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Portable nuclear magnetic resonance (NMR) spectrometers are used in various scientific fields. A vast number of applications are suitable for low-field permanent magnets. However, most of these systems lack the ability of pulsed-field gradients as these require cumbersome additional hardware. We herein report an NMR probe head that incorporates a radio frequency (RF)-coil equipped with pulsed-field gradient capabilities in a single center-tapped solenoid. We developed a circuitry allowing for the application of direct currents without disturbing the RF reception capabilities. Furthermore, we present a System-on-Chip-based NMR spectrometer. Combined with the NMR probe head, it represents a versatile low-cost system capable of field gradient generation. The probe head is characterized in terms of scatter parameters, quality factor, and transversal field homogeneity. We exhibit simulation data of the field gradient and present the required external circuitry. Experimental results show further the dephasing capabilities of the gradient and give insights into the spatial shape. Finally, the system is applied for the mapping of J-couplings in 1-butanol via zero-quantum coherences. A theoretical analysis of the pulse sequence is given for a homonuclear two-spin system. The experimental results demonstrate the potential use of this setup.

Purpose The linear change of the water proton resonance frequency shift (PRFS) with temperature is used to monitor temperature change based on the temporal difference of image phase. Here, the effect of motion-induced susceptibility artifacts on the phase difference was studied in the context of mild radio frequency hyperthermia in the pelvis. Methods First, the respiratory-induced field variations were disentangled from digestive gas motion in the pelvis. The projection onto dipole fields (PDF) as well as the Laplacian boundary value (LBV) algorithm were applied on the phase difference data to eliminate motion-induced susceptibility artifacts. Both background field removal (BFR) algorithms were studied using simulations of susceptibility artifacts, a phantom heating experiment, and volunteer and patient heating data. Results Respiratory-induced field variations were negligible in the presence of the filled water bolus. Even though LBV and PDF showed comparable results for most data, LBV seemed more robust in our data sets. Some data sets suggested that PDF tends to overestimate the background field, thus removing phase attributed to temperature. The BFR methods even corrected for susceptibility variations induced by a subvoxel displacement of the phantom. The method yielded successful artifact correction in 2 out of 4 patient treatment data sets during the entire treatment duration of mild RF heating of cervical cancer. The heating pattern corresponded well with temperature probe data. Conclusion The application of background field removal methods in PRFS-based MR thermometry has great potential in various heating applications and body regions to reduce motion-induced susceptibility artifacts that originate outside the region of interest, while conserving temperature-induced PRFS. In addition, BFR automatically removes up to a first-order spatial B0 drift.

OBJECTIVE: Mild hyperthermia (HT) treatments are generally monitored by phase-referenced proton resonance frequency shift calculations. A novel phase and thus temperature-sensitive fast spin echo (TFSE) sequence is introduced and compared to the double echo gradient echo (DEGRE) sequence.THEORY AND METHODS: For a proton resonance frequency shift (PRFS)-sensitive TFSE sequence, a phase cycling method is applied to separate even from odd echoes. This method compensates for conductivity change-induced bias in temperature mapping as does the DEGRE sequence. Both sequences were alternately applied during a phantom heating experiment using the clinical setup for deep radio frequency HT (RF-HT). The B0 drift-corrected temperature values in a region of interest around temperature probes are compared to the temperature probe data and further evaluated in Bland-Altman plots. The stability of both methods was also tested within the thighs of three volunteers at a constant temperature using the subcutaneous fat layer for B0-drift correction.RESULTS: During the phantom heating experiment, on average TFSE temperature maps achieved double temperature-to-noise ratio (TNR) efficiency in comparison with DEGRE temperature maps. In-vivo images of the thighs exhibit stable temperature readings of ± 1 °C over 25 min of scanning in three volunteers for both methods. On average, the TNR efficiency improved by around 25% for in vivo data.CONCLUSION: A novel TFSE method has been adapted to monitor temperature during mild HT.

BACKGROUND Field inhomogeneities in MRI caused by interactions between the radiofrequency field and the patient anatomy can lead to artifacts and contrast variations, consequently degrading the overall image quality and thereby compromising diagnostic value of the images. PURPOSE To develop an efficient free-breathing and motion-robust B1+ mapping method that allows for the investigation of spatial homogeneity of the transmitted radiofrequency field in the myocardium at 3.0T. Three joint approaches are used to adapt the dual refocusing echo acquisition mode (DREAM) sequence for cardiac applications: (1) electrocardiograph triggering; (2) a multi-snapshot undersampling scheme, which relies on the Golden Ratio, to accelerate the acquisition; and (3) motion-compensation based on low-resolution images acquired in each snapshot. STUDY TYPE Prospective. PHANTOM/SUBJECTS Eurospin II T05 system, torso phantom, and five healthy volunteers. FIELD STRENGTH/SEQUENCE 3.0T/DREAM. ASSESSMENT The proposed method was compared with the Bloch-Siegert shift (BSS) method and validated against the standard DREAM sequence. Cardiac B1+ maps were obtained in free-breathing and breath-hold as a proof of concept of the in vivo performance of the proposed method. STATISTICAL TESTS Mean and standard deviation (SD) values were analyzed for six standard regions of interest within the myocardium. Repeatability was assessed in terms of SD and coefficient of variation. RESULTS Phantom results indicated low deviation from the BSS method (mean difference = 3%). Equivalent B1+ distributions for free-breathing and breath-hold in vivo experiments demonstrated the motion robustness of this method with good repeatability (SD

