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PurposeThe combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research.MethodsA co-polarization system was developed where [1-13 C]pyruvic acid (PA) and [13 C, 15 N2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1-13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [13 C, 15 N2 ]urea.ResultsThe combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1-13 C]pyruvate, [1-13 C]lactate, [1-13 C]alanine, and [13 C, 15 N2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the JCN coupling.ConclusionThe reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate.

PurposeTo develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate-to-lactate conversion rates (kPL ) in patients with liver tumors.MethodsSeven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B1+ ) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate kPL .ResultsDenoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated kPL and under-flipped regions overestimated kPL . B1+ correction addressed this issue.ConclusionThe new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.

BackgroundOptimal treatment selection for localized renal tumors is challenging because of their variable biologic behavior and limitations in the preoperative assessment of tumor aggressiveness. The authors investigated the emerging hyperpolarized (HP) 13 C magnetic resonance imaging (MRI) technique to noninvasively assess tumor lactate production, which is strongly associated with tumor aggressiveness.MethodsEleven patients with renal tumors underwent HP 13 C pyruvate MRI before surgical resection. Tumor 13 C pyruvate and 13 C lactate images were acquired dynamically. Five patients underwent 2 scans on the same day to assess the intrapatient reproducibility of HP 13 C pyruvate MRI. Tumor metabolic data were compared with histopathology findings.ResultsEight patients had tumors with a sufficient metabolite signal-to-noise ratio for analysis; an insufficient tumor signal-to-noise ratio was noted in 2 patients, likely caused by poor tumor perfusion and, in 1 patient, because of technical errors. Of the 8 patients, 3 had high-grade clear cell renal cell carcinoma (ccRCC), 3 had low-grade ccRCC, and 2 had chromophobe RCC. There was a trend toward a higher lactate-to-pyruvate ratio in high-grade ccRCCs compared with low-grade ccRCCs. Both chromophobe RCCs had relatively high lactate-to-pyruvate ratios. Good reproducibility was noted across the 5 patients who underwent 2 HP 13 C pyruvate MRI scans on the same day.ConclusionsThe current results demonstrate the feasibility of HP 13 C pyruvate MRI for investigating the metabolic phenotype of localized renal tumors. The initial data indicate good reproducibility of metabolite measurements. In addition, the metabolic data indicate a trend toward differentiating low-grade and high-grade ccRCCs, the most common subtype of renal cancer.Lay summaryRenal tumors are frequently discovered incidentally because of the increased use of medical imaging, but it is challenging to identify which aggressive tumors should be treated. A new metabolic imaging technique was applied to noninvasively predict renal tumor aggressiveness. The imaging results were compared with tumor samples taken during surgery and showed a trend toward differentiating between low-grade and high-grade clear cell renal cell carcinomas, which are the most common type of renal cancers.

PurposeTo use fiducial markers containing manganese 55 to rapidly localize carbon 13 (13 C) RF coils for correcting images for B1 variation.MethodsHollow 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 quasi-static 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.ResultsIn 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.ConclusionManganese 55 fiducial markers are an inexpensive and reliable method for rapidly localizing 13 C RF coils and correcting 13 C images for B1 variation without user intervention.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X211018317 for Metabolic MRI with hyperpolarized [1-13C]pyruvate separates benign oligemia from infarcting penumbra in porcine stroke by Nikolaj Bøgh, Rie B Olin, Esben SS Hansen, Jeremy W Gordon, Sabrina K Bech, Lotte B Bertelsen, Juan D Sánchez-Heredia, Jakob U Blicher, Leif Østergaard, Jan H Ardenkjær-Larsen, Robert A Bok, Daniel B Vigneron and Christoffer Laustsen in Journal of Cerebral Blood Flow & Metabolism

PurposeWith the initiation of human hyperpolarized 13 C (HP-13 C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP-13 C MR spectroscopic imaging through means of Tensor Rank truncation-Image enhancement (TRI) and optimal receiver combination (ORC).MethodsA data-driven processing framework for dynamic HP 13 C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single-element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first-point phasing. Optimal conditions for TRI were derived based on bias-variance trade-off.ResultsTRI and ORC techniques together provided a 63-fold mean apparent signal-to-noise ratio (aSNR) gain for receiver arrays and a 31-fold gain for single-element configurations, which particularly improved quantification of the lower-SNR-[13 C]bicarbonate and [1-13 C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information.ConclusionOverall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13 C MRI research through major aSNR improvements.

