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PURPOSE This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-13 C]pyruvate in the human brain. METHODS Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/1 H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO3- . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval. RESULTS [1-13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [13 C] HCO3- /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO3- were calculated as 0.014-0.018 s-1 and 0.0043-0.0056 s-1 , respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1-13 C]pyruvate. CONCLUSIONS Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1-13 C]pyruvate.

PURPOSE The 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. METHODS A 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. RESULTS The 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. CONCLUSION The 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.

PURPOSE This study aimed to investigate the role of regional f0 inhomogeneity in spiral hyperpolarized 13 C image quality and to develop measures to alleviate these effects. METHODS Field map correction of hyperpolarized 13 C cardiac imaging using spiral readouts was evaluated in healthy subjects. Spiral readouts with differing duration (26 and 45 ms) but similar resolution were compared with respect to off-resonance performance and image quality. An f0 map-based image correction based on the multifrequency interpolation (MFI) method was implemented and compared to correction using a global frequency shift alone. Estimation of an unknown frequency shift was performed by maximizing a sharpness objective based on the Sobel variance. The apparent full width half at maximum (FWHM) of the myocardial wall on [13 C]bicarbonate was used to estimate blur. RESULTS Mean myocardial wall FWHM measurements were unchanged with the short readout pre-correction (14.1 ± 2.9 mm) and post-MFI correction (14.1 ± 3.4 mm), but significantly decreased in the long waveform (20.6 ± 6.6 mm uncorrected, 17.7 ± 7.0 corrected, P = .007). Bicarbonate signal-to-noise ratio (SNR) of the images acquired with the long waveform were increased by 1.4 ± 0.3 compared to those acquired with the short waveform (predicted 1.32). Improvement of image quality was observed for all metabolites with f0 correction. CONCLUSIONS f0 -map correction reduced blur and recovered signal from dropouts, particularly along the posterior myocardial wall. The low image SNR of [13 C]bicarbonate can be compensated with longer duration readouts but at the expense of increased f0 artifacts, which can be partially corrected for with the proposed methods.

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 With 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). Methods A 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. Results TRI 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. Conclusion Overall, 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.

Purpose Asymmetric in-plane k-space sampling of EPI can reduce the minimum achievable TE in hyperpolarized 13 C with spectral-spatial radio frequency pulses, thereby reducing T 2 * weighting and signal-losses. Partial Fourier image reconstruction exploits the approximate Hermitian symmetry of k-space data and can be applied to asymmetric data sets to synthesize unmeasured data. Here we tested whether the application of partial Fourier image reconstruction would improve spatial resolution from hyperpolarized [1- 13 C ]pyruvate scans in the human brain. Methods Fifteen healthy control subjects were imaged using a volumetric dual-echo echo-planar imaging sequence with spectral-spatial radio frequency excitation. Images were reconstructed by zero-filling as well as with the partial Fourier reconstruction algorithm projection-on-convex-sets. Resulting images were quantitatively evaluated with a no-reference image quality assessment. Results The no-reference image sharpness metric agreed with perceived improvements in image resolution and contrast. The [1- 13 C ]lactate images benefitted most, followed by the [1- 13 C ]pyruvate images. The 13 C -bicarbonate images were improved by the smallest degree, likely owing to relatively lower SNR. Conclusions Partial Fourier imaging and reconstruction were shown to improve the sharpness and contrast of human HP 13 C brain data and is a viable method for enhancing resolution.

Hyperpolarized (HP) [1-13 C]lactate is an attractive alternative to [1-13 C]pyruvate as a substrate to investigate cardiac metabolism in vivo: it can be administered safely at a higher dose and can be polarized to a degree similar to pyruvate via dynamic nuclear polarization. While 13 C cardiac experiments using HP lactate have been performed in small animal models, they have not been demonstrated in large animal models or humans. Utilizing the same hardware and data acquisition methods as the first human HP 13 C cardiac study, 13 C metabolic images were acquired following injections of HP [1-13 C]lactate in porcine hearts. Data were also acquired using HP [1-13 C]pyruvate for comparison. The 13 C bicarbonate signal was localized to the myocardium and had a similar appearance with both substrates for all animals. No 13 C pyruvate signal was detected in the experiments following injection of HP 13 C lactate. The signal-to-noise ratio (SNR) of injected lactate was 88 ± 4% of the SNR of injected pyruvate, and the SNR of bicarbonate in the experiments using lactate as the substrate was 52 ± 19% of the SNR in the experiments using pyruvate as the substrate. The lower SNR was likely due to the shorter T1 of [1-13 C]lactate as compared with [1-13 C]pyruvate and the additional enzyme-catalyzed metabolic conversion step before the 13 C nuclei from [1-13 C]lactate were detected as 13 C bicarbonate. While challenges remain, the potential of HP lactate as a substrate for clinical metabolic imaging of human heart has been demonstrated.

