Chemical Exchange Saturation Transfer Signal Research Articles

Free-breathing abdominal chemical exchange saturation transfer imaging using water presaturation and respiratory gating at 3.0 T.

Free-breathing abdominal chemical exchange saturation transfer (CEST) has great potential for clinical application, but its technical implementation remains challenging. This study aimed to propose and evaluate a free-breathing abdominal CEST sequence. The proposed sequence employed respiratory gating (ResGat) to synchronize the data acquisition with respiratory motion and performed a water presaturation module before the CEST saturation to abolish the influence of respiration-induced repetition time variation. In vivo experiments were performed to compare different respiratory motion-control strategies and B0 offset correction methods, and to evaluate the effectiveness and necessity of the quasi-steady-state (QUASS) approach for correcting the influence of the water presaturation module on CEST signal. ResGat with a target expiratory phase of 0.5 resulted in a higher structural similarity index and a lower coefficient of variation on consecutively acquired CEST S0 images than breath-holding (BH) and respiratory triggering (all p < 0.05). B0 maps derived from the abdominal CEST dataset itself were more stable for B0 correction, compared with the separately acquired B0 maps by a dual-echo time scan and B0 maps derived from the water saturation shift referencing approach. Compared with BH, ResGat yielded more homogeneous magnetization transfer ratio asymmetry maps at 3.5 ppm (standard deviation: 3.96% vs. 3.19%, p = 0.036) and a lower mean squared difference between scan and rescan (27.52‱ vs. 16.82‱, p = 0.004). The QUASS approach could correct the water presaturation-induced CEST signal change, but its necessity for in vivo scanning needs further verification. The proposed free-breathing abdominal CEST sequence using ResGat had an acquisition efficiency of approximately four times that using BH. In conclusion, the proposed free-breathing abdominal CEST sequence using ResGat and water presaturation has a higher acquisition efficiency and image quality than abdominal CEST using BH.

Imaging of brain clearance pathways via MRI assessment of the glymphatic system.

Glymphatic clearance dysfunction may play an important role in a variety of neurodegenerative diseases and the progression of ageing. However, in vivo imaging of the glymphatic system is challenging. In this study, we describe an MRI method based on chemical exchange saturation transfer (CEST) of the Angiopep-2 probe to visualize the clearance function of the glymphatic system. We injected rats with Angiopep-2 via the tail vein and performed in vivo MRI at 7 T to track differences in Angiopep-2 signal changes; we then applied the same principles in a bilateral deep cervical lymph node ligation rat model and in ageing rats. We demonstrated the feasibility of Angiopep-2 CEST for visualizing the clearance function of the glymphatic system. Finally, a pathological assessment was performed. Within the model group, the deep cervical lymph node ligation group and the ageing group showed higher CEST signal than the control group. We conclude that this new MRI method can visualize clearance in the glymphatic system.

A rapid method for phosphocreatine-weighted imaging in muscle using double saturation power-chemical exchange saturation transfer.

Monitoring the variation in phosphocreatine (PCr) levels following exercise provides valuable insights into muscle function. Chemical exchange saturation transfer (CEST) has emerged as a sensitive method with which to measure PCr levels in muscle, surpassing conventional MR spectroscopy. However, existing approaches for quantifying PCr CEST signals rely on time-consuming fitting methods that require the acquisition of the entire or a section of the CEST Z-spectrum. Additionally, traditional fitting methods often necessitate clear CEST peaks, which may be challenging to obtain at low magnetic fields. This paper evaluated the application of a new model-free method using double saturation power (DSP), termed DSP-CEST, to estimate the PCr CEST signal in muscle. The DSP-CEST method requires the acquisition of only two or a few CEST signals at the PCr frequency offset with two different saturation powers, enabling rapid dynamic imaging. Additionally, the DSP-CEST approach inherently eliminates confounding signals, offering enhanced robustness compared with fitting methods. Furthermore, DSP-CEST does not demand clear CEST peaks, making it suitable for low-field applications. We evaluated the capability of DSP-CEST to enhance the specificity of PCr CEST imaging through simulations and experiments on muscle tissue phantoms at 4.7 T. Furthermore, we applied DSP-CEST to animal leg muscle both before and after euthanasia and observed successful reduction of confounding signals. The DSP-CEST signal still has contaminations from a residual magnetization transfer (MT) effect and an aromatic nuclear Overhauser enhancement effect, and thus only provides a PCr-weighted imaging. The residual MT effect can be reduced by a subtraction of DSP-CEST signals at 2.6 and 5 ppm. Results show that the residual MT-corrected DSP-CEST signal at 2.6 ppm has significant variation in postmortem tissues. By contrast, both the CEST signal at 2.6 ppm and a conventional Lorentzian difference analysis of CEST signal at 2.6 ppm demonstrate no significant variation in postmortem tissues.