PurposeTo ameliorate tradeoffs between a fixed spatial resolution and signal-to-noise ratio (SNR) for hyperpolarized 13 C MRI.MethodsIn MRI, SNR is proportional to voxel volume but retrospective downsampling or voxel averaging only improves SNR by the square root of voxel size. This can be exploited with a metabolite-selective imaging approach that independently encodes each compound, yielding high-resolution images for the injected substrate and coarser resolution images for downstream metabolites, while maintaining adequate SNR for each. To assess the efficacy of this approach, hyperpolarized [1-13 C]pyruvate data were acquired in healthy Sprague-Dawley rats (n = 4) and in two healthy human subjects.ResultsCompared with a constant resolution acquisition, variable-resolution data sets showed improved detectability of metabolites in pre-clinical renal studies with a 3.5-fold, 8.7-fold, and 6.0-fold increase in SNR for lactate, alanine, and bicarbonate data, respectively. Variable-resolution data sets from healthy human subjects showed cardiac structure and neuro-vasculature in the higher resolution pyruvate images (6.0 × 6.0 mm2 for cardiac and 7.5 × 7.5 mm2 for brain) that would otherwise be missed due to partial-volume effects and illustrates the level of detail that can be achieved with hyperpolarized substrates in a clinical setting.ConclusionWe developed a variable-resolution strategy for hyperpolarized 13 C MRI using metabolite-selective imaging and demonstrated that it mitigates tradeoffs between a fixed spatial resolution and SNR for hyperpolarized substrates, providing both high resolution pyruvate and coarse resolution metabolite data sets in a single exam. This technique shows promise to improve future studies by maximizing metabolite SNR while minimizing partial-volume effects from the injected substrate.

PurposeThe balanced steady-state free precession sequence has been previously explored to improve the efficient use of nonrecoverable hyperpolarized 13C magnetization, but suffers from poor spectral selectivity and long acquisition time. The purpose of this study was to develop a novel metabolite-specific 3D bSSFP ("MS-3DSSFP") sequence with stack-of-spiral readouts for improved lactate imaging in hyperpolarized [1-13 C]pyruvate studies on a clinical 3T scanner.MethodsSimulations were performed to evaluate the spectral response of the MS-3DSSFP sequence. Thermal 13C phantom experiments were performed to validate the MS-3DSSFP sequence. In vivo hyperpolarized [1-13 C], pyruvate studies were performed to compare the MS-3DSSFP sequence with metabolite-specific gradient echo ("MS-GRE") sequences for lactate imaging.ResultsSimulations, phantom, and in vivo studies demonstrate that the MS-3DSSFP sequence achieved spectrally selective excitation on lactate while minimally perturbing other metabolites. Compared with MS-GRE sequences, the MS-3DSSFP sequence showed approximately a 2.5-fold SNR improvement for lactate imaging in rat kidneys, prostate tumors in a mouse model, and human kidneys.ConclusionsImproved lactate imaging using the MS-3DSSFP sequence in hyperpolarized [1-13 C]pyruvate studies was demonstrated in animals and humans. The MS-3DSSFP sequence could be applied for other clinical applications such as in the brain or adapted for imaging other metabolites such as pyruvate and bicarbonate.

Based on the expanding set of applications for hyperpolarized carbon-13 (HP-(13)C) MRI, this work aims to communicate standardized methodology implemented at our institution (UCSF) as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP-(13)C acquisition, data processing/reconstruction, and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP-(13)C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging (EPSI) of the human prostate and frequency-specific 2D multi-slice echo-planar imaging (EPI) of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available via hyperlinks to the Supplementary Material.

We developed methods for the preparation of hyperpolarized (HP) sterile [2-13C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conversion of HP [2-13C]pyruvate to [2-13C]lactate and [5-13C]glutamate in the brain of four healthy volunteers. Metabolite kinetics, signal-to-noise (SNR) and area-under-curve (AUC) ratios, and calculated [2-13C]pyruvate to [2-13C]lactate conversion rates (kPL) were measured and showed similar but not identical inter-subject values. The kPL measurements were equivalent with prior human HP [1-13C]pyruvate measurements.

