Dynamic glucose enhanced (DGE) MRI studies employ CEST or spin lock (CESL) to study glucose uptake. Currently, these methods are hampered by low effect size and sensitivity to motion. To overcome this, we propose to utilize exchange-based linewidth (LW) broadening of the direct water saturation (DS) curve of the water saturation spectrum (Z-spectrum) during and after glucose infusion (DS-DGE MRI).

To estimate the glucose-infusion-induced LW changes (ΔLW), Bloch-McConnell simulations were performed for normoglycemia and hyperglycemia in blood, gray matter (GM), white matter (WM), CSF, and malignant tumor tissue. Whole-brain DS-DGE imaging was implemented at 3 T using dynamic Z-spectral acquisitions (1.2 s per offset frequency, 38 s per spectrum) and assessed on four brain tumor patients using infusion of 35 g of D-glucose. To assess ΔLW, a deep learning-based Lorentzian fitting approach was used on voxel-based DS spectra acquired before, during, and post-infusion. Area-under-the-curve (AUC) images, obtained from the dynamic ΔLW time curves, were compared qualitatively to perfusion-weighted imaging parametric maps.

In simulations, ΔLW was 1.3%, 0.30%, 0.29/0.34%, 7.5%, and 13% in arterial blood, venous blood, GM/WM, malignant tumor tissue, and CSF, respectively. In vivo, ΔLW was approximately 1% in GM/WM, 5% to 20% for different tumor types, and 40% in CSF. The resulting DS-DGE AUC maps clearly outlined lesion areas.

DS-DGE MRI is highly promising for assessing D-glucose uptake. Initial results in brain tumor patients show high-quality AUC maps of glucose-induced line broadening and DGE-based lesion enhancement similar and/or complementary to perfusion-weighted imaging.

Diamagnetic CEST (diaCEST) MRI contrast agents (CAs) have recently gained immense popularity by virtue of the fact that contrast can be switched on or off by merely changing a few experimental parameters, even after the agent is administered. However, the low efficiency and small solute-solvent offset of the contrast-generating exchangeable protons have so far prevented them from becoming a practical option for in vivo applications. Low efficiency demands high dosage, while small offset invites unwanted interference from the endogenous metabolites present in the human body. So far, the strategy for finding efficient diaCEST CAs involved searching for suitable molecules in which the exchangeable protons resonate as far as possible from water and have an optimum exchange rate. Very little effort has been devoted toward designing or converting to an efficient one from a less efficient existing CA. It was recently shown that hydrothermally synthesized carbon nanodots (CDs) have the ability to enhance contrast efficiency and to tune the pH response of certain diaCEST CAs. Here we show that a suitable combination of the synthesis technique and synthesis parameters can simultaneously enhance solute-solvent offset and contrast efficiency. In particular, we demonstrate 300% enhancement in offset and 100% enhancement in efficiency following the formation of carbon-dots from a urea-citric acid mixture.

The aim of this study was to create a user-friendly CEST simulation tool with a GUI for both spectral (1D Z-spectra) and spatial (2D phantom) CEST experiments, making the CEST simulation easier to perform.

CESTsimu was developed using MATLAB App Designer. It consists of three modules: Saturation Settings, Exchange Settings, and Phantom Settings. CESTsimu can not only import/export files in the defined format but can also import files generated by other existing simulation platforms (e.g. pulseq-CEST).

The 1D Z-spectrum simulation results demonstrated the effectiveness of CESTsimu in simulating Z-spectra under various saturation (B 0 $$ {\mathrm{B}}_0 $$ andB 1 $$ {\mathrm{B}}_1 $$ ) and exchange settings (concentration and exchange rate). The 2D simulation results showed that CESTsimu can generate an arbitrary number of phantoms with different shapes under different noise conditions. Notably, CESTsimu could also simulateB 0 $$ {\mathrm{B}}_0 $$ andB 1 $$ {\mathrm{B}}_1 $$ inhomogeneity in 2D patterns that mimicked practical conditions. Moreover, the accuracy of CESTsimu was validated by simulating 8 cases in the BMsim challenge.

We developed a user-friendly CESTsimu GUI for intuitively simulating CEST experiments under diverse saturation and exchange settings in 1D and 2D conditions. CESTsimu has the potential to facilitate the broad utilization of CEST MRI among a wide range of users.

Chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) enables the imaging of many endogenous and exogenous compounds with exchangeable protons and protons experiencing dipolar coupling by using a label-free approach. This provides an avenue for following interesting molecular events in vivo by detecting the natural protons of molecules, such as the increase in amide protons of proteins in brain tumors and the concentration of drugs reaching the target site. Neither of these detections require metallic or radioactive labels and thus will not perturb the molecular events happening in vivo. Yet, magnetization transfer processes such as chemical exchange and dipolar coupling of protons are sensitive to the local environment. Hence, the use of nanocarriers could enhance the CEST contrast by providing a relatively high local concentration of contrast agents, considering the portion of the protons available for exchange, optimizing the exchange rate, and utilizing molecular interactions. This review provides an overview of these factors to be considered for designing efficient CEST contrast agents (CAs), and the molecular events that can be imaged using CEST MRI during disease progression and treatment, as well as the nanocarriers for drug delivery and distribution for the evaluation of treatments.

