Chemical exchange saturation transfer (CEST) imaging is a relatively new MRI contrast approach in which exogenous or endogenous compounds containing either exchangeable protons or exchangeable molecules are selectively saturated and, after transfer of this saturation, detected indirectly through the water signal with enhanced sensitivity. The focus of this review is on basic MR principles underlying CEST and similarities to and differences with conventional magnetization transfer contrast (MTC). In CEST MRI, transfer of magnetization is studied in mobile compounds instead of semisolids. Similar to MTC, CEST has contributions of both chemical exchange and dipolar cross-relaxation, but the latter can often be neglected if exchange is fast. Contrary to MTC, CEST imaging requires sufficiently slow exchange on the MR time scale to allow selective irradiation of the protons of interest. As a consequence, magnetic labeling is not limited to radio-frequency saturation but can be expanded with slower frequency-selective approaches such as inversion, gradient dephasing and frequency labeling. The basic theory, design criteria, and experimental issues for exchange transfer imaging are discussed. A new classification for CEST agents based on exchange type is proposed. The potential of this young field is discussed, especially with respect to in vivo application and translation to humans.

Purpose Chemical exchange saturation transfer (CEST) imaging is a new MRI technology allowing the detection of low concentration endogenous cellular proteins and metabolites indirectly through their exchangeable protons. A new technique, variable delay multi-pulse CEST (VDMP-CEST), is proposed to eliminate the need for recording full Z-spectra and performing asymmetry analysis to obtain CEST contrast. Methods The VDMP-CEST scheme involves acquiring images with two (or more) delays between radiofrequency saturation pulses in pulsed CEST, producing a series of CEST images sensitive to the speed of saturation transfer. Subtracting two images or fitting a time series produces CEST and relayed-nuclear Overhauser enhancement CEST maps without effects of direct water saturation and, when using low radiofrequency power, minimal magnetization transfer contrast interference. Results When applied to several model systems (bovine serum albumin, crosslinked bovine serum albumin, l-glutamic acid) and in vivo on healthy rat brain, VDMP-CEST showed sensitivity to slow to intermediate range magnetization transfer processes (rate < 100–150 Hz), such as amide proton transfer and relayed nuclear Overhauser enhancement-CEST. Images for these contrasts could be acquired in short scan times by using a single radiofrequency frequency. Conclusions VDMP-CEST provides an approach to detect CEST effect by sensitizing saturation experiments to slower exchange processes without interference of direct water saturation and without need to acquire Z-spectra and perform asymmetry analysis.

The current study aims to assign and estimate the total creatine (tCr) signal contribution to the Z-spectrum in mouse brain at 11.7 Tesla. Creatine (Cr), phosphocreatine (PCr) and protein phantoms were used to confirm presence of a guanidinium resonance at this field strength. Wild type (WT) and knockout mice with Guanidinoacetate N-Methyltransferase deficiency (GAMT−/−) that have low Cr and PCr concentrations in the brain were used to assign the tCr contribution to the Z-spectrum. To estimate the total guanidinium concentrations, two pools for the Z-spectrum around 2 ppm were assumed: (i) a Lorentzian function representing the guanidinium CEST at 1.95 ppm in the 11.7 T Z-spectrum; (ii) a background signal that can be fitted by a polynomial function. Comparison between the WT and GAMT−/− mice provided strong evidence for three types of contributions to the peak in the Z-spectrum at 1.95 ppm, namely proteins, Cr and PCr, the latter fitted as tCr. A ratio of 20±7% (Protein) and 80±7% tCr was found in brain with 2 μT and 2 s saturation. Based on phantom experiments, the tCr peak was estimated to consist of about 83±5% Cr and 17±5% PCr. Maps for tCr of mouse brain were generated based on the peak at 1.95 ppm after concentration calibration with in vivo MRS.

Recent animal studies have shown that D-glucose is a potential biodegradable MRI contrast agent for imaging glucose uptake in tumors. Here, we show the first translation of that use of D-glucose to human studies. Chemical exchange saturation transfer (CEST) MRI at a single frequency offset optimized for detection of hydroxyl protons in D-glucose (glucoCEST) was used to image dynamic signal changes in the human brain at 7T during and after infusion of D-glucose. Dynamic glucose-enhanced (DGE) image data from four normal volunteers and three glioma patients showed strong signal enhancement in blood vessels, while the enhancement varied spatially over the tumor. Areas of enhancement differed spatially between DGE and conventional Gd-enhanced imaging, suggesting complementary image information content for these two types of agents. In addition, different tumor areas enhanced with D-glucose at different times post-infusion, suggesting a sensitivity to perfusion-related properties such as substrate delivery and blood-brain barrier (BBB) permeability. These preliminary results suggest that DGE MRI is feasible to study glucose uptake in humans, providing a time-dependent set of data that contains information regarding arterial input function (AIF), tissue perfusion, glucose transport across the BBB and cell membrane, and glucose metabolism.