Improved postprocessing of dynamic glucose-enhanced CEST MRI for imaging brain metastases at 3 T

BackgroundDynamic glucose-enhanced (DGE) chemical exchange saturation transfer (CEST) has the potential to characterize glucose metabolism in brain metastases. Since the effect size of DGE CEST is small at 3 T (< 1%), measurements of signal-to-noise ratios are challenging. To improve DGE detection, we developed an acquisition pipeline and extended image analysis for DGE CEST on a hybrid 3-T positron emission tomography/magnetic resonance imaging system.MethodsThis cross-sectional study was conducted after local ethical approval. Static Z-spectra (from -100 to 100 ppm) were acquired to compare the use of 1.2 versus 2 ppm to calculate static glucose-enhanced (glucoCEST) maps in 10 healthy volunteers before and after glucose infusion. Dynamic CEST images were acquired during glucose infusion. Image analysis was optimized using motion correction, dynamic B0 correction, and principal component analysis (PCA) to improve the detection of DGE CEST in the sagittal sinus, cerebrospinal fluid, and grey and white matter. The developed DGE CEST pipeline was applied to four patients diagnosed with brain metastases.ResultsGlucoCEST was strongest in healthy tissues at 2 ppm. Correcting for motion, B0, and use of PCA locally improved DGE maps. A larger contrast between healthy tissues and enhancing regions in brain metastases was found when dynamic B0 correction and PCA denoising were applied.ConclusionWe demonstrated the feasibility of DGE CEST with our developed acquisition and analysis pipeline at 3 T in patients with brain metastases. This work enables a direct comparison of DGE CEST to 18F-fluoro-deoxy-D-glucose positron emission tomography of glucose metabolism in patients with brain metastases.Relevance statementContrast between brain metastasis and healthy brain tissue in DGE CEST MR images is improved by including principle component analysis and dynamic magnetic field correction during postprocessing. This approach enables the detection of increased DGE CEST signal in brain metastasis, if present.Key points• Despite the low signal-to-noise ratio, dynamic glucose-enhanced CEST MRI is feasible at 3 T.• Principal component analyses and dynamic magnetic field correction improve DGE CEST MRI.• DGE CEST MRI does not consequently show changes in brain metastases compared to healthy brain tissue.• Increased DGE CEST MRI in brain metastases, if present, shows overlap with contrast enhancement on T1-weighted images.Graphical

Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy

Recently, radiotherapy (RT) has entered a new realm of precision cancer therapy with the introduction of magnetic resonance (MR) imaging guided radiotherapy systems into the clinic. Nonetheless, identifying an optimized radiotherapy time window (ORTW) is still critical for the best therapeutic efficacy of RT. Here we describe pH and O2 dual-sensitive, perfluorooctylbromide (PFOB)-based and glycerol-weighted chemical exchange saturation transfer (CEST) nano-molecular imaging probes (Gly-PFOBs) with dual fluorine and hydrogen proton based CEST MR imaging properties (19F/1H-CEST). Oxygenated Gly-PFOBs ameliorate tumor hypoxia and improve O2-dependent radiotherapy. Moreover, the pH and O2 dual-sensitive properties of Gly-PFOBs could be quantitatively, spatially, and temporally monitored by 19F/1H-CEST imaging to optimize ORTW. In this study, we describe the CEST signal characteristics exhibited by the glycerol components of Gly-PFOBs. The pH and O2 dual-sensitive Gly-PFOBs with19F/1H-CEST MR dual-modality imaging properties, with superior therapeutic efficacy and biosafety, are employed for sensitive imaging-guided lung cancer RT, illustrating the potential of multi-functional imaging to noninvasively monitor and enhance RT-integrated effectiveness.