Aberrant pH is characteristic of many pathologies such as ischemia, inflammation or cancer. Therefore, a non-invasive and spatially resolved pH determination is valuable for disease diagnosis, characterization of response to treatment and the design of pH-sensitive drug-delivery systems. We recently introduced hyperpolarized [1,5-13C2]zymonic acid (ZA) as a novel MRI probe of extracellular pH utilizing dissolution dynamic polarization (DNP) for a more than 10000-fold signal enhancement of the MRI signal. Here we present a strategy to enhance the sensitivity of this approach by deuteration of ZA yielding [1,5-13C2, 3,6,6,6-D4]zymonic acid (ZAd), which prolongs the liquid state spin lattice relaxation time (T1) by up to 39 % in vitro. Measurements with ZA and ZAd on subcutaneous MAT B III adenocarcinoma in rats show that deuteration increases the signal-to-noise ratio (SNR) by up to 46 % in vivo. Furthermore, we demonstrate a proof of concept for real-time imaging of dynamic pH changes in vitro using ZAd, potentially allowing for the characterization of rapid acidification/basification processes in vivo.

To analyze 2D NMR relaxation data based on a discrete delta-like relaxation map we extended the Pade-Laplace method to two dimensions. We approximate the forward Laplace image of the time domain signal by a Chisholm approximation, i.e. a rational polynomial in two dimensions. The poles and residues of this approximation correspond to the relaxation rates and weighting factors of the underlying relaxation map. In this work we explain the principle ideas of our algorithm and demonstrate its applicability. Therefore we compare the inversion results of the Chisholm approximation and Tikhonov regularization method as a function of SNR when the investigated signal is based on a given discrete relaxation map. Our algorithm proved to be reliable for SNRs larger than 50 and is able to compete with the Tikhonov regularization method. Furthermore we show that our method is also able to detect the simulated relaxation compartments of narrow Gaussian distributions with widths less or equal than 0.05s-1. Finally we investigate the resolution limit with experimental data. For a SNR of 750 the Chisholm approximation method was able to resolve two relaxation compartments in 8 of 10 cases when both compartments differ by a factor of 1.7.

Magnetic nanoparticles (MNPs) can be used as carriers for magnetic drug targeting and for stem cell tracking by magnetic resonance imaging (MRI). For these applications, it is crucial to quantitatively determine the spatial distribution of the MNP concentration, which can be approached by MRI relaxometry. Theoretical considerations and experiments have shown that R2 relaxation rates are sensitive to the aggregation state of the particles, whereas R 2 * is independent of aggregation state and therefore suited for MNP quantification if the condition of static dephasing is met. We present a new experimental approach to characterize an MNP system with respect to quantitative MRI based on hydrodynamic fractionation. The first results qualitatively confirm the outer sphere relaxation theory for small MNPs and show that the two commercial MRI contrast agents Resovist ® and Endorem ® should not be used for quantitative MRI because they do not fulfill the condition for static dephasing. Our approach could facilitate the choice of MNPs for quantitative MRI and help clarifying the relationship between size, magnetism and relaxivity of MNPs in the future.

PURPOSE To introduce a robust methodology for fast 1 H MRSI of the brain at 3T with improved SNR and reduced phase-related artifacts. METHOD An accelerated acquisition scheme using echo-planar spectroscopic imaging (EPSI) was combined with the overdiscrete reconstruction framework. This approach enables the interleaved acquisition of a water reference scan at each phase encoding step, maximizing its correlation with the water-suppressed measurement. Moreover, a generalized high-order phase correction was incorporated into the reconstruction pipeline. The spatial-temporal phase correction term was estimated from the reference scan and interpolated to high resolution using a polynomial basis. The method was implemented at 3T and validated with phantom and in vivo experiments. RESULTS The methodology showed the elimination of spectral artifacts generated by phase disturbances and achieved mean SNR gains in vivo of 3.18 and 1.19 compared to standard reconstructions with corrections performed at nominal and high resolution, respectively. EPSI scans with interleaved water acquisition showed to be robust to system instabilities and potentially to patient motion. Moreover, phase distortions were effectively corrected in a single step, avoiding additional reference measurements and post-processing steps. CONCLUSION The overdiscrete reconstruction framework with high-order phase correction allowed to effectively correct for distortions, related to B0 inhomogeneities, B0 drift, eddy currents, and system vibrations. Furthermore, the presented reconstruction method, combined with EPSI acquisitions, demonstrated improved measurement stability, substantial SNR enhancement, better spectral linewidth, and effective artifact removal.

