Chemical Exchange Saturation Transfer Acquisition Research Articles

RF Heating Effects in CEST NMR with Hyperpolarized 129Xe Considering Different Spin Exchange Kinetics and Saturation Schemes.

Chemical exchange saturation transfer (CEST) improves the sensitivity of NMRbut depending on the spin exchange kinetics, it can require substantial RF energy deposition to label magnetization. Potential side effects like RF-induced heating may occur and must be monitored. Here, we explore the parameter space considering not only undesired heating but efficient CEST build-up (depolarization rate), spectral resolution (line width), and subsequent effects like changes in chemical shifts of CEST responses must be considered, too. We present a systematic study to compare conventional block pulse with shaped-pulse saturation and quantify how the effective average saturation power impacts these parameters. Pulse shape and nominal excitation bandwidth, however, turned out to have little impact on acquired z-spectra and temperature changes. This study illustrates how different exchange kinetics define different regimes of suitable RF power within the dynamic range of fully saturable magnetization from hyperpolarized 129Xe. Temperature-related changes in the resonance frequency of bound spins were also quantified for the two Xe hosts CB6 and CrA-ma and put into context for typically used CEST acquisition parameters, including the stability of the magnetic field.

Joint K-space and Image-space Parallel Imaging (KIPI) for accelerated chemical exchange saturation transfer acquisition.

To develop an auto-calibrated technique by joint K-space and Image-space Parallel Imaging (KIPI) for accelerated CEST acquisition. The KIPI method selects a calibration frame with a low acceleration factor (AF) and auto-calibration signals (ACS) acquired, from which the coil sensitivity profiles and artifact correction maps are calculated after restoring the k-space by GRAPPA. Then the other frames with high AF and without ACS can be reconstructed by SENSE and artifact suppression. The signal leakage due to the T2 -decay filtering in k-space compromises the SENSE reconstruction, which can be corrected by the artifact suppression algorithm of KIPI. The 2D and 3D imaging experiments were done on the phantom, healthy volunteer, and brain tumor patient with a 3T scanner. The proposed KIPI method was evaluated by retrospectively undersampled data with variable AFs and compared against existing parallel imaging methods (SENSE/auto, GRAPPA, and ESPIRiT). KIPI enabled CEST frames with random AFs to achieve similar image quality, eliminated the strong aliasing artifacts, and generated significantly smaller errors than the other methods (p < 0.01). The KIPI method permitted an AF up to 12-fold in both phase-encoding and slice-encoding directions for 3D CEST source images, achieving an overall 8.2-fold speedup in scan time. KIPI is a novel auto-calibrated parallel imaging method that enables variable AFs for different CEST frames, achieves a significant reduction in scan time, and does not compromise the accuracy of CEST maps.

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.

Linear projection-based chemical exchange saturation transfer parameter estimation.

Isolated evaluation of multiparametric in vivo chemical exchange saturation transfer (CEST) MRI often requires complex computational processing for both correction of B0 and B1 inhomogeneity and contrast generation. For that, sufficiently densely sampled Z-spectra need to be acquired. The list of acquired frequency offsets largely determines the total CEST acquisition time, while potentially representing redundant information. In this work, a linear projection-based multiparametric CEST evaluation method is introduced that offers fast B0 and B1 inhomogeneity correction, contrast generation and feature selection for CEST data, enabling reduction of the overall measurement time. To that end, CEST data acquired at 7T in six healthy subjects and in one brain tumor patient were conventionally evaluated by interpolation-based inhomogeneity correction and Lorentzian curve fitting. Linear regression was used to obtain coefficient vectors that directly map uncorrected data to corrected Lorentzian target parameters. L1-regularization was applied to find subsets of the originally acquired CEST measurements that still allow for such a linear projection mapping. The linear projection method allows fast and interpretable mapping from acquired raw data to contrast parameters of interest, generalizing from healthy subject training data to unseen healthy test data and to the tumor patient dataset. The L1-regularization method shows that a fraction of the acquired CEST measurements is sufficient to preserve tissue contrasts, offering up to a 2.8-fold reduction of scan time. Similar observations as for the 7-T data can be made for data from a clinical 3-T scanner. Being a fast and interpretable computation step, the proposed method is complementary to neural networks that have recently been employed for similar purposes. The scan time acceleration offered by the L1-regularization ("CEST-LASSO") constitutes a step towards better applicability of multiparametric CEST protocols in a clinical context.

