Pulse sequences for measuring exchange rates between proton species: From unlocalised NMR spectroscopy to chemical exchange saturation transfer imaging

Within the field of NMR spectroscopy, the study of chemical exchange processes through saturation transfer techniques has a long history. In the context of MRI, chemical exchange techniques have been adapted to increase the sensitivity of imaging to small fractions of exchangeable protons, including the labile protons of amines, amides and hydroxyls. The MR contrast is generated by frequency-selective irradiation of the labile protons, which results in a reduction of the water signal associated with transfer of the labile protons’ saturated magnetization to the protons of the surrounding free water. The signal intensity depends on the rate of chemical exchange and the concentration of labile protons as well as on the properties of the irradiation field. This methodology is referred to as CEST (chemical exchange saturation transfer) imaging. Applications of CEST include imaging of molecules with short transverse relaxation times and mapping of physiological parameters such as pH, temperature, buffer concentration and chemical composition due to the dependency of this chemical exchange effect on all these parameters. This article aims to describe these effects both theoretically and experimentally. In depth analysis and mathematical modelling are provided for all pulse sequences designed to date to measure the chemical exchange rate. Importantly, it has become clear that the background signal from semi-solid protons and the presence of the Nuclear Overhauser Effect (NOE), either through direct dipole-dipole mechanisms or through exchange-relayed signals, complicates the analysis of CEST effects. Therefore, advanced methods to suppress these confounding factors have been developed, and these are also reviewed. Finally, the experimental work conducted both in vitro and in vivo is discussed and the progress of CEST imaging towards clinical practice is presented

Exchange-dependent relaxation in the rotating frame for slow and intermediate exchange - modeling off-resonant spin-lock and chemical exchange saturation transfer

Chemical exchange observed by NMR saturation transfer (CEST) and spin-lock (SL) experiments provide an MRI contrast by indirect detection of exchanging protons. The determination of the relative concentrations and exchange rates is commonly achieved by numerical integration of the Bloch-McConnell equations. We derive an analytical solution of the Bloch-McConnell equations that describes the magnetization of coupled spin populations under radiofrequency irradiation.As CEST and off-resonant SL are equivalent, their steady-state magnetization and dynamics can be predicted by the same single eigenvalue: the longitudinal relaxation rate in the rotating frame R1rho. For the case of slowly exchanging systems, e.g. amide protons, the saturation of the small proton pool is affected by transverse relaxation (R2b). It turns out, that R2b is also significant for intermediate exchange, such as amine- or hydroxyl-exchange or paramagnetic CEST agents, if pools are only partially saturated. We propose a solution for R1rho that includes R2 of the exchanging pool by extending existing approaches, and verify it by numerical simulations. With the appropriate projection factors, we obtain an analytical solution for CEST and SL for nonzero R2 of the exchanging pool, whilst considering the dilution by direct water saturation across the entire Z-spectra. This allows the optimization of irradiation parameters and the quantification of pH-dependent exchange rates and metabolite concentrations. In addition, we propose evaluation methods that correct for concomitant direct saturation effects. It is shown that existing theoretical treatments for CEST are special cases of this approach

Characterization of amine proton exchange for analyzing the specificity and intensity of the CEST effect: from humans to fish

Chemical exchange saturation transfer (CEST) at about 2.8 ppm downfield from water is characterized besides other compounds by exchanging amine protons of relatively high concentration amino acids and is determined by several physiological (pH, T) and experimental (B0, B1, tsat) parameters. Although the weighting of the CEST effect observed in vivo can be attributed mainly to one compound depending on the organism and organ, there are still several other amino acids, proteins and molecules that also contribute. These contributions in turn exhibit dependences and thus can lead to possible misinterpretation of the measured changes in the CEST effect. With this in mind, this work aimed to determine the exchange rates of six important amino acids as a function of pH and temperature, and thus to create multi-pool models that allow the accurate analysis of the CEST effect concerning different physiological and experimental parameters for a wide variety of organisms. The results show that small changes in the above parameters have a significant impact on the CEST effect at about 2.8 ppm for the chosen organisms, i.e. the human brain (37 °C) and the brain of polar cod (1.5 °C), furthermore, the specificity of the CEST effect observed in vivo can be significantly affected. Based on the exchange rates ksw(pH, T) determined for six metabolites in this study, it is possible to optimize the intensity and the specificity for the CEST effect of amino acids at about 2.8 ppm for different organisms with their specific physiological characteristics. By adjusting experimental parameters accordingly, this optimization will help to avoid possible misinterpretations of CEST measurements. Furthermore, the multi-pool models can be utilized to further optimize the saturation

Dynamic glucose enhanced chemical exchange saturation transfer MRI : Optimization of methodology and characterization of cerebral transport kinetics

Dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) MRI is an emerging imaging technique that provides a molecular-specific type of image contrast, based on magnetic labelling of exchangeable protons. The technique enables the use of biodegradable sugars as contrast agents, and such compounds are believed to have less side effects than conventional MRI contrast agents. However, as with most novel techniques, DGE MRI is associated with technical challenges, including small contrast enhancement compared to conventional techniques, sensitivity to motion and long scan durations. Therefore, DGE MRI is not yet ready for clinical implementation, and further evaluation and methodological development are required. The focus of the work presented in this thesis has been on the optimization and development of DGE MRI in humans. We first implemented the DGE MRI technique at 7 T for evaluation in healthy volunteers, and subsequently optimized and applied the DGE imaging protocol at 3 T. We demonstrated that it is possible to measure arterial input functions using DGE MRI data, and that the arterial DGE MRI signal is correlated to the venous blood glucose level. Our experiments also showed that the glucose infusion duration should preferably be prolonged to minimize the sensory side effects of the injection. We also evaluated and compared DGE MRI tissue response curves in healthy tissue and in brain tumours and confirmed that DGE MRI enables differentiation of tumour from normal tissue, but that motion-related artefacts may complicate the interpretation. We developed a post-processing method for DGE MRI based on visualization of tissue response curve types with different characteristic temporal enhancement patterns. Finally, we developed a model for kinetic analysis of DGE MRI, accounting for the different signal origin and uptake kinetics of normal D-glucose. In summary, DGE MRI has potential for tumour detection in humans and can provide information on glucose delivery, transport, and metabolism. However, further optimization of imaging and post-processing techniques is necessary, especially at lower field strengths