The Feasibility of Dose-Escalated Radiation Therapy for Glioblastoma Using Biological Image Guided Adaptive Radiotherapy (BIGART)

Radiotherapy dose escalation (DE) for glioblastoma (GBM) has been an area of active research. We aimed to study the imaging changes within residual gross tumor volumes (GTV) through the course of concurrent chemo-radiotherapy (CCRT) using multiparametric magnetic resonance imaging (mpMRI). Diffusion, perfusion and chemical exchange saturation transfer (CEST) characteristics of the tumor and its microenvironment were investigated to identify a GTV subvolume potentially associated with radio resistance. We used biological image-guided adaptive radiotherapy (BIGART) to study the feasibility of DE to this GTV subvolume using either photon or proton beam therapy (PBT). We prospectively identified GBM patients with >5cc residual tumor post-resection who were candidates for radical CCRT (60 Gy in 30 daily fractions over 6-weeks with concurrent temozolomide 75mg/m2 daily). We observed the imaging changes with serial mpMRI scans done at baseline, after 2, 4 and 6-weeks of CCRT. Regions of interest (ROIs) within the GTV associated with the following abnormal values at week 2 were identified: apparent diffusion coefficient (ADC): 750-1000 ×10-6 mm2/s; relative cerebral blood volume (rCBV): 1.75-6; and APT-w CEST signal intensity >1.79%. The overlap regions of these ROIs were defined as a novel biological target volume (BTV), identifying the potential area of maximal radioresistance. An in silico study was performed using a technology company's treatment planning system to evaluate the feasibility of planning adaptive treatment to the BTV to total dose of 75 Gy in 30 fractions. This is given in two phases: 30 Gy/15# to the whole PTV as per standard practice, followed by a simultaneous integrated boost (SIB) of 45 Gy/15 fractions while maintaining the dose to the rest of the of the PTV to 60 Gy. Either photons or PBT were used to keep doses to organs at risk (OARs) within standard clinical tolerances. Nine patients were recruited for this analysis and a total of 27 mpMRI scans were studied. Median BTVs to GTVs ratio was 35% (range 22-47%). Volumetric-modulated arc (VMAT) photon and PBT adaptive plans for dose escalation to BTVs were created in all cases whilst maintaining OAR tolerances. Both VMAT and PBT provided acceptable target coverage with average BTV-PTV D98% of 73 Gy (range 71.5-73.8 Gy) and average D2% of 76 Gy (range 75.4-77 Gy) while effectively sparing OARs. Sharper dose gradient between DE-BTV and PTV was achieved with VMAT. PBT was particularly advantageous in minimizing the low-dose spillage outside the BTV. We hereby propose a platform for adaptive radiotherapy to GBM tumors with biological-image guidance through the utilization of mpMRI to evaluate the tumor and its microenvironment during CCRT. We identified thresholds for tumor sub volumes showing the most resistant imaging features and created precise BTVs that allowed for dose escalation. PBT represents an additional useful tool for BIGART planning that will be investigated further in our ongoing work.

Concurrent Dual-Contrast Enhancement Using Fe3O4 Nanoparticles to Achieve a CEST Signal Controllability.

Traditional T2 magnetic resonance imaging (MRI) contrast agents have defects inherent to negative contrast agents, while chemical exchange saturation transfer (CEST) contrast agents can quantify substances at trace concentrations. After reaching a certain concentration, iron-based contrast agents can "shut down" CEST signals. The application range of T2 contrast agents can be widened through a combination of CEST and T2 contrast agents, which has promising application prospects. The purpose of this study is to develop a T2 MRI negative contrast agent with a controllable size and to explore the feasibility of dual contrast enhancement by combining T2 with CEST contrast agents. The study was carried out in vitro with HCT-116 human colon cancer cells. A GE SIGNA Pioneer 3.0 T medical MRI scanner was used to acquire CEST images with different saturation radio-frequency powers (1.25/2.5/3.75/5 μT) by 2D spin echo-echo planar imaging (SE-EPI). Magnetic resonance image compilation (MAGiC) was acquired by a multidynamic multiecho 2D fast spin-echo sequence. The feasibility of this dual-contrast enhancement method was assessed by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, dynamic light scattering, ζ potential analysis, inductively coupled plasma, X-ray photoelectron spectroscopy, X-ray powder diffraction, vibrating-sample magnetometry, MRI, and a Cell Counting Kit-8 assay. The association between the transverse relaxation rate r2 and the pH of the iron-based contrast agents was analyzed by linear fitting, and the linear relationship between the CEST effect in different B1 fields and pH was analyzed by the ratio method. Fe3O4 nanoparticles (NPs) with a mean particle size of 82.6 ± 22.4 nm were prepared by a classical process, and their surface was successfully modified with -OH active functional groups. They exhibited self-aggregation in an acidic environment. The CEST effect was enhanced as the B1 field increased, and an in vitro pH map was successfully plotted using the ratio method. Fe3O4 NPs could stably serve as reference agents at different pH values. At a concentration of 30 μg/mL, Fe3O4 NPs "shut down" the CEST signals, but when the concentration of Fe3O4 NPs was less than 10 μg/mL, the two contrast agents coexisted. The prepared Fe3O4 NPs had almost no toxicity, and when their concentration rose to 200 μg/mL at pH 6.5 or 7.4, they did not reach the half-maximum inhibitory concentration (IC50). Fe3O4 magnetic NPs with a controllable size and no toxicity were successfully synthesized. By combining Fe3O4 NPs with a CEST contrast agent, the two contrast agents could be imaged simultaneously; at higher concentrations, the iron-based contrast agent "shut down" the CEST signal. An in vitro pH map was successfully plotted by the ratio method. CEST signal inhibition can be used to realize the pH mapping of solid tumors and the identification of tumor active components, thus providing a new imaging method for tumor efficacy evaluation.