Purpose To propose a phase error correction scheme for monopolar time-interleaved multi-echo gradient echo water–fat imaging that allows accurate and robust complex-based quantification of the proton density fat fraction (PDFF). Methods A three-step phase correction scheme is proposed to address a) a phase term induced by echo misalignments that can be measured with a reference scan using reversed readout polarity, b) a phase term induced by the concomitant gradient field that can be predicted from the gradient waveforms, and c) a phase offset between time-interleaved echo trains. Simulations were carried out to characterize the concomitant gradient field-induced PDFF bias and the performance estimating the phase offset between time-interleaved echo trains. Phantom experiments and in vivo liver and thigh imaging were performed to study the relevance of each of the three phase correction steps on PDFF accuracy and robustness. Results The simulation, phantom, and in vivo results showed in agreement with the theory an echo time-dependent PDFF bias introduced by the three phase error sources. The proposed phase correction scheme was found to provide accurate PDFF estimation independent of the employed echo time combination. Conclusion Complex-based time-interleaved water–fat imaging was found to give accurate and robust PDFF measurements after applying the proposed phase error correction scheme. Magn Reson Med 78:984–996, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose To assess the ability of dynamic contrast-enhanced myocardial perfusion MRI to measure extracellular volume (ECV) and to investigate the possibility of estimating capillary transit time heterogeneity (CTH) in patients after myocardial infarction and successful revascularization. Methods Twenty-four perfusion data sets were acquired on a 3 Tesla positron emission tomography (PET)/MRI scanner. Three perfusion models of different complexity were implemented in a hierarchical fashion with an Akaike information criterion being used to determine the number of fit parameters supported by the data. Results were compared sector-wise to ECV from an equilibrium T1 mapping method (modified look-locker inversion recovery (MOLLI)). Results ECV derived from the perfusion analysis correlated well with equilibrium measurements (R² = 0.76). Estimation of CTH was supported in 16% of sectors (mostly remote). Inclusion of a nonzero CTH parameter usually led to lower estimates of first-pass extraction and slightly higher estimates of blood volume and flow. Estimation of the capillary permeability-surface area product was feasible in 81% of sectors. Conclusion Transit time heterogeneity has a measurable effect on the kinetic analysis of myocardial perfusion MRI data, and Gd-DTPA extravasation in the myocardium is usually not flow-limited in infarct-related pathology. Measurement of myocardial ECV using perfusion imaging could provide a scan-time efficient alternative to methods based on T1 mapping. Magn Reson Med 77:2320–2330, 2017. © 2016 International Society for Magnetic Resonance in Medicine

Most tumours exhibit a high rate of glycolysis and predominantly produce energy by lactic acid fermentation. To maintain energy production and prevent toxicity, the lactate generated needs to be rapidly transported out of the cell. This is achieved by monocarboxylate transporters (MCTs), which therefore play an essential role in cancer metabolism and development. In vivo experiments were performed on eight male Fisher F344 rats bearing a subcutaneous mammary carcinoma after injection of hyperpolarised [1-13C]pyruvate. A Gd(III)DO3A complex that binds to pyruvate and its metabolites was used to efficiently destroy the extracellular magnetisation after hyperpolarised lactate had been formed. Moreover, a pulse sequence including a frequency-selective saturation pulse was designed so that the pyruvate magnetisation could be destroyed to exclude effects arising from further conversion. Given this preparation, metabolite transport out of the cell manifested as additional decay and apparent cell membrane transporter rates could thus be obtained using a reference measurement without a relaxation agent. In addition to slice-selective spectra, spatially resolved maps of apparent membrane transporter activity were acquired using a single-shot spiral gradient readout. A considerable increase in decay rate was detected for lactate, indicating rapid transport out of the cell. The alanine signal was unaltered, which corresponds to a slower efflux rate. This technique could allow for better understanding of tumour metabolism and progression, and enable treatment response measurements for MCT-targeted cancer therapies. Moreover, it provides vital insights into the signal kinetics of hyperpolarised [1-13C]pyruvate examinations. Copyright © 2016 John Wiley & Sons, Ltd.

Individual tumor characterization and treatment response monitoring based on current medical imaging methods remain challenging. This work investigates hyperpolarized (13) C compounds in an orthotopic rat hepatocellular carcinoma (HCC) model system before and after transcatheter arterial embolization (TAE). HCC ranks amongst the top six most common cancer types in humans and accounts for one-third of cancer-related deaths worldwide. Early therapy response monitoring could aid in the development of personalized therapy approaches and novel therapeutic concepts. Measurements with selectively (13) C-labeled and hyperpolarized urea, pyruvate and fumarate were performed in tumor-bearing rats before and after TAE. Two-dimensional, slice-selective MRSI was used to obtain spatially resolved maps of tumor perfusion, cell energy metabolic conversion rates and necrosis, which were additionally correlated with immunohistochemistry. All three injected compounds, taken together with their respective metabolites, exhibited similar signal distributions. TAE induced a decrease in blood flow into the tumor and thus a decrease in tumor to muscle and tumor to liver ratios of urea, pyruvate and its metabolites, alanine and lactate, whereas conversion rates remained stable or increased on TAE in tumor, muscle and liver tissue. Conversion from fumarate to malate successfully indicated individual levels of necrosis, and global malate signals after TAE suggested the washout of fumarase or malate itself on necrosis. This study presents a combination of three (13) C compounds as novel candidate biomarkers for a comprehensive characterization of genetically and molecularly diverse HCC using hyperpolarized MRSI, enabling the simultaneous detection of differences in tumor perfusion, metabolism and necrosis. If, as in this study, bolus dynamics are not required and qualitative perfusion information is sufficient, the desired information could be extracted from hyperpolarized fumarate and pyruvate alone, acquired at higher fields with better spectral separation. Copyright © 2016 John Wiley & Sons, Ltd.

