Fluid suppression in amide proton transfer-weighted (APTw) CEST imaging: New theoretical insights and clinical benefits.

PURPOSE: Amide proton transfer-weighted (APTw) MRI at 3T provides a unique contrast for brain tumor imaging. However, APTw imaging suffers from hyperintensities in liquid compartments such as cystic or necrotic structures and provides a distorted APTw signal intensity. Recently, it has been shown that heuristically motivated fluid suppression can remove such artifacts and significantly improve the readability of APTw imaging. THEORY AND METHODS: In this work, we show that the fluid suppression can actually be understood by the known concept of spillover dilution, which itself can be derived from the Bloch-McConnell equations in comparison to the heuristic approach. Therefore, we derive a novel post-processing formula that efficiently removes fluid artifact, and explains previous approaches. We demonstrate the utility of this APTw assessment in silico, in vitro, and in vivo in brain tumor patients acquired at MR scanners from different vendors. RESULTS: Our results show a reduction of the CEST signals from fluid environments while keeping the APTw-CEST signal intensity almost unchanged for semi-solid tissue structures such as the contralateral normal appearing white matter. This further allows us to use the same color bar settings as for conventional APTw imaging. CONCLUSION: Fluid suppression has considerable value in improving the readability of APTw maps in the neuro-oncological field. In this work, we derive a novel post-processing formula from the underlying Bloch-McConnell equations that efficiently removes fluid artifact, and explains previous approaches which justify the derivation of this metric from a theoretical point of view, to reassure the scientific and medical field about its use.

Sidebands in CEST MR-How to recognize and avoid them.

PURPOSE: Clinical scanners require pulsed CEST sequences to maintain amplifier and specific absorption rate limits. During off-resonant RF irradiation and interpulse delay, the magnetization can accumulate specific relative phases within the pulse train. In this work, we show that these phases are important to consider, as they can lead to unexpected artifacts when no interpulse gradient spoiling is performed during the saturation train. METHODS: We investigated sideband artifacts using a CEST-3D snapshot gradient-echo sequence at 3 T. Initially, Bloch-McConnell simulations were carried out with Pulseq-CEST, while measurements were performed in vitro and in vivo. RESULTS: Sidebands can be hidden in Z-spectra, and their structure becomes clearly visible only at high sampling. Sidebands are further influenced by B0 inhomogeneities and the RF phase cycling within the pulse train. In vivo, sidebands are mostly visible in liquid compartments such as CSF. Multi-pulse sidebands can be suppressed by interpulse gradient spoiling. CONCLUSION: We provide new insights into sidebands occurring in pulsed CEST experiments and show that, similar as in imaging sequences, gradient and RF spoiling play an important role. Gradient spoiling avoids misinterpretations of sidebands as CEST effects especially in liquid environments including pathological tissue or for CEST resonances close to water. It is recommended to simulate pulsed CEST sequences in advance to avoid artifacts.

Applications of chemical exchange saturation transfer magnetic resonance imaging in identifying genetic markers in gliomas.

Chemical exchange saturation transfer (CEST) imaging is an important molecular magnetic resonance imaging technique that can image numerous low-concentration biomolecules with water-exchangeable protons (such as cellular proteins) and tissue pH. CEST, or more specially amide proton transfer-weighted imaging, has been widely used for the detection, diagnosis, and response assessment of brain tumors, and its feasibility in identifying molecular markers in gliomas has also been explored in recent years. In this paper, after briefing on the basic principles and quantification methods of CEST imaging, we review its early applications in identifying isocitrate dehydrogenase mutation status, MGMT methylation status, 1p/19q deletion status, and H3K27M mutation status in gliomas. Finally, we discuss the limitations or weaknesses in these studies.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.

Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH.

Cancer cells are characterized by a metabolic shift in cellular energy production, orchestrated by the transcription factor HIF-1α, from mitochondrial oxidative phosphorylation to increased glycolysis, regardless of oxygen availability (Warburg effect). The constitutive upregulation of glycolysis leads to an overproduction of acidic metabolic products, resulting in enhanced acidification of the extracellular pH (pHe ~ 6.5), which is a salient feature of the tumor microenvironment. Despite the importance of pH and tumor acidosis, there is currently no established clinical tool available to image the spatial distribution of tumor pHe. The purpose of this review is to describe various imaging modalities for measuring intracellular and extracellular tumor pH. For each technique, we will discuss main advantages and limitations, pH accuracy and sensitivity of the applied pH-responsive probes and potential translatability to the clinic. Particular attention is devoted to methods that can provide pH measurements at high spatial resolution useful to address the task of tumor heterogeneity and to studies that explored tumor pH imaging for assessing treatment response to anticancer therapies.