The goal of the study was to establish early hyperpolarized (HP) 13 C MRI metabolic and perfusion changes that predict effective high-intensity focused ultrasound (HIFU) ablation and lead to improved adjuvant treatment of partially treated regions. To accomplish this a combined HP dual-agent (13 C pyruvate and 13 C urea) 13 C MRI/multiparametric 1 H MRI approach was used to measure prostate cancer metabolism and perfusion 3-4h, 1 d, and 5 d after exposure to ablative and sub-lethal doses of HIFU within adenocarcinoma of mouse prostate tumors using a focused ultrasound applicator designed for murine studies. Pathologic and immunohistochemical analysis of the ablated tumor demonstrated fragmented, non-viable cells and vasculature consistent with coagulative necrosis, and a mixture of destroyed tissue and highly proliferative, poorly differentiated tumor cells in tumor tissues exposed to sub-lethal heat doses in the ablative margin. In ablated regions, the intensity of HP 13 C lactate or HP 13 C urea and dynamic contrast-enhanced (DCE) MRI area under the curve images were reduced to the level of background noise by 3-4h after treatment with no recovery by the 5 d time point in either case. In the tissues that received sub-lethal heat dose, there was a significant 60%±12.4% drop in HP 13 C lactate production and a significant 30±13.7% drop in urea perfusion 3-4h after treatment, followed by recovery to baseline by 5 d after treatment. DCE MRI Ktrans showed a similar trend to HP 13 C urea, demonstrating a complete loss of perfusion with no recovery in the ablated region, while having a 40%-50% decrease 3-4h after treatment followed by recovery to baseline values by 5 d in the margin region. The utility of the HP 13 C MR measures of perfusion and metabolism in optimizing focal HIFU, either alone or in combination with adjuvant therapy, deserves further testing in future studies.

PurposeRapid chemical exchange can affect SNR and pH measurement accuracy for hyperpolarized pH imaging with [13 C]bicarbonate. The purpose of this work was to investigate chemical exchange effects on hyperpolarized imaging sequences to identify optimal sequence parameters for high SNR and pH accuracy.MethodsSimulations were performed under varying rates of bicarbonate-CO2 chemical exchange to analyze exchange effects on pH quantification accuracy and SNR under different sampling schemes. Four pulse sequences, including 1 new technique, a multiple-excitation 2D EPI (multi-EPI) sequence, were compared in phantoms using hyperpolarized [13 C]bicarbonate, varying parameters such as tip angles, repetition time, order of metabolite excitation, and refocusing pulse design. In vivo hyperpolarized bicarbonate-CO2 exchange measurements were made in transgenic murine prostate tumors to select in vivo imaging parameters.ResultsModeling of bicarbonate-CO2 exchange identified a multiple-excitation scheme for increasing CO2 SNR by up to a factor of 2.7. When implemented in phantom imaging experiments, these sampling schemes were confirmed to yield high pH accuracy and SNR gains. Based on measured bicarbonate-CO2 exchange in vivo, a 47% CO2 SNR gain is predicted.ConclusionThe novel multi-EPI pulse sequence can boost CO2 imaging signal in hyperpolarized 13 C bicarbonate imaging while introducing minimal pH bias, helping to surmount a major hurdle in hyperpolarized pH imaging.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

PurposeTo compare the performance of an 8-channel surface coil/clamshell transmitter and 32-channel head array coil/birdcage transmitter for hyperpolarized 13 C brain metabolic imaging.MethodsTo determine the field homogeneity of the radiofrequency transmitters, B1 + mapping was performed on an ethylene glycol head phantom and evaluated by means of the double angle method. Using a 3D echo-planar imaging sequence, coil sensitivity and noise-only phantom data were acquired with the 8- and 32-channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency-specific 13 C dynamic echo-planar imaging was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1-13 C]pyruvate. Signal-to-noise ratio (SNR) was evaluated from pre-whitened phantom and temporally summed patient data after coil combination based on optimal weights.ResultsThe birdcage transmitter produced more uniform B1 + compared with the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8- versus 32-channel mean transceiver-normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8-channel receiver array showed SNR benefits along lateral aspects, the 32-channel array exhibited greater coverage and a more uniform coil-combined profile. Temporally summed, parameter-normalized patient data showed SNRmean,slice ratios (8-channel/32-channel) ranging 0.5-2.00 from apical to central brain. White matter lactate-to-pyruvate ratios were conserved across hardware: 0.45 ± 0.12 (8-channel) versus 0.43 ± 0.14 (32-channel).ConclusionThe 8- and 32-channel hardware configurations each have advantages in particular brain anatomy.

Hyperpolarized (HP) carbon 13 (13C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathway-specific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. This technique has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular disease, and metabolic diseases of the liver and kidney. This review provides an overview of the methods of hyperpolarization and 13C probes investigated to date in preclinical models of disease. The article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-13C]pyruvate MRI will be highlighted. The future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.