This study shows the use of hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) to assess therapeutic efficacy in a preclinical tumor model. 13C-labeled pyruvate was used to monitor early changes in tumor metabolism based on the Warburg effect. High-grade malignant tumors exhibit increased glycolytic activity and lactate production to promote proliferation. A rodent glioma model was used to explore altered lactate production after therapy as an early imaging biomarker for therapeutic response. Rodents were surgically implanted with C6 glioma cells and separated into 4 groups, namely, no therapy, radiotherapy, chemotherapy and combined therapy. Animals were imaged serially at 6 different time points with magnetic resonance imaging at 3 T using hyperpolarized [1-13C]pyruvate MRSI and conventional 1H imaging. Using hyperpolarized [1-13C]pyruvate MRSI, alterations in tumor metabolism were detected as changes in the conversion of lactate to pyruvate (measured as Lac/Pyr ratio) and compared with the conventional method of detecting therapeutic response using the Response Evaluation Criteria in Solid Tumors. Moreover, each therapy group expressed different characteristic changes in tumor metabolism. The group that received no therapy showed a gradual increase of Lac/Pyr ratio within the tumor. The radiotherapy group showed large variations in tumor Lac/Pyr ratio. The chemo- and combined-therapy groups showed a statistically significant reduction in tumor Lac/Pyr ratio, however, only combined therapy was capable of suppressing tumor growth, which resulted in low endpoint mortality rate. Hyperpolarized 13C MRSI detected a prompt reduction in Lac/Pyr ratio as early as 2 days post combined chemo- and radiotherapies.

Hyperpolarized (HP) 13 C MRI provides the means to monitor lactate metabolism noninvasively in tumours. Since 13 C -lactate signal levels obtained from HP 13 C imaging depend on multiple factors, such as the rate of 13 C substrate delivery via the vasculature, the expression level of monocarboxylate transporters (MCTs) and lactate dehydrogenase (LDH), and the local lactate pool size, the interpretation of HP 13 C metabolic images remains challenging. In this study, ex vivo tissue extract measurements (i.e., NMR isotopomer analysis, western blot analysis) derived from an MDA-MB-231 xenograft model in nude rats were used to test for correlations between the in vivo 13 C data and the ex vivo measures. The lactate-to-pyruvate ratio from HP 13 C MRI was strongly correlated with [1- 13 C ]lactate concentration measured from the extracts using NMR (R = 0.69, p 0.05), as well as negatively correlated with tumour wet weight (R = - 0.60, p 0.05). In this tumour model, both MCT1 and MCT4 expressions were positively correlated with wet weight ( ρ = 0.78 and 0.93, respectively, p 0.01). Lactate pool size and the lactate-to-pyruvate ratio were not significantly correlated.

Dynamic nuclear polarization (DNP) provides the opportunity to boost liquid state magnetic resonance (MR) signals from selected nuclear spins by several orders of magnitude. A cryostat running at a temperature of ~ 1 K and a superconducting magnet set to between 3 and 10 T are required to efficiently hyperpolarize nuclear spins. Several DNP polarizers have been implemented for the purpose of hyperpolarized MR and recent systems have been designed to avoid the need for user input of liquid cryogens. We herein present a zero boil‐off DNP polarizer that operates at 1.35 ± 0.01 K and 7 T, and which can polarize two samples in parallel. The samples are cooled by a static helium bath thermally connected to a 1 K closed‐cycle 4He refrigerator. Using a modified version of the commercial fluid path developed for the SPINlab polarizer, we demonstrate that, within a 12‐minute interval, the system can produce two separate hyperpolarized 13C solutions. The 13C liquid‐state polarization of [1‐13C]pyruvate measured 26 seconds after dissolution was 36%, which can be extrapolated to a 55% solid state polarization. The system is well adapted for in vitro and in vivo preclinical hyperpolarized MR experiments and it can be modified to polarize up to four samples in parallel., European Union's Horizon 2020 European Research Council (ERC Consolidator Grant). Grant Number: 682574

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 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 provide built-in off-resonance correction in time-resolved, volumetric hyperpolarized 13 C metabolic imaging by implementing a novel dual-echo 3D echo-planar imaging (EPI) sequence and reconstruction. METHODS A spectral-spatial pulse for single-resonance excitation followed by a dual-echo 3D EPI readout was implemented to provide 64 × 8 × 6 cm3 coverage at 5 × 5 × 5 mm3 nominal resolution. Multiple sources of EPI distortions were encoded using a multi-echo 1 H EPI reference scan. Phase maps computed from the reference scans were combined with a bulk 13 C frequency offset encoded in the dual-echo [1-13 C]pyruvate images to correct geometric distortion and improve spatial registration. The proposed scheme was validated in a phantom study, and in vivo [1-13 C]pyruvate and [1-13 C]lactate rat images were acquired with intentional transmit frequency deviations to assess the dual-echo 3D EPI sequence. RESULTS The phantom study demonstrated improved spatial registration in off-resonance corrected images. Close agreement was observed between metabolic kidney signal and the underlying anatomy in rat imaging experiments. Relative to a single-echo acquisition, the coherent addition of the two corrected echoes provided the expected increase in signal-to-noise ratio by approximately 2. CONCLUSION A novel dual-echo 3D EPI acquisition sequence for integrated off-resonance correction in hyperpolarized 13 C imaging was developed and demonstrated. The proposed sequence offers clear advantages over flyback EPI for time-resolved metabolic mapping. Magn Reson Med 79:643-653, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to measure the apparent diffusion coefficients (ADCs) of brain metabolites beyond N-acetylaspartic acid (NAA), creatine (Cr), and choline (Cho) at 3T. This technique will be useful to probe tissue microstructures in vivo, as the various metabolites have different physiological characteristics. Methods Two JPRESS spectra were collected (high b-value and low b-value), and the ADCs of 16 different metabolites were estimated. Two analysis pipelines were developed: 1) a 2D pipeline that uses ProFit software to extract ADCs from metabolites not typically accessible at 3T and 2) a 1D pipeline that uses TARQUIN software to extract the metabolite concentrations from each line in the 2D dataset, allowing for scaling as well as validation. Results The ADCs of 16 different metabolites were estimated from within six subjects in parietal white matter. There was excellent agreement between the results obtained from the 1D and 2D pipelines for NAA, Cr, and Cho. Conclusion The proposed technique provided consistent estimates for the ADCs of NAA, Cr, Cho, glutamate + glutamine, and myo-inositol in all subjects and additionally glutathione and scyllo-inositol in all but one subject. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

