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Although hyperpolarization (HP) greatly increases the sensitivity of 13C MR, the usefulness of HP in vivo is limited by the short lifetime of HP agents. To address this limitation, we developed an echo-planar (EPI) sequence with spectral-spatial radiofrequency (SSRF) pulses for fast and efficient metabolite-specific imaging of HP [1-13C]pyruvate and [1-13C]lactate at 4.7 T. The spatial and spectral selectivity of each SSRF pulse was verified using simulations and phantom testing. EPI and CSI imaging of the rat abdomen were compared in the same rat after injecting HP [1-13C]pyruvate. A procedure was also developed to automatically set the SSRF excitation pulse frequencies based on real-time scanner feedback. The most significant results of this study are the demonstration that a greater spatial and temporal resolution is attainable by metabolite-specific EPI as compared with CSI, and the enhanced lifetime of the HP signal in EPI, which is attributable to the independent flip angle control between metabolites. Real-time center frequency adjustment was also highly effective for minimizing off-resonance effects. To the best of our knowledge, this is the first demonstration of metabolite-specific HP 13C EPI at 4.7 T. In conclusion, metabolite-specific EPI using SSRF pulses is an effective way to image HP [1-13C]pyruvate and [1-13C]lactate at 4.7 T.

PURPOSE: The purpose of this study was to directly compare two isotopic metabolic imaging approaches, hyperpolarized (HP) (13)C MRI and deuterium metabolic imaging (DMI), for imaging specific closely-related segments of cerebral glucose metabolism at 4.7 T. METHODS: Comparative HP (13)C and DMI neuroimaging experiments were conducted consecutively in normal rats during the same scanning session. Localized conversions of [1-(13)C]pyruvate and [6,6-(2)H(2)]glucose to their respective downstream metabolic products were measured by spectroscopic imaging, using an identical 2D CSI sequence with parameters optimized for the respective experiments. To facilitate direct comparison, a pair of substantially-equivalent 2.5-cm double-tuned X / (1)H RF surface coils was developed. For improved results, multi-dimensional low-rank reconstruction was applied to denoise the raw DMI data. RESULTS: Localized conversion of HP [1-(13)C]pyruvate to [1-(13)C]lactate, and [6,6-(2)H(2)]glucose to [3,3-(2)H(2)]lactate and Glx-d (glutamate and glutamine), was detected in rat brain by spectroscopic imaging at 4.7 T. The SNR and spatial resolution of HP (13)C MRI was superior to DMI but limited to a short time window, while the lengthy DMI acquisition yielded maps of not only lactate but also Glx production, albeit with relatively poor spectral discrimination between metabolites at this field strength. Across the individual rats, there was an apparent inverse correlation between cerebral production of HP [1-(13)C]lactate and Glx-d, along with a trend toward increased [3,3-(2)H(2)]lactate. CONCLUSION: HP (13)C MRI and DMI are both feasible at 4.7 T and have significant potential for metabolic imaging of specific segments of glucose metabolism.

PURPOSE: The purpose of this study was to investigate hyperpolarization and in vivo imaging of [(15)N]carnitine, a novel endogenous MRI probe with long signal lifetime. METHODS: L-[(15)N]carnitine-d(9) was hyperpolarized by the method of dynamic nuclear polarization (DNP) followed by rapid dissolution. T(1) signal lifetimes were estimated in aqueous solution and in vivo following intravenous injection in rats, using a custom-built dual-tuned (15)N/(1)H radiofrequency coil at 4.7 T. (15)N chemical shift imaging (CSI) and (15)N fast spin echo (FSE) images of rat abdomen were acquired three minutes after [(15)N]carnitine injection. RESULTS: Estimated T(1)’s of [(15)N]carnitine at 4.7 T were 210 s (in H(2)O) and 160 s (in vivo), with an estimated polarization level of 10%. Remarkably, the [(15)N]carnitine coherence was detectable in rat abdomen for five minutes after injection for the non-localized acquisition. No downstream metabolites were detected on localized or non-localized (15)N spectra. Diffuse liver enhancement was detected on (15)N FSE imaging three minutes after injection, with mean hepatic SNR of 18 ± 5 at a spatial resolution of 4 mm x 4 mm. CONCLUSIONS: This study showed the feasibility of hyperpolarizing and imaging the biodistribution of HP [(15)N]carnitine.

PURPOSE: To use fiducial markers containing manganese 55 to rapidly localize carbon 13 ((13)C) RF coils for correcting images for B(1) variation. METHODS: Hollow high-density polyethylene spheres were filled with 3M sodium permanganate and affixed to a rectangular (13)C-tuned RF coil. The relative positions of the markers and coil conductors were mapped using CT. Marker positions were measured by MRI using a series of 1D projections and automated peak detection. Once the coil location was determined, coil sensitivity was estimated using a quasistatic calculation. Simulations were performed to determine the minimum number of projections required for robust localization. Phantom experiments were used to confirm the accuracy of marker localization as well as the calculated coil sensitivity. Finally, in vivo validation was performed using hyperpolarized (13)C pyruvate in a rat model. RESULTS: In simulations, our algorithm was accurate in determining marker positions when at least 6 projections were used (RMSE 1.4 ± 0.9 mm). These estimates were verified in phantom experiments, where markers locations were determined with an RMS accuracy of 1.3 mm. A minimum SNR of 4 was required for automated detection to perform accurately. Computed coil sensitivity had a median error of 17% when taken over the entire measured area and 5.7% over a central region. In a rat, correction for nonuniform reception and flip angle was able to normalize the signals arising from asymmetrically positioned kidneys. CONCLUSION: Manganese 55 fiducial markers are an inexpensive and reliable method for rapidly localizing (13)C RF coils and correcting (13)C images for B(1) variation without user intervention.