3D APT and NOE CEST-MRI of healthy volunteers and patients with non-enhancing glioma at 3\xa0T

ObjectiveClinical application of chemical exchange saturation transfer (CEST) can be performed with investigation of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects. Here, we investigated APT- and NOE-weighted imaging based on advanced CEST metrics to map tumor heterogeneity of non-enhancing glioma at 3 T.Materials and methodsAPT- and NOE-weighted maps based on Lorentzian difference (LD) and inverse magnetization transfer ratio (MTRREX) were acquired with a 3D snapshot CEST acquisition at 3 T. Saturation power was investigated first by varying B1 (0.5–2 µT) in 5 healthy volunteers then by applying B1 of 0.5 and 1.5 µT in 10 patients with non-enhancing glioma. Tissue contrast (TC) and contrast-to-noise ratios (CNR) were calculated between glioma and normal appearing white matter (NAWM) and grey matter, in APT- and NOE-weighted images. Volume percentages of the tumor showing hypo/hyperintensity (VPhypo/hyper,CEST) in APT/NOE-weighted images were calculated for each patient.ResultsLD APT resulting from using a B1 of 1.5 µT was found to provide significant positive TCtumor,NAWM and MTRREX NOE (B1 of 1.5 µT) provided significant negative TCtumor,NAWM in tissue differentiation. MTRREX-based NOE imaging under 1.5 µT provided significantly larger VPhypo,CEST than MTRREX APT under 1.5 µT.ConclusionThis work showed that with a rapid CEST acquisition using a B1 saturation power of 1.5 µT and covering the whole tumor, analysis of both LD APT and MTRREX NOE allows for observing tumor heterogeneity, which will be beneficial in future studies using CEST-MRI to improve imaging diagnostics for non-enhancing glioma.

Deep learning-based classification of preclinical breast cancer tumor models using chemical exchange saturation transfer magnetic resonance imaging.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging has shown promise for classifying tumors based on their aggressiveness, but CEST contrast is complicated by multiple signal sources and thus prolonged acquisition times are often required to extract the signal of interest. We investigated whether deep learning could help identify pertinent Z-spectral features for distinguishing tumor aggressiveness as well as the possibility of acquiring only the pertinent spectral regions for more efficient CEST acquisition. Human breast cancer cells, MDA-MB-231 and MCF-7, were used to establish bi-lateral tumor xenografts in mice to represent higher and lower aggressive tumors, respectively. A convolutional neural network (CNN)-based classification model, trained on simulated data, utilized Z-spectral features as input to predict labels of different tissue types, including MDA-MB-231, MCF-7, and muscle tissue. Saliency maps reported the influence of Z-spectral regions on classifying tissue types. The model was robust to noise with an accuracy of more than 91.5% for low and moderate noise levels in simulated testing data (SD of noise less than 2.0%). For in vivo CEST data acquired with a saturation pulse amplitude of 2.0 μT, the model had a superior ability to delineate tissue types compared with Lorentzian difference (LD) and magnetization transfer ratio asymmetry (MTRasym ) analysis, classifying tissues to the correct types with a mean accuracy of 85.7%, sensitivity of 81.1%, and specificity of 94.0%. The model's performance did not improve substantially when using data acquired at multiple saturation pulse amplitudes or when adding LD or MTRasym spectral features, and did not change when using saliency map-based partial or downsampled Z-spectra. This study demonstrates the potential of CNN-based classification to distinguish between different tumor types and muscle tissue, and speed up CEST acquisition protocols.