Dimethyl sulfoxide (DMSO) has wide biomedical applications such as cryoprotectant and hydrophobic drug carrier. Here, we report for the first time that DMSO can generate a distinctive chemical exchange saturation transfer (CEST) signal at around -2 ppm. Structural analogs of DMSO, including aprotic and protic solvents, also demonstrated CEST signals from -1.4 to -3.8 ppm. When CEST detectable barbituric acid (BA) was dissolved in DMSO solution and was co-loaded to liposome, two obvious peaks at 5 and -2 ppm were observed, indicating that DMSO and related solvent system can be monitored in a label-free manner via CEST, which can be further applied to imaging drug nanocarriers. With reference to previous studies, there could be molecular interactions or magnetization transfer pathways, such as the relayed nuclear Overhauser enhancement (rNOE), that lead to this detectable CEST contrast at negative offset frequencies of the Z-spectrum. Our findings suggest that small molecules of organic solvents could be involved in magnetization transfer processes with water and readily detected by CEST magnetic resonance imaging (MRI), providing a new avenue for detecting solvent-water and solvent-drug interactions.

To evaluate the utility of glucose chemical exchange saturation transfer (glucoCEST) MRI with non-contrast injection in predicting the histological grade of rectal cancer.

This prospective analysis included 60 patients with preoperative rectal cancer who underwent pelvic glucoCEST, amide proton transfer-weighted imaging (APTWI), and diffusion-weighted imaging (DWI). In total, 21 low-grade and 39 high-grade cases were confirmed by postoperative pathology. The MTRasym (1.2 ppm), MTRasym (3.5 ppm), and apparent diffusion coefficient (ADC) values of lesions between the low-grade and high-grade groups were compared. The area under the receiver operating characteristic curve (AUC) was generated to evaluate the diagnostic performance of each technique. Logistic regression (LR) analysis was applied to determine independent predictors and for multi-parameter combined diagnosis.

Elevated MTRasym (1.2 ppm), MTRasym (3.5 ppm) values and lower ADC values were observed in the high-grade group compared with low-grade cases (all p < 0.01). The AUCs of MTRasym (1.2 ppm), MTRasym (3.5 ppm), and ADC for differentiating between low- and high-grade rectal cancer cases were 0.792, 0.839, and 0.855, respectively. The diagnostic performance of the combination of the three indexes was improved (AUC, 0.969; sensitivity, 95.24%; specificity, 87.18%). The good consistency and reliability of the combination of independent predictors were demonstrated by calibration curve analysis and DCA.

The glucoCEST MRI without contrast injection, APTWI, and DWI all facilitate the assessment of histological grade in rectal cancer, and the combination of the three can effectively discriminate between high- and low-grade rectal cancer, which is expected to be a promising imaging marker.

The glucose chemical exchange saturation transfer MRI method facilitates the assessment of histological grade in rectal cancer and offers additional information to improve the diagnostic performance of amide proton transfer-weighted imaging, and diffusion-weighted imaging.

Glucose chemical exchange saturation transfer imaging could differentiate histological grade. Amide proton transfer-weighted and diffusion-weighted were associated with histological grade. The combination of different parameters showed the best diagnostic performance.

Introduction: While obesity has been linked to both increased and decreased rate of cognitive decline in Alzheimer's Disease (AD) patients, there is no consensus on the interaction between obesity and AD. Methods: The TgF344-AD rat model was used to investigate the effects of high carbohydrate, high fat (HCHF) diet on brain glucose metabolism and hemodynamics in the presence or absence of AD transgenes, in presymptomatic (6-month-old) vs. symptomatic (12-month-old) stages of AD progression using non-invasive neuroimaging. Results: In presymptomatic AD, HCHF exerted detrimental effects, attenuating both hippocampal glucose uptake and resting perfusion in both non-transgenic and TgAD cohorts, when compared to CHOW-fed cohorts. In contrast, HCHF consumption was beneficial in established AD, resolving the AD-progression associated attenuation in hippocampal glucose uptake and functional hyperemia. Discussion: Whereas HCHF was harmful to the presymptomatic AD brain, it ameliorated deficits in hippocampal metabolism and neurovascular coupling in symptomatic TgAD rats.

Dynamic glucose enhanced (DGE) MRI studies employ chemical exchange saturation transfer (CEST) or spin lock (CESL) to study glucose uptake. Currently, these methods are hampered by low effect size and sensitivity to motion. To overcome this, we propose to utilize exchange-based linewidth (LW) broadening of the direct water saturation (DS) curve of the water saturation spectrum (Z-spectrum) during and after glucose infusion (DS-DGE MRI).

To estimate the glucose-infusion-induced LW changes ( ΔLW ), Bloch-McConnell simulations were performed for normoglycemia and hyperglycemia in blood, gray matter (GM), white matter (WM), CSF, and malignant tumor tissue. Whole-brain DS-DGE imaging was implemented at 3 tesla using dynamic Z-spectral acquisitions (1.2 s per offset frequency, 38 s per spectrum) and assessed on four brain tumor patients using infusion of 35 g of D-glucose. To assess ΔLW , a deep learning-based Lorentzian fitting approach was employed on voxel-based DS spectra acquired before, during, and post-infusion. Area-under-the-curve (AUC) images, obtained from the dynamic ΔLW time curves, were compared qualitatively to perfusion-weighted imaging (PWI).

In simulations, ΔLW was 1.3%, 0.30%, 0.29/0.34%, 7.5%, and 13% in arterial blood, venous blood, GM/WM, malignant tumor tissue, and CSF, respectively. In vivo, ΔLW was approximately 1% in GM/WM, 5-20% for different tumor types, and 40% in CSF. The resulting DS-DGE AUC maps clearly outlined lesion areas.

DS-DGE MRI is highly promising for assessing D-glucose uptake. Initial results in brain tumor patients show high-quality AUC maps of glucose-induced line broadening and DGE-based lesion enhancement similar and/or complementary to PWI.