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&nbsp

PurposeAcquisition timing and B1 calibration are two key factors that affect the quality and accuracy of hyperpolarized 13 C MRI. The goal of this project was to develop a new approach using regional bolus tracking to trigger Bloch-Siegert B1 mapping and real-time B1 calibration based on regional B1 measurements, followed by dynamic imaging of hyperpolarized 13 C metabolites in vivo.MethodsThe proposed approach was implemented on a system which allows real-time data processing and real-time control on the sequence. Real-time center frequency calibration upon the bolus arrival was also added. The feasibility of applying the proposed framework for in vivo hyperpolarized 13 C imaging was tested on healthy rats, tumor-bearing mice and a healthy volunteer on a clinical 3T scanner following hyperpolarized [1-13 C]pyruvate injection. Multichannel receive coils were used in the human study.ResultsAutomatic acquisition timing based on either regional bolus peak or bolus arrival was achieved with the proposed framework. Reduced blurring artifacts in real-time reconstructed images were observed with real-time center frequency calibration. Real-time computed B1 scaling factors agreed with real-time acquired B1 maps. Flip angle correction using B1 maps results in a more consistent quantification of metabolic activity (i.e, pyruvate-to-lactate conversion, kPL ). Experiment recordings are provided to demonstrate the real-time actions during the experiment.ConclusionsThe proposed method was successfully demonstrated on animals and a human volunteer, and is anticipated to improve the efficient use of the hyperpolarized signal as well as the accuracy and robustness of hyperpolarized 13 C imaging.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

PurposeThe purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1-13 C]pyruvate to [1-13 C]lactate with whole gland coverage at high spatial and temporal resolution.MethodsA 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1-13 C]pyruvate. 3D dynamic 13 C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm3 , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time.ResultsThrough preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13 C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1-13 C]pyruvate to [1-13 C]lactate in a biopsy-proven prostate cancer patient with full gland coverage.ConclusionThe results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure kPL , the kinetic rate constant of [1-13 C]pyruvate to [1-13 C]lactate conversion.

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.

PurposeThe 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.MethodsA 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.ResultsOperation 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.ConclusionThe results show clear feasibility for effective 13 C->1 H hyperpolarization transfer in a clinical MRI scanner with customized heteronuclear RF system.

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.

A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin-lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C]valine), significant increase of their T1 was observed at 3 T with deuterium labeling (+26%, 22%, +16%, +25% and +29%, respectively). Remarkably, in the case of [2-13C]alanine, [2-13C]serine and [2-13C]lactate, deuterium labeling led to a greater than four fold increase in T1. [1-13C,2-2H]alanine, produced using this method, was applied to in vitro enzyme assays with alanine aminotransferase, demonstrating a kinetic isotope effect.

Acceleration of dynamic 2D (T2 Mapping) and 3D hyperpolarized 13C MRI acquisitions using the balanced steady-state free precession sequence was achieved with a specialized reconstruction method, based on the combination of low rank plus sparse and local low rank reconstructions. Methods were validated using both retrospectively and prospectively undersampled in vivo data from normal rats and tumor-bearing mice. Four-fold acceleration of 1-2 mm isotropic 3D dynamic acquisitions with 2-5 s temporal resolution and two-fold acceleration of 0.25-1 mm2 2D dynamic acquisitions was achieved. This enabled visualization of the biodistribution of [2-13C]pyruvate, [1-13C]lactate, [13C, 15N2]urea, and HP001 within heart, kidneys, vasculature, and tumor, as well as calculation of high resolution T2 maps.

PurposeThe 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).ResultsPolarizations 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.ConclusionRapid 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.

PurposeTo compare the apparent diffusion coefficient (ADC) of hyperpolarized (HP) [13 C,15 N]urea to the ADC of endogenous water in healthy and fibrotic mouse liver.Materials and methodsADC measurements for water and [13 C]urea were made in agarose phantoms at 14.1T. Next, the ADC of water and injected HP [13 C,15 N]urea were measured in eight CD1 mouse livers before and after induction of liver fibrosis using CCl4 . Liver fibrosis was quantified pathologically using the modified Brunt fibrosis score and compared to the measured ADC of water and urea.ResultsIn cell-free phantoms with 12.5% agarose, water ADC was nearly twice the ADC of urea (1.93 × 10-3 mm2 /s vs. 1.00 × 10-3 mm2 /s). The mean ADC values of water and [13 C,15 N]urea in healthy mouse liver (±SD) were nearly identical [(0.75 ± 0.11) × 10-3 mm2 /s and (0.75 ± 0.22) × 10-3 mm2 /s, respectively]. Mean water and [13 C,15 N]urea ADC values in fibrotic liver (±SD) were (0.84 ± 0.22) × 10-3 mm2 /s and (0.75 ± 0.15) × 10-3 mm2 /s, respectively. Neither water nor urea ADCs were statistically different in the fibrotic livers compared to baseline (P = 0.14 and P = 0.99, respectively). Water and urea ADCs were positively correlated at baseline (R2 = 0.52 and P = 0.045) but not in fibrotic livers (R2 = 0.23 and P = 0.23).ConclusionADC of injected hyperpolarized urea in healthy liver reflects a smaller change as compared to free solution than ADC of water. This may reflect differences in cellular compartmentalization of the two compounds. No significant change in ADC of either water or urea were observed in relatively mild stages of liver fibrosis.Level of evidence1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:141-151.