PURPOSE The purpose of this study was to investigate the feasibility of in vivo 13 C->1 H hyperpolarization transfer, which has significant potential advantages for detecting the distribution and metabolism of hyperpolarized 13 C probes in a clinical MRI scanner. METHODS A standalone pulsed 13 C RF transmit channel was developed for operation in conjunction with the standard 1 H channel of a clinical 3T MRI scanner. Pulse sequences for 13 C power calibration and polarization transfer were programmed on the external hardware and integrated with a customized water-suppressed 1 H MRS acquisition running in parallel on the scanner. The newly developed RF system was tested in both phantom and in vivo polarization transfer experiments in 1 JCH -coupled systems: phantom experiments in thermally polarized and hyperpolarized [2-13 C]glycerol, and 1 H detection of [2-13 C]lactate generated from hyperpolarized [2-13 C]pyruvate in rat liver in vivo. RESULTS Operation of the custom pulsed 13 C RF channel resulted in effective 13 C->1 H hyperpolarization transfer, as confirmed by the characteristic antiphase appearance of 1 H-detected, 1 JCH -coupled doublets. In conjunction with a pulse sequence providing 190-fold water suppression in vivo, 1 H detection of hyperpolarized [2-13 C]lactate generated in vivo was achieved in a rat liver slice. CONCLUSION The results show clear feasibility for effective 13 C->1 H hyperpolarization transfer in a clinical MRI scanner with customized heteronuclear RF system.

Purpose The bSSFP acquisition enables high spatiotemporal resolution for hyperpolarized 13C MRI at 3T, but is limited by spectral contamination from adjacent resonances. The purpose of this study was to develop a framework for in vivo dynamic high resolution imaging of hyperpolarized [1-13C]pyruvate and [1-13C]lactate generated in vivo at 3T by simplifying the spectrum through the use of selective suppression pulses. Methods Spectral suppression pulses were incorporated into the bSSFP sequence for suppression of [1-13C]alanine and [1-13C]pyruvate-hydrate signals, leaving only the pyruvate and lactate resonances. Subsequently, the bSSFP pulse width, time-bandwidth, and repetition time were optimized for imaging these dual resonances. Results The spectral suppression reduced both the alanine and pyruvate-hydrate signals by 85.5 ± 4.9% and had no significant effect on quantitation of pyruvate to lactate conversion (liver: P = 0.400, kidney: P = 0.499). High resolution (2 × 2 mm2 and 3 × 3 mm2) sub-second 2D coronal projections and 3D 2.5 mm isotropic images were obtained in rats and tumor-bearing mice with 1.8-5 s temporal resolution, allowing for calculation of lactate-to-pyruvate ratios and kPL. Conclusion The developed framework presented here shows the capability for dynamic high resolution volumetric hyperpolarized bSSFP imaging of pyruvate-to-lactate conversion on a clinical 3T MR scanner.

Purpose The purpose of this study was to investigate the hyperpolarized ketone body 13 C-acetoacetate (AcAc) and its conversion to 13 C-β-hydroxybutyrate (βOHB) in vivo, catalyzed by β-hydroxybutyrate dehydrogenase (BDH), as a novel direct marker of mitochondrial redox state. Methods [1,3-13 C2 ]AcAc was synthesized by hydrolysis of the ethyl ester, and hyperpolarized via dissolution DNP. Cold storage under basic conditions resulted in sufficient chemical stability for use in hyperpolarized (HP) MRI studies. Polarizations and relaxation times of HP [1,3-13 C2 ]AcAc were measured in a clinical 3T MRI scanner, and 8 rats were scanned by dynamic HP 13 C MR spectroscopy of a slab through the kidneys. Four rats were scanned after acute treatment with high dose metformin (125 mg/kg, intravenous), which is known to modulate mitochondrial redox via inhibition of mitochondrial complex I. An additional metformin-treated rat was scanned by abdominal 2D CSI (8 mm × 8 mm). Results Polarizations of 7 ± 1% and 7 ± 3%, and T1 relaxation times of 58 ± 5 s and 52 ± 3 s, were attained at the C1 and C3 positions, respectively. Rapid conversion of HP AcAc to βOHB was detected in rat kidney in vivo, via the C1 label. The product HP βOHB was resolved from closely resonating acetate. Conversion to βOHB was also detected via 2D CSI, in both kidney as well as liver regions. Metformin treatment resulted in a significant increase (40%, P = 0.01) of conversion of HP AcAc to βOHB. Conclusion Rapid conversion of HP AcAc to βOHB was observed in rat kidney in vivo and is a promising new non-invasive marker of mitochondrial redox state. Magn Reson Med 79:1862-1869, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

