Coherence pathway analysis of J-coupled lipids and lactate and effective suppression of lipids upon the selective multiple quantum coherence lactate editing sequence.

Objective.The selective multiple quantum coherence (Sel-MQC) sequence is a magnetic resonance spectroscopy (MRS) technique used to detect lactate and suppress co-resonant lipid signalsin vivo. The coherence pathways of J-coupled lipids upon the sequence, however, have not been studied, hindering a logical design of the sequence to fully attenuate lipid signals. The objective of this study is to elucidate the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and find a strategy to effectively suppress lipid signals from these pathways while keeping the lactate signal.Approach.The product operator formalism was used to express the evolutions of the J-coupled spins of lipids and lactate. The transformations of the product operators by the spectrally selective pulses of the sequence were calculated by using the off-resonance rotation matrices. The coherence pathways and the conversion rates of the individual pathways were derived from them. Experiments were performed on phantoms and two human subjects at 3 T.Main results.The coherence pathways contributing to the various lipid resonance signals by the Sel-MQC sequence depending on the gradient ratios and RF pulse lengths were identified. Theoretical calculations of the signals from the determined coherence pathways and signal attenuations by gradients matched the experimental data very well. Lipid signals from fatty tissues of the subjects were successfully suppressed to the noise level by using the gradient ratio -0.8:-1:2 or 1:0.8:2. The new gradient ratios kept the lactate signal the same as with the previously used gradient ratio 0:-1:2.Significance.The study has elucidated the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and demonstrated how lipid signals can be effectively suppressed while keeping lactate signals by using information from the coherence pathway analysis. The findings enable applying the Sel-MQC sequence to lactate detection in an environment of high concentrations of lipids.

Volumetric glutamate imaging (GluCEST) using 7T MRI can lateralize nonlesional temporal lobe epilepsy: A preliminary study.

INTRODUCTION: Drug-resistant epilepsy patients show worse outcomes after resection when standard neuroimaging is nonlesional, which occurs in one-third of patients. In prior work, we employed 2-D glutamate imaging, Glutamate Chemical Exchange Saturation Transfer (GluCEST), to lateralize seizure onset in nonlesional temporal lobe epilepsy (TLE) based on increased ipsilateral GluCEST signal in the total hippocampus and hippocampal head. We present a significant advancement to single-slice GluCEST imaging, allowing for three-dimensional analysis of brain glutamate networks. METHODS: The study population consisted of four MRI-negative, nonlesional TLE patients (two male, two female) with electrographically identified left temporal onset seizures. Imaging was conducted on a Siemens 7T MRI scanner using the CEST method for glutamate, while the advanced normalization tools (ANTs) pipeline and the Automated Segmentation of the Hippocampal Subfields (ASHS) method were employed for image analysis. RESULTS: Volumetric GluCEST imaging was validated in four nonlesional TLE patients showing increased glutamate lateralized to the hippocampus of seizure onset (p = .048, with a difference among ipsilateral to contralateral GluCEST signal percentage ranging from -0.05 to 1.37), as well as increased GluCEST signal in the ipsilateral subiculum (p = .034, with a difference among ipsilateral to contralateral GluCEST signal ranging from 0.13 to 1.57). CONCLUSIONS: The ability of 3-D, volumetric GluCEST to localize seizure onset down to the hippocampal subfield in nonlesional TLE is an improvement upon our previous 2-D, single-slice GluCEST method. Eventually, we hope to expand volumetric GluCEST to whole-brain glutamate imaging, thus enabling noninvasive analysis of glutamate networks in epilepsy and potentially leading to improved clinical outcomes.

Improved method for post-processing correction of B1 inhomogeneity in glutamate-weighted CEST images of the human brain.

