Development of chemical exchange saturation transfer at 7T

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging method that has previously been successful at reporting variations in tissue protein and glycogen contents and pH. We have implemented amide proton transfer (APT), a specific form of chemical exchange saturation transfer imaging, at high field (7T) and used it to study healthy human subjects and patients with multiple sclerosis. The effects of static field inhomogeneities were mitigated using a water saturation shift referencing method to center each z‐spectrum on a voxel‐by‐voxel basis. Contrary to results obtained at lower fields, APT imaging at 7T revealed significant contrast between white and gray matters, with a higher APT signal apparent within the white matter. Preliminary studies of multiple sclerosis showed that the APT asymmetry varied with the type of lesion examined. An increase in APT asymmetry relative to healthy tissue was found in some lesions. These results indicate the potential utility of APT at high field as a noninvasive biomarker of white matter pathology, providing complementary information to other MRI methods in current clinical use. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Iopamidol as a responsive MRI‐chemical exchange saturation transfer contrast agent for pH mapping of kidneys: In vivo studies in mice at 7 T

Iopamidol (Isovue®—Bracco Diagnostic Inc.) is a clinically approved X‐Ray contrast agent used in the last 30 years for a wide variety of diagnostic applications with a very good clinical acceptance. Iopamidol contains two types of amide functionalities that can be exploited for the generation of chemical exchange saturation transfer effect. The exchange rate of the two amide proton pools is markedly pH‐dependent. Thus, a ratiometric method for pH assessment has been set‐up based on the comparison of the saturation transfer effects induced by selective irradiation of the two resonances. This ratiometric approach allows to rule out the concentration effect of the contrast agent and provides accurate pH measurements in the 5.5–7.4 range. Upon injection of Iopamidol into healthy mice, it has been possible to acquire pH maps of kidney regions. Furthermore, it has been also shown that the proposed method is able to report about pH‐changes induced in control mice fed with acidified or basified water for a period of a week before image acquisition. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Optimizing pulsed‐chemical exchange saturation transfer imaging sequences

Chemical exchange saturation transfer (CEST) provides a new imaging contrast mechanism sensitive to labile proton exchange. Pulsed‐CEST imaging is better suited to the hardware constraints on clinical imaging systems when compared with traditional continuous wave‐CEST imaging methods. However, designing optimum pulsed‐CEST imaging sequences entails complicated and time‐consuming numerical integrations. In this work, a simplified and computationally efficient technique is provided to optimize the pulsed‐CEST imaging sequence. An analysis was performed of the optimal average irradiation power and the optimal irradiation flip angle as a function of the acquisition parameters and sample properties in both a two‐pool model and a three‐pool model of endogenous amine exchange. Key simulated and experimental results based on a creatine/agar tissue phantom show that ( 1 ) the average irradiation power is a more meaningful sequence metric than is the average irradiation field amplitude, ( 2 ) the optimal average powers for continuous wave and pulsed‐CEST imaging are approximately equal to each other for a relevant range of solute frequency offsets, exchange rates, and concentrations, ( 3 ) an irradiation flip angle of 180° is optimal or near optimal, independent of the other acquisition parameters and the sample properties, and ( 4 ) higher duty cycles yield higher CEST contrast. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

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.     

Diffusion-prepared fast imaging with steady-state free precession (DP-FISP): a rapid diffusion MRI technique at 7 T

