Chemical exchange saturation transfer (CEST) MRI has generated great interest for molecular imaging applications because it can image low‐concentration solute molecules in vivo with enhanced ...sensitivity. CEST effects are detected indirectly through a reduction in the bulk water signal after repeated perturbation of the solute proton magnetization using one or more radiofrequency (RF) irradiation pulses. The parameters used for these RF pulses—frequency offset, duration, shape, strength, phase, and interpulse spacing—determine molecular specificity and detection sensitivity, thus their judicious selection is critical for successful CEST MRI scans. This review article describes the effects of applying RF pulses on spin systems and compares conventional saturation‐based RF labeling with more recent excitation‐based approaches that provide spectral editing capabilities for selectively detecting molecules of interest and obtaining maximal contrast.
CEST MRI is a promising technique that measures low‐concentration metabolites with enhanced sensitivity by indirectly detecting the signal reduction of bulk water after applying RF irradiation pulses. However, the generated Z‐spectrum includes multiple signal components, which confounds quantitative analysis. The judicious selection of RF pulse parameters used can improve detection specificity and sensitivity. This review begins with the RF labeling effects on spin systems, and details broadly used approaches that are based on saturation, excitation, or hybrid form labeling.
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.
Magnetic resonance (MR) is a powerful technique for noninvasively probing molecular species in vivo but suffers from low signal sensitivity. Saturation transfer (ST) MRI approaches, including ...chemical exchange saturation transfer (CEST) and conventional magnetization transfer contrast (MTC), allow imaging of low‐concentration molecular components with enhanced sensitivity using indirect detection via the abundant water proton pool. Several recent studies have shown the utility of chemical exchange relayed nuclear Overhauser effect (rNOE) contrast originating from nonexchangeable carbon‐bound protons in mobile macromolecules in solution. In this review, we describe the mechanisms leading to the occurrence of rNOE‐based signals in the water saturation spectrum (Z‐spectrum), including those from mobile and immobile molecular sources and from molecular binding. While it is becoming clear that MTC is mainly an rNOE‐based signal, we continue to use the classical MTC nomenclature to separate it from the rNOE signals of mobile macromolecules, which we will refer to as rNOEs. Some emerging applications of the use of rNOEs for probing macromolecular solution components such as proteins and carbohydrates in vivo or studying the binding of small substrates are discussed.
Comparison of possible magnetization transfer pathways from tissue molecules to water. In addition to direct chemical exchange saturation transfer (CEST), three of these pathways include relayed nuclear Overhauser (rNOE) effects, leading to signals in the aliphatic frequency range of the water saturation spectrum (Z‐spectrum). These occur in mobile macromolecules, semisolid macromolecules (magnetization transfer contrast or MTC) and upon binding of ligands to immobile receptors (IMaging of MOlecular BInding using Ligand Immobilization and Saturation Exchange IMMOBILISE). Some emerging applications of the use of rNOEs for probing macromolecular solution components such as proteins and carbohydrates in vivo or studying the binding of small substrates are discussed.
Purpose
3‐O‐Methyl‐D‐glucose (3‐OMG) is a nonmetabolizable structural analog of glucose that offers potential to be used as a CEST‐contrast agent for tumor detection. Here, we explore it for ...CEST‐detection of malignant brain tumors and compare it with D‐glucose.
Methods
Glioma xenografts of a U87‐MG cell line were implanted in five mice. Dynamic 3‐OMG weighted images were collected using CEST‐MRI at 11.7 T at a single offset of 1.2 ppm, showing the effect of accumulation of the contrast agent in the tumor, following an intravenous injection of 3‐OMG (3 g/kg).
Results
Tumor regions showed higher enhancement as compared to contralateral brain. The CEST contrast enhancement in the tumor region ranged from 2.5‐5.0%, while it was 1.5‐3.5% in contralateral brain. Previous D‐glucose studies of the same tumor model showed an enhancement of 1.5‐3.0% and 0.5‐1.5% in tumor and contralateral brain, respectively. The signal gradually stabilized to a value that persisted for the length of the scan.
Conclusions
3‐OMG shows a CEST contrast enhancement that is approximately twice as much as that of D‐glucose for a similar tumor line. In view of its suggested low toxicity and transport properties across the BBB, 3‐OMG provides an option to be used as a nonmetallic contrast agent for evaluating brain tumors.
Purpose
Dynamic glucose enhanced (DGE) MRI has shown potential for imaging glucose delivery and blood–brain barrier permeability at fields of 7T and higher. Here, we evaluated issues involved with ...translating d‐glucose weighted chemical exchange saturation transfer (glucoCEST) experiments to the clinical field strength of 3T.