Glutamate-weighted CEST (gluCEST) imaging is nearly unique in its ability to provide non-invasive, spatially resolved measurements of glutamate in vivo. In this article, we present an improved correction for B1 inhomogeneity of gluCEST images of the human brain. Images were obtained on a Siemens 7.0 T Terra outfitted with a single-volume transmit/32-channel receive phased array head coil. Numerical Bloch-McConnell simulations, fitting and data processing were performed using in-house code written in MATLAB and MEX (MATLAB executable). "Calibration" gluCEST data was acquired and fit with a phenomenological functional form first described here. The resulting surfaces were used to correct experimental data in accordance with a newly developed method. Healthy volunteers of varying ages were used for both fitted "calibration" data and corrected "experimental" data. Simulations allowed us to describe the dependence of CEST at 3.0 ppm (gluCEST) on saturation B1 using a new functional form, whose validity was confirmed by successful fitting to real human data. This functional form was used to parameterize surfaces over the space (B1 , T1 ), which could then be used to correct the signal from each pixel. The resulting images show less signal loss in areas of low B1 and greater contrast than those generated using the previously published method. We demonstrate that, using this method with appropriate nominal saturation B1 , the major limitation of correcting for B1 inhomogeneity becomes the effective flip angle of the acquisition module, rather than inability to correct for inhomogeneous saturation. The lower limit of our correction ability with respect to both saturation and acquisition B1 is about 40% of the nominal value. In summary, we demonstrate a more rigorous and successful approach to correcting gluCEST images for B1 inhomogeneity. Limitations of the method and further improvements to enable correction in regions with severe pathology are discussed.

Recovery kinetics of creatine in mild plantar flexion exercise using 3D creatine CEST imaging at 7 Tesla.

PURPOSE: Two-dimensional creatine CEST (2D-CrCEST), with a slice thickness of 10-20 mm and temporal resolution (τRes ) of about 30 seconds, has previously been shown to capture the creatine-recovery kinetics in healthy controls and in patients with abnormal creatine-kinase kinetics following the mild plantar flexion exercise. Since the distribution of disease burden may vary across the muscle length for many musculoskeletal disorders, there is a need to increase coverage in the slice-encoding direction. Here, we demonstrate the feasibility of 3D-CrCEST with τRes of about 30 seconds, and propose an improved voxel-wise B1+ -calibration approach for CrCEST. METHODS: The current 7T study with enrollment of 5 volunteers involved collecting the baseline CrCEST imaging for the first 2 minutes, followed by 2 minutes of plantar flexion exercise and then 8 minutes of postexercise CrCEST imaging, to detect the temporal evolution of creatine concentration following exercise. RESULTS: Very good repeatability of 3D-CrCEST findings for activated muscle groups on an intraday and interday basis was established, with coefficient of variance of creatine recovery constants (τCr ) being 7%-15.7%, 7.5%, and 5.8% for lateral gastrocnemius, medial gastrocnemius, and peroneus longus, respectively. We also established a good intraday and interday scan repeatability for 3D-CrCEST and also showed good correspondence between τCr measurements using 2D-CrCEST and 3D-CrCEST acquisitions. CONCLUSION: In this study, we demonstrated for the first time the feasibility and the repeatability of the 3D-CrCEST method in calf muscle with improved B1+ correction to measure creatine-recovery kinetics within a large 3D volume of calf muscle.

Accelerating GluCEST imaging using deep learning for B0 correction.

PURPOSE: Glutamate weighted Chemical Exchange Saturation Transfer (GluCEST) MRI is a noninvasive technique for mapping parenchymal glutamate in the brain. Because of the sensitivity to field (B0 ) inhomogeneity, the total acquisition time is prolonged due to the repeated image acquisitions at several saturation offset frequencies, which can cause practical issues such as increased sensitivity to patient motions. Because GluCEST signal is derived from the small z-spectrum difference, it often has a low signal-to-noise-ratio (SNR). We proposed a novel deep learning (DL)-based algorithm armed with wide activation neural network blocks to address both issues. METHODS: B0 correction based on reduced saturation offset acquisitions was performed for the positive and negative sides of the z-spectrum separately. For each side, a separate deep residual network was trained to learn the nonlinear mapping from few CEST-weighted images acquired at different ppm values to the one at 3 ppm (where GluCEST peaks) in the same side of the z-spectrum. RESULTS: All DL-based methods outperformed the "traditional" method visually and quantitatively. The wide activation blocks-based method showed the highest performance in terms of Structural Similarity Index (SSIM) and peak signal-to-noise ratio (PSNR), which were 0.84 and 25dB respectively. SNR increases in regions of interest were over 8dB. CONCLUSION: We demonstrated that the new DL-based method can reduce the entire GluCEST imaging time by ˜50% and yield higher SNR than current state-of-the-art.

Glutamate-Weighted CEST Contrast After Removal of Magnetization Transfer Effect in Human Brain and Rat Brain with Tumor.