Diffusion MRI is a useful imaging technique with many clinical applications. Many diffusion MRI studies have utilized echo-planar imaging (EPI) acquisition techniques. In this study, we have developed a rapid diffusion-prepared fast imaging with steady-state free precession MRI acquisition for a preclinical 7T scanner providing diffusion-weighted images in less than 500 ms and diffusion tensor imaging assessments in ～1 min with minimal image artifacts in comparison with EPI. Phantom apparent diffusion coefficient (ADC) and fractional anisotropy (FA) assessments obtained from the diffusion-prepared fast imaging with steady-state free precession (DP-FISP) acquisition resulted in good agreement with EPI and spin echo diffusion methods. The mean apparent diffusion coefficient was 2.0 × 10(-3) mm(2) /s, 1.90 × 10(-3) mm(2) /s, and 1.97 × 10(-3) mm(2) /s for DP-FISP, diffusion-weighted spin echo, and diffusion-weighted EPI, respectively. The mean fractional anisotropy was 0.073, 0.072, and 0.070 for diffusion-prepared fast imaging with steady-state free precession, diffusion-weighted spin echo, and diffusion-weighted EPI, respectively. Initial in vivo studies show reasonable ADC values in a normal mouse brain and polycystic rat kidneys.     

Imaging pH using the chemical exchange saturation transfer (CEST) MRI: Correction of concomitant RF irradiation effects to quantify CEST MRI for chemical exchange rate and pH

Chemical exchange saturation transfer (CEST) MRI has been shown capable of detecting dilute labile protons and abnormal tissue glucose/oxygen metabolism, and thus, may serve as a complementary imaging technique to the conventional MRI methods. CEST imaging, however, is also dependent on experimental parameters such as the power, duration, and waveform of the irradiation RF pulse. As a result, its sensitivity and specificity for microenvironment properties such as pH is not optimal. In this study, the dependence of CEST contrast on experimental parameters was solved and an iterative compensation algorithm was proposed that corrects the experimentally measured CEST contrast from the concomitant RF irradiation effects. The proposed algorithm was verified with both numerical simulation and experimental measurements from a tissue‐like pH phantom, and showed that pH derived from the compensated CEST imaging agrees reasonably well with pH‐electrode measurements within 0.1 pH unit. In sum, our study validates the use of a correction algorithm to compensate CEST imaging from concomitant RF irradiation effects for accurate calibration of the chemical exchange rate, and demonstrates the feasibility of pH imaging with CEST MRI. Magn Reson Med 60:390–397, 2008. © 2008 Wiley‐Liss, Inc.     

Optimal sampling schedule for chemical exchange saturation transfer

The sampling schedule for chemical exchange saturation transfer imaging is normally uniformly distributed across the saturation frequency offsets. When this kind of evenly distributed sampling schedule is used to quantify the chemical exchange saturation transfer effect using model‐based analysis, some of the collected data are minimally informative to the parameters of interest. For example, changes in labile proton exchange rate and concentration mainly affect the magnetization near the resonance frequency of the labile pool. In this study, an optimal sampling schedule was designed for a more accurate quantification of amine proton exchange rate and concentration, and water center frequency shift based on an algorithm previously applied to magnetization transfer and arterial spin labeling. The resulting optimal sampling schedule samples repeatedly around the resonance frequency of the amine pool and also near to the water resonance to maximize the information present within the data for quantitative model‐based analysis. Simulation and experimental results on tissue‐like phantoms showed that greater accuracy and precision (>30% and >46%, respectively, for some cases) were achieved in the parameters of interest when using optimal sampling schedule compared with evenly distributed sampling schedule. Hence, the proposed optimal sampling schedule could replace evenly distributed sampling schedule in chemical exchange saturation transfer imaging to improve the quantification of the chemical exchange saturation transfer effect and parameter estimation. Magn Reson Med 70:1251–1262, 2013. © 2013 Wiley Periodicals, Inc.     