PURPOSE Because of the intrinsic low signal-to-noise ratio in diffusion-weighted imaging (DWI), magnitude processing often causes an overestimation of the signal's amplitude. This results in low-estimation accuracy of diffusion models and reduced contrast because of a superposition of the image signal and the noise floor. We adopt a new phase correction (PC) technique that yields real valued diffusion data while maintaining a Gaussian noise distribution. METHODS We conduct simulations of the noise propagation in the echo-planar imaging reconstruction chain to determine the spatial noise correlation in the image. Using the correlation pattern, optimized filter kernels are derived to estimate the true phase of the signal in each voxel. Furthermore, we adopt an outlier detection technique to replace the real value by the magnitude in case of substantial signal loss resulting from incorrect PC. RESULTS The benefits of our method are demonstrated on Monte Carlo simulations, DWI data acquired from healthy volunteer experiments, estimated parameters of the diffusion kurtosis imaging model, and the model-free diffusion spectrum imaging technique. The improved PC approach significantly reduces the noise bias and only slightly increases the sensitivity to local phase variations. CONCLUSION PC can enhance the usefulness of higher b-values, allowing deeper insights into tissue microstructure. Magn Reson Med 77:559-570, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose Diffusional kurtosis imaging (DKI) is an approach to characterizing the non-Gaussian fraction of water diffusion in biological tissue. However, DKI is highly susceptible to the low signal-to-noise ratio of diffusion-weighted images, causing low precision and a significant bias due to Rician noise distribution. Here, we evaluate precision and bias using weighted linear least squares fitting of different acquisition schemes including several multishell schemes, a diffusion spectrum imaging (DSI) scheme, as well as a compressed sensing reconstruction of undersampled DSI scheme. Methods Monte Carlo simulations were performed to study the three-dimensional distribution of the apparent kurtosis coefficient (AKC). Experimental data were acquired from one healthy volunteer with multiple repetitions, using the same acquisition schemes as for the simulations. Results The angular distribution of the bias and precision were very inhomogeneous. While axial kurtosis was significantly overestimated, radial kurtosis was underestimated. The precision of radial kurtosis was up to 10-fold lower than axial kurtosis. Conclusion The noise bias behavior of DKI is highly complex and can cause overestimation as well as underestimation of the AKC even within one voxel. The acquisition scheme with three shells, suggested by Poot et al, provided overall the best performance. Magn Reson Med 76:1684–1696, 2016. © 2016 International Society for Magnetic Resonance in Medicine

Purpose We characterized the performance of a novel hyperpolarized perfusion marker, α-trideuteromethyl[15N]glutamine, for direct comparison with a 13C-based hyperpolarized perfusion marker, [13C, 15N2]urea. Methods A hardware platform and pulse sequence for in vivo 15N experiments were established. Hyperpolarized solutions of α-trideuteromethyl[15N]glutamine and [13C, 15N2]urea were injected into healthy male Lewis rats. Kidney slice images were acquired using a single-shot spiral readout. Both compounds were compared to determine in vivo signal lifetime and tracer distribution. Mass spectrometry was performed to evaluate excretion of the compound. Results Compared with 13C-labeled urea, a significantly increased signal lifetime was observed. While the urea signal was gone after 90 s, decay of the glutamine compound was sufficiently slow to obtain a quantifiable signal, even after 5 min. The glutamine derivative showed strong localization in the kidneys with little background signal. Effective T1 of α-trideuteromethyl[15N]glutamine was approximately eight-fold higher than that of urea. Mass spectrometry results confirmed rapid excretion within the time scale of the measurement. Conclusion Hyperpolarized α-trideuteromethyl[15N]glutamine is a highly promising candidate for renal studies because of its long signal lifetime, strong localization and rapid excretion. Magn Reson Med 76:1900–1904, 2016. © 2016 International Society for Magnetic Resonance in Medicine