PURPOSE: To mitigate the effect of magnetization transfer (MT) from glutamate-weighted chemical exchange saturation transfer (GluCEST) contrast in healthy human brain and its demonstration in a rat brain tumor model. PROCEDURES: GluCEST data was acquired from six healthy human volunteers at 7T and on a rat brain with tumor at 9.4 T. Single voxel proton magnetic resonance spectroscopy (1HMRS) data was acquired from three human volunteers. The magnetic resonance imaging protocol included CEST data acquisition at multiple frequencies for generating Z-spectra, B0 and B1 map. Partial Z-spectra at offset frequencies from ± 100 to ± 14 ppm were fitted to model semi-solid MT component by Lorentzian, Gaussian, super-Lorentzian, and 6th degree polynomial function lineshapes. Average residual errors per pixel was calculated. The MT effect of the Z-spectra was removed by subtracting fitted MT component from Z-spectra. GluCEST was computed as GluCESTNeg (normalized with signal at - 3 ppm) and GluCESTM0 (normalized with unsaturated signal). The difference between GluCEST maps before and after MT removal was compared using T test. RESULTS: Better accuracy of fitting off-resonance Z-spectra was achieved with super-Lorentzian (σ = 0.0009) and Lorentzian (σ = 0.0017) compared to other lineshapes. There was significant (p < 0.01) increase in GluCESTM0 and decrease in GluCESTNeg contrast after MT removal. GluCESTNeg and GluCESTM0 maps after MT removal using Lorentzian lineshape showed gray matter (GM) to white matter (WM) contrast ratio of 1.47 and 1.52 respectively. These ratios are close to glutamate concentration ratio in GM/WM as observed from 1HMRS data. Thus, the quantity of the MT removed from Z-spectra is appropriate using Lorentzian lineshape due to preservation of GluCEST contrast-ratio in GM/WM. The amount of MT removed from Z-spectra is overestimated using super-Lorentzian and underestimated using Gaussian and polynomial lineshapes. Tumor tissue showed unexpected increase in GluCEST contrast compared to contra-lesional tissue, which represents normal appearing tissue in the brain on contra-lateral side of tumor region, due to decrease in MT component. CONCLUSIONS: Removal of MT effect from Z-spectra using Lorentzian lineshape increased the specificity of GluCEST contrast to glutamate in healthy human brain and was demonstrated in rat brain tumor model.

Single-Voxel 1 H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD+ ) in humans at 7T using a 32-channel volume coil.

PURPOSE: Reliable monitoring of tissue nicotinamide adenine dinucleotide (NAD+ ) concentration may provide insights on its roles in normal and pathological aging. In the present study, we report a 1 H MRS pulse sequence for the in vivo, localized 1 H MRS detection of NAD+ from the human brain. METHODS: Studies were carried out on a 7T Siemens MRI scanner using a 32-channel product volume coil. The pulse sequence consisted of a spectrally selective low bandwidth E-BURP-1 90° pulse. PRESS localization was achieved using optimized Shinnar-Le Roux 180° pulses and overlapping gradients were used to minimize the TE. The reproducibility of NAD+ quantification was measured in 11 healthy volunteers. The association of cerebral NAD+ with age was assessed in 16 healthy subjects 26-78 years old. RESULTS: Spectra acquired from a voxel placed in subjects' occipital lobe consisted of downfield peaks from the H2 , H4 , and H6 protons of the nicotinamide moiety of NAD+ between 8.9-9.35 ppm. The mean ± SD within-session and between-session coefficients of variation were found to be 6.14 ± 2.03% and 6.09 ± 3.20%, respectively. In healthy volunteers, an age-dependent decline of the NAD+ levels in the brain was also observed (ß = -1.24 µM/y, SE = 0.21, P < 0.001). CONCLUSION: We demonstrated the feasibility and robustness of a newly developed 1 H MRS technique to measure localized cerebral NAD+ at 7T MRI using a commercially available RF head coil. This technique may be further applied to detect and quantify NAD+ from different regions of the brain as well as from other tissues.

Evaluating the feasibility of creatine-weighted CEST MRI in human brain at 7 T using a Z-spectral fitting approach.