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 (1)J(CH) = ~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.

PurposeBalanced steady-state free precession (bSSFP) sequences can provide superior signal-to-noise ratio efficiency for hyperpolarized (HP) carbon-13 (13 C) 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 13 C metabolites with high spatiotemporal resolution.Theory and methodsThis 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.ResultsThe sequence enabled subsecond 3D dynamic spectrally selective imaging of 13 C metabolites of copolarized [1-13 C]pyruvate and [13 C]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.ConclusionThis sequence is expected to benefit applications requiring dynamic volumetric imaging of metabolically active 13 C compounds at high spatiotemporal resolution, including preclinical studies at high field and, potentially, clinical studies. Magn Reson Med 78:963-975, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PurposeThe purpose of this work was to explore the impact of slice profile effects on apparent diffusion coefficient (ADC) mapping of hyperpolarized (HP) substrates.MethodsSlice profile effects were simulated using a Gaussian radiofrequency (RF) pulse with a variety of flip angle schedules and b-value ordering schemes. A long T1 water phantom was used to validate the simulation results, and ADC mapping of HP [13 C,15 N2 ]urea was performed on the murine liver to assess these effects in vivo.ResultsSlice profile effects result in excess signal after repeated RF pulses, causing bias in HP measurements. The largest error occurs for metabolites with small ADCs, resulting in up to 10-fold overestimation for metabolites that are in more-restricted environments. A mixed b-value scheme substantially reduces this bias, whereas scaling the slice-select gradient can mitigate it completely. In vivo, the liver ADC of hyperpolarized [13 C,15 N2 ]urea is nearly 70% lower (0.99 ± 0.22 vs 1.69 ± 0.21 × 10-3 mm2 /s) when slice-select gradient scaling is used.ConclusionSlice profile effects can lead to bias in HP ADC measurements. A mixed b-value ordering scheme can reduce this bias compared to sequential b-value ordering. Slice-select gradient scaling can also correct for this deviation, minimizing bias and providing more-precise ADC measurements of HP substrates. Magn Reson Med 78:1087-1092, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PurposeThe 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.MethodsSeven 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.ResultsMultiple 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.ConclusionMRI 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.

PurposeTo 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.MethodsSpecialized 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.ResultsThe 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.ConclusionA 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.

PurposeTo develop symmetric echo planar imaging (EPI) and a reference scan framework for hyperpolarized 13 C metabolic imaging.MethodsSymmetric, ramp-sampled EPI with partial Fourier reconstruction was implemented on a 3T scanner. The framework for acquiring a reference scan on the 1 H channel and applied to 13 C data was described and validated in both phantoms and in vivo metabolism of [1-13 C]pyruvate.ResultsRamp-sampled, symmetric EPI provided a substantial increase in the signal-to-noise ratio of the phantom experiments. The reference scan acquired on the 1 H channel yielded 13 C phantom images that varied in mean signal intensity

PurposeDissolution 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.MethodsDynamic 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.ResultsDistinct 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.ConclusionThe 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.

Item does not contain fulltext A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article.

PurposeTo develop a compressed sensing (CS) acceleration method with a high spectral bandwidth exploiting the spatial-spectral sparsity of MR spectroscopic imaging (MRSI).MethodsAccelerations were achieved using blip gradients during the readout to perform nonoverlapped and stochastically delayed random walks in kx -ky -t space, combined with block-Hankel matrix completion for efficient reconstruction. Both retrospective and prospective CS accelerations were applied to (13) C MRSI experiments, including in vivo rodent brain and liver studies with administrations of hyperpolarized [1-(13) C] pyruvate at 7.0 Tesla (T) and [2-(13) C] dihydroxyacetone at 3.0 T, respectively.ResultsIn retrospective undersampling experiments using in vivo 7.0 T data, the proposed method preserved spectral, spatial, and dynamic fidelities with R(2) ≥ 0.96 and ≥ 0.87 for pyruvate and lactate signals, respectively, 750-Hz spectral separation, and up to 6.6-fold accelerations. In prospective in vivo experiments, with 3.8-fold acceleration, the proposed method exhibited excellent spatial localization of metabolites and peak recovery for pyruvate and lactate at 7.0 T as well as for dihydroxyacetone and its metabolic products with a 4.5-kHz spectral span (140 ppm at 3.0 T).ConclusionsThis study demonstrated the feasibility of a new CS approach to accelerate high spectral bandwidth MRSI experiments. Magn Reson Med 76:369-379, 2016. © 2016 Wiley Periodicals, Inc.