The aim of this study was to develop a time-efficient inversion technique to measure the T1 relaxation time of the methyl group of lactate (Lac) in the presence of contaminating lipids and to measure T1 at 3 T in a cohort of primary high-grade gliomas. Three numerically optimized inversion times (TIs) were chosen to minimize the expected error in T1 estimates for a given input total scan duration (set to be 30 min). A two-cycle spectral editing scheme was used to suppress contaminating lipids. The T1 values were then estimated from least-squares fitting of signal measurements versus TI. Lac T1 was estimated as 2000 ± 280 ms. After correcting for T1 (and T2 from literature values), the mean absolute Lac concentration was estimated as 4.3 ± 2.6 mm. The technique developed agrees with the results obtained by standard inversion recovery and can be used to provide rapid T1 estimates of other spectral components as required. Lac T1 exhibits similar variations to other major metabolites observable by MRS in high-grade gliomas. The T1 estimate provided here will be useful for future MRS studies wishing to report relaxation-corrected estimates of Lac concentration as an objective tumor biomarker. Copyright © 2016 John Wiley & Sons, Ltd.

In this study, a mixture of pyruvic acid and the perfusion agent HP001 was co-polarized for simultaneous assessment of perfusion and metabolism in vivo. The pre-polarized mixture was administered to rats with subcutaneous MDA-MB-231 breast cancer xenografts and imaged using an interleaved sequence with designed spectral-spatial pulses and flyback echo-planar readouts. Voxel-by-voxel signal correlations from 10 animals (15 data sets) were analyzed for tumour, kidney, and muscle regions of interest. The relationship between perfusion and hyperpolarized signal was explored on a voxel-by-voxel basis in various metabolically active tissues, including tumour, healthy kidneys, and skeletal muscle. Positive pairwise correlations between lactate, pyruvate, and HP001 observed in all 10 tumours suggested that substrate delivery was the dominant factor limiting the conversion of pyruvate to lactate in the tumour model used in this study. On the other hand, in cases where conversion is the limiting factor, such as in healthy kidneys, both pyruvate and lactate can act as excellent perfusion markers. In intermediate cases between the two limits, such as in skeletal muscle, some perfusion information may be inferred from the (pyruvate + lactate) signal distribution. Co-administration of pyruvate with a dynamic nuclear polarization (DNP) perfusion agent is an effective approach for distinguishing between slow metabolism and poor perfusion and a practical strategy for lactate signal normalization to account for substrate delivery, especially in cases of rapid pyruvate-to-lactate conversion and in poorly perfused regions with inadequate pyruvate signal-to-noise ratio for reliable determination of the lactate-to-pyruvate ratio. Copyright © 2016 John Wiley & Sons, Ltd.

PURPOSE To enable large field-of-view, time-resolved volumetric coverage in hyperpolarized 13 C metabolic imaging by implementing a novel data acquisition and image reconstruction method based on the compressed sensing framework. METHODS A spectral-spatial pulse for single-resonance excitation followed by a symmetric echo-planar imaging (EPI) readout was implemented for encoding a 72 × 18 cm2 field of view at 5 × 5 mm2 resolution. Random undersampling was achieved with blipped z-gradients during the ramp portion of the echo-planar imaging readout. The sequence and reconstruction were tested with phantom studies and consecutive in vivo hyperpolarized 13 C scans in rats. Retrospectively and prospectively undersampled data were compared on the basis of structural similarity in the reconstructed images and the quantification of the lactate-to-pyruvate ratio in rat kidneys. RESULTS No artifacts or loss of resolution are evident in the compressed sensing reconstructed images acquired with the proposed sequence. Structural similarity analysis indicate that compressed sensing reconstructions can accurately recover spatial features in the metabolic images evaluated. CONCLUSION A novel z-blip acquisition sequence for compressed sensing accelerated hyperpolarized 13 C 3D echo-planar imaging was developed and demonstrated. The close agreement in lactate-to-pyruvate ratios from both retrospectively and prospectively undersampled data from rats shows that metabolic information is preserved with acceleration factors up to 3-fold with the developed method. Magn Reson Med 77:538-546, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose Develop and test an analytic correction method to correct the signal intensity variation caused by the inhomogeneous reception profile of an eight-channel phased array for hyperpolarized 13C imaging. Theory and Methods Fiducial markers visible in anatomical images were attached to the individual coils to provide three dimensional localization of the receive hardware with respect to the image frame of reference. The coil locations and dimensions were used to numerically model the reception profile using the Biot-Savart Law. The accuracy of the coil sensitivity estimation was validated with images derived from a homogenous 13C phantom. Numerical coil sensitivity estimates were used to perform intensity correction of in vivo hyperpolarized 13C cardiac images in pigs. Results In comparison to the conventional sum-of-squares reconstruction, improved signal uniformity was observed in the corrected images. Conclusion The analytical intensity correction scheme was shown to improve the uniformity of multichannel image reconstruction in hyperpolarized [1-13C]pyruvate and 13C-bicarbonate cardiac MRI. The method is independent of the pulse sequence used for 13C data acquisition, simple to implement and does not require additional scan time, making it an attractive technique for multichannel hyperpolarized 13C MRI. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Previous studies have demonstrated that using hyperpolarized [2-13C]pyruvate as a contrast agent can reveal 13C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle-mediated oxidation of [2-13C]pyruvate are the result of several metabolic steps. In the instance of the [5-13C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate–aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate–α-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial α-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2-13C]pyruvate metabolism. Using hyperpolarized [1,2-13C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13C–glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1-13C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1-13C]lactate and [1-13C]alanine with higher workload. 13C–Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2-13C]pyruvate label, we observed that 13C–acetylcarnitine production increased 2.5-fold in proportion to the 13C–bicarbonate signal, whereas the 13C–glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13C–glutamate signal relative to the amount of 13C–labeled acetyl-coenzyme A (acetyl-CoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate–aspartate shuttle is limited on adrenergic activation. Changes in [5-13C]glutamate production from [2-13C]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required.