The current study aims to evaluate the feasibility of creatine (Cr) chemical exchange saturation transfer (CEST)-weighted MRI at 7 T in the human brain by optimizing the saturation pulse parameters and computing contrast using a Z-spectral fitting approach. The Cr-weighted (Cr-w) CEST contrast was computed from phantoms data. Simulations were carried out to obtain the optimum saturation parameters for Cr-w CEST with lower contribution from other brain metabolites. CEST-w images were acquired from the brains of four human subjects at different saturation parameters. The Cr-w CEST contrast was computed using both asymmetry analysis and Z-spectra fitting approaches (models 1 and 2, respectively) based on Lorentzian functions. For broad magnetization transfer (MT) effect, Gaussian and Super-Lorentzian line shapes were also evaluated. In the phantom study, the Cr-w CEST contrast showed a linear dependence on concentration in physiological range and a nonlinear dependence on saturation parameters. The in vivo Cr-w CEST map generated using asymmetry analysis from the brain represents mixed contrast with contribution from other metabolites as well and relayed nuclear Overhauser effect (rNOE). Simulations provided an estimate for the optimum range of saturation parameters to be used for acquiring brain CEST data. The optimum saturation parameters for Cr-w CEST to be used for brain data were around B1rms  = 1.45 µT and duration = 2 seconds. The Z-spectral fitting approach enabled computation of individual components. This also resulted in mitigating the contribution from MT and rNOE to Cr-w CEST contrast, which is a major source of underestimation in asymmetry analysis. The proposed modified z-spectra fitting approach (model 2) is more stable to noise compared with model 1. Cr-w CEST contrast obtained using fitting was 6.98 ± 0.31% in gray matter and 5.45 ± 0.16% in white matter. Optimal saturation parameters reduced the contribution from other CEST effects to Cr-w CEST contrast, and the proposed Z-spectral fitting approach enabled computation of individual components in Z-spectra of the brain. Therefore, it is feasible to compute Cr-w CEST contrast with a lower contribution from other CEST and rNOE.

Sugar alcohol provides imaging contrast in cancer detection.

Clinical imaging is widely used to detect, characterize and stage cancers in addition to monitoring the therapeutic progress. Magnetic resonance imaging (MRI) aided by contrast agents utilizes the differential relaxivity property of water to distinguish between tumorous and normal tissue. Here, we describe an MRI contrast method for the detection of cancer using a sugar alcohol, maltitol, a common low caloric sugar substitute that exploits the chemical exchange saturation transfer (CEST) property of the labile hydroxyl group protons on maltitol (malCEST). In vitro studies pointed toward concentration and pH-dependent CEST effect peaking at 1 ppm downfield to the water resonance. Studies with control rats showed that intravenously injected maltitol does not cross the intact blood-brain barrier (BBB). In glioma carrying rats, administration of maltitol resulted in the elevation of CEST contrast in the tumor region only owing to permeable BBB. These preliminary results show that this method may lead to the development of maltitol and other sugar alcohol derivatives as MRI contrast agents for a variety of preclinical imaging applications.

Glutamate weighted imaging contrast in gliomas with 7 Tesla magnetic resonance imaging.

INTRODUCTION: Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively. METHODS: We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns. RESULTS: Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113). CONCLUSION: This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.

Glutamate-Weighted Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Detects Glutaminase Inhibition in a Mouse Model of Triple-Negative Breast Cancer.

Glutamate is an important metabolite of glutaminolysis, a metabolic pathway used by many aggressive cancers, including triple-negative breast cancer (TNBC). With the exception of the brain, in vivo detection of glutamate in tissues using 1H magnetic resonance spectroscopy (MRS) is challenging. Compared with MRS, glutamate-weighted chemical exchange saturation transfer MR imaging (GluCEST MRI) offers a more sensitive detection mechanism that is free of glutamine interference. Here, we developed a robust, highly repeatable GluCEST MRI protocol in mice bearing human TNBC xenografts and treated with a potent glutaminase inhibitor, CB-839. In paired studies, treatment with CB-839 for 2 days reduced the GluCEST asymmetry value compared with baseline (P < 0.05, n = 10). The absolute change of the GluCEST asymmetry value was -2.5 percent points after CB-839 treatment versus +0.3 after vehicle (P < 0.01). Correspondingly, treatment with CB-839 reduced tumor glutamate concentrations by 1.5 mmol/L, consistent with prior calibration between changes of the GluCEST value versus tissue glutamate concentration; CB-839, however, did not change tumor intracellular pH. These results demonstrate in a mouse model of breast cancer the utility of GluCEST MRI to detect the early response to glutaminase inhibition.Significance: A sensitive method enables noninvasive detection of tumor response to inhibitors of glutamine metabolism. Cancer Res; 78(19); 5521-6. ©2018 AACR.