Chemical exchange saturation transfer imaging for epilepsy secondary to tuberous sclerosis complex at 3T: Optimization and analysis.

The homeostasis of various metabolites is impaired in epilepsy secondary to the tuberous sclerosis complex (TSC). Chemical exchange saturation transfer (CEST) imaging is an emerging molecular MRI technique that can detect various metabolites and proteins in vivo. However, the role of CEST imaging for TSC-associated epilepsy has not been assessed. Here, we aim to investigate the feasibility of applying CEST imaging to TSC-associated epilepsy, optimize the CEST acquisition parameters, and provide an analysis method for exploring the dominant molecular contributors to the CEST signal measured. Nine TSC epilepsy patients were scanned on a 3-T MRI system. The CEST saturation frequencies were swept from -6 to 6ppm with 12 different combinations of saturation power (4, 3, 2 and 1 μT) and duration (1000, 700 and 400 ms). Furthermore, a two-stage simulation method based on the seven-pool Bloch-McConnell model was proposed to assess the contribution of each exchangeable pool to the CEST signal in normal-appearing white matter and cortical tubers, which avoided the complexity and uncertainty of full Bloch-McConnell fitting. The results showed that under the optimal saturation duration of 1000 ms, the greatest contrast between tubers and normal tissues occurred around 3, 2.5, 1.75 and 3.5ppm for B1 of 4, 3, 2 and 1 μT, respectively. At the optimal frequency offsets, the CEST values of tubers were significantly higher than those in the normal brain tissues (P<0.01). Furthermore, the two-stage analysis suggested that the amine pool played a dominant role in yielding the contrast between cortical tubers and normal tissues. These results indicate that CEST MRI may serve as a potentially useful tool for identifying tubers in TSC, and the two-stage analysis method may provide a route for investigating the molecular contributions to the CEST contrast in biological tissues.

Abstract PS3-08: Assessment of early response to neoadjuvant systemic therapy (NAST) of triple-negative breast cancer (TNBC) using chemical exchange saturation transfer (CEST) MRI: A pilot study

Abstract PS3-08: Assessment of early response to neoadjuvant systemic therapy (NAST) of triple-negative breast cancer (TNBC) using chemical exchange saturation transfer (CEST) MRI: A pilot study

Dual assessment of kidney perfusion and pH by exploiting a dynamic CEST-MRI approach in an acute kidney ischemia-reperfusion injury murine model.

Several factors can lead to acute kidney injury, but damage following ischemia and reperfusion injuries is the main risk factor and usually develops into chronic disease. MRI has often been proposed as a method with which to assess renal function. It does so by measuring the renal perfusion of an injected Gd-based contrast agent. The use of pH-responsive agents as part of the CEST (chemical exchange saturation transfer)-MRI technique has recently shown that pH homeostasis is also an important indicator of kidney functionality. However, there is still a need for methods that can provide more than one type of information following the injection of a single contrast agent for the characterization of renal function. Herein we propose, for the first time, dynamic CEST acquisition following iopamidol injection to quantify renal function by assessing both perfusion and pH homeostasis. The aim of this study is to assess renal functionality in a murine unilateral ischemia-reperfusion injury model at two time points (3 and 7 days) after acute kidney injury. The renal-perfusion estimates measured with iopamidol were compared with those obtained with a gadolinium-based agent, via a dynamic contrast enhanced (DCE)-MRI approach, to validate the proposed method. Compared with the contralateral kidneys, the clamped ones showed a significant decrease in renal perfusion, as measured using the DCE-MRI approach, which is consistent with reduced filtration capability. Dynamic CEST-MRI findings provided similar results, indicating that the clamped kidneys displayed significantly reduced renal filtration that persisted up to 7 days after the damage. In addition, CEST-MRI pH imaging showed that the clamped kidneys displayed significantly increased pH values, reflecting the disturbance to pH homeostasis. Our results demonstrate that a single CEST-MRI contrast agent can provide multiple types of information related to renal function and can discern healthy kidneys from pathological ones by combining perfusion measurements with renal pH mapping.

