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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mapping the alterations in glutamate with GluCEST MRI in a mouse model of dopamine deficiency.

Glutamate chemical exchange saturation transfer (GluCEST) MRI was used to measure metabolic changes in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by mapping regional cerebral glutamate. The GluCEST contrast following MPTP treatment was correlated with 1 H-MR spectroscopy, motor function, and immunohistochemical measures. The GluCEST contrast was found to be significantly higher in the striatum and motor cortex of mice treated with MPTP than in controls (p < 0.001), which was confirmed by localized 1 H-MR spectroscopy. Elevated striatal GluCEST was positively associated with local astrogliosis measured by immunohistochemistry for glial fibrillary acidic protein. Additionally, a negative correlation was found between motor function, measured by the four-limb grip strength test, and GluCEST of the striatum (R = -0.705, p < 0.001) and the motor cortex (R = -0.617, p < 0.01), suggesting a role of elevated glutamate in the abnormal cerebral motor function regulation. The GluCEST contrast and glial fibrillary acidic protein immunostaining were unaltered in the thalamus indicating glutamate elevation was localized to the striatum and the motor cortex. These findings suggest that in addition to measuring spatial changes in glutamate, GluCEST may serve as an in vivo biomarker of metabolic and functional changes that may be applied to the assessment of a broad range of neuropathologies. Read the Editorial Highlight for this article on page 346.

Fully automated macromolecule suppressed single voxel glutamate spectroscopy (FAMOUS SVGS).

PURPOSE: The aim of the study was to develop and validate a new localized (1)H MRS pulse sequence and automated post-processing software for the quantification of brain Glutamate (Glu) in clinical conditions at 7.0T in order to get reliable and reproducible results for acute intervention studies. METHODS: Here we describe a new localized proton MRS method "Fully Automated MacrOmolecUle Suppressed Single Voxel Glutamate Spectroscopy (FAMOUS SVGS)" for measuring Glu. FAMOUS SVGS method consists of a new pulse sequence with optimized switchable water, metabolites and outer volume suppression modules, as well as a frequency selective inversion pulse and automated post-processing of the five spectra obtained. FAMOUS SVGS method was first validated with glutamate phantoms and then validated with test-retest repeatability studies in the occipital cortex of five normal volunteers at 7.0T. RESULTS: Glutamate concentrations estimated from phantoms with FAMOUS SVGS method correlated well with actual concentrations. Test-retest repeatability studies in human brain in vivo yielded less than 0.3 mM intra-subject variations in Glu concentrations. CONCLUSIONS: FAMOUS SVGS method enables Glu quantification in vivo at 7.0T with test-retest variability of less than 0.3 mM. We expect that we can reliably measure ≥0.5 mM change in glutamate due to any acute intervention.

Characterization of viscosupplementation formulations using chemical exchange saturation transfer (ViscoCEST).

BACKGROUND: Osteoarthritis (OA) is characterized by progressive loss of cartilage in joints, and is a major cause of pain and disability, and imposes significant health care expense. New therapies are being developed to treat the symptomatic effect of OA, one of which is intra-articular injection of viscosupplementations of different forms of hyaluronic acid (HA). The current study evaluates the chemical exchange saturation transfer (CEST) effect from two popular viscosupplementations [Hylan gf-20 (Synvisc) and hyaluronan (Orthovisc)] by targeting the exchangeable hydroxyl protons present on these molecules (ViscoCEST). METHODS: ViscoCEST imaging from two viscosupplementations (Synvisc and Orthovisc) was performed on a 7T Siemens whole body MRI scanner. ViscoCEST images were collected with different combination of saturation pulse power and saturation duration. Z spectra were acquired at B1rms of 3.6 µT and 1 s saturation duration by varying the frequency from -4 to +4 ppm in step size of 0.1 ppm. Field inhomogeneity (B0) and radiofrequency (B1) maps were also acquired to correct ViscoCEST contrast map for any inhomogeneity. RESULTS: Both viscosupplementations showed broad CEST effect (ViscoCEST), which peaked ~0.8 ppm from down field of water resonance. Orthovisc showed 20 % higher ViscoCEST contrast than Synvisc suggestive of more HA component in Orthovisc. Increased ViscoCEST contrast was observed from both viscosupplementations with increase in B1rms and saturation pulse duration. CONCLUSION: ViscoCEST has a potential to image the spatial distribution of viscosupplements in vivo in patients' intra-articular space as well as temporal variation in their spatial distribution.

Localized, gradient-reversed ultrafast z-spectroscopy in vivo at 7T.

PURPOSE: To collect ultrafast z-spectra in vivo in situations where voxel homogeneity cannot be assured. THEORY: Saturating in the presence of a gradient encodes the frequency offset spatially across a voxel. This encoding can be resolved by applying a similar gradient during readout. Acquiring additional scans with the gradient polarity reversed effectively mirrors the spatial locations of the frequency offsets so that the same physical location of a positive offset in the original scan will contribute a negative offset in the gradient-reversed scan. METHODS: Gradient-reversed ultrafast z-spectroscopy (GRUFZS) was implemented and tested in a modified, localized PRESS sequence at 7T. Lysine phantoms were scanned at various concentrations and compared with coventionally-acquired z-spectra. Scans were acquired in vivo in human brain from homogeneous and inhomogeneous voxels with the ultrafast direction cycled between read, phase, and slice. Results were compared to those from a similar conventional z-spectroscopy PRESS-based sequence. RESULTS: Asymmetry spectra from GRUFZS are more consistent and reliable than those without gradient reversal and are comparable to those from conventional z-spectroscopy. GRUFZS offers significant acceleration in data acquisition compared to traditional chemical exchange saturation transfer methods with high spectral resolution and showed higher relative SNR effficiency. CONCLUSION: GRUFZS offers a method of collecting ultrafast z-spectra in voxels with the inhomogeneity often found in vivo. Magn Reson Med 76:1039-1046, 2016. © 2016 Wiley Periodicals, Inc.