Reproducibility of 2D GluCEST in healthy human volunteers at 7 T.

PURPOSE: To investigate the reproducibility of gray and white matter glutamate contrast of a brain slice among a small group of healthy volunteers by using the 2D single-slice glutamate CEST (GluCEST) imaging technique. METHODS: Six healthy volunteers were scanned multiple times for within-day and between-day reproducibility. One more volunteer was scanned for within-day reproducibility at 7T MRI. Glutamate CEST contrast measurements were calculated for within subjects and among the subjects and the coefficient of variations are reported. RESULTS: The GluCEST measurements were highly reproducible in the gray and white matter area of the brain slice, whether it was within-day or between-day with a coefficient of variation of less than 5%. CONCLUSION: This preliminary study in a small group of healthy volunteers shows a high degree of reproducibility of GluCEST MRI in brain and holds promise for implementation in studying age-dependent changes in the brain.

Using 3D spatial correlations to improve the noise robustness of multi component analysis of 3D multi echo quantitative T2 relaxometry data.

PURPOSE: We present a computationally feasible and iterative multi-voxel spatially regularized algorithm for myelin water fraction (MWF) reconstruction. This method utilizes 3D spatial correlations present in anatomical/pathological tissues and underlying B1+-inhomogeneity or flip angle inhomogeneity to enhance the noise robustness of the reconstruction while intrinsically accounting for stimulated echo contributions using T2-distribution data alone. METHODS: Simulated data and in vivo data acquired using 3D non-selective multi-echo spin echo (3DNS-MESE) were used to compare the reconstruction quality of the proposed approach against those of the popular algorithm (the method by Prasloski et al.) and our previously proposed 2D multi-slice spatial regularization spatial regularization approach. We also investigated whether the inter-sequence correlations and agreements improved as a result of the proposed approach. MWF-quantifications from two sequences, 3DNS-MESE vs 3DNS-gradient and spin echo (3DNS-GRASE), were compared for both reconstruction approaches to assess correlations and agreements between inter-sequence MWF-value pairs. MWF values from whole-brain data of six volunteers and two multiple sclerosis patients are being reported as well. RESULTS: In comparison with competing approaches such as Prasloski's method or our previously proposed 2D multi-slice spatial regularization method, the proposed method showed better agreements with simulated truths using regression analyses and Bland-Altman analyses. For 3DNS-MESE data, MWF-maps reconstructed using the proposed algorithm provided better depictions of white matter structures in subcortical areas adjoining gray matter which agreed more closely with corresponding contrasts on T2-weighted images than MWF-maps reconstructed with the method by Prasloski et al. We also achieved a higher level of correlations and agreements between inter-sequence (3DNS-MESE vs 3DNS-GRASE) MWF-value pairs. CONCLUSION: The proposed algorithm provides more noise-robust fits to T2-decay data and improves MWF-quantifications in white matter structures especially in the sub-cortical white matter and major white matter tract regions.

In vivo GluCEST MRI: Reproducibility, background contribution and source of glutamate changes in the MPTP model of Parkinson's disease.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI is a recently developed technique to image glutamate. In the present study, we evaluated the reproducibility and background contamination to the GluCEST and source of the GluCEST changes in a mouse model of Parkinson's disease. Repeated measurements in five mice demonstrated an intra-animal coefficient of variation (CV) of GluCEST signal to be 2.3 ± 1.3% and inter-animal CV of GluCEST to be 3.3 ± 0.3%. Mice were treated with MPTP to create a localized striatal elevation of glutamate. We found an elevation in the GluCEST contrast of the striatum following MPTP treatment (Control: 23.3 ± 0.8%, n = 16; MPTP: 26.2 ± 0.8%, n = 19; p ≤ 0.001). Additionally, the positive association between glutamate concentration measured via 1H MRS and GluCEST signal was used to estimate background contribution to the measured GluCEST. The contribution of signal from non-glutamate sources was found to be ~28% of the total GluCEST. Immunohistochemical analysis of the brain showed co-localization of glutamate with GFAP in the striatum. This suggests that the elevated glutamate present in the striatum in this mouse model reflects astroglial proliferation or reactivity due to the action of MPTP. The potential of GluCEST as a biomarker for imaging inflammation mediated gliosis is discussed.