ObjectiveZero echo time (ZTE) and ultrashort echo time (UTE) pulse sequences for MRI offer unique advantages of being able to detect signal from rapidly decaying short-T2 tissue components. In this paper, we applied 3D ZTE and UTE pulse sequences at 7T to assess differences between these methods.Materials and methodsWe matched the ZTE and UTE pulse sequences closely in terms of readout trajectories and image contrast. Our ZTE used the water- and fat-suppressed solid-state proton projection imaging method to fill the center of k-space. Images from healthy volunteers obtained at 7T were compared qualitatively, as well as with SNR and CNR measurements for various ultrashort, short, and long-T2 tissues.ResultsWe measured nearly identical contrast-to-noise and signal-to-noise ratios (CNR/SNR) in similar scan times between the two approaches for ultrashort, short, and long-T2 components in the brain, knee and ankle. In our protocol, we observed gradient fidelity artifacts in UTE, and our chosen flip angle and readout also resulted in shading artifacts in ZTE due to inadvertent spatial selectivity. These can be corrected by advanced reconstruction methods or with different chosen protocol parameters.ConclusionThe applied ZTE and UTE pulse sequences achieved similar contrast and SNR efficiency for volumetric imaging of ultrashort-T2 components. Key differences include that ZTE is limited to volumetric imaging, but has substantially reduced acoustic noise levels during the scan. Meanwhile, UTE has higher acoustic noise levels and greater sensitivity to gradient fidelity, but offers more flexibility in image contrast and volume selection.

PurposeThe purpose of this study was to investigate (13) C 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.MethodsHyperpolarized (HP) (13) C MR experiments were conducted using [(13) C]αKB with rats in vivo and with isolated LDH enzyme in vitro, along with comparative experiments using [(13) C]pyruvate. Based on differences in the kinetics of its reaction with individual LDH isoforms, HP [(13) C]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).ResultsComparable 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 [(13) C]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.ConclusionsHP [(13) C]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).

The purpose of this study was to characterize tissue-specific alterations in metabolism of hyperpolarized (HP) gluconeogenic precursorsSeven normal rats were studied by MR spectroscopic imaging of both HPMultiple 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 ofMRI of HP

To develop a specialized multislice, single-acquisition approach to detect the metabolites of hyperpolarized (HP) [2-Specialized multiband SPSP RF pulses were designed, tested, and applied to investigate HP [2-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-A multiband SPSP RF pulse covering a spectral range over 144 ppm enabled in vivo characterization of HP [2

We have developed a 3D cell/tissue culture bioreactor compatible with hyperpolarized (HP) (13)C MR and interrogated HP [1-(13)C]lactate production and efflux in human renal cell carcinoma (RCC) cells. This platform is capable of resolving intracellular and extracellular HP lactate pools, allowing the kinetic measurement of lactate production and efflux in the context of cancer aggressiveness and response to therapy. HP (13)C MR studies were performed on three immortalized human renal cell lines: HK2, a normal renal proximal tubule cell line from which a majority of RCCs arise, UMRC6, a cell line derived from a localized RCC, and UOK262, an aggressive and metastatic RCC. The intra- (Lacin ) and extracellular (Lacex ) HP lactate signals were robustly resolved in dynamic (13)C spectra of the cell lines due to a very small but reproducible chemical shift difference (0.031 ± 0.0005 ppm). Following HP [1-(13)C]pyruvate delivery, the ratio of HP Lacin /Lacex was significantly lower for UOK262 cells compared with both UMRC6 and HK2 cells due to a significant (p < 0.05) increase in the Lacex pool size. Lacin /Lacex correlated with the MCT4 mRNA expression of the cell lines, and inhibition of MCT4 transport using DIDS resulted in a significant reduction in the HP Lacex pool size. The extension of these studies to living patient-derived RCC tissue slices using HP [1,2-(13)C2]pyruvate demonstrated a similarly split lactate doublet with a high Lacex pool fraction; in contrast, only a single NMR resonance is noted for HP [5-(13)C]glutamate, consistent with intracellular localization. These studies support the importance of lactate efflux as a biomarker of cancer aggressiveness and metastatic potential, and the utility of the MR compatible 3D cell/tissue culture bioreactor to study not only cellular metabolism but also transport. Additionally, this platform offers a sophisticated way to follow therapeutic interventions and screen novel therapies that target lactate export.