Motion correction of chemical exchange saturation transfer MRI series using robust principal component analysis (RPCA) and PCA.

Chemical exchange saturation transfer (CEST) MRI requires the acquisition of multiple saturation-weighted images and can last several minutes. Misalignments among these images, which are often due to the inevitable motion of the subject, will corrupt CEST contrast maps and result in large quantification errors. Therefore, the registration of the CEST series is critical. However, registration is challenging since common intensity-based registration algorithms may fail to differentiate CEST signals from motion artifacts. Herein, we studied how different patterns of motion affect CEST quantification and proposed a cascaded two-step registration scheme by utilizing features extracted from the entire Z-spectral image series instead of direct registration to a single image. The proposed approach is conducted in two stages: during the first coarse registration, the Z-spectral image series is decomposed by robust principal component analysis (RPCA) to separate CEST contrast from motion. The recomposed image series using only the low-rank component, which contains minimized motion, are averaged to generate a reference for the alignment of the image series. To further remove residual misalignments, the coarse registration is followed by a refinement stage, which uses PCA iteratively to generate motionless synthetic reference series with the first few principal components (PCs) that correspond to CEST contrast. In the end, the quality check is performed to exclude the images with unsuccessful registration. The proposed registration scheme (RPCA + PCA_R) was assessed by both phantom experiments and in vivo data of tumor-bearing mouse brain, with simulated random rigid motion in different patterns applied to the acquired static Z-spectral image series. For comparison, previous correction schemes using an explicit image [either S0 or Ssat(∆ω)] as registration reference were also performed, named as S0_R and Ssat_R respectively. To illustrate the advantage of combination of RPCA and PCA, registration was also exploited using either only the RPCA-based method (RPCA_R) or only the PCA-based one (PCA_R). Compared with the above four methods, RPCA + PCA_R allowed for more accurate correction of the corrupted Z-spectral images, exhibiting smaller MTRasym(∆ω) error maps and lower residual Z-spectra referring to the static data. Among all the five correction methods, the corrected Z-spectral image series by RPCA + PCA_R and the resulting MTRasym(∆ω) maps achieved the highest correlation coefficients (CC) with respect to the static ones. The registration scheme of RPCA + PCA_R provides robust motion correction between two specific Z-spectral images and among an entire image series, through extraction of the static component from the entire Z-spectra set and inclusion of a PCA-based refinement step. Therefore, this method can help improve CEST acquisition and quantification.

Multiple frequency saturation pulses reduce CEST acquisition time for quantifying conformational exchange in biomolecules.

Exchange between conformational states is required for biomolecular catalysis, allostery, and folding. A variety of NMR experiments have been developed to quantify motional regimes ranging from nanoseconds to seconds. In this work, we describe an approach to speed up the acquisition of chemical exchange saturation transfer (CEST) experiments that are commonly used to probe millisecond to second conformational exchange in proteins and nucleic acids. The standard approach is to obtain CEST datasets through the acquisition of a series of 2D correlation spectra where each experiment utilizes a single saturation frequency to 1H, 15N or 13C. These pseudo 3D datasets are time consuming to collect and are further lengthened by reduced signal to noise stemming from the long saturation pulse. In this article, we show how usage of a multiple frequency saturation pulse (i.e., MF-CEST) changes the nature of data collection from series to parallel, and thus decreases the total acquisition time by an integer factor corresponding to the number of frequencies in the pulse. We demonstrate the applicability of MF-CEST on a Src homology 2 (SH2) domain from phospholipase Cγ and the secondary active transport protein EmrE as model systems by collecting 13C methyl and 15N backbone datasets. MF-CEST can also be extended to additional sites within proteins and nucleic acids. The only notable drawback of MF-CEST as applied to backbone 15N experiments occurs when a large chemical shift difference between the major and minor populations is present (typically greater than ~ 8ppm). In these cases, ambiguity may arise between the chemical shift of the minor population and the multiple frequency saturation pulse. Nevertheless, this drawback does not occur for methyl group MF-CEST experiments or in cases where somewhat smaller chemical shift differences occur are present.