Non-caloric sweetener provides magnetic resonance imaging contrast for cancer detection.

BACKGROUND: Image contrast enhanced by exogenous contrast agents plays a crucial role in the early detection, characterization, and determination of the precise location of cancers. Here, we investigate the feasibility of using a non-nutritive sweetener, sucralose (commercial name, Splenda), as magnetic resonance imaging (MRI) contrast agent for cancer studies. METHODS: High-resolution nuclear-magnetic-resonance spectroscopy and MR studies on sucralose solution phantom were performed to detect the chemical exchange saturation transfer (CEST) property of sucralose hydroxyl protons with bulk water (sucCEST). For the animal experiments, female Fisher rats (F344/NCR) were used to generate 9L-gliosarcoma model. MRI with CEST experiments were performed on anesthetized rats at 9.4 T MR scanner. Following the baseline CEST scans, sucralose solution was intravenously administered in control and tumor bearing rats. CEST acquisitions were continued during and following the administration of sucralose. Following the sucCEST, Gadolinium-diethylenetriamine pentaacetic acid was injected to perform Gd-enhanced imaging for visualizing the tumor. RESULTS: The sucCEST contrast in vitro was found to correlate positively with the sucralose concentration and negatively with the pH, indicating the potential of this technique in cancer imaging. In a control animal, the CEST contrast from the brain was found to be unaffected following the administration of sucralose, demonstrating its blood-brain barrier impermeability. In a 9L glioma model, enhanced localized sucCEST contrast in the tumor region was detected while the unaffected brain region showed unaltered CEST effect implying the specificity of sucralose toward the tumorous tissue. The CEST asymmetry plots acquired from the tumor region before and after the sucralose infusion showed elevation of asymmetry at 1 ppm, pointing towards the role of sucralose in increased contrast. CONCLUSIONS: We show the feasibility of using sucralose and sucCEST in study of preclinical models of cancer. This study paves the way for the potential development of sucralose and other sucrose derivatives as contrast agents for clinical MRI applications.

Molecular imaging biomarkers for cell-based immunotherapies.

While many decades of scientific research studies have gone into harnessing the power of the immune system to fight cancer, only recently have cancer immunotherapeutic approaches begun to show robust clinical responses in patients with a variety of cancers. These treatments are adding to the current arsenal of cancer treatments; surgery, radiation and chemotherapy, and increasing the therapeutic options for cancer patients. Despite these advances, issues associated with these therapies include that not all patients respond to these therapies, and some patients who respond experience varying degrees of toxicities. One of the major issues affecting immunotherapy is the inability to evaluate trafficking of activated T-cells into sites of tumor. The current diagnostic imaging based on conventional anatomic imaging, which is the mainstay to monitor response to cytotoxic chemotherapy or radiation, is not adequate to assess initial response to immunotherapy or disease evolution. Patients' prognosis by histological analysis has limited use in regards to immunotherapy. Thus, there is a crucial need for noninvasive biomarkers for screening patients that show long term response to therapy. Here, we provide a brief account of emerging molecular magnetic resonance imaging biomarkers that have potential to exploit the metabolism and metabolic products of activated T cells.

Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice.

Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer's disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late-stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross-sectional study of histologic markers of tauopathy to determine whether (1) early GluCEST changes are associated with synapse loss before volume loss occurs in the hippocampus, and whether (2) subhippocampal dynamics in GluCEST are associated with histopathologic events related to glutamate alterations in tauopathy. Live imaging of the hippocampus in three serial slices was performed without exogenous contrast agents, and subregions were segmented based on a k-means cluster model. Subregions of the hippocampus were analyzed (cornu ammonis CA1, CA3, dentate gyrus DG, and ventricle) in order to associate local MRI-observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA-NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, P ≤ 0.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6 months. Volume was not significantly reduced in any subregion until 13 months. Further, a gradient in glutamate levels was observed in vivo along hippocampal axes that became polarized as tauopathy progressed. Dynamics in hippocampal glutamate levels throughout lifetime were most closely correlated with combined changes in synaptophysin and GFAP, indicating that GluCEST imaging may be a surrogate marker of glutamate concentration in glial cells and at the synaptic level. © 2016 Wiley Periodicals, Inc.