Lateralization of temporal lobe epileptic foci with automated chemical exchange saturation transfer measurements at 3Tesla.

Magnetic Resonance Imaging (MRI) is an indispensable tool for the diagnosis of temporal lobe epilepsy (TLE). However, about 30% of TLE patients show no lesion on structural MRI (sMRI-negative), posing a significant challenge for presurgical evaluation. This study aimed to investigate whether chemical exchange saturation transfer (CEST) MRI at 3 Tesla can lateralize the epileptic focus of TLE and study the metabolic contributors to the CEST signal measured. Forty TLE subjects (16 males and 24 females) were included in this study. An automated data analysis pipeline was established, including segmentation of the hippocampus and amygdala (HA), calculation of four CEST metrics and quantitative relaxation times (T1 and T2), and construction of prediction models by logistic regression. Furthermore, a modified two-stage Bloch-McConnell fitting method was developed to investigate the molecular imaging mechanism of 3T CEST in identifying epileptic foci of TLE. The mean CEST ratio (CESTR) metric within 2.25-3.25ppm in the HA was the most powerful index in predicting seizure laterality, with an area under the receiver-operating characteristic curve (AUC) of 0.84. And, the combination of T2 and CESTR further increased the AUC to 0.92. Amine and guanidinium moieties were the two leading contributors to the CEST contrast between the epileptogenic HA and the normal HA. CEST at 3 Tesla is a powerful modality that can predict seizure laterality with high accuracy. This study can potentially facilitate the clinical translation of CEST MRI in identifying the epileptic foci of TLE or other localization-related epilepsies. National Natural Science Foundation of China, Science Technology Department of Zhejiang Province, and Zhejiang University.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) quantification of transient ischemia using a combination method of 5-pool Lorentzian fitting and inverse Z-spectrum analysis.

Chemical exchange saturation transfer (CEST) is a promising method for the detection of biochemical alterations in cancers and neurological diseases. However, the sensitivity of the currently existing quantitative method for detecting ischemia needs further improvement. To further improve the quantification of the CEST signal and enhance the CEST detection for ischemia, we used a quantitative analysis method that combines an inverse Z-spectrum analysis and a 5-pool Lorentzian fitting. Specifically, a 5-pool Lorentzian simulation was conducted with the following brain tissue parameters: water, amide (3.5 ppm), amine (2.2 ppm), magnetization transfer (MT), and nuclear Overhauser enhancement (NOE; -3.5 ppm). The parameters were first calculated offline and stored as the initial value of the Z-spectrum fitting. Then, the measured Z-spectrum with the peak value set to 0 was fitted via the stored initial value, which yielded the reference Z-spectrum. Finally, the difference between the inverse of the Z-spectrum and the inverse of the reference Z-spectrum was used as the CEST definite spectrum. The simulation results demonstrated that the Z-spectra of the rat brain were well simulated by a 5-pool Lorentzian fitting. Further, the proposed method detected a larger difference than did either the saturation transfer difference or the 5-pool Lorentzian fitting, as demonstrated by simulations. According to the results of the cerebral ischemia rat model, the proposed method provided the highest contrast-to-noise ratio (CNR) between the contralateral and the ipsilateral striatum under various acquisition conditions. The results indicated that the difference of fitted amplitudes generated with a 5-pool Lorentzian fitting in amide at 3.5 ppm (6.04%±0.39%; 6.86%±0.39%) was decreased in a stroke lesion compared to the contralateral normal tissue. Moreover, the difference of the residual of inversed Z-spectra in which 5-pool Lorentzian fitting was used to calculate the reference Z-spectra ( ) amplitudes in amide at 3.5 ppm (13.83%±2.20%, 15.69%±1.99%) was reduced in a stroke lesion compared to the contralateral normal tissue. is predominantly pH-sensitive and is suitable for detecting tissue acidosis following an acute stroke.