Nuclear overhauser enhancement is a confounding factor arising from the in vivo application of a chemical exchange saturation transfer technique in which two nuclei in close proximity undergo dipole cross-relaxation. Several studies have shown applicability and efficacy of nuclear overhauser enhancement in observing tumors and other lesions in vivo. Thus, this effect could become an emerging molecular imaging research tool for many diseases. Moreover, nuclear overhauser enhancement has the advantages of simplicity, noninvasiveness, and high resolution and has become a major focus of current research. In this review, we summarize the principles and applications of nuclear overhauser enhancement. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging tool that provides physiological information about tissues, making it an invaluable tool for disease diagnosis and guided treatment. Its clinical application requires the acquisition of high-resolution images capable of accurately identifying subtle regional changes in vivo, while simultaneously maintaining a high level of spectral resolution. However, the acquisition of such high-resolution images is time consuming, presenting a challenge for practical implementation in clinical settings. Among several techniques that have been explored to reduce the acquisition time in MRI, deep-learning-based super-resolution (DLSR) is a promising approach to address this problem due to its adaptability to any acquisition sequence and hardware. However, its translation to CEST MRI has been hindered by the lack of the large CEST datasets required for network development. Thus, we aim to develop a DLSR method, named DLSR-CEST, to reduce the acquisition time for CEST MRI by reconstructing high-resolution images from fast low-resolution acquisitions. This is achieved by first pretraining the DLSR-CEST on human brain T1w and T2w images to initialize the weights of the network and then training the network on very small human and mouse brain CEST datasets to fine-tune the weights. Using the trained DLSR-CEST network, the reconstructed CEST source images exhibited improved spatial resolution in both peak signal-to-noise ratio and structural similarity index measure metrics at all downsampling factors (2-8). Moreover, amide CEST and relayed nuclear Overhauser effect maps extrapolated from the DLSR-CEST source images exhibited high spatial resolution and low normalized root mean square error, indicating a negligible loss in Z-spectrum information. Therefore, our DLSR-CEST demonstrated a robust reconstruction of high-resolution CEST source images from fast low-resolution acquisitions, thereby improving the spatial resolution and preserving most Z-spectrum information.

To investigate the effect of inhaled oxygen level on dynamic glucose enhanced (DGE) MRI in mouse brain tissue and CSF at 3 T.

DGE data of brain tissue and CSF from mice under normoxia or hyperoxia were acquired in independent and interleaved experiments using on-resonance variable delay multi-pulse (onVDMP) MRI. A bolus of 0.15 mL filtered 50% D-glucose was injected through the tail vein over 1 min during DGE acquisition. MRS was acquired before and after DGE experiments to confirm the presence of D-glucose.

A significantly higher DGE effect under normoxia than under hyperoxia was observed in brain tissue (p = 0.0001 and p = 0.0002 for independent and interleaved experiments, respectively), but not in CSF (p > 0.3). This difference is attributed to the increased baseline MR tissue signal under hyperoxia induced by a shortened T1 and an increased BOLD effect. When switching from hyperoxia to normoxia without glucose injection, a signal change of ˜3.0% was found in brain tissue and a signal change of ˜1.5% was found in CSF.

DGE signal was significantly lower under hyperoxia than that under normoxia in brain tissue, but not in CSF. The reason is that DGE effect size of brain tissue is affected by the baseline signal, which could be influenced by T1 change and BOLD effect. Therefore, DGE experiments in which the oxygenation level is changed from baseline need to be interpreted carefully.

Spinal cord ischemia and hypoxia can be caused by compression, injury, and vascular alterations. Measuring ischemia and hypoxia directly in the spinal cord noninvasively remains challenging. Ischemia and hypoxia alter tissue pH, providing a physiologic parameter that may be more directly related to tissue viability. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that can be made sensitive to pH. More specifically, amine/amide concentration independent detection (AACID) is a recently developed endogenous CEST contrast that has demonstrated sensitivity to intracellular pH at 9.4 T. The goal of this study was to evaluate the reproducibility of AACID CEST measurements at different levels of the healthy cervical spinal cord at 3.0 T incorporating B1 correction. Using a 3.0 T MRI scanner, two 3D CEST scans (saturation pulse train followed by a 3D snapshot gradient-echo readout) were performed on 12 healthy subjects approximately 10 days apart, with the CEST volume centered at the C4 level for all subjects. Scan-rescan reproducibility was evaluated by examining between and within-subject coefficients of variation (CVs) and absolute AACID value differences. The C4 level of the spinal cord demonstrated the lowest within-subject CVs (4.1%-4.3%), between-subject CVs (5.6%-6.3%), and absolute AACID percent difference (5.8-6.1%). The B1 correction scheme significantly improved reproducibility (adjusted p-value = 0.002) compared with the noncorrected data, suggesting that implementing B1 corrections in the spinal cord is beneficial. It was concluded that pH-weighted AACID measurements, incorporating B1-inhomogeneity correction, were reproducible within subjects along the healthy cervical spinal cord and that optimal image quality was achieved at the center of the 3D CEST volume.

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease. These disorders are characterized by the accumulation and propagation of misfolded or mutant proteins, a process in which the glymphatic system is likely involved. Impaired glymphatic clearance could lead to the buildup of these toxic proteins, contributing to neurodegeneration. Understanding the glymphatic system's role in these disorders could provide insights into their pathophysiology and pave the way for new therapeutic strategies. Pharmacological enhancement of glymphatic clearance could reduce the burden of toxic proteins and slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools for studying the glymphatic system in vivo. These techniques allow for the visualization of glymphatic flow, providing insights into its function under healthy and pathological conditions. This narrative review highlights current MRI-based methodologies, such as motion-sensitizing pulsed field gradient (PFG) based methods, as well as dynamic gadolinium-based and glucose-enhanced methodologies currently used in the study of neurodegenerative disorders.