PurposeHyperpolarized (13) C magnetic resonance allows for the study of real-time metabolism in vivo, including significant hyperpolarized (13) C lactate production in many tumors. Other studies have shown that aggressive and highly metastatic tumors rapidly transport lactate out of cells. Thus, the ability to not only measure the production of hyperpolarized (13) C lactate but also understand its compartmentalization using diffusion-weighted MR will provide unique information for improved tumor characterization.MethodsWe used a bipolar, pulsed-gradient, double spin echo imaging sequence to rapidly generate diffusion-weighted images of hyperpolarized (13) C metabolites. Our methodology included a simultaneously acquired B1 map to improve apparent diffusion coefficient (ADC) accuracy and a diffusion-compensated variable flip angle scheme to improve ADC precision.ResultsWe validated this sequence and methodology in hyperpolarized (13) C phantoms. Next, we generated ADC maps of several hyperpolarized (13) C metabolites in a normal rat, rat brain tumor, and prostate cancer mouse model using both preclinical and clinical trial-ready hardware.ConclusionADC maps of hyperpolarized (13) C metabolites provide information about the localization of these molecules in the tissue microenvironment. The methodology presented here allows for further studies to investigate ADC changes due to disease state that may provide unique information about cancer aggressiveness and metastatic potential.

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized (13)C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its (13)C chemical shift within the physiologic range.

PurposeA novel application of two-dimensional (2D) spatially selective radiofrequency (2DRF) excitation pulses in hyperpolarized 13C imaging is proposed for monitoring the bolus injection with highly efficient sampling of the initially polarized substrate, thus leaving more polarization available for detection of the subsequently generated metabolic products.MethodsA 2DRF pulse was designed with a spiral trajectory and conventional clinical gradient performance. To demonstrate the ability of our 2DRF bolus tracking pulse sequence, hyperpolarized [1-(13)ruvate in vivo imaging experiments were performed in normal rats, with a comparison to 1DRF excitation pulses.ResultsOur designed 2DRF pulse was able to rapidly and efficiently monitor the injected bolus dynamics in vivo, with an 8-fold enhanced time resolution in comparison with 1DRF in our experimental settings. When applied at the pyruvate frequency for bolus tracking, our 2DRF pulse demonstrated reduced saturation of the hyperpolarization for the substrate and metabolic products compared to a 1DRF pulse, while being immune to ±0.5 ppm magnetic field inhomogeneity at 3T.Conclusion2DRF pulses in hyperpolarized 13C imaging can be used to efficiently monitor the bolus injection with reduced hyperpolarization saturation compared to 1DRF pulses. The parameters of our design are based on clinical scanner limits, which allows for rapid translation to human studies.

\textit{In vivo} spin spin relaxation time ($T_2$) heterogeneity of hyperpolarized \textsuperscript{13}C urea in the rat kidney was investigated. Selective quenching of the vascular hyperpolarized \textsuperscript{13}C signal with a macromolecular relaxation agent revealed that a long-$T_2$ component of the \textsuperscript{13}C urea signal originated from the renal extravascular space, thus allowing the vascular and renal filtrate contrast agent pools of the \textsuperscript{13}C urea to be distinguished via multi-exponential analysis. The $T_2$ response to induced diuresis and antidiuresis was performed with two imaging agents: hyperpolarized \textsuperscript{13}C urea and a control agent hyperpolarized bis-1,1-(hydroxymethyl)-1-\textsuperscript{13}C-cyclopropane-$^2\textrm{H}_8$. Large $T_2$ increases in the inner-medullar and papilla were observed with the former agent and not the latter during antidiuresis suggesting that $T_2$ relaxometry may be used to monitor the inner-medullary urea transporter (UT)-A1 and UT-A3 mediated urea concentrating process. Two high resolution imaging techniques - multiple echo time averaging and ultra-long echo time sub-2 mm$^3$ resolution 3D imaging - were developed to exploit the particularly long relaxation times observed.

PurposeTo demonstrate simultaneous hyperpolarization and imaging of three (13)C-labeled perfusion MRI contrast agents with dissimilar molecular structures ([(13)C]urea, [(13)C]hydroxymethyl cyclopropane, and [(13)C]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.MethodsRapid 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.ResultsDynamic 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.ConclusionTripolarized perfusion MRI provides new molecular imaging measures for specifically monitoring permeability, perfusion, and transport simultaneously in vivo.

