Elena Vinogradov

High-resolution proton solid-state NMR spectroscopy by phase-modulated Lee–Goldburg experiment

Abstract In this Letter, we present a pulse scheme for coherent averaging of spin–spin interactions called phase-modulated Lee–Goldburg (PMLG) which is aimed at achieving high-resolution proton NMR spectra in the solid state. Our objective is mainly to discuss the design and execution of this experiment and to show some preliminary experimental results as evidence of the far-reaching potentials of this technique.

CEST: From basic principles to applications, challenges and opportunities

Chemical Exchange Saturation Transfer (CEST) offers a new type of contrast for MRI that is molecule specific. In this approach, a slowly exchanging NMR active nucleus, typically a proton, possessing a chemical shift distinct from water is selectively saturated and the saturated spin is transferred to the bulk water via chemical exchange. Many molecules can act as CEST agents, both naturally occurring endogenous molecules and new types of exogenous agents. A large variety of molecules have been demonstrated as potential agents, including small diamagnetic molecules, complexes of paramagnetic ions, endogenous macromolecules, dendrimers and liposomes. In this review we described the basic principles of the CEST experiment, with emphasis on the similarity to earlier saturation transfer experiments described in the literature. Interest in quantitative CEST has also resulted in the development of new exchange-sensitive detection schemes. Some emerging clinical applications of CEST are described and the challenges and opportunities associated with translation of these methods to the clinical environment are discussed.

A Concentration-Independent Method to Measure Exchange Rates in PARACEST Agents

The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determined by their water or proton exchange kinetics, yet methods to measure such exchange rates are variable and many are not applicable to in vivo measurements. In this work, the water exchange kinetics of two prototype paramagnetic agents (PARACEST) are compared by using data from classic NMR line‐width measurements, by fitting CEST spectra to the Bloch equations modified for chemical exchange, and by a method where CEST intensity is measured as a function of applied amplitude of radiofrequency field. A relationship is derived that provides the water exchange rate from the X‐intercept of a plot of steady‐state CEST intensity divided by reduction in signal caused by CEST irradiation versus 1/ω12, referred to here as an omega plot. Furthermore, it is shown that this relationship is independent of agent concentration. Exchange rates derived from omega plots using either high‐resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and line‐width methods. Thus, this new method potentially allows access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown. Magn Reson Med 63:625–632, 2010.

Proton spectroscopy in solid state nuclear magnetic resonance with windowed phase modulated Lee-Goldburg decoupling sequences

We demonstrate here a new windowed multiple pulse sequence for the detection of protons in solid state NMR. Acquisition windows are inserted in the phase modulated Lee–Goldburg scheme (PMLG). This enables one-dimensional acquisition as against two-dimensional in windowless schemes. The pulse scheme, theoretical justifications and experimental spectra of a few samples are presented. In addition two-dimensional proton–proton and carbon–proton correlation experiments are performed with windowed PMLG proton detection.

Phase modulated Lee-Goldburg magic angle spinning proton nuclear magnetic resonance experiments in the solid state: A bimodal Floquet theoretical treatment

Interference phenomena between sample spinning and radio frequency (RF) irradiation in solid state high resolution proton nuclear magnetic resonance (NMR) spectroscopy are examined. A bimodal Floquet treatment is exploited in order to overcome the limitations of the average Hamiltonian theory (AHT) approach. Frequency switched Lee Goldburg (FSLG) and its variant, phase modulated Lee Goldburg (PMLG-n), homonuclear dipolar decoupling experiments on protons that are rotating at the magic angle are examined. Average Hamiltonian theory (AHT) is used for the synchronous application of FSLG and PMLG-n RF sequences with the sample spinning. A bimodal Floquet approach is introduced to treat both synchronous and nonsynchronous cases. The Floquet approach, providing a general theoretical framework for describing rotating spin systems exposed to periodically applied RF field, reveals several features of the interference between the sample spinning and the RF irradiation. These features can be characterized by mapping...