PURPOSE Although 1 H spin coupling is generally avoided in probes for hyperpolarized (HP) 13 C MRI, enzymatic transformations of biological interest can introduce large 13 C-1 H couplings in vivo. The purpose of this study was to develop and investigate the application of 1 H decoupling for enhancing the sensitivity for detection of affected HP 13 C metabolic products. METHODS A standalone 1 H decoupler system and custom concentric 13 C/1 H paddle coil setup were integrated with a clinical 3T MRI scanner for in vivo 13 C MR studies using HP [2-13 C]dihydroxyacetone, a novel sensor of hepatic energy status. Major 13 C-1 H coupling JCH = ∼150 Hz) is introduced after adenosine triphosphate-dependent enzymatic transformation of HP [2-13 C]dihydroxyacetone to [2-13 C]glycerol-3-phosphate in vivo. Application of WALTZ-16 1 H decoupling for elimination of large 13 C-1 H couplings was first tested in thermally polarized glycerol phantoms and then for in vivo HP MR studies in three rats, scanned both with and without decoupling. RESULTS As configured, 1 H-decoupled 13 C MR of thermally polarized glycerol and the HP metabolic product [2-13 C]glycerol-3-phosphate was achieved at forward power of approximately 15 W. High-quality 3-s dynamic in vivo HP 13 C MR scans were acquired with decoupling duty cycle of 5%. Application of 1 H decoupling resulted in sensitivity enhancement of 1.7-fold for detection of metabolic conversion of [2-13 C]dihydroxyacetone to HP [2-13 C]glycerol-3-phosphate in vivo. CONCLUSIONS Application of 1 H decoupling provides significant sensitivity enhancement for detection of HP 13 C metabolic products with large 1 H spin couplings, and is therefore expected to be useful for preclinical and potentially clinical HP 13 C MR studies. Magn Reson Med 80:36-41, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose To investigate acute changes in glucose metabolism in liver and kidneys in vivo after a bolus injection of either fructose or glucose, using hyperpolarized [2-13 C]dihydroxyacetone. Methods Spatially registered, dynamic, multislice MR spectroscopy was acquired for the metabolic products of [2-13 C]dihydroxyacetone in liver and kidneys. Metabolism was probed in 13 fasted rats at three time points: 0, 70, and 140 min. At 60 min, rats were injected intravenously with fructose (n = 5) or glucose (n = 4) at 0.8 g/kg to initiate acute response. Controls (n = 4) did not receive a carbohydrate challenge. Results Ten minutes after fructose infusion, levels of [2-13 C]phosphoenolpyruvate and [2-13 C]glycerol-3-phosphate halved in liver: 51% (P = 0.0010) and 47% (P = 0.0001) of baseline, respectively. Seventy minutes later, levels returned to baseline. The glucose challenge did not alter the signals significantly, nor did repeated administration of the dihydroxyacetone imaging bolus. In kidneys, no statistically significant changes were detected after sugar infusion other than a 20% increase of the glycerol-3-phosphate signal between 10 and 80 min after fructose injection (P = 0.0028). Conclusion Hyperpolarized [2-13 C]dihydroxyacetone detects a real-time, transient metabolic response of the liver to an acute fructose challenge. Observed effects possibly include ATP depletion and changes in the unlabeled pool sizes of glycolytic intermediates. Magn Reson Med 77:65-73, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Hyperpolarized 13 C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, kPL , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID-Delay,Crush /kPL,FID-Delay = 1.37 ± 0.33, P

Purpose Balanced steady-state free precession (bSSFP) sequences can provide superior signal-to-noise ratio efficiency for hyperpolarized (HP) carbon-13 (13C) magnetic resonance imaging by efficiently utilizing the nonrecoverable magnetization, but managing their spectral response is challenging in the context of metabolic imaging. A new spectrally selective bSSFP sequence was developed for fast imaging of multiple HP 13C metabolites with high spatiotemporal resolution. Theory and Methods This novel approach for bSSFP spectral selectivity incorporates optimized short-duration spectrally selective radiofrequency pulses within a bSSFP pulse train and a carefully chosen repetition time to avoid banding artifacts. Results The sequence enabled subsecond 3D dynamic spectrally selective imaging of 13C metabolites of copolarized [1-13C]pyruvate and [13C]urea at 2-mm isotropic resolution, with excellent spectral selectivity (∼100:1). The sequence was successfully tested in phantom studies and in vivo studies with normal mice. Conclusion This sequence is expected to benefit applications requiring dynamic volumetric imaging of metabolically active 13C compounds at high spatiotemporal resolution, including preclinical studies at high field and, potentially, clinical studies.Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE Hyperpolarized 13 C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types. METHODS Baseline gadoxetate uptake kinetics were measured using T1 -weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1-13 C]pyruvate, [1-13 C]lactate, and [1-13 C]alanine. Four healthy rats were imaged with hyperpolarized [1-13 C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney. RESULTS Overall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively (P