A bridged loop gap resonator (BLGR) was developed as a transmit and receive coil for a mobile insert to be used for small animal proton imaging by 1.5 T MRI devices. The insert system has its own gradient system, radio frequency (RF) transmit and receive coil, and control and signal processing unit. The reflection S11 and transmission S21 parameters, quality factor (Q), sensitivity, signal to noise ratio (SNR), and maps of the static (B0) and RF (B1) magnetic flux densities were measured. The RF coil was developed starting from a loop gap resonator (LGR) for a balanced LGR and a shielded balanced LGR for a shielded bridged balanced LGR. The purpose of developing this device is to minimize the influence of the sample and surroundings on the RF coil parameters. The final design of the BLGR does not require retuning after a sample change. A 3D image of a mouse in formalin was acquired with a fast low angle shot (FLASH) MRI sequence. The SNR was calculated from one FLASH image. The signal for SNR calculation was acquired from a gadolinium-doped water sample and the noise from the air outside of the sample. This article verifies that the BLGR is viable for small animal nuclear magnetic resonance imaging at 1.5 T and is independent of sample size and material.

Low-field, mobile NMR systems are increasingly used across diverse fields, including medical diagnostics, food quality control, and forensics. The throughput and functionality of these systems, however, are limited due to their conventional single-channel detection: one NMR probe exclusively uses an NMR console at any given time. Under this design, multi-channel detection could only be accomplished by either serially accessing individual probes or stacking up multiple copies of NMR electronics; this approach still retains limitations such as long assay times and increased system complexity. Here we present a new scalable architecture, HERMES (hetero-nuclear resonance multichannel electronic system), for versatile, high-throughput NMR analyses. HERMES exploits the concept of software-defined radio by virtualizing NMR electronics in the digital domain. This strategy i) creates multiple NMR consoles without adding extra hardware; ii) acquires signals from multiple NMR channels in parallel; and iii) operates in wide frequency ranges. All of these functions could be realized on-demand in a single compact device. We interfaced HERMES with an array of NMR probes; the combined system simultaneously measured NMR relaxation from multiple samples and resolved spectra of hetero-nuclear spins ((1)H, (19)F, (13)C). For potential diagnostic uses, we applied the system to detect dengue fever and molecularly profile cancer cells through multi-channel protein assays. HERMES holds promise as a powerful analytical tool that enables rapid, reconfigurable, and parallel detection.

Using compact desktop NMR systems for rapid characterization of relaxation properties directly after synthesis can expedite the development of functional magnetic nanoparticles. Therefore, an automated system that combines a miniaturized NMR relaxometer and a flow-based microreactor for online synthesis and characterization of magnetic iron oxide nanoparticles is constructed and tested. NMR relaxation properties are quantified online with a 0.5 T permanent magnet for measurement of transverse (T2) and longitudinal (T1) relaxation times. Nanoparticles with a primary particle size of about 25 nm are prepared by coprecipitation in a tape-based microreactor that utilizes 3D hydrodynamic flow focusing to avoid channel clogging. Cluster sizes are expeditiously optimized for maximum transverse relaxivity of 115.5 mM s–1. The compact process control system is an efficient tool that speeds up synthesis optimization and product characterization of magnetic nanoparticles for nanomedical, theranostic, and NMR-based b...

pH is a tightly regulated physiological parameter that is often altered in diseased states like cancer. The development of biosensors that can be used to non-invasively image pH with hyperpolarized (HP) magnetic resonance spectroscopic imaging has therefore recently gained tremendous interest. However, most of the known HP-sensors have only individually and not comprehensively been analyzed for their biocompatibility, their pH sensitivity under physiological conditions, and the effects of chemical derivatization on their logarithmic acid dissociation constant (pKa). Proteinogenic amino acids are biocompatible, can be hyperpolarized and have at least two pH sensitive moieties. However, they do not exhibit a pH sensitivity in the physiologically relevant pH range. Here, we developed a systematic approach to tailor the pKa of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, we identified several derivatives such as [1-13C]serine amide and [1-13C]-2,3-diaminopropionic acid as novel pH sensors. They bear several spin-1/2 nuclei (13C, 15N, 31P) with high sensitivity up to 4.8 ppm/pH and we show that 13C spins can be hyperpolarized with dissolution dynamic polarization (DNP). Our findings elucidate the molecular mechanisms of chemical shift pH sensors that might help to design tailored probes for specific pH in vivo imaging applications.

Field inhomogeneities in MRI caused by interactions between the radiofrequency field and the patient anatomy can lead to artifacts and contrast variations, consequently degrading the overall image quality and thereby compromising diagnostic value of the images.To develop an efficient free-breathing and motion-robustProspective.Eurospin II T05 system, torso phantom, and five healthy volunteers.3.0T/DREAM.The proposed method was compared with the Bloch-Siegert shift (BSS) method and validated against the standard DREAM sequence. CardiacMean and standard deviation (SD) values were analyzed for six standard regions of interest within the myocardium. Repeatability was assessed in terms of SD and coefficient of variation.Phantom results indicated low deviation from the BSS method (mean difference = 3%). EquivalentThe feasibility of a cardiac1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:499-507.

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information. Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters. Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data. Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information. Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters. Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data. Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.