Free-base porphyrins as CEST MRI contrast agents with highly upfield shifted labile protons.

PURPOSE: CEST has become a preeminent technology for the rapid detection and grading of tumors, securing its widespread use in both laboratory and clinical research. However, many existing CEST MRI agents exhibit a sensitivity limitation due to small chemical shifts between their exchangeable protons and water. We propose a new group of CEST MRI agents, free-base porphyrins and chlorin, with large exchangeable proton chemical shifts from water for enhanced detection. METHODS: To test these newly identified CEST agents, we acquired a series of Z-spectra at multiple pH values and saturation field strengths to determine their CEST properties. The data were analyzed using the quantifying exchange using saturation power method to quantify exchange rates. After identifying several promising candidates, a porphyrin solution was injected into tumor-bearing mice, and MR images were acquired to assess detection feasibility in vivo. RESULTS: Based on the Z-spectra, the inner nitrogen protons in free-base porphyrins and chlorin resonate from -8 to -13.5 ppm from water, far shifted from the majority of endogenous metabolites (0-4 ppm) and Nuclear Overhauser enhancements (-1 to -3.5 ppm) and far removed from the salicylates, imidazoles, and anthranillates (5-12 ppm). The exchange rates are sufficiently slow to intermediate (500-9000 s-1 ) to allow robust detection and were sensitive to substituents on the porphyrin ring. CONCLUSION: These results highlight the capabilities of free-base porphyrins and chlorin as highly upfield CEST MRI agents and provide a new scaffold that can be integrated into a variety of diagnostic or theranostic agents for biomedical applications.

CEST MRI of 3-O-methyl-D-glucose uptake and accumulation in brain tumors.

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.

APT-weighted MRI: Techniques, current neuro applications, and challenging issues.

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.

Selecting the reference image for registration of CEST series.

BACKGROUND: To compare different reference images selected for registration among chemical exchange saturation transfer (CEST) series. MATERIALS AND METHODS: Five normal volunteers and eight brain tumor patients were studied on a 3 Tesla scanner. Image registration was performed by choosing each of the acquired CEST saturation or unsaturation dynamic images as the reference. CEST images at 3.5 ppm (amide proton transfer, APT) were computed for each motion-corrected data set after main magnetic field inhomogeneity correction. A uniformity index was defined to quantify the efficacy of image registration using different reference images. Joint histograms and the structural similarity index (SSIM) were used to analyze the intrinsic image similarity between various dynamic images. RESULTS: Image registration increased the average uniformity index by 18% if the 3.5 ppm saturated image was selected as the reference image. However, registering to the unsaturated dynamic image reduced the uniformity index by 13% on average. The joint histogram analysis showed that the saturated dynamic images were highly similar (SSIM = 0.89 ± 0.01), and were considerably different from the unsaturated dynamic image (SSIM = 0.58 ± 0.03). CONCLUSION: The selection of the 3.5 ppm dynamic image as the reference image generated the highest uniformity index for APT imaging though other saturated images were equally suited as reference images.

[Functional MRI 2.0. ²³Na and CEST imaging]. / Funktionelle MRT 2.0. ²³Na- und CEST-Bildgebung.

In recent years the purely morphological magnetic resonance imaging (MRI) has been increasingly flanked by so-called functional imaging methods, such as diffusion-weighted imaging (DWI), to obtain additional information about tissue or pathological processes. This review article presents two MR techniques that can detect physiological processes in the human body. In contrast to all other functional MR imaging techniques, which are based on hydrogen protons, the first technique presented (X-nuclei imaging) uses the spin of other nuclei for imaging and consequently allows a completely different insight into the human body. In this article X-nuclei imaging is focused on sodium ((23)Na) MRI because it currently represents the main focus of research in this field due to the favorable MR properties of sodium. The second MR technique presented is the relatively novel chemical exchange saturation transfer (CEST) imaging that can detect exchange processes between protons in metabolites and protons in free water. The first part of this article introduces the basic technical principles, problems, advantages and disadvantages of these two MR techniques, whereas the second part highlights the potential clinical applications. Examples illustrate several potential applications in neuroimaging (e. g. stroke and tumors), musculoskeletal imaging (e. g. osteoarthritis and degenerative processes) and abdominal imaging (e. g. kidneys and hypertension). Both techniques inherently contain an incredible potential for future imaging but are still on the threshold of clinical use and are currently under evaluation in many university centers.