Purpose The purpose of this study was to characterize tissue-specific alterations in metabolism of hyperpolarized (HP) gluconeogenic precursors 13 C-lactate and 13 C-pyruvate by rat liver and kidneys under conditions of fasting or insulin-deprived diabetes. Methods Seven normal rats were studied by MR spectroscopic imaging of both HP 13 C-lactate and 13 C-pyruvate in both normal fed and 24 h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with insulin withdrawal. Phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ-treated rats. Results Multiple sets of significant signal modulations were detected, with graded intensity in general between fasting and diabetic states. An approximate two-fold reduction in the ratio of 13 C-bicarbonate to total 13 C signal was observed in both organs in fasting. The ratio of HP lactate-to-alanine was markedly altered, ranging from a liver-specific 54% increase in fasting, to increases of 69% and 92% in liver and kidney, respectively, in diabetes. Diabetes resulted in a 40% increase in renal lactate signal. STZ resulted in 5.86-fold and 2.73-fold increases in PEPCK expression in liver and kidney, respectively. Conclusion MRI of HP 13 C gluconeogenic precursors may advance diabetes research by clarifying organ-specific roles in abnormal diabetic metabolism. Magn Reson Med 77:1429-1437, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE To develop a specialized multislice, single-acquisition approach to detect the metabolites of hyperpolarized (HP) [2-13 C]dihydroxyacetone (DHAc) to probe gluconeogenesis in vivo, which have a broad 144 ppm spectral range (∼4.6 kHz at 3T). A novel multiband radio-frequency (RF) excitation pulse was designed for independent flip angle control over five to six spectral-spatial (SPSP) excitation bands, each corrected for chemical shift misregistration effects. METHODS Specialized multiband SPSP RF pulses were designed, tested, and applied to investigate HP [2-13 C]DHAc metabolism in kidney and liver of fasted rats with dynamic 13 C-MR spectroscopy and an optimal flip angle scheme. For comparison, experiments were also performed with narrow-band slice-selective RF pulses and a sequential change of the frequency offset to cover the five frequency bands of interest. RESULTS The SPSP pulses provided a controllable spectral profile free of baseline distortion with improved signal to noise of the metabolite peaks, allowing for quantification of the metabolic products. We observed organ-specific differences in DHAc metabolism. There was two to five times more [2-13 C]phosphoenolpyruvate and about 19 times more [2-13 C]glycerol 3-phosphate in the liver than in the kidney. CONCLUSION A multiband SPSP RF pulse covering a spectral range over 144 ppm enabled in vivo characterization of HP [2-13 C]DHAc metabolism in rat liver and kidney. Magn Reson Med 77:1419-1428, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE Dissolution dynamic nuclear polarization (DNP) enables the acquisition of 13 C magnetic resonance data with a high sensitivity. Recently, metabolically inactive hyperpolarized 13 C-labeled compounds have shown to be potentially useful for perfusion imaging. The purpose of this study was to validate hyperpolarized perfusion imaging methods by comparing with conventional gadolinium (Gd)-based perfusion MRI techniques and pathology. METHODS Dynamic 13 C data using metabolically inactive hyperpolarized bis-1,1-(hydroxymethyl)-[1-13 C]cyclopropane-d8 (HMCP) were obtained from an orthotopic human glioblastoma (GBM) model for the characterization of tumor perfusion and compared with standard Gd-based dynamic susceptibility contrast (DSC) MRI data and immunohistochemical analysis from resected brains. RESULTS Distinct HMCP perfusion characteristics were observed within the GBM tumors compared with contralateral normal brain tissue. The perfusion parameters obtained from the hyperpolarized HMCP data in tumor were strongly correlated with normalized peak height measured from the DSC images. The results from immunohistochemical analysis supported these findings by showing a high level of vascular staining for tumor that exhibited high levels of hyperpolarized HMCP signal. CONCLUSION The results from this study have demonstrated that hyperpolarized HMCP data can be used as an indicator of tumor perfusion in an orthotopic xenograft model for GBM. Magn Reson Med 77:841-847, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Magnetic resonance (MR) based hyperpolarized (HP) (13)C metabolic imaging is under active pursuit as a new clinical diagnostic method for cancer detection, grading, and monitoring of therapeutic response. Following the tremendous success of metabolic imaging by positron emission tomography (PET), which already plays major roles in clinical oncology, the added value of HP (13)C MRI is emerging. Aberrant glycolysis and central carbon metabolism is a hallmark of many forms of cancer. The chemical transformations associated with these pathways produce metabolites ranging in general from 3 to 6 carbons, and are dependent on the redox state and energy charge of the tissue. The significant changes in chemistry associated with flux through these pathways imply HP imaging can take advantage of the underlying chemical shift information encoded into an MR experiment to produce images of the injected substrate as well as its metabolites. However, imaging of HP metabolites poses unique constraints on pulse sequence design related to detection of X-nuclei, decay of the HP magnetization due to T(1), and the consumption of HP signal by the inspection pulses. Advancements in the field continue to depend critically on customization of MRI systems and pulse sequences for optimized detection of HP (13)C signals, focused largely on extracting the maximum amount of information during the short lifetime of the HP magnetization. From a clinical perspective, the success of HP (13)C MRI of cancer will largely depend upon the utility of HP pyruvate for the detection of lactate pools associated with the Warburg effect, though several other agents are also under investigation, with novel agents continually being formulated. In this review, the salient aspects of HP (13)C imaging will be highlighted, with an emphasis on both technological challenges and the biochemical aspects of HP experimental design.