Chemical exchange saturation transfer (CEST) imaging with fast variably-accelerated sensitivity encoding (vSENSE).

The widespread clinical use of chemical exchange saturation transfer (CEST) imaging is hampered by relatively long scan times due to its requirement that multiple saturation-offset image frames be acquired. Here, a novel variably-accelerated sensitivity encoding (vSENSE) method is proposed that provides faster CEST acquisition than conventional SENSE. The vSENSE method fully samples one CEST saturation frame, then undersamples the other frames variably. The fully-sampled frame, in conjunction with newly proposed incoherence absorption and artifact suppression strategies, improves the accuracy of sensitivity maps and permits higher acceleration factors for the other undersampled frames than regular SENSE. vSENSE is validated in a phantom, a normal volunteer and eight brain tumor patients at 3 Tesla. vSENSE with an acceleration factor of four generated a 3-6 times smaller error on average than conventional SENSE (P ≤ 0.02), with acceleration factors of 2-4, as compared with full k-space reconstruction. vSENSE permitted four-fold acceleration for amide proton transfer-weighted images, while regular SENSE could only provide a factor of two. When conventional SENSE is used with vSENSE's variable undersampling pattern, erroneous (∼9%) z-spectra result. The vSENSE method enabled twice the acceleration and generated more accurate images than conventional SENSE. Magn Reson Med 77:2225-2238, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

SU‐E‐J‐225: CEST Imaging in Head and Neck Cancer Patients

Purpose:Chemical Exchange Saturation Transfer (CEST) imaging is an MRI technique enables the detection and imaging of metabolically active compounds in vivo. It has been used to differentiate tumor types and metabolic characteristics. Unlike PET/CT,CEST imaging does not use isotopes so it can be used on patient repeatedly. This study is to report the preliminary results of CEST imaging in Head and Neck cancer (HNC) patients.Methods:A CEST imaging sequence and the post‐processing software was developed on a 3T clinical MRI scanner. Ten patients with Human papilloma virus positive oropharyngeal cancer were imaged in their immobilized treatment position. A 5 mm slice CEST image was acquired (128×128, FOV=20∼24cm) to encompass the maximum dimension of tumor. Twenty‐nine off‐set frequencies (from −7.8ppm to +7.8 ppm) were acquired to obtain the Z‐spectrum. Asymmetry analysis was used to extract the CEST contrasts. ROI at the tumor, node and surrounding tissues were measured.Results:CEST images were successfully acquired and Zspectrum asymmetry analysis demonstrated clear CEST contrasts in tumor as well as the surrounding tissues. 3∼5% CEST contrast in the range of 1 to 4 ppm was noted in tumor as well as grossly involved nodes. Injection of glucose produced a marked increase of CEST contrast in tumor region (∼10%). Motion and pulsation artifacts tend to smear the CEST contrast, making the interpretation of the image contrast difficult. Field nonuniformity, pulsation in blood vesicle and susceptibility artifacts caused by air cavities were also problematic for CEST imaging.Conclusion:We have demonstrated successful CEST acquisition and Z‐spectrum reconstruction on HNC patients with a clinical scanner. MRI acquisition in immobilized treatment position is critical for image quality as well as the success of CEST image acquisition. CEST images provide novel contrast of metabolites in HNC and present great potential in the pre‐ and post‐treatment assessment of patients undergoing radiation therapy.

A review of optimization and quantification techniques for chemical exchange saturation transfer MRI toward sensitive in vivo imaging.