Purpose To test the feasibility of hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI) for noninvasive examination of guinea pig fetoplacental metabolism and nutrient transport. Materials and Methods Seven pregnant guinea pigs with a total of 30 placentae and fetuses were anesthetized and scanned at 3T. T1-weighted 1H images were obtained from the maternal abdomen. An 80 mM solution of hyperpolarized [1-13C]pyruvate (hereafter referred to as pyruvate) was injected into a vein in the maternal foot. Time-resolved 3D 13C images were acquired starting 10 seconds after the beginning of bolus injection and every 10 seconds after to 50 seconds. The pregnant guinea pigs were recovered after imaging. Regions of interest (ROIs) were drawn around the maternal heart and each placenta and fetal liver in all slices in the 1H images. These ROIs were copied to the 13C images and were used to calculate the sum of the pyruvate and lactate signal intensities for each organ. The signal intensities were normalized by the volume of the organ and the maximum signal in the maternal heart. Results No adverse events were observed in the pregnant guinea pigs and natural pupping occurred at term (∼68 days). Pyruvate signal was observed in all 30 placentae, and lactate, a by-product of pyruvate metabolism, was also observed in all placentae. The maximum pyruvate and lactate signals in placentae occurred at 20 seconds. In addition to the observation of pyruvate and lactate signals in the placentae, both pyruvate and lactate signals were observed in all fetal livers. The maximum pyruvate and lactate signals in the fetal livers occurred at 10 seconds and 20 seconds, respectively. Conclusion This work demonstrates the feasibility of using hyperpolarized [1-13C]pyruvate MRI to noninvasively examine fetoplacental metabolism and transport of pyruvate in guinea pigs. Hyperpolarized 13C MRI may provide a novel method for longitudinal studies of fetoplacental abnormalities. J. Magn. Reson. Imaging 2015.

Purpose Hyperpolarized [1-13C]lactate in solution may be a clinically relevant and safe substrate for real time MR investigations of key metabolic pathways. The potential of using hyperpolarized [1-13C]lactate for magnetic resonance studies of cardiac metabolism in vivo was explored. Methods Neat [1-13C]lactic acid was hyperpolarized using the dynamic nuclear polarization process. Cardiac MR spectroscopy experiments were performed in vivo using hyperpolarized [1-13C]lactate and [1-13C]pyruvate in solutions. Results A high degree of polarization was achieved for [1-13C]lactate in solution (16.7%). 13C-bicarbonate was observed in rat hearts in vivo after either hyperpolarized [1-13C]lactate or hyperpolarized [1-13C]pyruvate was infused, but lower 13C-bicarbonate to substrate ratio was observed with hyperpolarized [1-13C]lactate infusions. The response of 13C-bicarbonate signal as a function of hyperpolarized [1-13C]lactate doses was also investigated and a saturation of 13C-bicarbonate signal was observed at the highest dose of [1-13C]lactate used (0.69 mmol/kg). Conclusion This study demonstrated that the use of neat [1-13C]lactic acid as the DNP sample is a potential alternative to [1-13C]pyruvic acid for cardiac hyperpolarized 13C MR studies. Hyperpolarized [1-13C]lactate may enable noninvasive assessment of cardiac PDH flux in cardiac patients in the near future. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc. Magn Reson Med 73:2087–2093, 2015. © 2014 Wiley Periodicals, Inc.

Background The purpose of this study was to evaluate the feasibility of using a short echo time, three-dimensional H-1 magnetic resonance spectroscopic imaging (MRSI) sequence at 7 Tesla (T) to assess the metabolic signature of lesions for patients with glioma. Methods Twenty-nine patients with glioma were studied. MRSI data were obtained using CHESS water suppression, spectrally selective adiabatic inversion-recovery pulses and automatically prescribed outer-volume-suppression for lipid suppression, and spin echo slice selection (echo time = 30 ms). An interleaved flyback echo-planar trajectory was applied to shorten the total acquisition time (∼10 min). Relative metabolite ratios were estimated in tumor and in normal-appearing white and gray matter (NAWM, GM). Results Levels of glutamine, myo-inositol, glycine, and glutathione relative to total creatine (tCr) were significantly increased in the T2 lesions for all tumor grades compared with those in the NAWM (P