T1ρ MRI of healthy and fibrotic human livers at 1.5 T.

BACKGROUND: Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based methods for better diagnosis of this disease. In the current study, we aim to evaluate the potential of T1ρ MRI technique in detecting and characterizing different grades of liver fibrosis in vivo in humans. METHODS: Healthy subjects and patients with liver fibrosis were prospectively recruited for T1ρ MRI of liver on a 1.5 T MR scanner. Single slice T1ρ weighted images were acquired at different spin lock duration (0, 10, 20 and 30 ms) with spin lock amplitude of 500 Hz in a single breath-hold. Additionally, liver's T1ρ images were acquired from five healthy subjects on the same day (n = 2) and different day (n = 2) sessions for test-retest study. Liver biopsy samples from patients were obtained and used to calculate the METAVIR score to define the stage of fibrosis and inflammation grade. T1ρ maps were generated followed by computation of mean and standard deviation (SD) values. Coefficient of variation (COV) of T1ρ values between two MRI scans was computed to determine reproducibility in liver. T test was used to compare T1ρ values between healthy and fibrotic liver. Pearson correlation was performed between stages of liver fibrosis and T1ρ values. RESULTS: The mean (SD) T1ρ value among subject with healthy liver was 51.04 (3.06) ms. The COV of T1ρ values between two repetitions in the same day session was 0.83 ± 0.8% and in different day session was 5.4 ± 2.7%. T1ρ values in fibrotic liver were significantly higher compared to those of healthy liver (p < 0.05). A statically significant correlation between stages of fibrosis and T1ρ values was observed (r = 0.99, p < 0.05). Inflammation score for one patient was 2 and for remaining patients it was 1. CONCLUSIONS: Proposed T1ρ pulse sequence design and protocol enabled acquisition of a single slice T1ρ weighted images in a single breath-hold and hence mitigated breathing motion related artifacts. Preliminary results have shown the sensitivity of T1ρ values to changes induced by liver fibrosis, and may potentially be used as a clinical biomarker to delineate the stages of liver fibrosis. Further, studies on a large number of subjects are required to validate the observations of the current study. Nevertheless, T1ρ imaging can be easily setup on a clinical scanner to monitor the progression of liver fibrosis and to the evaluate efficacy of anti-fibrotic drugs.

Molecular magnetic resonance imaging in cancer.

The ability to identify key biomolecules and molecular changes associated with cancer malignancy and the capacity to monitor the therapeutic outcome against these targets is critically important for cancer treatment. Recent developments in molecular imaging based on magnetic resonance (MR) techniques have provided researchers and clinicians with new tools to improve most facets of cancer care. Molecular imaging is broadly described as imaging techniques used to detect molecular signature at the cellular and gene expression levels. This article reviews both established and emerging molecular MR techniques in oncology and discusses the potential of these techniques in improving the clinical cancer care. It also discusses how molecular MR, in conjunction with other structural and functional MR imaging techniques, paves the way for developing tailored treatment strategies to enhance cancer care.

CEST signal at 2ppm (CEST@2ppm) from Z-spectral fitting correlates with creatine distribution in brain tumor.

In general, multiple components such as water direct saturation, magnetization transfer (MT), chemical exchange saturation transfer (CEST) and aliphatic nuclear Overhauser effect (NOE) contribute to the Z-spectrum. The conventional CEST quantification method based on asymmetrical analysis may lead to quantification errors due to the semi-solid MT asymmetry and the aliphatic NOE located on a single side of the Z-spectrum. Fitting individual contributors to the Z-spectrum may improve the quantification of each component. In this study, we aim to characterize the multiple exchangeable components from an intracranial tumor model using a simplified Z-spectral fitting method. In this method, the Z-spectrum acquired at low saturation RF amplitude (50 Hz) was modeled as the summation of five Lorentzian functions that correspond to NOE, MT effect, bulk water, amide proton transfer (APT) effect and a CEST peak located at +2 ppm, called CEST@2ppm. With the pixel-wise fitting, the regional variations of these five components in the brain tumor and the normal brain tissue were quantified and summarized. Increased APT effect, decreased NOE and reduced CEST@2ppm were observed in the brain tumor compared with the normal brain tissue. Additionally, CEST@2ppm decreased with tumor progression. CEST@2ppm was found to correlate with the creatine concentration quantified with proton MRS. Based on the correlation curve, the creatine contribution to CEST@2ppm was quantified. The CEST@2ppm signal could be a novel imaging surrogate for in vivo creatine, the important bioenergetics marker. Given its noninvasive nature, this CEST MRI method may have broad applications in cancer bioenergetics.

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy.

Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy ((1)H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional (1)H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy were carried out on tau transgenic mice with the P301S mutation (PS19, n=9) and their wild-type littermates (WT, n=8), followed by immunohistochemistry of their brain tissue. GluCEST imaging resolution allowed for sub-hippocampal analysis of glutamate. Glutamate was significantly decreased by 29% in the CA sub-region of the PS19 hippocampus, and by 15% in the thalamus, where synapse loss was also measured. Glutamate levels and synapse density remained high in the dentate gyrus sub-region of the hippocampus, where neurogenesis is known to occur. The further development of GluCEST imaging for preclinical applications will be valuable, as therapies are being tested in mouse models of tauopathy.