Simultaneous detection and separation of hyperacute intracerebral hemorrhage and cerebral ischemia using amide proton transfer MRI.

PURPOSE: To explore the capability of amide proton transfer (APT) imaging in the detection of hemorrhagic and ischemic strokes using preclinical rat models. METHODS: The rat intracerebral hemorrhage (ICH) model (n = 10) was induced by injecting bacterial collagenase VII-S into the caudate nucleus, and the permanent ischemic stroke model (n = 10) was induced by using a 4-0 nylon suture to occlude the origin of the middle cerebral artery. APT-weighted (APTw) MRI was acquired on a 4.7T animal imager and quantified using the magnetization transfer-ratio asymmetry at 3.5 ppm from water. RESULTS: There was a consistently high APTw MRI signal in hyperacute ICH during the initial 12 h after injection of collagenase compared with the contralateral brain tissue. When hemorrhagic and ischemic stroke were compared, hyperacute ICH and cerebral ischemia demonstrated opposite APTw MRI contrasts-namely, hyperintense versus hypointense compared with contralateral brain tissue, respectively. There was a stark contrast in APTw signal intensity between these two lesions. CONCLUSION: APT-MRI could accurately detect hyperacute ICH and distinctly differentiate hyperacute ICH from cerebral ischemia, thus opening up the possibility of introducing to the clinic a single MRI scan for the simultaneous visualization and separation of hemorrhagic and ischemic strokes at the hyperacute stage. Magn Reson Med 74:42-50, 2015. © 2014 Wiley Periodicals, Inc.

Comparing different analysis methods for quantifying the MRI amide proton transfer (APT) effect in hyperacute stroke patients.

Amide proton transfer (APT) imaging is a pH mapping method based on the chemical exchange saturation transfer phenomenon that has potential for penumbra identification following stroke. The majority of the literature thus far has focused on generating pH-weighted contrast using magnetization transfer ratio asymmetry analysis instead of quantitative pH mapping. In this study, the widely used asymmetry analysis and a model-based analysis were both assessed on APT data collected from healthy subjects (n = 2) and hyperacute stroke patients (n = 6, median imaging time after onset = 2 hours 59 minutes). It was found that the model-based approach was able to quantify the APT effect with the lowest variation in grey and white matter (≤ 13.8 %) and the smallest average contrast between these two tissue types (3.48 %) in the healthy volunteers. The model-based approach also performed quantitatively better than the other measures in the hyperacute stroke patient APT data, where the quantified APT effect in the infarct core was consistently lower than in the contralateral normal appearing tissue for all the patients recruited, with the group average of the quantified APT effect being 1.5 ± 0.3 % (infarct core) and 1.9 ± 0.4 % (contralateral). Based on the fitted parameters from the model-based analysis and a previously published pH and amide proton exchange rate relationship, quantitative pH maps for hyperacute stroke patients were generated, for the first time, using APT imaging.

Quantification of amide proton transfer effect pre- and post-gadolinium contrast agent administration.

PURPOSE: To compare quantification of the amide proton transfer (APT) effect pre- and post-gadolinium contrast agent (Gd) administration in order to establish to what extent Gd alters quantification of the APT effect. MATERIALS AND METHODS: Four patients with internal carotid stenosis were recruited. APT imaging was acquired pre- and post-contrast in two sessions (before and after surgery) to assess the extent of relaxation time, T1 , change on APT effect calculated using magnetization transfer ratio asymmetry analysis at offsets of ±3.5 ppm relative to water resonance. Statistical and modeling evaluations were performed on the pre- and post-contrast APT effect to study the sensitivity to contrast administration. RESULTS: Before surgery, the post-contrast T1 was estimated to drop <10% of the pre-value for the majority of the patients. After surgery, higher post-contrast T1 reductions were observed in all the patients (maximum decrease was about 20% of the pre-value). Consistent differences between pre- and post-contrast were seen in the APT effect quantified using the asymmetry measure in most regions of the brain, with significant differences found in the white matter at the group level and in 25% of the individual patient results. CONCLUSION: APT imaging should be performed prior to Gd administration to avoid potential misinterpretation of the APT effect.