Purpose To assess the feasibility of choline MRI using a new choline molecular probe for dynamic nuclear polarization (DNP) hyperpolarized MRI. Materials and Methods Male Sprague-Dawley rats with an average weight of 400 ± 20 g (n = 5), were anesthetized and injection tubing was placed in the tail vein. [1,1,2,2-D4, 1-13C]choline chloride (CMP1) was hyperpolarized by DNP and injected into rats at doses ranging from 12.6 to 50.0 mg/kg. Coronal projection 13C imaging was performed on a 3 Tesla clinical MRI scanner (bore size 60 cm) using a variable flip angle gradient echo sequence. Images were acquired 15 to 45 s after the start of bolus injection. Signal intensities in regions of interest were determined at each time point and compared. Results 13C MRI images of hyperpolarized CMP1 at a 50 mg/kg dose showed time-dependent organ distribution patterns. At 15 s, high intensities were observed in the inferior vena cava, heart, aorta, and kidneys. At 30 s, most of the signal intensity was localized to the kidneys. These distribution patterns were reproduced using 12.6 and 25 mg/kg doses. At 45 s, only signal in the kidneys was detected. Conclusion Hyperpolarized choline imaging with MRI is feasible using a stable-isotope labeled choline analog (CMP1). Nonradioactive imaging of choline accumulation may provide a new investigatory dimension for kidney physiology. J. Magn. Reson. Imaging 2015;41:917–923. © 2014 Wiley Periodicals, Inc.

Purpose Radiation Pneumonitis (RP) limits radiotherapy. Detection of early metabolic changes in the lungs associated with RP may provide an opportunity to adjust treatment before substantial toxicities occur. In this work, regional lactate-to-pyruvate signal ratio (lac/pyr) was quantified in rat lungs and heart following administration of hyperpolarized 13 C-pyruvate magnetic resonance imaging (MRI) at day 5, 10, 15 and 25-post conformal radiotherapy. These results were also compared to histology and blood analyses. Methods The lower right lungs of 12 Sprague Dawley rats were irradiated in 2 fractions with a total dose of 18.5Gy using a modified micro-CT system. Regional lactate and pyruvate data were acquired from three irradiated and three age-matched healthy rats at each time point on days 5, 10, 15 and 25-post radiotherapy. Arterial blood was collected from each animal prior to the 13 C-pyruvate injection and was analyzed for blood lactate concentration and arterial oxygen concentration (p a O 2 ). Macrophage count was computed from the histology of all rat lungs. Results A significant increase in lac/pyr was observed in both right and left lungs of the irradiated cohort compared to the healthy cohort for all time points. No increase in lac/pyr was observed in the hearts of the irradiated cohort compared to the hearts of the healthy cohorts. Blood lactate concentration and p a O 2 did not show a significant change between the irradiated and the healthy cohorts. Macrophage count in both right and left lungs was elevated for the irradiated cohort compared to the healthy cohort. Conclusions Metabolic changes associated with RP may be mapped as early as five days post conformal radiotherapy. Over the small sample size in each cohort, elevated macrophage count, consistent with early phase of inflammation was highly correlated to increases in lac/pyr in both the irradiated and unirradiated lungs. Further experiments with larger sample size may improve the confidence of this finding.

Blip-reversed echo-planar imaging (EPI) is investigated as a method for measuring and correcting the spatial shifts that occur due to bulk frequency offsets in 13C metabolic imaging in vivo. By reversing the k-space trajectory for every other time point, the direction of the spatial shift for a given frequency is reversed. Here, mutual information is used to find the ‘best’ alignment between images and thereby measure the frequency offset. Time-resolved 3D images of pyruvate/lactate/urea were acquired with 5 s temporal resolution over a 1 min duration in rats (N = 6). For each rat, a second injection was performed with the demodulation frequency purposely mis-set by +35 Hz, to test the correction for erroneous shifts in the images. Overall, the shift induced by the 35 Hz frequency offset was 5.9 ± 0.6 mm (mean ± standard deviation). This agrees well with the expected 5.7 mm shift based on the 2.02 ms delay between k-space lines (giving 30.9 Hz per pixel). The 0.6 mm standard deviation in the correction corresponds to a frequency-detection accuracy of 4 Hz. A method was presented for ensuring the spatial registration between 13C metabolic images and conventional anatomical images when long echo-planar readouts are used. The frequency correction method was shown to have an accuracy of 4 Hz. Summing the spatially corrected frames gave a signal-to-noise ratio (SNR) improvement factor of 2 or greater, compared with the highest single frame. Copyright © 2013 John Wiley & Sons, Ltd.

A calibration-based technique for real-time measurement of pyruvate polarization by partial integral analysis of the doublet from the neighbouring J-coupled carbon is presented. In vitro calibration data relating the C2 and C1 asymmetries to the instantaneous C1 and C2 polarizations, respectively, were acquired in blood. The feasibility of using the in vitro calibration data to determine the instantaneous in vivo C1 and C2 polarizations was demonstrated in the analysis of rat kidney and pig heart spectral data. An approach for incorporating this technique into in vivo protocols is proposed. Copyright © 2013 John Wiley & Sons, Ltd.

Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non-invasively study real-time metabolic rocesses occurring in vivo using 13C-labeled substrates. Recently, hyperpolarized 13C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig. Conventional 3D spectroscopic imaging methods require in excess of 100 excitations, making it challenging to acquire a full cardiac-gated, breath-held, whole-heart volume. In this article, the development of a rapid multislice cardiac-gated spiral 13C imaging pulse sequence consisting of a large flip-angle spectral-spatial excitation RF pulse combined with a single-shot spiral k-space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole-heart coverage (6 slices, 8.8-mm in-plane resolution) in any plane, allowing imaging of the metabolites of interest, [1- 13C] pyruvate, [1- 13C] lactate, and 13C bicarbonate, within a single breathhold. Pyruvate and bicarbonate cardiac volumes were acquired, while lactate images were not acquired due to low lactate levels in the animal model studied. The sequence was demonstrated with phantom experiments and in vivo testing in a pig model. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc.

Radiation-induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation-induced lung injury (2-4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized (13)C-pyruvate (pyruvate) and (13)C-lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole-thorax irradiation (14 Gy). Lactate-to-pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age-matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate-to-pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized (13)C metabolic MR spectroscopy and imaging for detection of early radiation-induced lung injury.

Spatially resolved images of hyperpolarized 13C substrates and their downstream products provide insight into real-time metabolic processes occurring in vivo. Recently, hyperpolarized 13C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig, but accurate and reproducible measurements remain challenging due to the limited period available for imaging as well as physiological motion. In this article, time-resolved cardiac- and respiratory-gated images of [1-13C] pyruvate, [1-13C] lactate, and 13C bicarbonate in the heart are acquired without the need for a breathhold. The robustness of these free-breathing measurements is demonstrated using the time-resolved data to produce a normalized metric of pyruvate dehydrogenase and lactate dehydrogenase activity in the heart. The values obtained are reproducible in a controlled metabolic state. In a 60-min ischemia/reperfusion model, significant differences in hyperpolarized bicarbonate and lactate, normalized using the left ventricular pyruvate signal, were detected between scans performed at baseline and 45 min after reperfusion. The sequence is anticipated to improve quantitative measurements of cardiac metabolism, leading to feasible validation studies using fewer subjects, and potentially improved diagnosis, serial monitoring, and treatment of cardiac disease in patients. Magn Reson Med 69:1063–1071, 2013. © 2012 Wiley Periodicals, Inc.

13C MR spectroscopy studies performed on hearts ex vivo and in vivo following perfusion of prepolarized [1-13C]pyruvate have shown that changes in pyruvate dehydrogenase (PDH) flux may be monitored non-invasively. However, to allow investigation of Krebs cycle metabolism, the 13C label must be placed on the C2 position of pyruvate. Thus, the utilization of either C1 or C2 labeled prepolarized pyruvate as a tracer can only afford a partial view of cardiac pyruvate metabolism in health and disease. If the prepolarized pyruvate molecules were labeled at both C1 and C2 positions, then it would be possible to observe the downstream metabolites that were the results of both PDH flux (13CO2 and H13CO3-) and Krebs cycle flux ([5-13C]glutamate) with a single dose of the agent. Cardiac pH could also be monitored in the same experiment, but adequate SNR of the 13CO2 resonance may be difficult to obtain in vivo. Using an interleaved selective RF pulse acquisition scheme to improve 13CO2 detection, the feasibility of using dual-labeled hyperpolarized [1,2-13C2]pyruvate as a substrate for dynamic cardiac metabolic MRS studies to allow simultaneous investigation of PDH flux, Krebs cycle flux and pH, was demonstrated in vivo. Copyright © 2011 John Wiley & Sons, Ltd.

Dynamic nuclear polarization and dissolution offer the exciting possibility of imaging biochemical reactions in vivo, including some of the key enzymatic reactions involved in cellular metabolism. The development of new pulse sequence strategies has been motivated by demanding applications, such as the imaging of hyperpolarized metabolite distributions in the heart. In this article, the key considerations surrounding the application of spectral–spatial imaging pulse sequences for hyperpolarized 13C metabolic imaging in cardiac and cancer applications are explored. Spiral pulse sequences for multislice imaging of [1-13C]pyruvate in the heart were developed, as well as time-resolved, three-dimensional, echo-planar imaging sequences for the imaging of [1-13C]pyruvate–lactate exchange in cancer. The advantages and challenges associated with these sequences were determined by testing in pig and rat models. Copyright © 2011 John Wiley & Sons, Ltd.

Hyperpolarization of 13C labeled substrates via dynamic nuclear polarization has been used as a method to noninvasively study real-time metabolic processes occurring in vivo. In these studies, proper calibration of radiofrequency transmit power is required to efficiently observe rapidly decaying magnetization. Conventional transmit radiofrequency field mapping methods rely on placing magnetization in a fixed, known state prior to imaging, making them unsuitable for imaging of hyperpolarized magnetization. Recently, a phase-based B1 mapping method based on the Bloch-Siegert shift has been reported. This method uses a B1-dependent shift in the resonance frequency of nuclei in the presence of an off-resonance radiofrequency pulse. In this article, we investigate the feasibility of Bloch-Siegert B1 mapping and observation of metabolism of hyperpolarized pyruvate in vivo, in a single injection. The technique is demonstrated with phantom experiments, and in normal rat and pigs in vivo. This method is anticipated to improve quantitative measurements of hyperpolarized 13C metabolism in vivo by enabling accurate flip-angle corrections. This work demonstrates the use of Bloch-Siegert B1 mapping under challenging out-of-equilibrium imaging conditions. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.