Chemical exchange saturation transfer (CEST) MRI is a versatile imaging method that probes the chemical exchange between bulk water and exchangeable protons. CEST imaging indirectly detects dilute labile protons via bulk water signal changes following selective saturation of exchangeable protons, which offers substantial sensitivity enhancement and has sparked numerous biomedical applications. Over the past decade, CEST imaging techniques have rapidly evolved owing to contributions from multiple domains, including the development of CEST mathematical models, innovative contrast agent designs, sensitive data acquisition schemes, efficient field inhomogeneity correction algorithms, and quantitative CEST (qCEST) analysis. The CEST system that underlies the apparent CEST-weighted effect, however, is complex. The experimentally measurable CEST effect depends not only on parameters such as CEST agent concentration, pH and temperature, but also on relaxation rate, magnetic field strength and more importantly, experimental parameters including repetition time, RF irradiation amplitude and scheme, and image readout. Thorough understanding of the underlying CEST system using qCEST analysis may augment the diagnostic capability of conventional imaging. In this review, we provide a concise explanation of CEST acquisition methods and processing algorithms, including their advantages and limitations, for optimization and quantification of CEST MRI experiments.

Chemical exchange saturation transfer MRI using intermolecular double-quantum coherences with multiple refocusing pulses

Chemical exchange saturation transfer (CEST) provides a new type of image contrast in MRI. Due to the intrinsically low CEST effect, new and improved experimental techniques are required to achieve reliable and quantitative CEST images. In the present work, we proposed a novel and more sensitive CEST acquisition approach, based on the intermolecular double-quantum coherence with a module of multiple refocusing pulses (iDQC-MRP). Experiments were performed on creatine and egg white phantoms using a Varian 7T animal MRI scanner. The iDQC-MRP CEST technique showed a substantial enhancement in CEST and nuclear Overhauser enhancement (NOE) signal intensities, compared to the standard single-quantum coherence approach. In addition, the iDQC-MRP approach increased the signal-to-noise ratio of acquired saturation images, compared to the conventional iDQC approach. The new iDQC-MRP CEST sequence provides a promising way for exploiting in vivo CEST and NOE imaging applications.

In vivo three‐dimensional whole‐brain pulsed steady‐state chemical exchange saturation transfer at 7 T

Chemical exchange saturation transfer (CEST) is a technique to indirectly detect pools of exchangeable protons through the water signal. To increase its applicability to human studies, it is needed to develop sensitive pulse sequences for rapidly acquiring whole-organ images while adhering to stringent amplifier duty cycle limitations and specific absorption rate restrictions. In addition, the interfering effects of direct water saturation and conventional magnetization transfer contrast complicate CEST quantification and need to be reduced as much as possible. It is shown that for protons exchanging with rates of less than 50-100 Hz, such as imaged in amide proton transfer experiments, these problems can be addressed by using a three-dimensional steady state pulsed acquisition of limited B(1) strength (≈ 1 μT). Such an approach exploits the fact that the direct water saturation width, magnetization transfer contrast magnitude, and specific absorption rate increase strongly with B(1) , while the size of the CEST effect for such protons depends minimally on B(1) . A short repetition time (65 ms) steady-state sequence consisting of a brief saturation pulse (25 ms) and a segmented echo-planar imaging train allowed acquisition of a three-dimensional whole-brain volume in approximately 11 s per saturation frequency, while remaining well within specific absorption rate and duty cycle limits. Magnetization transfer contrast was strongly reduced, but substantial saturation effects were found at frequencies upfield from water, which still confound the use of magnetization transfer asymmetry analysis. Fortunately, the limited width of the direct water saturation signal could be exploited to fit it with a Lorentzian function allowing CEST quantification. Amide proton transfer effects ranged between 1.5% and 2.5% in selected white and grey matter regions. This power and time-efficient 3D pulsed CEST acquisition scheme should aid endogenous CEST quantification at both high and low fields.