Purpose To explore the relationship of APT and NOE signal intensities with respect to different World Health Organization (WHO) brain tumor grades (II to IV) at 7T. Materials and Methods APT-based and NOE-based signals at 7T using low-power steady-state CEST were compared among de novo primary gliomas of different WHO grades (II to IV). The quantitative APT and NOE signals, calculated by fitting approach using extrapolated semi-solid MT reference (EMR) signals, were compared with the magnetization transfer ratio asymmetry (MTRasym) analysis, commonly used in APT-weighted MRI. Results The observed NOE signals of all glioma grades were significantly lower than normal brain tissue (p < 0.01). NOE signals significantly differed between low-grade (II) gliomas and high-grade (III & IV) gliomas (p < 0.05). APT signals showed no difference between the tumor regions for any glioma grades (M = 3.08 %, 2.64 %, and 3.10 %, 95% CI = 2.81 % ~ 3.33 %, 2.36 % ~ 2.91 %, and 2.85 % ~ 3.36 % for grade II, III, and IV, respectively), and between normal brain tissue and all glioma grades (p = 0.08, M = 4.29 % and 2.94 %, 95% CI = 3.57 % ~ 4.99 % and 2.47 % ~ 3.41 % for normal and average grade II, III, and IV), while MTRasym differed significantly between normal tissue and all glioma grades (p < 0.05). Conclusion NOE contributes substantially to APT weighted MRI at 7T at low RF saturation power and provides a promising biomarker for glioma grading.

Glycogen plays a central role in glucose homeostasis and is abundant in several types of tissue. We report an MRI method for imaging glycogen noninvasively with enhanced detection sensitivity and high specificity, using the magnetic coupling between glycogen and water protons through the nuclear Overhauser enhancement (NOE). We show in vitro that the glycogen NOE (glycoNOE) signal is correlated linearly with glycogen concentration, while pH and temperature have little effect on its intensity. For validation, we imaged glycoNOE signal changes in mouse liver, both before and after fasting and during glucagon infusion. The glycoNOE signal was reduced by 88 ± 16% (n = 5) after 24 h of fasting and by 76 ± 22% (n = 5) at 1 h after intraperitoneal (i.p.) injection of glucagon, which is known to rapidly deplete hepatic glycogen. The ability to noninvasively image glycogen should allow assessment of diseases in which glucose metabolism or storage is altered, for instance, diabetes, cardiac disease, muscular disorders, cancer, and glycogen storage diseases.

Purpose To use the Variable Delay Multi-Pulse (VDMP) CEST approach to obtain clean Amide Proton Transfer (APT) and relayed Nuclear Overhauser (rNOE) Chemical Exchange Saturation Transfer (CEST) images in human brain by suppressing the conventional magnetization transfer contrast (MTC) and reducing the direct water saturation (DS) contribution. Methods The VDMP CEST scheme consists of a train of RF pulses with a specific mixing time. The CEST signal with respect to the mixing time shows distinguishable characteristics for protons with different exchange rates. Exchange rate filtered CEST images are generated by subtracting images acquired at two mixing times at which the MTC signals are equal, while the APT and rNOE-CEST signals differ. Since the subtraction is done at the same frequency offset for each voxel and the CEST signals are broad, no B0 correction is needed. Results MTC-suppressed APT and rNOE-CEST images of human brain were obtained using the VDMP method. The APT-CEST data shows hyper-intensity in gray matter versus white matter while the rNOE-CEST images show negligible contrast between gray and white matter. Conclusion The VDMP approach provides a simple and rapid way of recording MTC-suppressed APT-CEST and rNOE-CEST images without a need for B0 field correction.

The local presence and concentration of metal ions in biological systems has been extensively studied ex vivo using fluorescent dyes. However, the detection of multiple metal ions in vivo remains a major challenge. We present a magnetic resonance imaging (MRI)-based method for noninvasive detection of specific ions that may be coexisting, using the tetrafluorinated derivative of the BAPTA (TF-BAPTA) chelate as a 19F chelate analogue of existing optical dyes. Taking advantage of the difference in the ion-specific 19F nuclear magnetic resonance (NMR) chemical shift offset (Δω) values between the ion-bound and free TF-BAPTA, we exploited the dynamic exchange between ion-bound and free TF-BAPTA to obtain MRI contrast with multi-ion chemical exchange saturation transfer (miCEST). We demonstrate that TF-BAPTA as a prototype single 19F probe can be used to separately visualize mixed Zn2+ and Fe2+ ions in a specific and simultaneous fashion, without interference from potential competitive ions.