CEST-MRI for body oncologic imaging: are we there yet?

Chemical exchange saturation transfer (CEST) MRI has gained recognition as a valuable addition to the molecular imaging and quantitative biomarker arsenal, especially for characterization of brain tumors. There is also increasing interest in the use of CEST-MRI for applications beyond the brain. However, its translation to body oncology applications lags behind those in neuro-oncology. The slower migration of CEST-MRI to non-neurologic applications reflects the technical challenges inherent to imaging of the torso. In this review, we discuss the application of CEST-MRI to oncologic conditions of the breast and torso (i.e., body imaging), emphasizing the challenges and potential solutions to address them. While data are still limited, reported studies suggest that CEST signal is associated with important histology markers such as tumor grade, receptor status, and proliferation index, some of which are often associated with prognosis and response to therapy. However, further technical development is still needed to make CEST a reliable clinical application for body imaging and establish its role as a predictive and prognostic biomarker.

Demonstration of accurate multi-pool chemical exchange saturation transfer MRI quantification – Quasi-steady-state reconstruction empowered quantitative CEST analysis

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute labile protons and microenvironment properties, yet CEST quantification has been challenging. This difficulty is because the CEST measurement depends not only on the underlying CEST system but also on the scan protocols, including RF saturation amplitude, duration, and repetition time. In addition, T1 normalization is not straightforward under non-equilibrium conditions. Recently, a quasi-steady-state (QUASS) algorithm was established to reconstruct the desired equilibrium state from experimental measurements. Our study aimed to determine the accuracy of spinlock-model-based multi-pool CEST quantification using numerical simulations and phantom experiments. In short, CEST Z-spectra were simulated for a representative 3-pool model, and CEST amplitudes were solved with spinlock model-based multi-pool fitting and assessed as a function of RF saturation time (Ts), repetition time (TR), and T1. Although the apparent CEST signals showed significant T1 dependence, such relationships were not observed following QUASS reconstruction. To test the accuracy of T1 correction, a multi-vial phantom of nicotinamide and creatine was doped with manganese chloride, resulting in T1 ranging from 1 s to beyond 2 s. The multi-labile signals determined from the routine measurements showed significant dependence on Ts, TR, and T1. In contrast, CEST signals from the QUASS reconstruction showed consistent quantification independent of such variables. To summarize, our study demonstrated that accurate CEST quantification is feasible in multi-pool CEST systems with the spinlock-model-based fitting of QUASS CEST MRI.

Exploring the potential of the novel imidazole-4,5-dicarboxyamide chemical exchange saturation transfer scaffold for pH and perfusion imaging.

Here, we describe and assess the potential of 14 newly synthesized imidazole-4,5-dicarboxyamides (I45DCs) for pH and perfusion imaging. A number of these aromatic compounds possess large labile proton chemical shifts (up to 7.7ppm from water) because of their intramolecular hydrogen bonds and a second labile proton to allow for chemical exchange saturation transfer (CEST) signal ratio-based pH measurements. We have found that the contrast produced is strong for a wide range of substitutions and that the inflection points in the CEST signal ratio versus pH plots used to generate concentration-independent pH maps can be adjusted based on these subsitutions to tune the pH range that can be measured. These I45DC CEST agents have advantages over the triiodobenzenes currently employed for tumor and kidney pH mapping, both preclinically and in initial human studies. Finally, as CEST MRI combined with exogenous contrast has the potential to detect functional changes in the kidneys, we evaluated our highest performing anionic compound (I45DC-diGlu) on a unilateral urinary obstruction mouse model and observed lower contrast uptake in the obstructed kidney compared with the unobstructed kidney and that the unobstructed kidney displayed a pH of ~6.5 while the obstructed kidney had elevated pH and an increased range in pH values. Based on this, we conclude that the I45DCs have excellent imaging properties and hold promise for a variety of medical imaging applications, particularly renal imaging.

Evaluation of the efficacy of creatine chemical exchange saturation transfer imaging in assessing testicular maturity.