Cancer diagnosis by metabolic MRI proposes to follow the fate of glycolytic precursors such as pyruvate or glucose, and their in vivo conversion into lactate. This study compares the 2H MRI outlooks afforded by these metabolites when targeting a pancreatic cancer model. Exogenously injected [3,3',3″-2H3]-pyruvate was visible only briefly; it generated a deuterated lactate signal throughout the body that faded after ~5 min, showing a minor concentration bias at the rims of the tumors. [6,6'-2H2]-glucose by contrast originated a lactate signal that localized clearly within the tumors, persisting for over an hour. Investigations alternating deuterated and nondeuterated glucose injections revealed correlations between the lactate generation and the glucose available at the tumor, evidencing a continuous and avid glucose consumption generating well-localized lactate signatures as driven by the Warburg effect. This is by contrast to the transient and more promiscuous pyruvate-to-lactate transformation, which seemed subject to transporter and kinetics effects. The consequences of these observations within metabolic MRI are briefly discussed.

Endogenous CEST signal usually has low specificity due to contaminations from the magnetization transfer contrast (MTC) and other labile protons with overlapping or close Larmor frequencies. We propose to improve CEST signal specificity with adjustment of rotation and saturation effects (AROSE).

The AROSE approach measures the difference between CEST signals acquired with the same average irradiation power but largely different duty cycles, for example, a continuous wave or a high duty cycle pulse train versus a low duty cycle pulse train with a flip angle φ. Simulation, phantom, and in vivo rodent studies were performed to evaluate the characteristics of the AROSEφ signal.

Simulation and experimental results show that AROSE2π is a low-pass filter that can suppress fast exchanging processes (e.g., >3000 s-1 ), whereas AROSEπ is a band-pass filter suppressing both fast and slow exchange (e.g., <30 s-1 ) rates. For other φ angles, the sensitivity and the exchange-rate filtering effect of AROSEφ falls between AROSEπ and AROSE2π . AROSE can also minimize MTC and improve the Larmor frequency selectivity of the CEST signal. The linewidth of the AROSE1.5π spectrum is about 60% to 65% when compared to the CEST spectrum measured by continuous wave. Depending on the needs of an application, the sensitivity, exchange-rate filtering, and Larmor frequency selectivity can be adjusted by varying the flip angle, duty cycle, and average irradiation power.

Compared to conventional CEST signals, AROSE can minimize MTC and improve exchange rate filtering and Larmor frequency specificity.

Dynamic 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.

This 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.

GlucoCEST 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.

We 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.

Contrast 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.

• 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.

Chemical exchange saturation transfer (CEST) MRI has been identified as a novel alternative to classical diagnostic imaging. Over the last several decades, many studies have been conducted to determine possible CEST agents, such as endogenously expressed compounds or proteins, that can be utilized to produce contrast with minimally invasive procedures and reduced or non-existent levels of toxicity. In recent years there has been an increased interest in the generation of genetically engineered CEST contrast agents, typically based on existing proteins with CEST contrast or modified to produce CEST contrast. We have developed an in silico method for the evolution of peptide sequences to optimize CEST contrast and showed that these peptides could be combined to create de novo biosensors for CEST MRI. A single protein, superCESTide, was designed to be 198 amino acids. SuperCESTide was expressed in E. coli and purified with size exclusion chromatography. The magnetic transfer ratio asymmetry generated by superCESTide was comparable to levels seen in previous CEST reporters, such as protamine sulfate (salmon protamine) and human protamine. These data show that novel peptides with sequences optimized in silico for CEST contrast that utilize a more comprehensive range of amino acids can still produce contrast when assembled into protein units expressed in complex living environments.

Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs.

The chemical exchange of labile protons of the hydroxyl groups can be exploited in a variety of magnetic resonance experiments to gain information about the groups and their physicochemical environment. The exchangeable -OH protons provide important contributions to the T2 of water signals thus contributing to the T2-weighted contrast of MRI images. This exchange can be exploited more specifically and sensitively in chemical exchange saturation transfer (CEST) or longitudinal rotating frame relaxation (T1,ρ) experiments. Since glucose is omnipresent in living organisms, it may be seen as a rather universal probe. Even though the potential was first recognized many years ago, practical use has remained scarce due to numerous challenges. The major limitation is the rather low glucose concentration in most tissues. The other obstacles are related to multiple dependencies of the exchange parameters, such as temperature, pH, and concentration of various ions that are not known in sufficient detail for glucose. Thus, we embarked on evaluating the exchange parameters of a model that included every relevant chemical site for all -OH protons in both dominant enantiomers of glucose. We have (1) obtained conventional one-dimensional proton NMR spectra of glucose solutions in suitable temperature ranges, (2) we have iterated through several exchange models with various degrees of freedom determined by the number of distinguishable -OH proton sites and compared their performance, (3) we extrapolated the parameters of the best model of physiological temperature and (4) we demonstrated the use of the parameters in virtual experiments. As the main results, (1) we have obtained the temperature dependence of exchange parameters with reliable confidence intervals in three different pH values, with two of them reaching physiological temperature, and (2) we show how the parameters can be used in virtual experiments, helping to develop new applications for glucose as an NMR/MRI probe.