Methods
Exchange rates of the different hydroxyl proton pools and the field‐dependent T2 relaxivity of water in d‐glucose solution were used to simulate the water saturation spectra (Z‐spectra) and DGE signal differences as a function of static field strength B0, radiofrequency field strength B1, and saturation time tsat. Multislice DGE experiments were performed at 3T on 5 healthy volunteers and 3 glioma patients.
Results
Simulations showed that DGE signal decreases with B0, because of decreased contributions of glucoCEST and transverse relaxivity, as well as coalescence of the hydroxyl and water proton signals in the Z‐spectrum. At 3T, because of this coalescence and increased interference of direct water saturation and magnetization transfer contrast, the DGE effect can be assessed over a broad range of saturation frequencies. Multislice DGE experiments were performed in vivo using a B1 of 1.6 µT and a tsat of 1 second, leading to a small glucoCEST DGE effect at an offset frequency of 2 ppm from the water resonance. Motion correction was essential to detect DGE effects reliably.
Conclusion
Multislice glucoCEST‐based DGE experiments can be performed at 3T with sufficient temporal resolution. However, the effects are small and prone to motion influence. Therefore, motion correction should be used when performing DGE experiments at clinical field strengths.
Amide‐, amine‐, and hydroxyl‐water proton exchange can generate MRI contrast through chemical exchange saturation transfer (CEST). In this study, we show that thiol‐water proton exchange can also ...generate quantifiable CEST effects under near‐physiological conditions (pH = 7.2 and 37°C) through the characterization of the pH dependence of thiol proton exchange in phosphate‐buffered solutions of glutathione, cysteine, and N‐acetylcysteine. The spontaneous, base‐catalyzed, and buffer‐catalyzed exchange contributions to the thiol exchange were analyzed. The thiol‐water proton exchange of glutathione and cysteine was found to be too fast to generate a CEST effect around neutral pH due to significant base catalysis. The thiol‐water proton exchange of N‐acetylcysteine was found to be much slower, yet still in the fast‐exchange regime with significant base and buffer catalysis, resulting in a 9.5% attenuation of the water signal at pH 7.2 in a slice‐selective CEST NMR experiment. Furthermore, the N‐acetylcysteine thiol CEST was also detectable in human serum albumin and agarose phantoms.
In this study, we show that a CEST effect can be generated from thiol functional groups, and quantify their proton exchange in aqueous solutions. The thiol‐containing compounds used in this study were glutathione (GSH), cysteine (Cys), and N‐acetylcysteine (NAC). Of these three compounds, only NAC was found to elicit detectable thiol CEST (9.5%) at near‐physiological conditions (pH = 7.2 and 37°C). Furthermore, the NAC thiol CEST was detectable in human serum albumin and agarose phantoms.
Purpose
Acquisition of high‐resolution Z‐spectra for CEST or magnetization transfer contrast (MTC) MRI requires excessive scan times. Ultrafast Z‐spectroscopy (UFZ) has been proposed to address this; ...however, the quality of in vivo UFZ spectra has been insufficient. Here, we present a simple approach to improve this.
Theory and Methods
UFZ imaging acquires full Z‐spectra by encoding the spectral dimension spatially via a gradient applied concurrently with the RF saturation pulse. Different from previous implementations, both this saturation gradient and its readout were applied in the slice direction, resulting in a relatively uniform voxel composition. Phase‐encoding was applied in both in‐plane directions, allowing additional under‐sampling and acceleration.
Results
In phantoms, UFZ imaging with through‐slice Z‐spectral encoding (TS‐UFZ) provided Z‐spectra of salicylic acid and egg white in excellent agreement with conventional acquisitions. In vivo brain Z‐spectra were influenced by flow through the imaging slice which affected the Z‐spectral baseline. Still, CEST signals could be quantified after baseline fitting and mapping the residual CEST signal. Amide proton transfer (APT) contrast intensities obtained by TS‐UFZ were on the same order of magnitude as conventional CEST but with different contrast across slice which likely is a result of different tissue regions contributing.
Conclusion
TS‐UFZ approach improves signal stability and spectral uniformity over previous implementations and allows high spectral‐resolution imaging of saturation transfer effects in the human brain at 3T. This implementation allows for further acceleration by reducing phase encoding steps and thus opens up the possibility of mapping dynamic CEST signals in vivo with a practical temporal resolution.
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