Amide Proton Transfer Chemical Exchange Saturation Transfer Research Articles

Convolutional neural network to predict IDH mutation status in glioma from chemical exchange saturation transfer imaging at 7 Tesla.

Noninvasive prediction of isocitrate dehydrogenase (IDH) mutation status in glioma guides surgical strategies and individualized management. We explored the capability on preoperatively identifying IDH status of combining a convolutional neural network (CNN) and a novel imaging modality, ultra-high field 7.0 Tesla (T) chemical exchange saturation transfer (CEST) imaging. We enrolled 84 glioma patients of different tumor grades in this retrospective study. Amide proton transfer CEST and structural Magnetic Resonance (MR) imaging at 7T were performed preoperatively, and the tumor regions are manually segmented, leading to the "annotation" maps that offers the location and shape information of the tumors. The tumor region slices in CEST and T1 images were further cropped out as samples and combined with the annotation maps, which were inputted to a 2D CNN model for generating IDH predictions. Further comparison analysis to radiomics-based prediction methods was performed to demonstrate the crucial role of CNN for predicting IDH based on CEST and T1 images. A fivefold cross-validation was performed on the 84 patients and 4090 slices. We observed a model based on only CEST achieved accuracy of 74.01% ± 1.15%, and the area under the curve (AUC) of 0.8022 ± 0.0147. When using T1 image only, the prediction performances dropped to accuracy of 72.52% ± 1.12% and AUC of 0.7904 ± 0.0214, which indicates no superiority of CEST over T1. However, when we combined CEST and T1 together with the annotation maps, the performances of the CNN model were further boosted to accuracy of 82.94% ± 1.23% and AUC of 0.8868 ± 0.0055, suggesting the importance of a joint analysis of CEST and T1. Finally, using the same inputs, the CNN-based predictions achieved significantly improved performances above those from radiomics-based predictions (logistic regression and support vector machine) by 10% to 20% in all metrics. 7T CEST and structural MRI jointly offer improved sensitivity and specificity of preoperative non-invasive imaging for the diagnosis of IDH mutation status. As the first study of CNN model on imaging acquired at ultra-high field MR, our results could demonstrate the potential of combining ultra-high-field CEST and CNN for facilitating decision-making in clinical practice. However, due to the limited cases and B1 inhomogeneities, the accuracy of this model will be improved in our further study.

Feasibility of clinical studies of chemical exchange saturation transfer magnetic resonance imaging of prostate cancer at 7 T.

Chemical exchange saturation transfer (CEST) has been explored for differentiation between tumour and benign tissue in prostate cancer (PCa) patients. With ultrahigh field strengths such as 7-T, the increase of spectral resolution and sensitivity could allow for selective detection of amide proton transfer (APT) at 3.5 ppm and a group of compounds that resonate at 2 ppm (i.e., [poly]amines and/or creatine). The potential of 7-T multipool CEST analysis of the prostate and the detection of PCa was studied in patients with proven localised PCa who were scheduled to undergo robot-assisted radical prostatectomy (RARP). Twelve patients were prospectively included (mean age 68.0 years, mean serum prostate-specific antigen 7.8ng/mL). A total of 24 lesions larger than 2 mm were analysed. Used were 7-T T2-weighted (T2W) imaging and 48 spectral CEST points. Patients received 1.5-T/3-T prostate magnetic resonance imaging and galium-68-prostate-specific membrane antigen-positron emission tomography/computerised tomography to determine the location of the single-slice CEST. Based on the histopathological results after RARP, three regions of interest were drawn on the T2W images from a known malignant zone and benign zone in the central and peripheral zones. These areas were transposed to the CEST data, from which the APT and 2-ppm CEST were calculated. The statistical significance of the CEST between the central zone, the peripheral zone, and tumour was calculated using a Kruskal-Wallis test. The z-spectra showed that APT and even a distinct pool that resonated at 2 ppm were detectable. This study showed a difference trend in the APT levels, but no difference in the 2-ppm levels when tested between the central zone, the peripheral zone, and tumour (H(2) = 4.8, p= 0.093 and H(2) = 0.86, p= 0.651, respectively). Thus, to conclude, we could most likely detect APT and amines and/or creatine levels noninvasively in prostate using the CEST effect. At group level, CEST showed a higher level of APT in the peripheral versus the central zone; however, no differences of APT and 2-ppm levels were observed in tumours.