With metabolic alterations of the tumor microenvironment (TME) contributing to cancer progression, metastatic spread and response to targeted therapies, non-invasive and repetitive imaging of tumor metabolism is of major importance. The purpose of this study was to investigate whether multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) allows to detect differences in the metabolic profiles of the TME in murine breast cancer models with divergent degrees of malignancy and to assess their response to immunotherapy.

Tumor characteristics of highly malignant 4T1 and low malignant 67NR murine breast cancer models were investigated, and their changes during tumor progression and immune checkpoint inhibitor (ICI) treatment were evaluated. For simultaneous analysis of different metabolites, multiparametric CEST-MRI with calculation of asymmetric magnetization transfer ratio (MTRasym) at 1.2 to 2.0 ppm for glucose-weighted, 2.0 ppm for creatine-weighted and 3.2 to 3.6 ppm for amide proton transfer- (APT-) weighted CEST contrast was conducted. Ex vivo validation of MRI results was achieved by 1H nuclear magnetic resonance spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry imaging with laser postionization and immunohistochemistry.

During tumor progression, the two tumor models showed divergent trends for all examined CEST contrasts: While glucose- and APT-weighted CEST contrast decreased and creatine-weighted CEST contrast increased over time in the 4T1 model, 67NR tumors exhibited increased glucose- and APT-weighted CEST contrast during disease progression, accompanied by decreased creatine-weighted CEST contrast. Already three days after treatment initiation, CEST contrasts captured response to ICI therapy in both tumor models.

Multiparametric CEST-MRI enables non-invasive assessment of metabolic signatures of the TME, allowing both for estimation of the degree of tumor malignancy and for assessment of early response to immune checkpoint inhibition.

Liver disease is a major health concern globally, with high morbidity and mor-tality rates. Precise diagnosis and assessment are vital for guiding treatment approaches, predicting outcomes, and improving patient prognosis. Magnetic resonance imaging (MRI) is a non-invasive diagnostic technique that has been widely used for detecting liver disease. Recent advancements in MRI technology, such as diffusion weighted imaging, intravoxel incoherent motion, magnetic resonance elastography, chemical exchange saturation transfer, magnetic resonance spectroscopy, hyperpolarized MR, contrast-enhanced MRI, and ra-diomics, have significantly improved the accuracy and effectiveness of liver disease diagnosis. This review aims to discuss the progress in new MRI technologies for liver diagnosis. By summarizing current research findings, we aim to provide a comprehensive reference for researchers and clinicians to optimize the use of MRI in liver disease diagnosis and improve patient prognosis.

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.

Dynamic glucose-enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable with dynamic contrast-enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE MRI, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 T and the area under the curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded "curve maps" showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (p < 0.007). Furthermore, the distribution of curve types differed between lesions and normal tissue for both DGE and DCE. The DGE and DCE response curves in a 6-min postinjection time interval were classified as the same curve type in 20% of the lesion voxels, which increased to 29% when a 12-min DGE time interval was considered. While both DGE and DCE tissue response curve-shape analysis enabled differentiation of lesions from normal brain tissue in humans, their enhancements were neither temporally identical nor confined entirely to the same regions. Curve maps can provide accessible and intuitive information about the shape of DGE response curves, which is expected to be useful in the continued work towards the interpretation of DGE uptake curves in terms of D-glucose delivery, transport, and metabolism.

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.

Since the inception of CEST MRI in the 1990s, a number of compounds have been identified as suitable for generating contrast, including paramagnetic lanthanide complexes, hyperpolarized atom cages and, most interesting, diamagnetic compounds. In the past two decades, there has been a major emphasis in this field on the identification and application of diamagnetic compounds that have suitable biosafety profiles for usage in medical applications. Even in the past five years there has been a tremendous growth in their numbers, with more and more emphasis being placed on finding those that can be ultimately used for patient studies on clinical 3 T scanners. At this point, a number of endogenous compounds present in tissue have been identified, and also natural and synthetic organic compounds that can be administered to highlight pathology via CEST imaging. Here we will provide a very extensive snapshot of the types of diamagnetic compound that can generate CEST MRI contrast, together with guidance on their utility on typical preclinical and clinical scanners and a review of the applications that might benefit the most from this new technology.

The ability of CEST MRI to detect the presence of millimolar concentrations of non-metallic contrast agents has made it possible to study, non-invasively, important biological molecules such as proteins and sugars, as well as drugs already approved for clinical use. Here, we review efforts to use sugar and sugar polymers as exogenous contrast agents, which is possible based on the exchange of their hydroxyl protons with water protons. While this capability has raised early enthusiasm, for instance about the possibility of imaging D-glucose metabolism with MRI in a way analogous to PET, experience over the past decade has shown that this is not trivial. On the other hand, many studies have confirmed the possibility of imaging a large variety of sugar analogues, each with potentially interesting applications to assess tissue physiology. Some promising applications are the study of (i) sugar delivery and transport to assess blood-brain barrier integrity and (ii) sugar uptake by cells for their characterization (e.g., cancer versus healthy), as well as (iii) clearance of sugars to assess tissue drainage-for instance, through the glymphatic system. To judge these opportunities and their challenges, especially in the clinic, it is necessary to understand the technical aspects of detecting the presence of rapidly exchanging protons through the water signal in MRI, especially as a function of magnetic field strength. We expect that novel approaches in terms of MRI detection (both saturation transfer and relaxation based), MRI data analysis, and sugar design will push this young field forward in the next decade.

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.