Microscopic testicular sperm extraction is the most effective treatment for NOA, but the sperm retrieval rate is low and depends on testicular maturity. However, there are limited useful tests to assess testicular maturity. Chemical exchange saturation transfer (CEST) imaging is a new magnetic resonance imaging (MRI) technique that can image the distribution of trace substances in vivo. We focused on the potential role of creatine (Cr) in testes and hypothesized that Cr-CEST could indicate intratesticular spermatogenesis. We performed Cr-CEST by using 7T MRI on wild-type C57B6/J mice and several types of male infertility models such as Sertoli-cell only (SCO) (Kitw/Kitwv), maturation arrest (MA) (Zfp541 knockout mouse and Kctd19 knockout mouse), and teratozoospermia (Tbc1d21 knockout mouse). After performing Cr-CEST, histological analysis was performed. The SCO and MA models showed decreased CEST signal intensity (p < 0.05), while no reduction was observed in the teratozoospermia model (p=1.0). CEST signal intensity increased as the spermatogenesis stage progressed from the SCO model to the MA and teratozoospermia models. Furthermore, CEST signal intensity was reduced in 4-week-old wild-type mice with immature testes (p < 0.05). This study suggests that Cr-CEST evaluates intratesticular spermatogenesis noninvasively and provides a new therapeutic strategy for treating male infertility.

Theory of chemical exchange saturation transfer MRI in the context of different magnetic fields.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a versatile MRI method that provides contrast based on the level of molecular and metabolic activity. This contrast arises from indirect measurement of protons in low concentration molecules that are exchanging with the abundant water proton pool. The indirect measurement is based on magnetization transfer of radio frequency (rf)-prepared magnetization from the small pool to the water pool. The signal can be modeled by the Bloch-McConnell equations combining standard magnetization dynamics and chemical exchange processes. In this article, we review analytical solutions of the Bloch-McConnell equations and especially the derived CEST signal equations and their implications. The analytical solutions give direct insight into the dependency of measurable CEST effects on underlying parameters such as the exchange rate and concentration of the solute pools, but also on the system parameters such as the rf irradiation field B1 , as well as the static magnetic field B0 . These theoretical field-strength dependencies and their influence on sequence design are highlighted herein. In vivo results of different groups making use of these field-strength benefits/dependencies are reviewed and discussed.

Ratiometric chemical exchange saturation transfer pH mapping using two iodinated agents with nonequivalent amide protons and a single low saturation power.

As an essential physiological parameter, pH plays a critical role in maintaining cellular and tissue homeostasis. The ratiometric chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) method using clinically approved iodinated agents has emerged as one of the most promising noninvasive techniques for pH assessment. In this study, we investigated the ability to use the combination of two different nonequivalent amide protons, chosen from five iodinated agents, namely iodixanol, iohexol, iobitridol, iopamidol, and iopromide, for pH measurement. The ratio of two nonequivalent amide CEST signals was calculated and compared for pH measurements in the range of 5.6 to 7.6. To quantify the CEST signals at 4.3 and 5.5 parts per million (ppm), we employed two analytic methods: magnetization transfer ratio asymmetry and Lorentzian fitting analysis. Lastly, the established protocol was used to measure the pH values in healthy rat kidneys (n=5). The combination of iodixanol and iobitridol at a ratio of 1:1 was found to be suitable for pH mapping. The saturation power level (B1) was also investigated, and a low B1 of 1.5 µT was adopted for subsequent pH measurements. Improved precision and an extended pH detection range were achieved using iodixanol and iobitridol (1:1 ratio) and a single low B1 of 1.5 µT in vitro. In vivo renal pH values were measured as 7.23±0.09, 6.55±0.15, and 6.29±0.23 for the cortex, medulla, and calyx, respectively. These results show that the ratiometric CEST method using two iodinated agents with nonequivalent amide protons could be used for in vivo pH mapping of the kidney under a single low B1 saturation power.

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice

BackgroundMultiple sclerosis (MS) is a neurodegenerative disease, wherein aberrant immune cells target myelin-ensheathed nerves. Conventional magnetic resonance imaging (MRI) can be performed to monitor damage to the central nervous system that results from previous inflammation; however, these imaging biomarkers are not necessarily indicative of active, progressive stages of the disease. The immune cells responsible for MS are first activated and sensitized to myelin in lymph nodes (LNs). Here, we present a new strategy for monitoring active disease activity in MS, chemical exchange saturation transfer (CEST) MRI of LNs.Methods and resultsWe studied the potential utility of conventional (T2-weighted) and CEST MRI to monitor changes in these LNs during disease progression in an experimental autoimmune encephalomyelitis (EAE) model. We found CEST signal changes corresponded temporally with disease activity. CEST signals at the 3.2 ppm frequency during the active stage of EAE correlated significantly with the cellular (flow cytometry) and metabolic (mass spectrometry imaging) composition of the LNs, as well as immune cell infiltration into brain and spinal cord tissue. Correlating primary metabolites as identified by matrix-assisted laser desorption/ionization (MALDI) imaging included alanine, lactate, leucine, malate, and phenylalanine.ConclusionsTaken together, we demonstrate the utility of CEST MRI signal changes in superficial cervical LNs as a complementary imaging biomarker for monitoring disease activity in MS. CEST MRI biomarkers corresponded to disease activity, correlated with immune activation (surface markers, antigen-stimulated proliferation), and correlated with LN metabolite levels.