Noninvasive Delineation of Glioma Infiltration with Combined 7T Chemical Exchange Saturation Transfer Imaging and MR Spectroscopy: A Diagnostic Accuracy Study.

For precise delineation of glioma extent, amino acid PET is superior to conventional MR imaging. Since metabolic MR sequences such as chemical exchange saturation transfer (CEST) imaging and MR spectroscopy (MRS) were developed, we aimed to evaluate the diagnostic accuracy of combined CEST and MRS to predict glioma infiltration. Eighteen glioma patients of different tumor grades were enrolled in this study; 18F-fluoroethyltyrosine (FET)-PET, amide proton transfer CEST at 7 Tesla(T), MRS and conventional MR at 3T were conducted preoperatively. Multi modalities and their association were evaluated using Pearson correlation analysis patient-wise and voxel-wise. Both CEST (R = 0.736, p < 0.001) and MRS (R = 0.495, p = 0.037) correlated with FET-PET, while the correlation between CEST and MRS was weaker. In subgroup analysis, APT values were significantly higher in high grade glioma (3.923 ± 1.239) and IDH wildtype group (3.932 ± 1.264) than low grade glioma (3.317 ± 0.868, p < 0.001) or IDH mutant group (3.358 ± 0.847, p < 0.001). Using high FET uptake as the standard, the CEST/MRS combination (AUC, 95% CI: 0.910, 0.907–0.913) predicted tumor infiltration better than CEST (0.812, 0.808–0.815) or MRS (0.888, 0.885–0.891) alone, consistent with contrast-enhancing and T2-hyperintense areas. Probability maps of tumor presence constructed from the CEST/MRS combination were preliminarily verified by multi-region biopsies. The combination of 7T CEST/MRS might serve as a promising non-radioactive alternative to delineate glioma infiltration, thus reshaping the guidance for tumor resection and irradiation.

Two point Dixon-based chemical exchange saturation transfer (CEST) MRI in renal transplant patients on 3 T

PurposeTo assess the performance of two point (2-pt) Dixon-based chemical exchange saturation transfer (CEST) imaging for fat suppression in renal transplant patients. MethodsThe 2-pt Dixon-based CEST MRI was validated in an egg-phantom and in fourteen renal transplant recipients (5 females and 9 males; age range: 23–78 years; mean age: 51 ± 16.8). All CEST experiments were performed on a 3 T clinical MRI scanner using a dual-echo CEST sequence. The 2-pt Dixon technique was applied to generate water-only CEST images at different frequency offsets, which were further used to calculate the z-spectra. The magnetization transfer ratio asymmetry (MTRasym) values in the frequency ranges of hydroxyl, amine and amide protons were estimated in the renal cortex and medulla. ResultsResults of the in vitro experiments suggest that the 2-pt Dixon technique enables effective fat peak removal and does not introduce additional asymmetries to the z-spectrum. Accordingly, our results in vivo show that the fat-corrected amide proton transfer (APT) effect in the kidney is significantly higher compared to that obtained from the CEST data acquired close to the in-phase condition both in the renal cortex (−0.1 [0.7] vs. −0.7 [1.2], P = 0.029) and medulla (0.3 [0.8] vs. 0.01 [1.3], P = 0.049), indicating that the 2-pt Dixon-based CEST method increases the specificity of the APT contrast by correcting the fat-induced artifacts. ConclusionCombination of the dual-echo CEST acquisition with Dixon post-processing provides effective water-fat separation, allowing more accurate quantification of the APT CEST effect in the transplanted kidney.

A fast and novel method for amide proton transfer-chemical exchange saturation transfer multislice imaging.