The goal of this project was to develop and apply techniques for T2 mapping and 3D high resolution (1.5 mm isotropic; 0.003 cm3) 13C imaging of hyperpolarized (HP) probes [1-13C]lactate, [1-13C]pyruvate, [2-13C]pyruvate, and [13C,15N2]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5 mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T2 mapping experiments yielded measurements of T2 values of greater than 1 s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2-13C]pyruvate which was ~730 ms and ~320 ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1-13C]lactate, [1-13C]pyruvate, and [2-13C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003 cm3) spatial and 2 s temporal resolution in vivo utilizing HP 13C substrates by exploiting their long T2 values. This 1.5 mm isotropic resolution is comparable to 1H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging.

Purpose To demonstrate simultaneous hyperpolarization and imaging of three 13C-labeled perfusion MRI contrast agents with dissimilar molecular structures ([13C]urea, [13C]hydroxymethyl cyclopropane, and [13C]t-butanol) and correspondingly variable chemical shifts and physiological characteristics, and to exploit their varying diffusibility for simultaneous measurement of vascular permeability and perfusion in initial preclinical studies. Methods Rapid and efficient dynamic multislice imaging was enabled by a novel pulse sequence incorporating balanced steady state free precession excitation and spectral-spatial readout by multiband frequency encoding, designed for the wide, regular spectral separation of these compounds. We exploited the varying bilayer permeability of these tracers to quantify vascular permeability and perfusion parameters simultaneously, using perfusion modeling methods that were investigated in simulations. “Tripolarized” perfusion MRI methods were applied to initial preclinical studies with differential conditions of vascular permeability, in normal mouse tissues and advanced transgenic mouse prostate tumors. Results Dynamic imaging revealed clear differences among the individual tracer distributions. Computed permeability maps demonstrated differential permeability of brain tissue among the tracers, and tumor perfusion and permeability were both elevated over values expected for normal tissues. Conclusion Tripolarized perfusion MRI provides new molecular imaging measures for specifically monitoring permeability, perfusion, and transport simultaneously in vivo. Magn Reson Med 72:1599–1609, 2014. © 2013 Wiley Periodicals, Inc.

The development of hyperpolarized technology utilizing dynamic nuclear polarization (DNP) has enabled the rapid measurement of 13 C metabolism in vivo with very high SNR. However, with traditional DNP equipment, consecutive injections of a hyperpolarized compound in an animal have been subject to a practical minimum time between injections governed by the polarization build-up time, which is on the order of an hour for [1- 13 C]pyruvate. This has precluded the monitoring of metabolic changes occurring on a faster time scale. In this study, we demonstrated the ability to acquire in vivo dynamic magnetic resonance spectroscopy (MRS) and 3D magnetic resonance spectroscopic imaging (MRSI) data in normal rats with a 5 min interval between injections of hyperpolarized [1- 13 C]pyruvate using a prototype, sub-Kelvin dynamic nuclear polarizer with the capability to simultaneously polarize up to 4 samples and dissolve them in rapid succession. There were minimal perturbations in the hyperpolarized spectra as a result of the multiple injections, suggesting that such an approach would not confound the investigation of metabolism occurring on this time scale. As an initial demonstration of the application of this technology and approach for monitoring rapid changes in metabolism as a result of a physiological intervention, we investigated the pharmacodynamics of the anti-cancer agent dichloroacetate (DCA), collecting hyperpolarized data before administration of DCA, 1 min after administration, and 6 min after administration. Dramatic increases in 13 C-bicarbonate were detected just 1 min (as well as 6 min) after DCA administration.

Metabolic imaging of hyperpolarized [1-13C] pyruvate co-polarized with [13C]urea by dynamic nuclear polarization with rapid dissolution is a promising new method for assessing tumor metabolism and perfusion simultaneously in vivo. Novel pulse sequences are required to enable dynamic imaging of multiple 13C spectral lines with high spatiotemporal resolution. The goal of this study was to investigate a new frequency-specific approach for rapid metabolic imaging of multiple 13C resonances using the spectral selectivity of steady-state free precession pulse (SSFP) trains. Methods developed in simulations were implemented in a dynamic frequency-cycled balanced SSFP pulse sequence on a 14.1-T animal magnetic resonance imaging scanner. This acquisition was tested in thermal and hyperpolarized phantom imaging studies and in a transgenic mouse with prostate cancer.

In vivo spin spin relaxation time (T2) heterogeneity of hyperpolarized [(13)C,(15)N2]urea in the rat kidney was investigated. Selective quenching of the vascular hyperpolarized (13)C signal with a macromolecular relaxation agent revealed that a long-T2 component of the [(13)C,(15)N2]urea signal originated from the renal extravascular space, thus allowing the vascular and renal filtrate contrast agent pools of the [(13)C,(15)N2]urea to be distinguished via multi-exponential analysis. The T2 response to induced diuresis and antidiuresis was performed with two imaging agents: hyperpolarized [(13)C,(15)N2]urea and a control agent hyperpolarized bis-1,1-(hydroxymethyl)-1-(13)C-cyclopropane-(2)H8. Large T2 increases in the inner-medullar and papilla were observed with the former agent and not the latter during antidiuresis. Therefore, [(13)C,(15)N2]urea relaxometry is sensitive to two steps of the renal urea handling process: glomerular filtration and the inner-medullary urea transporter (UT)-A1 and UT-A3 mediated urea concentrating process. Simple motion correction and subspace denoising algorithms are presented to aid in the multi exponential data analysis. Furthermore, a T2-edited, ultra long echo time sequence was developed for sub-2 mm(3) resolution 3D encoding of urea by exploiting relaxation differences in the vascular and filtrate pools.