Chemical exchange saturation transfer (CEST) MRI has generated great interest for molecular imaging applications because it can image low-concentration solute molecules in vivo with enhanced sensitivity. CEST effects are detected indirectly through a reduction in the bulk water signal after repeated perturbation of the solute proton magnetization using one or more radiofrequency (RF) irradiation pulses. The parameters used for these RF pulses-frequency offset, duration, shape, strength, phase, and interpulse spacing-determine molecular specificity and detection sensitivity, thus their judicious selection is critical for successful CEST MRI scans. This review article describes the effects of applying RF pulses on spin systems and compares conventional saturation-based RF labeling with more recent excitation-based approaches that provide spectral editing capabilities for selectively detecting molecules of interest and obtaining maximal contrast.

Biomedical imaging, especially molecular imaging, has been a driving force in scientific discovery, technological innovation, and precision medicine in the past two decades. While substantial advances and discoveries in chemical biology have been made to develop molecular imaging probes and tracers, translating these exogenous agents to clinical application in precision medicine is a major challenge. Among the clinically accepted imaging modalities, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) exemplify the most effective and robust biomedical imaging tools. Both MRI and MRS enable a broad range of chemical, biological and clinical applications from determining molecular structures in biochemical analysis to imaging diagnosis and characterization of many diseases and image-guided interventions. Using chemical, biological, and nuclear magnetic resonance properties of specific endogenous metabolites and native MRI contrast-enhancing biomolecules, label-free molecular and cellular imaging with MRI can be achieved in biomedical research and clinical management of patients with various diseases. This review article outlines the chemical and biological bases of several label-free chemically and molecularly selective MRI and MRS methods that have been applied in imaging biomarker discovery, preclinical investigation, and image-guided clinical management. Examples are provided to demonstrate strategies for using endogenous probes to report the molecular, metabolic, physiological, and functional events and processes in living systems, including patients. Future perspectives on label-free molecular MRI and its challenges as well as potential solutions, including the use of rational design and engineered approaches to develop chemical and biological imaging probes to facilitate or combine with label-free molecular MRI, are discussed.

Dynamic glucose-enhanced (DGE) MRI relates to a group of exchange-based MRI techniques where the uptake of glucose analogues is studied dynamically. However, motion artifacts can be mistaken for true DGE effects, while motion correction may alter true signal effects. The aim was to design a numerical human brain phantom to simulate a realistic DGE MRI protocol at 3T that can be used to assess the influence of head movement on the signal before and after retrospective motion correction.

MPRAGE data from a tumor patient were used to simulate dynamic Z-spectra under the influence of motion. The DGE responses for different tissue types were simulated, creating a ground truth. Rigid head movement patterns were applied as well as physiological dilatation and pulsation of the lateral ventricles and head-motion-induced B0 -changes in presence of first-order shimming. The effect of retrospective motion correction was evaluated.

Motion artifacts similar to those previously reported for in vivo DGE data could be reproduced. Head movement of 1 mm translation and 1.5 degrees rotation led to a pseudo-DGE effect on the order of 1% signal change. B0 effects due to head motion altered DGE changes due to a shift in the water saturation spectrum. Pseudo DGE effects were partly reduced or enhanced by rigid motion correction depending on tissue location.

DGE MRI studies can be corrupted by motion artifacts. Designing post-processing methods using retrospective motion correction including B0 correction will be crucial for clinical implementation. The proposed phantom should be useful for evaluation and optimization of such techniques.

Chemical exchange saturation transfer (CEST) MRI is a versatile molecular imaging approach that holds great promise for clinical translation. A number of compounds have been identified as suitable for performing CEST MRI, including paramagnetic CEST (paraCEST) agents and diamagnetic CEST (diaCEST) agents. DiaCEST agents are very attractive because of their excellent biocompatibility and potential for biodegradation, such as glucose, glycogen, glutamate, creatine, nucleic acids, et al. However, the sensitivity of most diaCEST agents is limited because of small chemical shifts (1.0-4.0 ppm) from water. To expand the catalog of diaCEST agents with larger chemical shifts, herein, we have systematically investigated the CEST properties of acyl hydrazides with different substitutions, including aromatic and aliphatic substituents. We have tuned the labile proton chemical shifts from 2.8-5.0 ppm from water while exchange rates varied from ~680 to 2340 s^-1 at pH 7.2, which allows strong CEST contrast on scanners down to B₀ = 3 T. One acyl hydrazide, adipic acid dihydrazide (ADH), was tested on a mouse model of breast cancer and showed nice contrast in the tumor region. We also prepared a derivative, acyl hydrazone, which showed the furthest shifted labile proton (6.4 ppm from water) and excellent contrast properties. Overall, our study expands the catalog of diaCEST agents and their application in cancer diagnosis.

Chemical Exchange Saturation Transfer (CEST) magnetic resonance imaging (MRI) has been identified as a novel alternative to classical diagnostic imaging. Over the last several decades, many studies have been conducted to determine possible CEST agents, such as endogenously expressed compounds or proteins, that can be utilized to produce contrast with minimally invasive procedures and reduced or non-existent levels of toxicity. In recent years there has been an increased interest in the generation of genetically engineered CEST contrast agents, typically based on existing proteins with CEST contrast or modified to produce CEST contrast. We have developed an in-silico method for the evolution of peptide sequences to optimize CEST contrast and showed that these peptides could be combined to create de novo biosensors for CEST MRI. A single protein, superCESTide 2.0, was designed to be 198 amino acids. SuperCESTide 2.0 was expressed in E. coli and purified with size-exclusion chromatography. The magnetic transfer ratio asymmetry (MTR asym ) generated by superCESTide 2.0 was comparable to levels seen in previous CEST reporters, such as protamine sulfate (salmon protamine, SP), Poly-L-Lysine (PLL), and human protamine (hPRM1). This data shows that novel peptides with sequences optimized in silico for CEST contrast that utilizes a more comprehensive range of amino acids can still produce contrast when assembled into protein units expressed in complex living environments.