Amide proton transfer-chemical exchange saturation transfer (APT-CEST) imaging provides important information for the diagnosis and monitoring of tumors. For such analysis, complete coverage of the brain is advantageous, especially when registration is performed with other magnetic resonance (MR) modalities, such as MR spectroscopy (MRS). However, the acquisition of Z-spectra across several slices via multislice imaging may be time-consuming. Therefore, in this paper, we present a new approach for fast multislice imaging, allowing us to acquire 16 slices per frequency offset within 8 s. The proposed fast CEST-EPI sequence employs a presaturation module, which drives the magnetization into the steady-state equilibrium for the first frequency offset. A second module, consisting of a single CEST pulse (for maintaining the steady-state) followed by an EPI acquisition, passes through a loop to acquire multiple slices and adjacent frequency offsets. Thus, the whole Z-spectrum can be recorded much faster than the conventional saturation scheme, which employs a presaturation for each single frequency offset. The validation of the CEST sequence parameters was performed by using the conventional saturation scheme. Subsequently, the proposed and a modified version of the conventional CEST sequence were compared in vitro on a phantom with different T1 times and in vivo on a brain tumor patient. No significant differences between both sequences could be found in vitro. The in vivo data yielded almost identical MTRasym contrasts for the white and gray matter as well as for tumor tissue. Our results show that the proposed fast CEST-EPI sequence allows for rapid data acquisition and provides similar CEST contrasts as the modified conventional scheme while reducing the scanning time by approximately 50%.

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

PurposeTo 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. MethodTen 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. ResultsAPT CEST signal in tumor tissue (6.70 ± 1.38%Hz) was increased compared to normal-appearing fibroglandular tissue of patients (3.56 ± 0.54%Hz, p = 0.001) and healthy volunteers (3.70 ± 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 ± 1.85%Hz) compared to patients’ (2.42 ± 0.45%Hz, p = 0.006) and volunteers’ (2.36 ± 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). ConclusionRelaxation-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.

The pH sensitivity of APT-CEST using phosphorus spectroscopy as a reference method.

The pH value is a potential physiological marker for clinical diagnosis as it is altered in pathologies such as tumors. While intracellular pH can be measured noninvasively via phosphorus spectroscopy (31 P MRSI), Amide Proton Transfer-Chemical Exchange Saturation Transfer (APT-CEST) MRI has been suggested as an alternative method for pH quantification. To assess the suitability of APT-CEST contrast for pH quantification, two approaches (magnetization transfer ratio asymmetry [MTRasym ] and Lorentzian difference analysis [LDA]) for analyzing the Z-spectrum have been correlated with pH values obtained by 31 P MRSI. Fourteen patients with glioblastoma and 12 healthy controls were included. In contrast to MTRasym , the LDA is modeling the direct water saturation and the semi-solid magnetization transfer, allowing a separate evaluation of the aliphatic nuclear Overhauser effect and the APT-CEST. The results of our study show that the pH values obtained by 31 P MRSI correspond well with both methods describing the APT-CEST contrast. Two-sample t-test showed significant differences in MTRasym , LDA and pH obtained by 31 P MRSI for regions of interest in glioblastoma, contralateral control areas and normal appearing white matter (P<0.001). A slightly improved correlation between the amide signal and pH was found after performing LDA (r=0.78) compared with MTRasym (r=0.70). While both methods can be used to monitor pH changes, the LDA approach appears to be better suited.

Amide proton transfer imaging of glioblastoma, neuroblastoma, and breast cancer cells on a 11.7 T magnetic resonance imaging system

