuclear Overhauser Enhancement imaging of glioblastoma at 7 Tesla: region specific correlation with apparent diffusion coefficient and histology.

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: Eight of 15 patients showed a weak or moderate positive correlation of MTRasym and ADC within the T2 edema (0.16≤rSp≤0.53, p<0.05). Seven correlations were statistically insignificant (p>0.05, n = 4) or yielded rSp≈0 (p<0.05, n = 3). No trend towards a correlation between MTRasym and ADC was found in CE-T1 tumor (-0.310.05, 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)). DISCUSSION: 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.

Nuclear overhauser enhancement mediated chemical exchange saturation transfer imaging at 7 Tesla in glioblastoma patients.

BACKGROUND AND PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.