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 non-exchangeable 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.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/nbm.4778

The relayed NOE mechanism in magnetization transfer and CEST MRI.

PURPOSE To optimize and apply deep neural network based CEST (deepCEST) and apparent exchange dependent-relaxation (deepAREX) for imaging the mouse brain with Alzheimer's disease (AD) at 3T MRI. METHODS CEST and T1 data of central and anterior brain slices of 10 AD mice and 10 age-matched wild type (WT) mice were acquired at a 3T animal MRI scanner. The networks of deepCEST/deepAREX were optimized and trained on the WT data. The CEST/AREX contrasts of AD and WT mice predicted by the networks were analyzed and further validated by immunohistochemistry. RESULTS After optimization and training on CEST data of WT mice, deepCEST/deepAREX could rapidly (~1 s) generate precise CEST and AREX results for unseen CEST data of AD mice, indicating the accuracy and generalization of the networks. Significant lower amide weighted (3.5 ppm) signal related to amyloid β-peptide (Aβ) plaque depositions, which was validated by immunohistochemistry results, was detected in both central and anterior brain slices of AD mice compared to WT mice. Decreased magnetization transfer (MT) signal was also found in AD mice especially in the anterior slice. CONCLUSION DeepCEST/deepAREX could rapidly generate accurate CEST/AREX contrasts in animal study. The well-optimized deepCEST/deepAREX have potential for AD differentiation at 3T MRI.

Deep neural network based CEST and AREX processing: Application in imaging a model of Alzheimer's disease at 3 T.

Chemical exchange saturation transfer (CEST) MRI has become a promising technique to assay target proteins and metabolites through their exchangeable protons, noninvasively. The ubiquity of creatine (Cr) and phosphocreatine (PCr) due to their pivotal roles in energy homeostasis through the creatine phosphate pathway has made them prime targets for CEST in the diagnosis and monitoring of disease pathologies, particularly in tissues heavily dependent on the maintenance of rich energy reserves. Guanidinium CEST from protein arginine residues (i.e. arginine CEST) can also provide information about the protein profile in tissue. However, numerous obfuscating factors stand as obstacles to the specificity of arginine, Cr, and PCr imaging through CEST, such as semisolid magnetization transfer, fast chemical exchanges such as primary amines, and the effects of nuclear Overhauser enhancement from aromatic and amide protons. In this review, the specific exchange properties of protein arginine residues, Cr, and PCr, along with their validation, are discussed, including the considerations necessary to target and tune their signal effects through CEST imaging. Additionally, strategies that have been employed to enhance the specificity of these exchanges in CEST imaging are described, along with how they have opened up possible applications of protein arginine residues, Cr and PCr CEST imaging in the study and diagnosis of pathology. A clear understanding of the capabilities and caveats of using CEST to image these vital metabolites and mitigation strategies is crucial to expanding the possibilities of this promising technology.

Chemical exchange saturation transfer imaging of creatine, phosphocreatine, and protein arginine residue in tissues

Chemical exchange saturation transfer (CEST) imaging is an emerging molecular magnetic resonance imaging (MRI) technique that has been developed and employed in numerous diseases. Based on the unique saturation transfer principle, a family of CEST‐detectable biomolecules in vivo have been found capable of providing valuable diagnostic information. However, CEST MRI needs a relatively long scan time due to the common long saturation labeling module and typical acquisition of multiple frequency offsets and signal averages, limiting its widespread clinical applications. So far, a plethora of imaging schemes and techniques has been developed to accelerate CEST MRI. In this review, the key acquisition and reconstruction methods for fast CEST imaging are summarized from a practical and systematic point of view. The first acquisition sequence section describes the major development of saturation schemes, readout patterns, ultrafast z‐spectroscopy, and saturation‐editing techniques for rapid CEST imaging. The second reconstruction method section lists the important advances of parallel imaging, compressed sensing, sparsity in the z‐spectrum, and algorithms beyond the Fourier transform for speeding up CEST MRI.

Acquisition sequences and reconstruction methods for fast chemical exchange saturation transfer imaging