PurposeThe purpose of this study was (i) to determine the optimal magnetization transfer (MT) pulse parameter for amide proton transfer (APT) chemical exchange saturation transfer (CEST) imaging on an ultra-high-field magnetic resonance imaging (MRI) system and (ii) to use APT CEST imaging to noninvasively assess brain orthotopic and ectopic tumor cells transplanted into the mouse brain. MethodsTo evaluate APT without the influence of other metabolites, we prepared egg white phantoms. Next, we used 7–11-week-old nude female mice and the following cell lines to establish tumors after injection into the left striatum of mice: C6 (rat glioma, n = 8) as primary tumors and Neuro-2A (mouse neuroblastoma, n = 11) and MDA-MB231 (human breast cancer, n = 8) as metastatic tumors. All MRI experiments were performed on an 11.7 T vertical-bore scanner. CEST imaging was performed at 1 week after injection of Neuro-2A cells and at 2 weeks after injection of C6 and MDA-MB231 cells. The MT pulse amplitude was set at 2.2 μT or 4.4 μT. We calculated and compared the magnetization transfer ratio (MTR) and difference of MTR asymmetry between normal tissue and tumor (ΔMTR asymmetry) on APT CEST images between mouse models of brain tumors. Then, we performed hematoxylin and eosin (HE) staining and Ki-67 immunohistochemical staining to compare the APT CEST effect on tumor tissues and the pathological findings. ResultsPhantom study of the amide proton phantom containing chicken egg white, z-spectra obtained at a pulse length of 500 ms showed smaller peaks, whereas those obtained at a pulse length of 2000 ms showed slightly higher peaks. The APT CEST effect on tumor tissues was clearer at a pulse amplitude of 2.2 μT than at 4.4 μT. For all mouse models of brain tumors, ΔMTR asymmetry was higher at 2.2 μT than at 4.4 μT. ΔMTR asymmetry was significantly higher for the Neuro-2A model than for the MDA-MB231 model. HE staining revealed light bleeding in Neuro-2A tumors. Immunohistochemical staining revealed that the density of Ki-67-positive cells was higher in Neuro-2A tumors than in C6 or MDA-MB231 tumors. ConclusionThe MTR was higher at 4.4 μT than at 2.2 μT for each concentration of egg white at a pulse length of 500 ms or 2000 ms. High-resolution APT CEST imaging on an ultra-high-field MRI system was able to provide tumor information such as proliferative potential and intratumoral bleeding, noninvasively.

Amide chemical exchange saturation transfer at 7\xa0T: a possible biomarker for detecting early response to neoadjuvant chemotherapy in breast cancer patients

BackgroundThe 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.MethodsCEST 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.ResultsSignificant 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).ConclusionsThis 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 registrationRegistration number, NL49333.041.14/NTR4980. Registered on 16 October 2014.

Hybrid MR-PET of brain tumours using amino acid PET and chemical exchange saturation transfer MRI.

PET using radiolabelled amino acids has become a promising tool in the diagnostics of gliomas and brain metastasis. Currentresearch is focused on the evaluation of amide proton transfer (APT) chemical exchange saturation transfer (CEST) MR imaging for brain tumour imaging. In this hybrid MR-PET study, brain tumours were compared using 3D data derived from APT-CEST MRI and amino acid PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). Eight patients with gliomas were investigated simultaneously with 18F-FET PET and APT-CEST MRI using a 3-T MR-BrainPET scanner. CEST imaging was based on a steady-state approach using a B1 average power of 1μT. B0 field inhomogeneities were corrected a Prametric images of magnetisation transfer ratio asymmetry (MTRasym) and differences to the extrapolated semi-solid magnetisation transfer reference method, APT# and nuclear Overhauser effect (NOE#), were calculated. Statistical analysis of the tumour-to-brain ratio of the CEST data was performed against PET data using the non-parametric Wilcoxon test. A tumour-to-brain ratio derived from APT# and 18F-FET presented no significant differences, and no correlation was found between APT# and 18F-FET PET data. Thedistance between local hot spot APT# and 18F-FET were different (average 20 ± 13mm, range 4-45mm). For the first time, CEST images were compared with 18F-FET in a simultaneous MR-PET measurement. Imaging findings derived from18F-FET PET and APT CEST MRI seem to provide different biological information. The validation ofthese imaging findings by histological confirmation is necessary, ideally using stereotactic biopsy.

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

PurposeTo detect neuronal activity–evoked pH changes by amide proton transfer–chemical exchange saturation transfer (APT‐CEST) MRI at 7 T.MethodsThree 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.ResultsIn 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.ConclusionsThe 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.

Amide proton transfer CEST of the cervical spinal cord in multiple sclerosis patients at 3T.

