While carbon dots (C‐dots) have been extensively investigated pertaining to their fluorescent, phosphorescent, electrochemiluminescent, optoelectronic, and catalytic features, their inherent chemical ...exchange saturation transfer magnetic resonance imaging (CEST MRI) properties are unknown. By virtue of their hydrophilicity and abundant exchangeable protons of hydroxyl, amine, and amide anchored on the surface, we report here that C‐dots can be adapted as effective diamagnetic CEST (diaCEST) MRI contrast agents. As a proof‐of‐concept demonstration, human glioma cells were labeled with liposomes with or without encapsulated C‐dots and implanted in mouse brain. In vivo CEST MRI was able to clearly differentiate labeled cells from non‐labeled cells. The present findings may encourage new applications of C‐dots for in vivo imaging in deep tissues, which is currently not possible using conventional fluorescent (near‐infrared) C‐dots.
Think differently: Metal‐free carbon dots (C‐dots) can be used as magnetic resonance imaging (MRI) agents owing to the chemical exchange of surface‐anchored protons with water. This inherent chemical exchange saturation transfer (CEST) magnetic resonance property of C‐dots enables them to be visualized in vivo in deep tissues.
Amide proton transfer‐weighted (APTw) imaging is a molecular MRI technique that generates image contrast based predominantly on the amide protons in mobile cellular proteins and peptides that are ...endogenous in tissue. This technique, the most studied type of chemical exchange saturation transfer imaging, has been used successfully for imaging of protein content and pH, the latter being possible due to the strong dependence of the amide proton exchange rate on pH. In this article we briefly review the basic principles and recent technical advances of APTw imaging, which is showing promise clinically, especially for characterizing brain tumors and distinguishing recurrent tumor from treatment effects. Early applications of this approach to stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury are also illustrated. Finally, we outline the technical challenges for clinical APT‐based imaging and discuss several controversies regarding the origin of APTw imaging signals in vivo.
Level of Evidence: 3
Technical Efficacy Stage: 3
J. Magn. Reson. Imaging 2019;50:347–364.
The purpose of this paper is to extend the single-subject Eve atlas from Johns Hopkins University, which currently contains diffusion tensor and T1-weighted anatomical maps, by including contrast ...based on quantitative susceptibility mapping. The new atlas combines a “deep gray matter parcellation map” (DGMPM) derived from a single-subject quantitative susceptibility map with the previously established “white matter parcellation map” (WMPM) from the same subject's T1-weighted and diffusion tensor imaging data into an MNI coordinate map named the “Everything Parcellation Map in Eve Space,” also known as the “EvePM.” It allows automated segmentation of gray matter and white matter structures. Quantitative susceptibility maps from five healthy male volunteers (30 to 33years of age) were coregistered to the Eve Atlas with AIR and Large Deformation Diffeomorphic Metric Mapping (LDDMM), and the transformation matrices were applied to the EvePM to produce automated parcellation in subject space. Parcellation accuracy was measured with a kappa analysis for the left and right structures of six deep gray matter regions. For multi-orientation QSM images, the Kappa statistic was 0.85 between automated and manual segmentation, with the inter-rater reproducibility Kappa being 0.89 for the human raters, suggesting “almost perfect” agreement between all segmentation methods. Segmentation seemed slightly more difficult for human raters on single-orientation QSM images, with the Kappa statistic being 0.88 between automated and manual segmentation, and 0.85 and 0.86 between human raters. Overall, this atlas provides a time-efficient tool for automated coregistration and segmentation of quantitative susceptibility data to analyze many regions of interest. These data were used to establish a baseline for normal magnetic susceptibility measurements for over 60 brain structures of 30- to 33-year-old males. Correlating the average susceptibility with age-based iron concentrations in gray matter structures measured by Hallgren and Sourander (1958) allowed interpolation of the average iron concentration of several deep gray matter regions delineated in the EvePM.
Display omitted
•We added a Quantitative Susceptibility Mapping (QSM) template to the Eve atlas.•We utilized MRI Studio software to coregister QSM images to the Eve atlas.•Automated segmentation took less than 24h for over sixty brain regions.•We derived a susceptibility-iron calibration curve based on known iron values.•This curve was used to determine iron concentration in other gray matter regions.
Magnetization Transfer Contrast (MTC) and Chemical Exchange Saturation Transfer (CEST) experiments measure the transfer of magnetization from molecular protons to the solvent water protons, an effect ...that becomes apparent as an MRI signal loss (“saturation”). This allows molecular information to be accessed with the enhanced sensitivity of MRI. In analogy to Magnetic Resonance Spectroscopy (MRS), these saturation data are presented as a function of the chemical shift of participating proton groups, e.g. OH, NH, NH2, which is called a Z-spectrum. In tissue, these Z-spectra contain the convolution of multiple saturation transfer effects, including nuclear Overhauser enhancements (NOEs) and chemical exchange contributions from protons in semi-solid and mobile macromolecules or tissue metabolites. As a consequence, their appearance depends on the magnetic field strength (B0) and pulse sequence parameters such as B1 strength, pulse shape and length, and interpulse delay, which presents a major problem for quantification and reproducibility of MTC and CEST effects.