Reporter-based cell detection and localization in vivo may become an important imaging tool with the emergence of cellular therapy. With the strong signal enhancement provided by dynamic nuclear polarization, an NMR-based reporter probe system utilizing specific enzyme expression and activity can potentially provide stable, high-resolution visualization of the cells of interest noninvasively. In this work, a proof-of-concept 13C MR reporter system, using the aminoacylase-1 reporter gene (Acy-1) and prepolarized [1-13C]N-acetyl-L-methionine as the paired substrate, was developed. Using a 3-T MR scanner, the feasibility of detecting and imaging de-acetylation of the prepolarized 13C-labeled substrate by the aminoacylase-1 enzyme was demonstrated with purified protein in solution by dynamic 13C MRS and two-dimensional MRSI experiments. The potential to perform targeted MRI of cells using this system was also demonstrated by 13C MR measurement of aminoacylase-1 activity in HEK 293 cells transfected with the Acy-1 gene. The de-acetylation of the substrate was not observed in control cells. Copyright © 2010 John Wiley & Sons, Ltd.

Formulation, polarization, and dissolution conditions were developed to obtain a stablehyperpolarized solution of [1- 13 C]-ethyl pyruvate. A maximum tolerated concentration andinjection rate were determined, and 13 C spectroscopic imaging was used to compare the uptake ofhyperpolarized [1- 13 C]-ethyl pyruvate relative to hyperpolarized [1- 13 C]-pyruvate intoanesthetized rat brain. Hyperpolarized [1- 13 C]-ethyl pyruvate and [1- 13 C]-pyruvate metabolicimaging in normal brain is demonstrated and quantified in this feasibility and range-finding study. Keywords hyperpolarized; carbon-13; ethyl-pyruvate; brain; pyruvate; lactateMR metabolic imaging of hyperpolarized [1- 13 C]-pyruvate has proven to be useful,especially in oncology and cardiology (1,2). Dynamic and tissue level changes in [1- 13 C]-pyruvate and its metabolic products, [1- 13 C]-lactate, [1- 13 C]-alanine, and [ 13 C] bicarbonate,have been shown to correlate with metabolic states of interest, including disease progression(3,4) and response to therapy (5,6). However, for potential neurologic applications, theblood-brain transport of pyruvate may be a limiting factor. Age, anesthesia, and dietary statecan all impact transport rates (7–9), and under some conditions, the 1- to 2-min window ofuseful hyperpolarized [1

While the current commercially available MRI/1H MR spectroscopic imaging (MRSI) examination has shown promise for improving the detection and characterization of prostate cancer in individual patients, there is clinical consensus that a need exists for more sensitive and specific imaging (1). In the study of this disease, the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse has been valuable as an established and well-studied murine model of prostate cancer (2,3). This model mimics human disease progression with a neoplastic evolution from early to late stages and has a very similar metabolic profile. Metastases are also common in this model, especially in the lymph nodes, but also to the lungs, kidneys, adrenal glands, liver, and bone (3). Carbon-13 MR spectroscopy has shown the ability to noninvasively probe the metabolic profile and distinguish between malignant and normal tissue (4). Recently, hyperpolarization techniques have been developed to retain dynamic nuclear polarization (DNP) signal enhancements of 13C compounds through a dissolution process that provides solutions with greater than 40,000-fold signal increases compared to thermal equilibrium (5–7). These hyperpolarized compounds have been used recently to investigate a variety of biological and cellular processes (5,6,8–28). This has allowed for the in vivo study in animals of 13C metabolism with rapid scan times, good signal-to-noise ratio (SNR), and no background signal. In particular, hyperpolarized [1-13C]-pyruvate has the potential to observe cellular bioenergetics, such as glycolysis, the citric acid cycle, and fatty acid synthesis. Its conversion to [1-13C]-lactate and [1-13C]-alanine has been observed extensively in vivo in animal models (5,6,8–19). Previous studies have begun to investigate the use of in vivo MRSI with hyperpolarized [1-13C]-pyruvate for the study of prostate cancer in the TRAMP mouse (11,18). In Chen et al. (11), differential conversion to [1-13C]-lactate and [1-13C]-alanine was detected using a fast three-dimensional MRSI acquired in a 14-sec interval starting 35 sec after injection. The tumors and metastases were characterized by increased [1-13C]-lactate and decreased [1-13C]-alanine. No studies have examined localized dynamics of [1-13C]-pyruvate and its metabolic products, but the study of the TRAMP mouse and potentially other animal models would benefit from rapid and serial observation of the metabolic signal evolution, thereby providing information of uptake, perfusion, vascularization, and tissue retention. Hyperpolarized MRSI poses several unique pulse sequence design challenges, particularly for time-resolved acquisitions. The duration of the hyperpolarized signal and thus the imaging window is determined by the T1 relaxation of the labeled molecules. For [1-13C]-pyruvate, this window is only a few minutes. Furthermore, each excitation pulse will use up some of the magnetization, which is unrecoverable. In dynamic imaging, particular care must be taken in selecting excitation parameters to preserve magnetization for later images. One method that addresses these challenges is the dynamic lactate-specific imaging (29). Only lactate is excited, which allows for fast temporally resolved imaging, as well as preserving pyruvate for conversion to lactate at later times. This method, however, provides no information about the pyruvate substrate or its conversion to alanine, thus limiting its value for monitoring dynamic metabolism. We have recently introduced a new dynamic spectroscopic imaging method for hyperpolarized agents that efficiently uses the magnetization through tailored multiband excitation pulses (30). Pyruvate is excited with a small flip angle to preserve its magnetization, while lactate and alanine are excited with larger flip angles to improve their SNR. In this paper, we improved and applied this new method to studies of prostate cancer in vivo using the TRAMP model. The goal of this project was to provide new unique dynamic metabolic information, including the perfusion of pyruvate, differential conversion to lactate and alanine, and the duration and detection times of the metabolites, creating a more detailed metabolic profile of tumors and normal tissue than previously reported (11,18).