The metabolically inactive hyperpolarized agents HP001 (bis-1,1-(hydroxymethyl)-[1-13C]cyclopropane-d8) and urea enable a new type of perfusion magnetic resonance imaging based on a direct signal source that is background-free. The addition of perfusion information to metabolic information obtained by spectroscopic imaging of hyperpolarized [1-13C]pyruvate would be of great value in exploring the relationship between perfusion and metabolism in cancer. In preclinical normal murine and cancer model studies, we performed both dynamic multislice imaging of the specialized hyperpolarized perfusion compound HP001 (T1=95 s ex vivo, 32 s in vivo at 3 T) using a pulse sequence with balanced steady-state free precession and ramped flip angle over time for efficient utilization of the hyperpolarized magnetization and three-dimensional echo-planar spectroscopic imaging of urea copolarized with [1-13C]pyruvate, with compressed sensing for resolution enhancement. For the dynamic data, peak signal maps and blood flow maps derived from perfusion modeling were generated. The spatial heterogeneity of perfusion was increased 2.9-fold in tumor tissues (P=.05), and slower washout was observed in the dynamic data. The results of separate dynamic HP001 imaging and copolarized pyruvate/urea imaging were compared. A strong and significant correlation (R=0.73, P=.02) detected between the urea and HP001 data confirmed the value of copolarizing urea with pyruvate for simultaneous assessment of perfusion and metabolism.

Ventral and rostral regions of the brain are of emerging importance for the MRI characterization of early dementia, traumatic brain injury and epilepsy. Unfortunately, standard single-shot echo planar diffusion-weighted imaging of these regions at high fields is contaminated by severe imaging artifacts in the vicinity of air-tissue interfaces. To mitigate these artifacts and improve visualization of the temporal and frontal lobes at 7 T, we applied a reduced field-of-view strategy, enabled by outer volume suppression (OVS) with novel quadratic phase radiofrequency (RF) pulses, combined with partial Fourier and parallel imaging methods. The new acquisition greatly reduced the level of artifacts in six human subjects (including four patients with early symptoms of dementia).

The aim of this study was to evaluate intracranial arterial stenoses and aneurysms with accelerated time-resolved three-dimensional (3D) phase-contrast MRI or 4D flow. The 4D flow technique was utilized to image four normal volunteers, two patients with intracranial stenoses and two patients with intracranial aneurysms. In order to reduce scan time, parallel imaging was combined with an acquisition strategy that eliminates the corners of k-space. In the two patients with intracranial stenoses, 4D flow velocity measurements showed that one patient had normal velocity profiles in agreement with a previous magnetic resonance angiogram (MRA), while the second showed increased velocities that indicated a less significant narrowing than suspected on a previous MRA, as confirmed by catheter angiography. This result may have prevented an invasive angiogram. In the two patients with 4-mm intracranial aneurysm, one had a stable helical flow pattern with a large jet, while the other had a temporally unstable flow pattern with a more focal jet possibly indicating that the second aneurysm may have a higher likelihood of rupture. Accelerated 4D flow provides time-resolved 3D velocity data in an 8- to 10-min scan. In the stenosis patients, the addition of 4D flow to a traditional MRA adds the velocity data provided from transcranial Doppler ultrasound (TCD) possibly allowing for more accurate grading of stenoses. In the aneurysm patients, visualization of flow patterns may help to provide prognostic information about future risk of rupture.

Purpose Greater spatial resolution in intracranial three-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA) is possible at higher field strengths, due to the increased contrast-to-noise ratio (CNR) from the higher signal-to-noise ratio and the improved background suppression. However, at very high fields, spatial resolution is limited in practice by the acquisition time required for sequential phase encoding. In this study, we applied parallel imaging to 7T TOF MRA studies of normal volunteers and patients with vascular disease, in order to obtain very high resolution (0.12 mm 3 ) images within a reasonable scan time. Materials and Methods Custom parallel imaging acquisition and reconstruction methods were developed for 7T MRA, based on generalized autocalibrating partially parallel acquisition (GRAPPA). The techniques were compared and applied to studies of seven normal volunteers and three patients with cerebrovascular disease. Results The technique produced high resolution studies free from discernible reconstruction artifacts in all subjects and provided excellent depiction of vascular pathology in patients. Conclusions 7T TOF MRA with parallel imaging is a valuable noninvasive angiographic technique that can attain very high spatial resolution.

A three-axis uniplanar gradient coil was designed and built to provide order-of-magnitude increases in gradient strength of up to 500 mT/m on the x- and y-axes, and 1000 mT/m for the z-axis at 640 A input over a limited FOV ( approximately 16 cm) for superficial regions, compared to conventional gradient coils, with significant gradient strengths extending deeper into the body. The gradient set is practically accommodated in the bore of a conventional whole-body, cylindrical-geometry MRI scanner, and operated using standard gradient supplies. The design was optimized for gradient linearity over a restricted volume while accounting for the practical problems of torque and heating. Tests at 320 A demonstrated up to 420-mT/m gradients near the surface at efficiencies of up to 1.4 mT/m/A. A new true 2D gradient-nonlinearity correction algorithm was developed to rectify gradient nonlinearities and considerably expand the imageable volumes. The gradient system and correction algorithm were implemented in a standard 1.5 T scanner and demonstrated by high-resolution imaging of phantoms and humans.