CEST and PARACEST MR contrast agents

In this review we describe the status of development for a new class of magnetic resonance (MR) contrast agents, based on chemical exchange saturation transfer (CEST). The mathematics and physics relevant to the description of the CEST effect in MR are presented in an appendix published in the online version only. We discuss the issues arising when translating in vitro results obtained with CEST agents to using these MR agents in in vivo model studies and in humans. Examples are given on how these agents are imaged in vivo. We summarize the status of development of these CEST agents, and speculate about the next steps that may be taken towards the demonstration of CEST MR imaging in clinical applications.

Amide proton transfer imaging with improved robustness to magnetic field inhomogeneity and magnetization transfer asymmetry using saturation with frequency alternating RF irradiation

Amide proton transfer (APT) imaging has shown promise as an indicator of tissue pH and as a marker for brain tumors. Sources of error in APT measurements include direct water saturation, and magnetization transfer (MT) from membranes and macromolecules. These are typically suppressed by postprocessing asymmetry analysis. However, this approach is strongly dependent on B0 homogeneity and can introduce additional errors due to intrinsic MT asymmetry, aliphatic proton features opposite the amide peak and radiation damping‐induced asymmetry. Although several methods exist to correct for B0 inhomogeneity, they tremendously increase scan times and do not address errors induced by asymmetry of the z‐spectrum. In this article, a novel saturation scheme—saturation with frequency alternating RF irradiation (SAFARI)—is proposed in combination with a new magnetization transfer ratio (MTR) parameter designed to generate APT images insensitive to direct water saturation and MT, even in the presence of B0 inhomogeneity. The feasibility of the SAFARI technique is demonstrated in phantoms and in the human brain. Experimental results show that SAFARI successfully removes direct water saturation and MT contamination from APT images. It is insensitive to B0 offsets up to 180 Hz without using additional B0 correction, thereby dramatically reducing scanning time. Magn Reson Med, 2011.

A bimodal Floquet analysis of phase modulated Lee-Goldburg high resolution proton magic angle spinning NMR experiments

A description of phase modulated Lee–Goldburg experiments PMLG-n, with 2n pulses per rf cycle, on coupled proton systems under magic angle spinning is presented using bimodal Floquet theory. Level crossing conditions between Floquet states are derived and perturbation theory is used to account for spectral changes as a function of the spinning frequency and the number of pulses per PMLG-n sequence. High resolution solid-state proton spectra are shown that are obtained for n equal to 9, 5 and 3. Line broadening and the rf rotor frequency line positions are correlated to level anticrossings.

Strategies for High-Resolution Proton Spectroscopy in Solid-State NMR

We describe radiofrequency (RF) pulse schemes in solid-state NMR applied to samples rotating at the magic angle (MAS) to obtain high-resolution (1)H spectra. Without combined RF schemes and MAS, (1)H spectra are normally severely broadened by the strong homonuclear proton-proton dipolar couplings. This review gives an outline of a representative class of multiple-pulse sequences, designed to work with and without MAS, and commonly used for high-resolution proton spectroscopy in solid-state NMR. We give a theoretical treatment of these sequences based on Floquet theory, both single-mode and bimodal. Using this approach, we define first-order homonuclear decoupling efficiency parameters which provide the line-narrowing characteristics of the various pulse sequences when applied to fast rotating samples. These parameters are used to compare the line-narrowing efficiencies of the multiple-pulse schemes.

MRI detection of paramagnetic chemical exchange effects in mice kidneys in vivo

In this report, the On resonance PARamagnetic CHemical Exchange Effects (OPARACHEE) method was implemented in vivo using WALTZ‐16* as a preparation pulse with a standard spin echo sequence to detect the accumulation and clearance of the TmDOTA‐4AmC− in mouse kidney. The performance of the technique in vivo is described in terms of the magnitude of the contrast effect versus the bolus agent concentration and signal‐to‐noise ratio (SNR) levels. The lowest injected concentration of TmDOTA‐4AmC−, 200 μL of a 2‐mM stock solution (corresponds to ∼0.2 mM agent in plasma), reduced the total water signal in the kidney papilla by 45% 3 min after the a bolus injection. The results show that the OPARACHEE methodology employing low‐amplitude RF trains can detect paramagnetic exchanging agents in vivo. Magn Reson Med 58:650–655, 2007.