The use of higher B0 can bring several advantages. In addition to higher detection sensitivity (signal-to-noise ratio, SNR), both MTC and CEST studies benefit from longer water T1 allowing the saturation transferred to water to be retained longer. While MTC studies are non-specific at any field strength, CEST specificity is expected to increase at higher field because of a larger chemical shift dispersion of the resonances of interest (similar to MRS). In addition, shifting to a slower exchange regime at higher B0 facilitates improved detection of the guanidinium protons of creatine and the inherently broad resonances of the amine protons in glutamate and the hydroxyl protons in myoinositol, glycogen, and glucosaminoglycans. Finally, due to the higher mobility of the contributing protons in CEST versus MTC, many new pulse sequences can be designed to more specifically edit for CEST signals and to remove MTC contributions.
•Basics of nuclear Overhauser enhancement (NOE) and chemical exchange saturation transfer (CEST).•Comprehensive description of the features of the endogenous saturation spectrum (Z-spectrum) in MRI.•Explanation of advantages of using higher magnetic field for CEST MRI.•Critical assessment of CEST data analysis approaches.•Critical assessment of early CEST applications for the brain.
Detection of glycogen in vivo would have utility in the study of normal physiology and many disorders. Presently, the only magnetic resonance (MR) method available to study glycogen metabolism in ...vivo is ¹³C MR spectroscopy, but this technology is not routinely available on standard clinical scanners. Here, we show that glycogen can be detected indirectly through the water signal by using selective radio frequency (RF) saturation of the hydroxyl protons in the 0.5- to 1.5-ppm frequency range downfield from water. The resulting saturated spins are rapidly transferred to water protons via chemical exchange, leading to partial saturation of the water signal, a process now known as chemical exchange saturation transfer. This effect is demonstrated in glycogen phantoms at magnetic field strengths of 4.7 and 9.4 T, showing improved detection at higher field in adherence with MR exchange theory. Difference images obtained during RF irradiation at 1.0 ppm upfield and downfield of the water signal showed that glycogen metabolism could be followed in isolated, perfused mouse livers at 4.7 T before and after administration of glucagon. Glycogen breakdown was confirmed by measuring effluent glucose and, in separate experiments, by ¹³C NMR spectroscopy. This approach opens the way to image the distribution of tissue glycogen in vivo and to monitor its metabolism rapidly and noninvasively with MRI.
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.
The classic definition of the ischemic penumbra is a hypoperfused region in which metabolism is impaired, but still sufficient to maintain cellular polarization. Perfusion- and diffusion-weighted MRI ...(PWI, DWI) can identify regions of reduced perfusion and cellular depolarization, respectively, but it often remains unclear whether a PWI—DWI mismatch corresponds to benign oligemia or a true penumbra. We hypothesized that pH-weighted MRI (pHWI) can subdivide the PWI—DWI mismatch into these regions. Twenty-one rats underwent permanent middle cerebral artery occlusion and ischemic evolution over the first 3.5 h post-occlusion was studied using multiparametric MRI. End point was the stroke area defined by T2-hyperintensity at 24 h. In the acute phase, areas of reduced pH were always larger than or equal to DWI deficits and smaller than or equal to PWI deficits. Group analysis showed that pHWI deficits during this phase coincided with the resulting infarct area at endpoint. Final infarcts were smaller than PWI deficits (range 65% to 90%, depending on the severity of the occlusion) and much larger than acute DWI deficits. These data suggest that the outer boundary of the hypoperfused area showing a decrease in pH without DWI abnormality may correspond to the outer boundary of the ischemic penumbra, while the hypoperfused region at normal pH may correspond to benign oligemia. These first results show that pHWI can provide information complementary to PWI and DWI in the delineation of ischemic tissue.
Purpose
To obtain high‐resolution Cr and PCr maps of mouse skeletal muscle using a polynomial and Lorentzian line‐shape fitting (PLOF) CEST method.
Methods
Wild‐type mice and guanidinoacetate ...N‐methyltransferase–deficient (GAMT‐/‐) mice that have low Cr and PCr concentrations in muscle were used to assign the Cr and PCr peaks in the Z‐spectrum at 11.7 T. A PLOF method was proposed to simultaneously extract and quantify the Cr and PCr by assuming a polynomial function for the background and 2 Lorentzian functions for the CEST peaks at 1.95 ppm and 2.5 ppm.
Results
The Z‐spectra of phantoms revealed that PCr has 2 CEST peaks (2 ppm and 2.5 ppm), whereas Cr only showed 1 peak at 2 ppm. Comparison of the Z‐spectra of wild‐type and GAMT‐/‐ mice indicated that, contrary to brain, there was no visible protein guanidinium peak in the skeletal‐muscle Z‐spectrum, which allowed us to extract clean PCr and Cr CEST signals. High‐resolution PCr and Cr concentration maps of mouse skeletal muscle were obtained by the PLOF CEST method after calibration with in vivo MRS.
Conclusions
The PLOF method provides an efficient way to map Cr and PCr concentrations simultaneously in the skeletal muscle at high MRI field.
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.
PDF