Ultrahigh Bifunctional Photocatalytic CO2 Reduction and H2 Evolution by Synergistic Interaction of Heteroatomic Pt-Ru Dimerization Sites.

Diatomic-site catalysts (DASCs) inherit the excellent performance of single-atom catalysts (SACs) by utilizing two adjacent atomic metal species to achieve functional complementarity and synergistic effects that improve the carbon dioxide reduction reaction (CO2RR) and H2 evolution reaction (HER) kinetics. Herein, we report a method to further improve the catalytic efficiency of Pt by using Pt and Ru single atoms randomly anchored on a g-C3N4 surface, yielding partial Pt-Ru dimers. The synthesized catalyst exhibits extraordinary photocatalytic activity and stability in both the CO2RR and HER processes. In-depth experimentation, the pH-dependent chemical exchange saturation transfer (CEST) imaging nuclear magnetic resonance (NMR) method, and theoretical analyses reveal that the excellent performance is attributed to orbital coupling between the Pt atoms and the neighboring Ru atoms (mainly dxy and dxz), which decreases the orbital energy levels and weakens the bond strength with intermediates, resulting in improved CO2RR and HER performance. This study successfully applies the pH-dependent CEST imaging NMR method to catalytic reactions, and CO2 adsorption is directly observed using CEST 2D imaging maps. This work presents significant potential for a variety of catalytic reaction applications by systematically designing bimetallic dimers with higher activity and stability.

APT-weighted and NOE-weighted image contrasts in glioma with different RF saturation powers based on magnetization transfer ratio asymmetry analyses.

PURPOSE: To investigate the saturation-power dependence of amide proton transfer (APT)-weighted and nuclear Overhauser enhancement-weighted image contrasts in a rat glioma model at 4.7 T. METHODS: The 9L tumor-bearing rats (n = 8) and fresh chicken eggs (n = 4) were scanned on a 4.7-T animal magnetic resonance imaging scanner. Z-spectra over an offset range of ±6 ppm were acquired with different saturation powers, followed by the magnetization transfer-ratio asymmetry analyses around the water resonance. RESULTS: The nuclear Overhauser enhancement signal upfield from the water resonance (-2.5 to -5 ppm) was clearly visible at lower saturation powers (e.g., 0.6 µT) and was larger in the contralateral normal brain tissue than in the tumor. Conversely, the APT effect downfield from the water resonance was maximized at relatively higher saturation powers (e.g., 2.1 µT) and was larger in the tumor than in the contralateral normal brain tissue. The nuclear Overhauser enhancement decreased the APT-weighted image signal, based on the magnetization transfer-ratio asymmetry analysis, but increased the APT-weighted image contrast between the tumor and contralateral normal brain tissue. CONCLUSION: The APT and nuclear Overhauser enhancement image signals in tumor are maximized at different saturation powers. The saturation power of roughly 2 µT is ideal for APT-weighted imaging at clinical B0 field strengths.

Three-dimensional amide proton transfer MR imaging of gliomas: Initial experience and comparison with gadolinium enhancement.

PURPOSE: To investigate the feasibility of a three-dimensional amide-proton-transfer (APT) imaging sequence with gradient- and spin-echo readouts at 3 Tesla in patients with high- or low-grade gliomas. MATERIALS AND METHODS: Fourteen patients with newly diagnosed gliomas were recruited. After B0 inhomogeneity correction on a voxel-by-voxel basis, APT-weighted images were reconstructed using a magnetization-transfer-ratio asymmetry at offsets of ±3.5 ppm with respect to the water resonance. Analysis of variance post hoc tests were used for statistical evaluations, and results were validated with pathology. RESULTS: In six patients with gadolinium-enhancing high-grade gliomas, enhancing tumors on the postcontrast T1 -weighted images were consistently hyperintense on the APT-weighted images. Increased APT-weighted signal intensity was also clearly visible in two pathologically proven, high-grade gliomas without gadolinium enhancement. The average APT-weighted signal was significantly higher in the lesions than in the contralateral normal-appearing brain tissue (P < 0.001). In six low-grade gliomas, including two with gadolinium enhancement, APT-weighted imaging showed iso-intensity or mild punctate hyperintensity within all the lesions, which was significantly lower than that seen in the high-grade gliomas (P < 0.001). CONCLUSION: The proposed three-dimensional APT imaging sequence can be incorporated into standard brain MRI protocols for patients with malignant gliomas.