Purpose To study the effects of refocusing angle modulation with 3D turbo spin echo (TSE) on signal and sharpness of small oblique nerves embedded in muscle and suppressed fat in the lumbar plexus. Materials and Methods Flip angle trains were generated with extended phase graphs (EPG) for a sequence parameter subspace. Signal loss and width broadening were simulated for a single-pixel nerve embedded in muscle and suppressed fat to prescribe a flip angle modulation that gives the best compromise between signal and sharpness of small nerves. Two flip angle trains were defined based on the simulations of small embedded nerves: design denoted A, predicting maximum global signal, and design denoted B, predicting maximum signal for minimum width broadening. In vivo data of the lumbar plexus in 10 healthy volunteers was acquired at 3.0T with 3D TSE employing flip angle trains A and B. Quantitative and qualitative analyses of the acquired data were made to assess changes in width and signal intensity. Results Changing flip angle modulation from A to B resulted in: 1) average signal losses of 23% in (larger) L5 nerves and 9% in (smaller) L3 nerves; 2) average width reductions of 4% in L5 nerves and of 16% in L3 nerves; and 3) statistically significant sharpness improvement (P = 0.005) in L3 nerves. Conclusion An optimized flip angle train in 3D TSE imaging of the lumbar plexus considering geometry-specific blurring effects from both the nerve and the surrounding tissue can improve the delineation of small nerves. J. Magn. Reson. Imaging 2015.

The aim of this study was to characterise and compare widely used acquisition strategies for hyperpolarised (13)C imaging. Free induction decay chemical shift imaging (FIDCSI), echo-planar spectroscopic imaging (EPSI), IDEAL spiral chemical shift imaging (ISPCSI) and spiral chemical shift imaging (SPCSI) sequences were designed for two different regimes of spatial resolution. Their characteristics were studied in simulations and in tumour-bearing rats after injection of hyperpolarised [1-(13)C]pyruvate on a clinical 3-T scanner. Two or three different sequences were used on the same rat in random order for direct comparison. The experimentally obtained lactate signal-to-noise ratio (SNR) in the tumour matched the simulations. Differences between the sequences were mainly found in the encoding efficiency, gradient demand and artefact behaviour. Although ISPCSI and SPCSI offer high encoding efficiencies, these non-Cartesian trajectories are more prone than EPSI and FIDCSI to artefacts from various sources. If the encoding efficiency is sufficient for the desired application, EPSI has been proven to be a robust choice. Otherwise, faster spiral acquisition schemes are recommended. The conclusions found in this work can be applied directly to clinical applications.

For the detection of small molecules, proteins or even cells in vitro , functionalised magnetic nanoparticles and nuclear magnetic resonance measurements can be applied. In this work, magnetic nanoparticles with the size of 5–7 nm were functionalised with antibodies to detect two model systems of different sizes, the protein avidin and Saccharomyces cerevisiae as the model organism. The synthesised magnetic nanoparticles showed a narrow size distribution, which was determined using transmission electron microscopy and dynamic light scattering. The magnetic nanoparticles were functionalised with the according antibodies via EDC/NHS chemistry. The binding of the antigen to magnetic nanoparticles was detected through the change in the NMR T 2 relaxation time at 0.5 T (≈21.7 MHz). In case of a specific binding the particles cluster and the T 2 relaxation time of the sample changes. The detection limit in buffer for FITC-avidin was determined to be 1.35 nM and 10 7 cells/ml for S. cerevisiae . For fluorescent microscopy the avidin molecules were labelled with FITC and for the detection of S. cerevisiae the magnetic nanoparticles were additionally functionalised with rhodamine. The binding of the particles to S. cerevisiae and the resulting clustering was also seen by transmission electron microscopy.

Purpose To propose and optimize diffusion-weighted stimulated echo acquisition mode (DW-STEAM) for measuring fat unsaturation in the presence of a strong water signal by suppressing the water signal based on a shorter T2 and higher diffusivity of water relative to fat. Methods A parameter study for point-resolved spectroscopy (PRESS) and STEAM using oil phantoms was performed and correlated with gas chromatography (GC). Simulations of muscle tissue signal behavior using DW-STEAM and long–echo time (TE) PRESS and a parameter optimization for DW-STEAM were conducted. DW-STEAM and long-TE PRESS were applied in the gastrocnemius muscles of nine healthy subjects. Results STEAM with TE and mixing time (TM) up to 45 ms exhibited R2 correlations above 0.98 with GC and little T2-weighting and J-modulation for the quantified olefinic/methylene peak ratio. The optimal parameters for muscle tissue using DW-STEAM were b-value = 1800 s/mm2, TE = 33 ms, TM = 30 ms, and repetition time = 2300 ms. In vivo measured mean olefinic signal-to-noise ratios were 72 and 40, mean apparent olefinic water fractions were 0.19 and 0.11 for DW-STEAM and long-TE PRESS, respectively. Conclusion Optimized DW-STEAM MR spectroscopy is superior to long-TE PRESS for measuring fat unsaturation, if a strong water peak prevents the olefinic fat signal's quantification at shorter TEs and water's tissue specific ADC is substantially higher than fat. Magn Reson Med 75:32–41, 2016. © 2015 Wiley Periodicals, Inc.