The ability to evaluate pathological changes in the spinal cord in multiple sclerosis (MS) is limited because T1 - and T2 -w MRI imaging are not sensitive to biochemical changes in vivo. Amide proton transfer (APT) chemical exchange saturation transfer (CEST) can indirectly detect amide protons associated with proteins and peptides, potentially providing more pathological specificity. Here, we implement APT CEST in the cervical spinal cord of healthy and MS cohorts at 3T. APT CEST of the cervical spinal cord was obtained in a cohort of 10 controls and 10 MS patients using a novel respiratory correction methodology. APT was quantified using two methods: 1) APTw , based off the conventional magnetization transfer ratio asymmetry, and 2) ΔAPT, a spatial characterization of APT changes in MS patients relative to the controls. Respiratory correction yielded highly reproducible z-spectra in white matter (intraclass correlation coefficient = 0.82). APTw signals in normal-appearing white matter (NAWM) of MS patients were significantly different from healthy controls (P = 0.04), whereas ΔAPT of MS patients highlighted large APT differences in NAWM. Respiration correction in the spinal cord is necessary to accurately quantify APT CEST, which can provide unique biochemical information regarding disease processes within the spinal cord. Magn Reson Med 79:806-814, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Systematic Evaluation of Amide Proton Chemical Exchange Saturation Transfer at 3 T: Effects of Protein Concentration, pH, and Acquisition Parameters.

The goal of this work was to systematically evaluate the reproducibility of amide proton transfer chemical exchange saturation transfer (APT-CEST) at 3 T and its signal dependence on pH, protein concentration, and acquisition parameters. An in vitro system based on bovine serum albumin (BSA) was used, and its limitations were tested by comparing it to in vivo measurements. The contribution of small endogenous metabolites on the APT-CEST signal at 3 T was also investigated. In addition, the reliability of different z-spectrum interpolations as well as the use of only a few frequency offset data points instead of a whole z-spectrum were tested. We created both a BSA phantom at different concentrations and pH values and a metabolite phantom with different small molecules. Chemical exchange saturation transfer data were acquired using a 2-dimensional fast spoiled gradient-echo sequence with pulsed CEST preparation at different saturation durations and power levels. Healthy volunteer measurements were taken for comparison. Z-spectra were interpolated using a 24th-order polynomial (Poly), an eighth-order Fourier series (Fourier), and a smoothing Spline (sSpline) algorithm. To evaluate reduced data sets, only 6 to 14 frequency offsets of the z-spectrum were used and interpolated via a cubic Spline. Region of interest (ROI) evaluations were used to investigate the reproducibility of amide magnetization transfer ratio asymmetry [MTRasym(3.5 ppm)] and to analyze the MTRasym and z-spectra. Interscan standard deviations of MTRasym(3.5 ppm) were always below 0.3%. MTRasym(3.5 ppm) increased when the BSA concentrations increased and decreased when the pH increased. The amine MTRasym signal of small molecules was very small compared with BSA and was only detectable using short saturation times and higher power levels. The MTRasym(3.5 ppm) between BSA concentration steps and between nearly all pH steps was significantly different for all 3 fitting methods. The Fourier and sSpline methods showed no statistically significant differences; however, the results for the Poly method were significantly higher at some concentrations and pH values. Using only few frequency offsets resulted in less significant differences compared with fitting the complete z-spectrum. In general, MTRasym(3.5 ppm) of gray matter, white matter, and ventricle ROIs from volunteer scans increased with an increase in saturation power and partially decreased with an increase in saturation duration. Intra-ROI covariances of MTRasym(3.5 ppm) revealed the highest variations for Poly, whereas using reduced spectral data resulted in an increased signal variation. Amide proton transfer-CEST imaging is a highly reproducible method in which absolute signal differences of approximately 0.5% are detectable in principle. For in vivo applications, Fourier or sSpline interpolations of z-spectra are preferable. Using reduced data sets delivers similar results but with increased variation and therefore decreased (pH/concentration) differentiation capability. Differentiation capability increases with increases in the saturation duration and power level. The results from the in vitro BSA system cannot be directly transferred to the in vivo situation due to different chemical environments resulting in, for example, higher asymmetric macromolecular cMT effects in vivo. Amine signals from small molecules are unlikely to contribute to APT-CEST at 3 T (except for creatine); however, signals can be enhanced by using short saturation times and higher power levels.