High quality three-dimensional gagCEST imaging of in vivo human knee cartilage at 7 Tesla.

PURPOSE: To develop a new faster and higher quality three-dimensional (3D) gagCEST MRI technique for reliable quantification of glycosaminoglycan (GAG) present in the human knee cartilages. METHODS: A new magnetization-prepared 3D gradient echo-based MRI pulse sequence has been designed to obtain the B0 inhomogeneity, B1 inhomogeneity, and CEST Z-spectra images. RESULTS: The gagCEST values of different compartments of knee cartilage are calculated using a newly developed technique for healthy subjects and a symptomatic knee cartilage degenerated subject. The effect of the acquired CEST saturation frequency offset step-size was investigated to establish the optimal step-size to obtain reproducible gagCEST maps. Our novel 3D gagCEST technique demonstrates markedly higher gagCEST contrast value than the previously reported 3D gagCEST studies. This study demonstrates the need for separate B0 and B1 inhomogeneity estimation and correction. CONCLUSION: The new technique provided high quality gagCEST maps with clearer visualization of different layers of knee cartilage with reproducible results. Magn Reson Med 77:1866-1873, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Perfusion has no effect on the in vivo CEST effect from Cr (CrCEST) in skeletal muscle.

Creatine, a key component of muscle energy metabolism, exhibits a chemical exchange saturation transfer (CEST) effect between its amine group and bulk water, which has been exploited to spatially and temporally map creatine changes in skeletal muscle before and after exercise. In addition, exercise leads to an increase in muscle perfusion. In this work, we determined the effects of perfused blood on the CEST effects from creatine in skeletal muscle. Experiments were performed on healthy human subjects (n = 5) on a whole-body Siemens 7T magnetic resonance imaging (MRI) scanner with a 28-channel radiofrequency (RF) coil. Reactive hyperemia, induced by inflation and subsequent deflation of a pressure cuff secured around the thigh, was used to increase tissue perfusion whilst maintaining the levels of creatine kinase metabolites. CEST, arterial spin labeling (ASL) and 31 P MRS data were acquired at baseline and for 6 min after cuff deflation. Reactive hyperemia resulted in substantial increases in perfusion in human skeletal muscle of the lower leg as measured by the ASL mean percentage difference. However, no significant changes in CrCEST asymmetry (CrCESTasym ) or 31 P MRS-derived PCr levels of skeletal muscle were observed following cuff deflation. This work demonstrates that perfusion changes do not have a major confounding effect on CrCEST measurements.

Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties.

Many women with no history of executive dysfunction report difficulties in this domain during the menopause transition. Lisdexamfetamine (LDX) has been suggested to be a safe and effective treatment option for these women. However, the mechanism by which LDX improves executive functioning in these women is not known. Here we investigated the effects of LDX on brain activation and neurochemistry, hypothesizing that LDX would be associated with increased activation and decreased glutamate in executive regions. Fourteen women underwent multimodal neuroimaging at 7T at three time points in this baseline-corrected, double-blind, placebo-controlled, crossover study. Effects of LDX on symptom severity, blood-oxygen-level-dependent (BOLD) signal, and dorsolateral prefrontal cortex (DLPFC) glutamate+glutamine (Glx) were measured using a clinician-administered questionnaire, fMRI during performance of a fractal n-back task, and 1H-MRS, respectively. The effect of treatment (LDX minus baseline vs placebo minus baseline) on these behavioral and neural markers of executive function was examined using repeated measures mixed effects models. LDX treatment was associated with decreased symptom severity, increased activation in the insula and DLPFC, and decreased DLPFC Glx. In addition, the magnitude of LDX-induced improvement in symptom severity predicted both direction and magnitude of LDX-induced change in insular and DLPFC activation. Moreover, symptom severity was positively correlated with Glx concentration in the left DLPFC at baseline. These findings provide novel evidence that the neural mechanisms by which LDX acts to improve self-reported executive functioning in healthy menopausal women with midlife onset of executive difficulties include modulation of insular and DLPFC recruitment as well as decrease in DLPFC Glx concentration.