Aberrant pH is characteristic of many pathologies such as ischemia, inflammation or cancer. Therefore, a non-invasive and spatially resolved pH determination is valuable for disease diagnosis, characterization of response to treatment and the design of pH-sensitive drug-delivery systems. We recently introduced hyperpolarized [1,5

Natural pH regulatory mechanisms can be overruled during several pathologies such as cancer, inflammation and ischaemia, leading to local pH changes in the human body. Here we demonstrate that 13C-labelled zymonic acid (ZA) can be used as hyperpolarized magnetic resonance pH imaging sensor. ZA is synthesized from [1-13C]pyruvic acid and its 13C resonance frequencies shift up to 3.0 p.p.m. per pH unit in the physiological pH range. The long lifetime of the hyperpolarized signal enhancement enables monitoring of pH, independent of concentration, temperature, ionic strength and protein concentration. We show in vivo pH maps within rat kidneys and subcutaneously inoculated tumours derived from a mammary adenocarcinoma cell line and characterize ZA as non-toxic compound predominantly present in the extracellular space. We suggest that ZA represents a reliable and non-invasive extracellular imaging sensor to localize and quantify pH, with the potential to improve understanding, diagnosis and therapy of diseases characterized by aberrant acid-base balance., Local pH alterations can be manifestations of pathologies such as cancer, inflammation and ischaemia. Here Düwel et al. show hyperpolarized 13C-labelled zymonic acid can be used as a non-invasive probe to map and measure pH in vivo, suggesting it as a candidate for clinical imaging and a diagnostic tool.

The metabolism of acetate in the heart resembles fatty acid metabolism, which is altered in several diseases like ischemia, diabetes mellitus, and heart failure. A signal-to-noise ratio (SNR) optimized imaging framework for in vivo measurements of hyperpolarized [1-(13) C]acetate and its metabolic product [1-(13) C]acetylcarnitine (ALCAR) in rats at 3 Tesla (T) is presented in this work.A spectrospatial pulse was combined with IDEAL encoding to acquire well separated metabolic maps. The influence of dobutamine induced stress onto this metabolic system was investigated in spectra and in an imaging study.An increase of the ALCAR to acetate ratio with dobutamine induced stress was shown in slice selective spectra containing the rat hearts and skeletal muscles. Metabolic maps of acetate and ALCAR were acquired with an acceptable SNR. Quantification of the apparent conversion rate showed stable results in the heart in a time-window of 30 s. The effect of dobutamine on the signal intensities was shown to originatemainly from skeletal than cardiac muscles.The acetate activation was mapped with hyperpolarized [1-(13) C]acetate in a clinical 3T system. Quantitative measurement of the activity was possible in the heart, indicating that dobutamine induced stress does not improve the ALCAR SNR in the heart.

Hyperpolarization of [1-13C]pyruvate in solution allows real-time measurement of uptake and metabolism using MR spectroscopic methods. After injection and perfusion, pyruvate is taken up by the cells and enzymatically metabolized into downstream metabolites such as lactate, alanine, and bicarbonate. In this work, we present comprehensive methods for the quantification and interpretation of hyperpolarized 13C metabolite signals. First, a time-domain spectral fitting method is described for the decomposition of FID signals into their metabolic constituents. For this purpose, the required chemical shift frequencies are automatically estimated using a matching pursuit algorithm. Second, a time-discretized formulation of the two-site exchange kinetic model is used to quantify metabolite signal dynamics by two characteristic rate constants in the form of (i) an apparent build-up rate (quantifying the build-up of downstream metabolites from the pyruvate substrate) and (ii) an effective decay rate (summarizing signal depletion due to repetitive excitation, T1-relaxation and backward conversion). The presented spectral and kinetic quantification were experimentally verified in vitro and in vivo using hyperpolarized [1-13C]pyruvate. Using temporally resolved IDEAL spiral CSI, spatially resolved apparent rate constant maps are also extracted. In comparison to single metabolite images, apparent build-up rate constant maps provide improved contrast by emphasizing metabolically active tissues (e.g. tumors) and suppression of high perfusion regions with low conversion (e.g. blood vessels). Apparent build-up rate constant mapping provides a novel quantitative image contrast for the characterization of metabolic activity. Its possible implementation as a quantitative standard will be subject to further studies.