A chemical shift separation technique for hyperpolarized (13) C metabolic imaging with high spatial and temporal resolution was developed. Specifically, a fast three-dimensional pulse sequence and a reconstruction method were implemented to acquire signals from multiple (13) C species simultaneously with subsequent separation into individual images.A stack of flyback echo-planar imaging readouts and a set of multiband excitation radiofrequency pulses were designed to spatially modulate aliasing patterns of the acquired metabolite images, which translated the chemical shift separation problem into parallel imaging reconstruction problem. An eight-channel coil array was used for data acquisition and a parallel imaging method based on nonlinear inversion was developed to separate the aliased images.Simultaneous acquisitions of pyruvate and lactate in a phantom study and in vivo rat experiments were performed. The results demonstrated successful separation of the metabolite distributions into individual images having high spatial resolution.This method demonstrated the ability to provide accelerated metabolite imaging in hyperpolarized (13) C MR using multichannel coils, tailored readout, and specialized RF pulses.

PurposeA calibrationless parallel imaging reconstruction method, termed simultaneous autocalibrating and k-space estimation (SAKE), is presented. It is a data-driven, coil-by-coil reconstruction method that does not require a separate calibration step for estimating coil sensitivity information.MethodsIn SAKE, an undersampled, multichannel dataset is structured into a single data matrix. The reconstruction is then formulated as a structured low-rank matrix completion problem. An iterative solution that implements a projection-onto-sets algorithm with singular value thresholding is described.ResultsReconstruction results are demonstrated for retrospectively and prospectively undersampled, multichannel Cartesian data having no calibration signals. Additionally, non-Cartesian data reconstruction is presented. Finally, improved image quality is demonstrated by combining SAKE with wavelet-based compressed sensing.ConclusionBecause estimation of coil sensitivity information is not needed, the proposed method could potentially benefit MR applications where acquiring accurate calibration data is limiting or not possible at all.

Hyperpolarized (13) C magnetic resonance allows for the study of real-time metabolism in vivo, including significant hyperpolarized (13) C lactate production in many tumors. Other studies have shown that aggressive and highly metastatic tumors rapidly transport lactate out of cells. Thus, the ability to not only measure the production of hyperpolarized (13) C lactate but also understand its compartmentalization using diffusion-weighted MR will provide unique information for improved tumor characterization.We used a bipolar, pulsed-gradient, double spin echo imaging sequence to rapidly generate diffusion-weighted images of hyperpolarized (13) C metabolites. Our methodology included a simultaneously acquired B1 map to improve apparent diffusion coefficient (ADC) accuracy and a diffusion-compensated variable flip angle scheme to improve ADC precision.We validated this sequence and methodology in hyperpolarized (13) C phantoms. Next, we generated ADC maps of several hyperpolarized (13) C metabolites in a normal rat, rat brain tumor, and prostate cancer mouse model using both preclinical and clinical trial-ready hardware.ADC maps of hyperpolarized (13) C metabolites provide information about the localization of these molecules in the tissue microenvironment. The methodology presented here allows for further studies to investigate ADC changes due to disease state that may provide unique information about cancer aggressiveness and metastatic potential.

Quadrature coils are often desired in MR applications because they can improve MR sensitivity and also reduce excitation power. In this work, we propose, for the first time, a quadrature array design strategy for parallel transmission at 298 MHz using single-feed circularly polarized (CP) patch antenna technique. Each array element is a nearly square ring microstrip antenna and is fed at a point on the diagonal of the antenna to generate quadrature magnetic fields. Compared with conventional quadrature coils, the single-feed structure is much simple and compact, making the quadrature coil array design practical. Numerical simulations demonstrate that the decoupling between elements is better than -35 dB for all the elements and the RF fields are homogeneous with deep penetration and quadrature behavior in the area of interest. Bloch equation simulation is also performed to simulate the excitation procedure by using an 8-element quadrature planar patch array to demonstrate its feasibility in parallel transmission at the ultrahigh field of 7 Tesla.

The accurate detection and characterization of cancerous tissue is still a major problem for the clinical management of individual cancer patients and for monitoring their response to therapy. MRI with hyperpolarized agents is a promising technique for cancer characterization because it can non-invasively provide a local assessment of the tissue metabolic profile. In this work, we measured the kinetics of hyperpolarized [1-(13)C] pyruvate and (13)C-urea in prostate and liver tumor models using a compressed sensing dynamic MRSI method. A kinetic model fitting method was developed that incorporated arbitrary RF flip angle excitation and measured a pyruvate to lactate conversion rate, Kpl, of 0.050 and 0.052 (1/s) in prostate and liver tumors, respectively, which was significantly higher than Kpl in healthy tissues [Kpl =0.028 (1/s), P