To develop an auto-calibrated technique by joint K-space and Image-space Parallel Imaging (KIPI) for accelerated CEST acquisition.

The KIPI method selects a calibration frame with a low acceleration factor (AF) and auto-calibration signals (ACS) acquired, from which the coil sensitivity profiles and artifact correction maps are calculated after restoring the k-space by GRAPPA. Then the other frames with high AF and without ACS can be reconstructed by SENSE and artifact suppression. The signal leakage due to the T₂ -decay filtering in k-space compromises the SENSE reconstruction, which can be corrected by the artifact suppression algorithm of KIPI. The 2D and 3D imaging experiments were done on the phantom, healthy volunteer, and brain tumor patient with a 3T scanner.

The proposed KIPI method was evaluated by retrospectively undersampled data with variable AFs and compared against existing parallel imaging methods (SENSE/auto, GRAPPA, and ESPIRiT). KIPI enabled CEST frames with random AFs to achieve similar image quality, eliminated the strong aliasing artifacts, and generated significantly smaller errors than the other methods (p < 0.01). The KIPI method permitted an AF up to 12-fold in both phase-encoding and slice-encoding directions for 3D CEST source images, achieving an overall 8.2-fold speedup in scan time.

KIPI is a novel auto-calibrated parallel imaging method that enables variable AFs for different CEST frames, achieves a significant reduction in scan time, and does not compromise the accuracy of CEST maps.

To optimize the homogeneity of the presaturation module in a Chemical Exchange Saturation Transfer (CEST) acquisition at 7 T using parallel transmission (pTx).

An optimized pTx-CEST presaturation scheme based on precomputed universal pulses was designed. The optimization was performed by minimizing the L2-norm between the effective B 1 , RMS + $$ {B}_{1,\mathrm{RMS}}^{+} $$ and a given target while imposing energy constraints under virtual observation points (VOPs) supervision. The proposed method was evaluated through simulations and experimentally, both in vitro, on a realistic human head phantom, and in vivo, on healthy volunteers. The results were compared with circular polarization (CP) presaturation and other pTx approaches previously proposed. All experiments were conducted on a 7 T MRI scanner using a commercial 8Tx/32Rx head coil.

The simulations show that the proposed pTx strategy boosted with VOPs is superior to the CP mode and existent pTx approaches. While the best results are obtained with subject specific pulses, the gain provided by the use of VOPs renders the universal pulses superior to tailored pulses optimized under vendor provided Specific Absorption Rate (SAR) management. In the phantom, the glucose MTR asym $$ {\mathrm{MTR}}_{\mathrm{asym}} $$ map was significantly more homogeneous than with CP (root mean square error [RMSE] 17% vs. 30%). The efficiency of the method for in vivo hydroxyl, glutamate and rNOE weighted CEST acquisitions was also demonstrated.

The use of a pTx presaturation scheme based on universal pulses optimized under VOP SAR management is significantly benefiting CEST imaging at high magnetic field.

Image guided nose-to-brain drug delivery provides a non-invasive way to monitor drug delivered to the brain, and the intranasal administration could increase effective dose via bypassing Blood Brain Barrier (BBB). Here, we investigated the imaging of liposome-based drug delivery to the brain via intranasal administration, in which the liposome could penetrate mucus and could be detected by chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) at 3T field strength. Liposomes were loaded with a computed tomography (CT) contrast agent, iohexol (Ioh-Lipo), which has specific amide protons exchanging at 4.3 ppm of Z-spectrum (or CEST spectrum). Ioh-Lipo generated CEST contrasts of 35.4% at 4.3 ppm, 1.8% at -3.4 ppm and 20.6% at 1.2 ppm in vitro. After intranasal administration, these specific CEST contrasts were observed in both olfactory bulb (OB) and frontal lobe (FL) in the case of 10% polyethylene glycol (PEG) Ioh-Lipo. We observed obvious increases in CEST contrast in OB half an hour after the injection of 10% PEG Ioh-Lipo, with a percentage increase of 62.0% at 4.3 ppm, 10.9% at -3.4 ppm and 25.7% at 1.2 ppm. Interestingly, the CEST map at 4.3 ppm was distinctive from that at -3.4 pm and 1.2 ppm. The highest contrast of 4.3 ppm was at the external plexiform layer (EPL) and the region between left and right OB (LROB), while the CEST contrast at -3.4 ppm had no significant difference among all investigated regions with slightly higher signal in olfactory limbus (OL, between OB and FL) and FL, as validated with histology. While no substantial increase of CEST contrast at 4.3 ppm, -3.4 ppm or 1.2 ppm was observed in OB and FL when 1% PEG Ioh-Lipo was administered. We demonstrated for the first time the feasibility of non-invasively detecting the nose-to-brain delivery of liposomes using CEST MRI. This multiple-contrast approach is necessary to image the specific distribution of iohexol and liposome simultaneously and independently, especially when designing drug carriers for nose-to-brain drug delivery.

The average saturation efficiency filter (ASEF) is a novel method of improving the specificity of CEST; however, there is a mismatch between the magnetization transfer (MT) effect under high-duty cycle and low-duty cycle pulse trains. We explore measures of mitigation and the sensitivity and potential of ASEF imaging in phantoms and stroke rats.