An eight-channel, nonoverlapping phased array coil was designed for conventional and parallel imaging of the brain and the hip at 3T. The nonoverlapping design was selected on the basis of reduced parallel reconstruction noise inflation, as predicted by the diminution of g-factor hotspots in SENSE reconstruction simulations, and the higher peripheral signal-to-noise ratio (SNR) expected from smaller coil elements. A capacitive bridging technique, modeled by a circuit simulation, reduced the crosstalk between nearest neighbors to a manageable level. The capacitive decoupling technique was effective enough to allow the coil to be operated using standard system preamplifiers. The coil was shown to be useful for several conventional and parallel imaging applications. SNR improvements over a commercial eight-channel head coil were demonstrated in important structures in EPI-SENSE diffusion-weighted imaging. High-resolution MRSI (0.22 cc) yielded SNR of up to 21 for the NAA peak in the cortical gray matter. The coil also provided excellent fourfold accelerated GRAPPA images of the hip. © 2007 Wiley Periodicals, Inc. Concepts Magn Reson Part B (Magn Reson Engineering) 31B: 37–43, 2007

Purpose Hyperpolarization of carbon-13 (13C) nuclei by dissolution dynamic nuclear polarization increases signal-to-noise ratio (SNR) by >10,000-fold for metabolic imaging, but care must be taken when transferring hyperpolarized (HP) samples from polarizer to MR scanner. Some 13C substrates relax rapidly in low ambient magnetic fields. A handheld electromagnet carrier was designed and constructed to preserve polarization by maintaining a sufficient field during sample transfer. Methods The device was constructed with a solenoidal electromagnet, powered by a nonmagnetic battery, holding the HP sample during transfer. A specially designed switch automated deactivation of the field once transfer was complete. Phantom and rat experiments were performed to compare MR signal enhancement with or without the device for HP [13C]urea and [1-13C]pyruvate. Results The magnetic field generated by this device was tested to be >50 G over a 6-cm central section. In phantom and rat experiments, [13C]urea transported via the device showed SNR improvement by a factor of 1.8–1.9 over samples transferred through the background field. Conclusion A device was designed and built to provide a suitably high yet safe magnetic field to preserve hyperpolarization during sample transfer. Comparative testing demonstrated SNR improvements of approximately two-fold for [13C]urea while maintaining SNR for [1-13C]pyruvate. Magn Reson Med 75:917–922, 2016. © 2015 Wiley Periodicals, Inc.

In this work we demonstrate for the first time directly detected manganese-55 ((55)Mn) magnetic resonance imaging (MRI) using a clinical 3T MRI scanner designed for human hyperpolarized (13)C clinical studies with no additional hardware modifications. Due to the similar frequency of the (55)Mn and (13)C resonances, the use of aqueous permanganate for large, signal-dense, and cost-effective "(13)C" MRI phantoms was investigated, addressing the clear need for new phantoms for these studies. Due to 100% natural abundance, higher intrinsic sensitivity, and favorable relaxation properties, (55)Mn MRI of aqueous permanganate demonstrates dramatically increased sensitivity over typical (13)C phantom MRI, at greatly reduced cost as compared with large (13)C-enriched phantoms. A large sensitivity advantage (22-fold) was demonstrated. A cylindrical phantom (d=8 cm) containing concentrated aqueous sodium permanganate (2.7 M) was scanned rapidly by (55)Mn MRI in a human head coil tuned for (13)C, using a balanced steady state free precession acquisition. The requisite penetration of radiofrequency magnetic fields into concentrated permanganate was investigated by experiments and high frequency electromagnetic simulations, and found to be sufficient for (55)Mn MRI with reasonably sized phantoms. A sub-second slice-selective acquisition yielded mean image signal-to-noise ratio of ~60 at 0.5 cm(3) spatial resolution, distributed with minimum central signal ~40% of the maximum edge signal. We anticipate that permanganate phantoms will be very useful for testing HP (13)C coils and methods designed for human studies.

Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease (CKD). Persistent oxidative stress and mitochondrial dysfunction are implicated across diverse forms of AKI and in the transition to CKD. In this study, we applied hyperpolarized (HP) 13 C dehydroascorbate (DHA) and 13 C pyruvate magnetic resonance spectroscopy (MRS) to investigate the renal redox capacity and mitochondrial pyruvate dehydrogenase (PDH) activity, respectively, in a murine model of AKI at baseline and 7 days after unilateral ischemia reperfusion injury (IRI). Compared with the contralateral sham-operated kidneys, the kidneys subjected to IRI showed a significant decrease in the HP 13 C vitamin C/(vitamin C + DHA) ratio, consistent with a decrease in redox capacity. The kidneys subjected to IRI also showed a significant decrease in the HP 13 C bicarbonate/pyruvate ratio, consistent with impaired PDH activity. The IRI kidneys showed a significantly higher HP 13 C lactate/pyruvate ratio at day 7 compared with baseline, although the 13 C lactate/pyruvate ratio was not significantly different between the IRI and contralateral sham-operated kidneys at day 7. Arterial spin labeling magnetic resonance imaging (MRI) demonstrated significantly reduced perfusion in the IRI kidneys. Renal tissue analysis showed corresponding increased reactive oxygen species (ROS) and reduced PDH activity in the IRI kidneys. Our results show the feasibility of HP 13 C MRS for the non-invasive assessment of oxidative stress and mitochondrial PDH activity following renal IRI.