Amide Proton Transfer-Weighted MR Imaging of Pediatric Central Nervous System Diseases.

Amide proton transfer-weighted (APTw) imaging is a molecular MR imaging technique that can detect the concentration of the amide protons in mobile cellular proteins and peptides or a pH change in vivo. Previous studies have indicated that APTw MR imaging can be used to detect malignant brain tumors, stroke, and other neurologic diseases, although the clinical application in pediatric patients remains limited. The authors briefly introduce the basic principles of APTw imaging. Then, they review early clinical applications of this approach to pediatric central nervous system diseases, including pediatric brain development, hypoxic-ischemic encephalopathy, intracranial infection, and brain tumors.

Amplified detection of phosphocreatine and creatine after supplementation using CEST MRI at high and ultrahigh magnetic fields.

Creatine is an important metabolite involved in muscle contraction. Administration of exogenous creatine (Cr) or phosphocreatine (PCr) has been used for improving exercise performance and protecting the heart during surgery including during valve replacements, coronary artery bypass grafting and repair of congenital heart defects. In this work we investigate whether it is possible to use chemical exchange saturation transfer (CEST) MRI to monitor uptake and clearance of exogenous creatine and phosphocreatine following supplementation. We were furthermore interested in determining the limiting conditions for distinguishing between creatine (1.9 ppm) and phosphocreatine (2.6 ppm) signals at ultra-high fields (21 T) and determine their concentrations could be reliably obtained using Bloch equation fits of the experimental CEST spectra. We have tested these items by performing CEST MRI of hind limb muscle and kidneys at 11.7 T and 21.1 T both before and after intravenous administration of PCr. We observed up to 4% increase in contrast in the kidneys at 2.6 ppm which peaked ~30 min after administration and a relative ratio of 1.3 in PCr:Cr signal. Overall, these results demonstrate the feasibility of independent monitoring of PCr and Cr concentration changes using CEST MRI.

Proton Exchange Magnetic Resonance Imaging: Current and Future Applications in Psychiatric Research.

Proton exchange provides a powerful contrast mechanism for magnetic resonance imaging (MRI). MRI techniques sensitive to proton exchange provide new opportunities to map, with high spatial and temporal resolution, compounds important for brain metabolism and function. Two such techniques, chemical exchange saturation transfer (CEST) and T1 relaxation in the rotating frame (T1ρ), are emerging as promising tools in the study of neurological and psychiatric illnesses to study brain metabolism. This review describes proton exchange for non-experts, highlights the current status of proton-exchange MRI, and presents advantages and drawbacks of these techniques compared to more traditional methods of imaging brain metabolism, including positron emission tomography (PET) and MR spectroscopy (MRS). Finally, this review highlights new frontiers for the use of CEST and T1ρ in brain research.

Differentiation of Malignant and Benign Head and Neck Tumors with Amide Proton Transfer-Weighted MR Imaging.

PURPOSE: To prospectively evaluate the feasibility and capability of amide proton transfer-weighted (APTw) imaging for the characterization of head and neck tumors. PROCEDURES: Twenty-nine consecutive patients with suspected head and neck tumors were enrolled in this study and underwent APTw magnetic resonance imaging (MRI) on a 3.0-T MRI scanner. The patients were divided into malignant (n = 16) and benign (n = 13) groups, based on pathological results. A map of magnetization transfer ratio asymmetry at 3.5 ppm [MTRasym (3.5 ppm)] was generated for each patient. Interobserver agreement was evaluated and comparisons of MTRasym (3.5 ppm) were made between the malignant and benign groups. Receiver operating characteristic analysis was used to determine the appropriate threshold value of MTRasym (3.5 ppm) for the differentiation of malignant from benign tumors. RESULTS: The intraclass correlation coefficients of the malignant and benign groups were 0.96 and 0.90, respectively, which indicated a good interobserver agreement. MTRasym (3.5 ppm) was significantly higher for the malignant group (3.66 ± 1.15 %) than for the benign group (1.94 ± 0.93 %, P < 0.001). APTw MRI revealed an area under the curve of 0.904 in discriminating these two groups, with a sensitivity of 81.3 %, a specificity of 92.3 %, and an accuracy of 86.2 %, at the threshold of 2.62 % of MTRasym (3.5 ppm). CONCLUSIONS: APTw MRI is feasible for use in the head and neck tumors and is a valuable imaging biomarker for distinguishing malignant from benign lesions.