Purpose Because pH plays a crucial role in several diseases, it is desirable to measure pH in vivo noninvasively and in a spatially localized manner. Spatial maps of pH were quantified in vitro, with a focus on method-based errors, and applied in vivo. Methods In vitro and in vivo 13C mapping were performed for various flip angles for bicarbonate (BiC) and CO2 with spectral-spatial excitation and spiral readout in healthy Lewis rats in five slices. Acute subcutaneous sterile inflammation was induced with Concanavalin A in the right leg of Buffalo rats. pH and proton images were measured 2 h after induction. Results After optimizing the signal to noise ratio of the hyperpolarized 13C-bicarbonate, error estimation of the spectral-spatial excited spectrum reveals that the method covers the biologically relevant pH range of 6 to 8 with low pH error (< 0.2). Quantification of pH maps shows negligible impact of the residual bicarbonate signal. pH maps reflect the induction of acute metabolic alkalosis. Inflamed, infected regions exhibit lower pH. Conclusion Hyperpolarized 13C-bicarbonate pH mapping was shown to be sensitive in the biologically relevant pH range. The mapping of pH was applied to healthy in vivo organs and interpreted within inflammation and acute metabolic alkalosis models. Magn Reson Med 73:2274–2282, 2015. © 2014 Wiley Periodicals, Inc.

Exploiting spatio-temporal redundancies in sub-Nyquist sampled dynamic MRI for the suppression of undersampling artifacts was shown to be of great success. However, temporally averaged and blurred structures in image space composite data poses the risk of false information in the reconstruction. Within this work we assess the possibility of employing the composite image histogram as a measure of undersampling artifacts and as basis of their suppression. The proposed algorithm utilizes a histogram, computed from a composite image within a dynamically acquired interleaved radial MRI measurement as reference to compensate for the impact of undersampling in temporally resolved data without the incorporation of temporal averaging. In addition an image space regularization utilizing a single frame low-resolution reconstruction is implemented to enforce overall contrast fidelity. The performance of the approach was evaluated on a simulated radial dynamic MRI acquisition and on two functional in vivo radial cardiac acquisitions. Results demonstrate that the algorithm maintained contrast properties, details and temporal resolution in the images, while effectively suppressing undersampling artifacts.

The purpose of this work was to investigate the performance of the modified BIR-4 T

Abnormalities of tumor metabolism can be exploited for molecular imaging. PET imaging of (18)F-FDG is a well-established method using the avid glucose uptake of tumor cells. (13)C MR spectroscopic imaging (MRSI) of hyperpolarized [1-(13)C]pyruvate and its metabolites, meanwhile, represents a new method to study energy metabolism by visualizing, for example, the augmented lactate dehydrogenase activity in tumor cells. Because of rapid signal loss, this method underlies strict temporal limitations, and the acquisition of data-encoding spatial, temporal, and spectral information within this time frame-is challenging. The object of our study was to compare spectroscopic images with (18)F-FDG PET images for visualizing tumor metabolism in a rat model.(13)C MRSI with IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation) chemical shift imaging in combination with single-shot spiral acquisition was used to obtain dynamic data from 23 rats bearing a subcutaneous hepatocellular carcinoma and from reference regions of the same animals. Static and dynamic analysis of (18)F-FDG PET images of the same animals was performed. The data were analyzed qualitatively (visual assessment) and quantitatively (magnitude and dynamics of (18)F-FDG uptake, (13)C MRSI dynamics, and physiologic parameters).In most animals increased [1-(13)C]lactate signals in the tumor could be detected by simple display of integrated [1-(13)C]lactate images with corresponding enhanced (18)F-FDG uptake. Low [1-(13)C]pyruvate or [1-(13)C]lactate signals did not correlate with histologic or physiologic parameters. Significantly less pyruvate reached the tumors than the gastrointestinal tract, but in tumors a significantly higher amount of pyruvate was converted to lactate and alanine within seconds after intravenous administration.This study reveals that PET and (13)C MRSI can be used to visualize increased glycolytic flux in malignant tissue. The combination of signals will allow the quantitative dissection of substrate metabolism, with respect to uptake and downstream metabolic pathways. Although hyperpolarized [1-(13)C]pyruvate increases the sensitivity of MR imaging, signal-to-noise ratio constraints still apply for spatially and temporally resolved (13)C MRSI, emphasizing the need for further MR methodologic development. These first imaging data suggest the feasibility of (13)C MRSI for future clinical use.

The detection of tumors noninvasively, the characterization of their progression by defined markers and the monitoring of response to treatment are goals of medical imaging techniques. In this article, a method which measures the apparent diffusion coefficients (ADCs) of metabolites using hyperpolarized 13C diffusion-weighted spectroscopy is presented. A pulse sequence based on the pulsed gradient spin echo (PGSE) was developed that encodes both kinetics and diffusion information. In experiments with MCF-7 human breast cancer cells, we detected an ADC of intracellularly produced lactate of 1.06 ± 0.15 µm2/ms, which is about one-half of the value measured with pyruvate in extracellular culture medium. When monitoring tumor cell spheroids during progressive membrane permeabilization with Triton X-100, the ratio of lactate ADC to pyruvate ADC increases as the fraction of dead cells increases. Therefore, 13C ADC detection can yield sensitive information on changes in membrane permeability and subsequent cell death. Our results suggest that both metabolic label exchange and 13C ADCs can be acquired simultaneously, and may potentially serve as noninvasive biomarkers for pathological changes in tumor cells. Copyright © 2012 John Wiley & Sons, Ltd.