Simulation and nicotinamide phantoms in denatured protein were used to investigate the effect of different average saturation powers and MT pool parameters on matching coefficients used for correction as well as the ASEF ratio signal and baseline. Then, in vivo studies were performed in stroke rodents to further investigate the sensitivity and fidelity of ASEF ratio spectra.

Simulation and studies of nicotinamide phantoms show that the matching coefficient needed to correct the baseline MT mismatch is strongly dependent on the average saturation power. In vivo studies in stroke rodents show that the matching coefficient required to correct the baseline MT mismatch is different for normal versus ischemic tissue. Thus, a baseline correction was performed to further suppress the residue MT mismatch. After correction of the mismatch, ASEF ratio achieved comparable contrast at 3.6 ppm between normal and ischemic tissue when compared to the apparent amide proton transfer (APT*) approach. Moreover, contrasts for 2.0 and 2.6 ppm were also ascertainable from the same spectra.

ASEF can improve the CEST signal specificity of slow exchange labile protons such as amide and guanidyl, with small loss to sensitivity. It has strong potential in the CEST imaging of various diseases.

Glucose is the main energy source in the brain and its regulated uptake and utilization are important biomarkers of pathological brain function. Glucose Chemical Exchange Saturation Transfer (GlucoCEST) and its time-resolved version Dynamic Glucose-Enhanced MRI (DGE) are promising approaches to monitor glucose and detect tumors, since they are radioactivity-free, do not require ¹³C labeling and are is easily translatable to the clinics. The main principle of DGE is clear. However, what remains to be established is to which extent the signal reflects vascular, extracellular or intracellular glucose. To elucidate the compartmental contributions to the DGE signal, we coupled it with FRET-based fiber photometry of genetically encoded sensors, a technique that combines quantitative glucose readout with cellular specificity. The glucose sensor FLIIP was used with fiber photometry to measure astrocytic and neuronal glucose changes upon injection of D-glucose, 3OMG and L-glucose, in the anaesthetized murine brain. By correlating the kinetic profiles of the techniques, we demonstrate the presence of a vascular contribution to the signal, especially at early time points after injection. Furthermore, we show that, in the case of the commonly used contrast agent 3OMG, the DGE signal actually anticorrelates with the glucose concentration in neurons and astrocytes.

Selenium nanoparticle (SeNP)-based nanotherapeutics have become an emerging cancer therapy, while effective drug delivery remains a technical hurdle. A theranostic approach, through which imaging companions are integrated with SeNPs, will allow image-guided drug delivery and, therefore, is highly desirable. Traditional methods require the chemical conjugation of imaging agents to the surface of nanoparticles, which may impede the later clinical translation. In this study, we developed a label-free strategy in which lentinan-functionalized SeNPs (LNT-SeNPs) are detected using MRI by the hydroxyl protons carried on LNT molecules. The in vitro phantom study showed that LNT and LNT-SeNPs have a strong CEST signal at 1.0 ppm apart from the water resonance, suggesting an in vivo detectability in the µM concentration range. Demonstrated on CT26 colon tumor cells, LNT-SeNPs exert a strong anticancer effect (IC50 = 4.8 μM), prominently attributed to the ability to generate intracellular reactive oxygen species. However, when testing in a mouse model of CT26 tumors, administration of LNT-SeNPs alone was found unable to deliver sufficient drugs to the tumor, leading to poor treatment responses. To improve the drug delivery, we co-injected LNT-SeNPs and TNF-α, a previously reported drug that could effectively damage the endothelial cells in the tumor vasculature, thereby increasing drug delivery to the tumor. Our results revealed a 75% increase in the intratumoral CEST MRI signal, indicating a markedly increased delivery efficiency of LNT-SeNPs when combined with TNF-α. The combination therapy also resulted in a significantly enhanced treatment outcome, as revealed by the tumor growth study. Taken together, our study demonstrates the first label-free, SeNP-based theranostic system, in which LNT was used for both functional surface coating and CEST MRI signal generating. Such a theranostic LNT-SeNP system is advantageous because it requires chemical labeling and, therefore, has high biocompatibility and low translatable barriers.

Mannitol is a hyperosmolar agent for reducing intracranial pressure and inducing osmotic blood-brain barrier opening (OBBBO). There is a great clinical need for a non-invasive method to optimize the safety of mannitol dosing. The aim of this study was to develop a label-free Chemical Exchange Saturation Transfer (CEST)-based MRI approach for detecting intracranial accumulation of mannitol following OBBBO.

In vitro MRI was conducted to measure the CEST properties of D-mannitol of different concentrations and pH. In vivo MRI and MRS measurements were conducted on Sprague-Dawley rats using a Biospec 11.7T horizontal MRI scanner. Rats were catheterized at the internal carotid artery (ICA) and randomly grouped to receive either 1 mL or 3 mL D-mannitol. CEST MR images were acquired before and at 20 min after the infusion.

In vitro MRI showed that mannitol has a strong, broad CEST contrast at around 0.8 ppm with a mM CEST MRI detectability. In vivo studies showed that CEST MRI could effectively detect mannitol in the brain. The low dose mannitol treatment led to OBBBO but no significant mannitol accumulation, whereas the high dose regimen resulted in both OBBBO and mannitol accumulation. The CEST MRI findings were consistent with ¹H-MRS and Gd-enhanced MRI assessments.

We demonstrated that CEST MRI can be used for non-invasive, label-free detection of mannitol accumulation in the brain following BBBO treatment. This method may be useful as a rapid imaging tool to optimize the dosing of mannitol-based OBBBO and improve its safety and efficacy.

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.