Assessing the influence of the menstrual cycle on APT CEST-MRI in the human breast

PurposeIn fibroglandular breast tissue, conventional dynamic contrast-enhanced MR-mammography is known to be affected by water content changes during the menstrual cycle. Likewise, amide proton transfer (APT) chemical exchange saturation transfer (CEST)-MRI might be inherently prone to the menstrual cycle, as CEST signals are indirectly detected via the water signal. The purpose of this study was to investigate the influence of the menstrual cycle on APT CEST-MRI in fibroglandular breast tissue. MethodTen healthy premenopausal women (19–34 years) were included in this IRB approved prospective study and examined twice during their menstrual cycle. Examination one and two were performed during the first half (day 2–8) and the second half (day 15–21) of the menstrual cycle, respectively. As a reference for the APT signal in malignant breast tumor tissue, previously reported data of nine breast cancer patients were included in this study. CEST-MRI (B1 = 0.7μT) was performed on a 7 T whole-body scanner followed by a multi-Lorentzian fit analysis. The APT signal was corrected for B0/B1-field inhomogeneities, fat signal contribution, and relaxation effects of the water signal and evaluated in the fibroglandular breast tissue. Intra-individual APT signal differences between examination one and two were compared using the Wilcoxon signed-rank test. The level of significance was set at p < 0.05. ResultsThe APT signal showed no significant difference in the fibroglandular breast tissue of healthy premenopausal volunteers throughout the menstrual cycle (p = 1.00) (examination 1 vs. examination 2: mean and standard deviation = 3.24 ± 0.68%Hz vs. 3.30 ± 0.73%Hz, median and IQR = 3.36%Hz and 0.87%Hz vs. 3.38%Hz and 0.71%Hz). ConclusionThe present study provides an important basis for the clinical application of APT CEST-MRI as an additional contrast mechanism in MR-mammography, as menstrual cycle-related APT signal fluctuations seem to be negligible compared to the APT signal increase in breast cancer tissue.

Breast cancer imaging with glucosamine CEST (chemical exchange saturation transfer) MRI: first human experience.

This study aims to evaluate the feasibility of imaging breast cancer with glucosamine (GlcN) chemical exchange saturation transfer (CEST) MRI technique to distinguish between tumor and surrounding tissue, compared to the conventional MRI method. Twelve patients with newly diagnosed breast tumors (median age, 53 years) were recruited in this prospective IRB-approved study, between August 2019 and March 2020. Informed consent was obtained from all patients. All MRI measurements were performed on a 3-T clinical MRI scanner. For CEST imaging, a fat-suppressed 3D RF-spoiled gradient echo sequence with saturation pulse train was applied. CEST signals were quantified in the tumor and in the surrounding tissue based on magnetization transfer ratio asymmetry (MTRasym) and a multi-Gaussian fitting. GlcN CEST MRI revealed higher signal intensities in the tumor tissue compared to the surrounding breast tissue (MTRasym effect of 8.12 ± 4.09%, N = 12, p = 2.2 E-03) with the incremental increase due to GlcN uptake of 3.41 ± 0.79% (N = 12, p = 2.2 E-03), which is in line with tumor location as demonstrated by T1W and T2W MRI. GlcN CEST spectra comprise distinct peaks corresponding to proton exchange between free water and hydroxyl and amide/amine groups, and relayed nuclear Overhauser enhancement (NOE) from aliphatic groups, all yielded larger CEST integrals in the tumor tissue after GlcN uptake by an averaged factor of 2.2 ± 1.2 (p = 3.38 E-03), 1.4 ± 0.4 (p =9.88 E-03), and 1.6 ± 0.6 (p = 2.09 E-02), respectively. The results of this initial feasibility study indicate the potential of GlcN CEST MRI to diagnose breast cancer in a clinical setup. • GlcN CEST MRI method is demonstrated for its the ability to differentiate between breast tumor lesions and the surrounding tissue, based on the differential accumulation of the GlcN in the tumors. • GlcN CEST imaging may be used to identify metabolic active malignant breast tumors without using a Gd contrast agent. • The GlcN CEST MRI method may be considered for use in a clinical setup for breast cancer detection and should be tested as a complementary method to conventional clinical MRI methods.