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detects molecules in their natural forms in a sensitive and non-invasive manner. This makes it a robust approach to assess brain tumors and related molecular alterations using endogenous molecules, such as proteins/peptides, and drugs approved for clinical use. In this review, we will discuss the promises of CEST MRI in the identification of tumors, tumor grading, detecting molecular alterations related to isocitrate dehydrogenase (IDH) and O-6-methylguanine-DNA methyltransferase (MGMT), assessment of treatment effects, and using multiple contrasts of CEST to develop theranostic approaches for cancer treatments. Promising applications include (i) using the CEST contrast of amide protons of proteins/peptides to detect brain tumors, such as glioblastoma multiforme (GBM) and low-grade gliomas; (ii) using multiple CEST contrasts for tumor stratification, and (iii) evaluation of the efficacy of drug delivery without the need of metallic or radioactive labels. These promising applications have raised enthusiasm, however, the use of CEST MRI is not trivial. CEST contrast depends on the pulse sequences, saturation parameters, methods used to analyze the CEST spectrum (i.e., Z-spectrum), and, importantly, how to interpret changes in CEST contrast and related molecular alterations in the brain. Emerging pulse sequence designs and data analysis approaches, including those assisted with deep learning, have enhanced the capability of CEST MRI in detecting molecules in brain tumors. CEST has become a specific marker for tumor grading and has the potential for prognosis and theranostics in brain tumors. With increasing understanding of the technical aspects and associated molecular alterations detected by CEST MRI, this young field is expected to have wide clinical applications in the near future.

/pdf/molecular-imaging-of-brain-tumors-and-drug-delivery-using-1n66smbc.pdf

Molecular Imaging of Brain Tumors and Drug Delivery Using CEST MRI: Promises and Challenges

PURPOSE To develop a steady-state saturation with radial readout chemical exchange saturation transfer (starCEST) for acquiring CEST images at 3 Tesla (T). The polynomial Lorentzian line-shape fitting approach was further developed for extracting amideCEST intensities at this field. METHOD StarCEST MRI using periodically rotated overlapping parallel lines with enhanced reconstruction-based spatial sampling was implemented to acquire Z-spectra that are robust to brain motion. Multi-linear singular value decomposition postprocessing was applied to enhance the CEST SNR. The egg white phantom studies were performed at 3T to reveal the contributions to the 3.5 ppm CEST signal. Based on the phantom validation, the amideCEST peak was quantified using the polynomial Lorentzian line-shape fitting, which exploits the inverse relationship between Z-spectral intensity and the longitudinal relaxation rate in the rotating frame. The 3D turbo spin echo CEST was also performed to compare with the starCEST method. RESULTS The amideCEST peak showed a negligible peak B1 dependence between 1.2 µT and 2.4 µT. The amideCEST images acquired with starCEST showed much improved image quality, SNR, and motion robustness compared to the conventional 3D turbo spin echo CEST method with the same scan time. The amideCEST contrast extracted by the polynomial Lorentzian line-shape fitting method trended toward a stronger gray matter signal (1.32% ± 0.30%) than white matter (0.92% ± 0.08%; P = .02, n = 5). When calculating the magnetization transfer contrast and T1 -corrected rotating frame relaxation rate maps, amideCEST again was not significantly different for white matter and gray matter. CONCLUSION Rapid multi-slice amideCEST mapping can be achieved by the starCEST method (< 5 min) at 3T by combing with the polynomial Lorentzian line-shape fitting method.

Whole-brain amide CEST imaging at 3T with a steady-state radial MRI acquisition.

Purpose To develop a pipeline for measuring the exchange rates and concentrations of in vivo excgangeable protons, and to demonstrate this for the amide and arginine (Arg) guanidinium (Guan) protons in mobile proteins in the mouse brain. Methods An ultra-short echo (UTE) CEST sequence with a continuous wave presaturation (preRadCEST) was applied to acquire Z-spectra with robustness to motion and physiological fluctuations. AmideCEST and Arginine guanCEST (ArgCEST) were extracted and their proton concentrations and exchange rates obtained using a two-step multi-B1 Bloch fitting approach that included the semisolid macromolecular background. To minimize contamination from the amine protons from creatine and phosphocreatine, ArgCEST measurements were performed on the Guanidinoacetate N-methyltransferase deficiency (GAMT-/-) mouse characterized by low creatine and phosphocreatine concentrations in the brain. Results For the amideCEST proton pool, the exchange rate and concentrations were found to be 59.6 ± 9.0 s-1 and 41.7 ± 7.0 mM, respectively, with the maximum signal observed at B1 = 0.8 μT. For the ArgCEST proton, the guanidinium exchange these were 70.1 ± 5.5 s-1 and 10.1 ± 1.3 mM, respectively, with the maximum effect observed at B1 = 0.9 μT. The current study suggests that the inverse pH dependence in GuanCEST of brain is led by the CrCEST component, not ArgCEST. Conclusion The current pipeline is expected to have general use for in vivo CEST quantitation and optimization of visible CEST resonances.

/pdf/the-exchange-rates-of-amide-and-arginine-guanidinium-cest-in-2x2246t7.pdf

The exchange rates of amide and arginine guanidinium CEST in the mouse brain

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Whole-brain amide CEST imaging at 3T with a steady-state radial MRI acquisition.

The exchange rates of amide and arginine guanidinium CEST in the mouse brain