Fast multislice pH‐weighted chemical exchange saturation transfer (CEST) MRI with Unevenly segmented RF irradiation

Chemical exchange saturation transfer (CEST) MRI is a versatile imaging technique for measuring microenvironment properties via dilute CEST labile groups. Conventionally, CEST MRI is implemented with a long radiofrequency irradiation module, followed by fast image acquisition to obtain the steady state CEST contrast. Nevertheless, the sensitivity, scan time, and spatial coverage of the conventional CEST MRI method may not be optimal. Our study proposed a segmented radiofrequency labeling scheme that includes a long primary radiofrequency irradiation module to generate the steady state CEST contrast and repetitive short secondary radiofrequency irradiation module immediately after the image acquisition so as to maintain the steady state CEST contrast for multislice acquisition and signal averaging. The proposed CEST MRI method was validated experimentally with a tissue‐like pH phantom and optimized for the maximal contrast‐to‐noise ratio. In addition, the proposed sequence was evaluated for imaging ischemic acidosis via pH‐weighted endogenous amide proton transfer MRI, which showed similar contrast as conventional amide proton transfer MRI. In sum, a fast multislice relaxation self‐compensated CEST MRI sequence was developed, with significantly improved sensitivity and suitable for in vivo applications. Magn Reson Med, 2011. © 2010 Wiley‐Liss, Inc.     

Simplified quantification of labile proton concentration‐weighted chemical exchange rate (kws) with RF saturation time dependent ratiometric analysis (QUESTRA): Normalization of relaxation and RF irradiation spillover effects for improved quantitative chemical exchange saturation transfer (CEST) MRI

Chemical exchange saturation transfer MRI is an emerging imaging technique capable of detecting dilute proteins/peptides and microenvironmental properties, with promising in vivo applications. However, chemical exchange saturation transfer MRI contrast is complex, varying not only with the labile proton concentration and exchange rate, but also with experimental conditions such as field strength and radiofrequency (RF) irradiation scheme. Furthermore, the optimal RF irradiation power depends on the exchange rate, which must be estimated in order to optimize the chemical exchange saturation transfer MRI experiments. Although methods including numerical fitting with modified Bloch‐McConnell equations, quantification of exchange rate with RF saturation time and power (QUEST and QUESP), have been proposed to address this relationship, they require multiple‐parameter non‐linear fitting and accurate relaxation measurement. Our work extended the QUEST algorithm with ratiometric analysis (QUESTRA) that normalizes the magnetization transfer ratio at labile and reference frequencies, which effectively eliminates the confounding relaxation and RF spillover effects. Specifically, the QUESTRA contrast approaches its steady state mono‐exponentially at a rate determined by the reverse exchange rate (k_ws), with little dependence on bulk water T₁, T₂, RF power and chemical shift. The proposed algorithm was confirmed numerically, and validated experimentally using a tissue‐like phantom of serially titrated pH compartments. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Investigation of optimizing and translating pH‐sensitive pulsed‐chemical exchange saturation transfer (CEST) imaging to a 3T clinical scanner

Chemical exchange saturation transfer (CEST) MRI provides a sensitive detection mechanism that allows characterization of dilute labile protons usually undetectable by conventional MRI. Particularly, amide proton transfer (APT) imaging, a variant of CEST MRI, has been shown capable of detecting ischemic acidosis, and may serve as a surrogate metabolic imaging marker. For preclinical CEST imaging, continuous‐wave (CW) radiofrequency (RF) irradiation is often applied so that the steady state CEST contrast can be reached. On clinical scanners, however, specific absorption rate (SAR) limit and hardware preclude the use of CW irradiation, and instead require an irradiation scheme of repetitive RF pulses (pulsed‐CEST imaging). In this work, CW‐ and pulsed‐CEST MRI were systematically compared using a tissue‐like pH phantom on an imager capable of both CW and pulsed RF irradiation schemes. The results showed that the maximally obtainable pulsed‐CEST contrast is approximately 95% of CW‐CEST contrast, and their optimal RF irradiation powers are equal. Moreover, the pulsed‐CEST sequence was translated to a 3 Tesla clinical scanner and detected pH contrast from the labile creatine amine groups (1.9 ppm). Furthermore, pilot endogenous APT imaging of normal human volunteers was demonstrated, warranting future APT MRI of stroke patients to elucidate its diagnostic value. Magn Reson Med 60:834–841, 2008. © 2008 Wiley‐Liss, Inc.