Relaxation-Compensated Chemical Exchange Saturation Transfer MRI in the Brain at 7T: Application in Relapsing-Remitting Multiple Sclerosis.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can probe tissue biochemistry in vivo with high resolution and sensitivity without requiring exogenous contrast agents. Applying CEST MRI at ultrahigh field provides advantages of increasing spectral resolution and improving sensitivity to metabolites with faster proton exchange rates such as glutamate, a critical neurotransmitter in the brain. Prior magnetic resonance spectroscopy and CEST MRI studies have revealed altered regulation of glutamate in patients with multiple sclerosis (MS). While CEST imaging facilitates new strategies for investigating the pathology underlying this complex and heterogeneous neurological disease, CEST signals are contaminated or diluted by concurrent effects (e.g., semi-solid magnetization transfer (MT) and direct water saturation) and are scaled by the T1 relaxation time of the free water pool which may also be altered in the context of disease. In this study of 20 relapsing-remitting MS patients and age- and sex-matched healthy volunteers, glutamate-weighted CEST data were acquired at 7.0 T. A Lorentzian fitting procedure was used to remove the asymmetric MT contribution from CEST z-spectra, and the apparent exchange-dependent relaxation (AREX) correction was applied using an R1 map derived from an inversion recovery sequence to further isolate glutamate-weighted CEST signals from concurrent effects. Associations between AREX and cognitive function were examined using the Minimal Assessment of Cognitive Function in MS battery. After isolating CEST effects from MT, direct water saturation, and T1 effects, glutamate-weighted AREX contrast remained higher in gray matter than in white matter, though the difference between these tissues decreased. Glutamate-weighted AREX in normal-appearing gray and white matter in MS patients did not differ from healthy gray and white matter but was significantly elevated in white matter lesions. AREX in some cortical regions and in white matter lesions correlated with disability and measures of cognitive function in MS patients. However, further studies with larger sample sizes are needed to confirm these relationships due to potential confounding effects. The application of MT and AREX corrections in this study demonstrates the importance of isolating CEST signals for more specific characterization of the contribution of metabolic changes to tissue pathology and symptoms in MS.

Dynamic alteration in myocardium creatine during acute infarction using MR CEST imaging.

Creatine (Cr) is an essential metabolite in the creatine kinase reaction, which plays a critical role in maintaining normal cardiac function. Chemical exchange saturation transfer (CEST) MRI offers a novel way to map myocardium Cr. This study aims to investigate the dynamic alteration in myocardium Cr during acute infarction using CEST MRI, which may facilitate understanding of the heart remodeling mechanism at the molecular level. Seven adult Bama pigs underwent cardiac cine, Cr CEST, and late gadolinium-enhanced (LGE) T1 -weighted (T1 w) imaging three and 14 days after myocardial infarction induction on a 3 T scanner. Cardiac structural and functional indices, including myocardium mass (MM), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF), were measured from cines. Infarct angle was determined from LGE T1 w images, based on which myocardium was classified into infarct, adjacent, and remote regions. Cr-weighted CEST signal was quantified from a three-pool Lorentzian fitting model and measured within each region and the entire myocardium. Student's t-test was conducted to evaluate any significant differences in measurements between the two time points. Correlation was assessed with Pearson correlation. P values less than 0.05 were considered statistically significant. Over the studied period, MM, EDV, and ESV did not alter significantly (P> 0.05), whereas significant increases of SV and EF and decrease of infarct angle were observed (P< 0.05). Meanwhile, the Cr-weighted CEST signal elevated significantly on Day 14 compared with Day 3 in the infarct (10.00 ± 1.28% versus 6.91 ± 1.54%, P< 0.01), adjacent (11.17 ± 2.00% versus 8.01 ± 1.58%, P= 0.01), and entire myocardium (11.03 ± 1.36% versus 8.19 ± 1.28%, P< 0.01). Moderate negative correlations were shown between the infarct angle and Cr-weighted CEST signals in the infarct (r= -0.80, P< 0.001), adjacent (r= -0.58, P= 0.03), and entire myocardium (r= -0.76, P< 0.01). In conclusion, the dynamic increase of myocardium Cr during acute infarction may interact with cardiac structural and functional recovery. The study provides supplementary insights into the heart remodeling process from the metabolic viewpoint.