Purpose The purpose of this study was to investigate 13C hyperpolarization of α-ketobutyrate (αKB), an endogenous molecular analog of pyruvate, and its in vivo enzymatic conversion via lactate dehydrogenase (LDH) using localized MR spectroscopy. Methods Hyperpolarized (HP) 13C MR experiments were conducted using [13C]αKB with rats in vivo and with isolated LDH enzyme in vitro, along with comparative experiments using [13C]pyruvate. Based on differences in the kinetics of its reaction with individual LDH isoforms, HP [13C]αKB was investigated as a novel MR probe, with added specificity for activity of LDHB-expressed H (“heart”-type) subunits of LDH (e.g., constituents of LDH-1 isoform). Results Comparable T1 and polarization values to pyruvate were attained (T1 = 52 s at 3 tesla [T], polarization = 10%, at C1). MR experiments showed rapid enzymatic conversion with substantially increased specificity. Formation of product HP [13C]α-hydroxybutyrate (αHB) from αKB in vivo was increased 2.7-fold in cardiac slabs relative to liver and kidney slabs. In vitro studies resulted in 5.0-fold higher product production from αKB with bovine heart LDH-1, as compared with pyruvate. Conclusions HP [13C]αKB may be a useful MR probe of cardiac metabolism and other applications where the role of H subunits of LDH is significant (e.g., renal cortex and brain). Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

To demonstrate dynamic imaging of a diffusible perfusion tracer, hyperpolarized [(13)C]urea, for regional measurement of blood flow in preclinical cancer models.A pulse sequence using balanced steady state free precession (bSSFP) was developed, with progressively increasing flip angles for efficient sampling of the hyperpolarized magnetization. This allowed temporal and volumetric imaging of the [(13)C]urea signal. Regional signal dynamics were quantified for kidneys and liver, and estimates of relative blood flows were derived from the data. Detailed perfusion simulations were performed to validate the methodology.Significant differences were observed in the signal patterns between normal and cancerous murine hepatic tissues. In particular, a 19% reduction in mean blood flow was observed in tumors, with 26% elevation in the tumor rim. The blood flow maps were also compared with metabolic imaging results with hyperpolarized [1-(13)C]pyruvate.Regional assessment of perfusion is possible by imaging of hyperpolarized [(13)C]urea, which is significant for the imaging of cancer.

Hyperpolarized technology utilizing dynamic nuclear polarization has enabled rapid and high-sensitivity measurements of (13)C metabolism in vivo. The most commonly used in vivo agent for hyperpolarized (13)C metabolic imaging thus far has been [1-(13)C]pyruvate. In preclinical studies, not only is its uptake detected, but also its intracellular enzymatic conversion to metabolic products including [1-(13)C]lactate and [1-(13)C]alanine. However, the ratio of (13)C-lactate/(13)C-pyruvate measured in this data does not accurately reflect cellular values since much of the [1-(13)C]pyruvate is extracellular depending on timing, vascular properties, and extracellular space and monocarboxylate transporter activity. In order to measure the relative levels of intracellular pyruvate and lactate, in this project we hyperpolarized [1-(13)C]alanine and monitored the in vivo conversion to [1-(13)C]pyruvate and then the subsequent conversion to [1-(13)C]lactate. The intracellular lactate-to-pyruvate ratio of normal rat tissue measured with hyperpolarized [1-(13)C]alanine was 4.89±0.61 (mean±S.E.) as opposed to a ratio of 0.41±0.03 when hyperpolarized [1-(13)C]pyruvate was injected.

In this work the generalized autocalibrating partially parallel acquisition (GRAPPA) technique was implemented with modified reconstruction and applied to in vivo high-resolution (HR) magnetic resonance imaging (MRI) of the trabecular bone microarchitecture at 3 Tesla (T) with a multiple-acquisition balanced steady-state free precession (b-SSFP) sequence. Trabecular bone is made up of a network of microstructures (80-140 microm), and its structural deterioration is associated with the skeletal metabolic disorder osteoporosis. HR-MRI is a promising noninvasive tool for assessing the trabecular microarchitecture in vivo, but it involves long acquisition times. Using partially parallel imaging (PPI) to accelerate the acquisition may help mitigate this shortcoming and allow more flexibility in protocol design. In this study the effects of GRAPPA-based reconstruction on image characteristics and the measurement of trabecular bone structural parameters were evaluated. Initial studies showed that image quality and depiction of microstructure were preserved in the GRAPPA-based reconstruction, indicating the feasibility of PPI in HR-MRI of trabecular bone. The results also demonstrated the potential of PPI for increasing the signal-to-noise ratio (SNR) efficiency of multiple-acquisition b-SSFP imaging protocols.