Purpose To investigate the signal-to-noise-ratio (SNR) and data quality of time-reduced three-dimensional (3D) proton magnetic resonance spectroscopic imaging (1H MRSI) techniques in the human brain at 3 Tesla. Materials and Methods Techniques that were investigated included ellipsoidal k-space sampling, parallel imaging, and echo-planar spectroscopic imaging (EPSI). The SNR values for N-acetyl aspartate, choline, creatine, and lactate or lipid peaks were compared after correcting for effective spatial resolution and acquisition time in a phantom and in the brains of human volunteers. Other factors considered were linewidths, metabolite ratios, partial volume effects, and subcutaneous lipid contamination. Results In volunteers, the median normalized SNR for parallel imaging data decreased by 34–42%, but could be significantly improved using regularization. The normalized signal to noise loss in flyback EPSI data was 11–18%. The effective spatial resolutions of the traditional, ellipsoidal, sensitivity encoding (SENSE) sampling scheme, and EPSI data were 1.02, 2.43, 1.03, and 1.01 cm3, respectively. As expected, lipid contamination was variable between subjects but was highest for the SENSE data. Patient data obtained using the flyback EPSI method were of excellent quality. Conclusion Data from all 1H 3D-MRSI techniques were qualitatively acceptable, based upon SNR, linewidths, and metabolite ratios. The larger field of view obtained with the EPSI methods showed negligible lipid aliasing with acceptable SNR values in less than 9.5 min without compromising the point-spread function. J. Magn. Reson. Imaging 2009;30:473–480. © 2009 Wiley-Liss, Inc.

One of the challenges of optimizing signal-to-noise ratio (SNR) and image quality in (13)C metabolic imaging using hyperpolarized (13)C-pyruvate is associated with the different MR signal time-courses for pyruvate and its metabolic products, lactate and alanine. The impact of the acquisition time window, variation of flip angles, and order of phase encoding on SNR and image quality were evaluated in mathematical simulations and rat experiments, based on multishot fast chemical shift imaging (CSI) and three-dimensional echo-planar spectroscopic imaging (3DEPSI) sequences. The image timing was set to coincide with the peak production of lactate. The strategy of combining variable flip angles and centric phase encoding (cPE) improved image quality while retaining good SNR. In addition, two aspects of EPSI sampling strategies were explored: waveform design (flyback vs. symmetric EPSI) and spectral bandwidth (BW = 500 Hz vs. 267 Hz). Both symmetric EPSI and reduced BW trended toward increased SNR. The imaging strategies reported here can serve as guidance to other multishot spectroscopic imaging protocols for (13)C metabolic imaging applications.

Single voxel spectroscopy has been used to access various diseases in the pediatric brain. The use of a localizing technique via PRESS (1) or STEAM (2) enables collecting information from a rectangular region of interest (ROI). For many cases this information suffices in determining the desired relevant metabolic information if the ROI can be well defined. However, there is need to expand the ROI to two dimensions (2D) or even three dimensions (3D) for certain applications. A wide scope of studies falls into this category where the spatial information can be an important factor. In addition, another realistic reason for multidimensional application can be that the region to acquire the spectroscopic information from might not be well characterized from the scout or other anatomical images. For example, when the targeted ROI is the corticospinal tract (CST), this region might not be readily visible in the conventional scout T1- or T2-weighted images when imaging infants. Multivoxel spectroscopy, 2D or 3D, can be used to overcome these limitations while increasing the spatial coverage. Conventional phase-encoded multivoxel spectroscopy is a robust and simple method but it accompanies an increase in scan time that is proportional to the number of voxels resolved. For 3D applications this can amount to a significant scan time, limiting its use for clinical applications. For pediatric exams the long scan time can be crucial due to the fact that they are more vulnerable to move during the longer scans. For this reason there is a strong desire for a faster scanning method for this population. Sedation is often used which decreases susceptibility to motion, but a faster scan would still be desirable to reduce the overall sedation time. The purpose of this study was to develop a 1H magnetic resonance spectroscopic imaging (MRSI) sequence that can be used to image infants/children at 3T and by combining it with diffusion tensor imaging (DTI) tractography, extract relevant metabolic information corresponding to the CST. By linking spectroscopic imaging with DTI to extract voxels corresponding to the CST, comprehensive metabolic assessment of the CST could be obtained. To demonstrate the potential usefulness of this approach, data were acquired from infant/children with developmental motor delay and controls and N-acetylaspartate (NAA) level ratios from the CSTs were compared. Previous studies have indicated the rapid metabolic alterations during development and its differences from abnormal developmental conditions (3-5). Polynomial, logarithmic, or exponential fits have been used to describe the changes for normal development. Specifically, these studies have noted the increase in NAA levels as normal development occurs. The main objective of this study was not to derive a clinical conclusion but rather to show the potential clinical utility of this approach. In demonstrating this feature we follow an approach similar to that of a clinical study. It should be noted that the limited number of subjects for this study does not validate any clinical suggestions. In the next section we illustrate the implementation of a fast 3D MRSI pulse sequence for use in pediatric patients. We apply the pulse sequence to pediatric patients with delayed motor development.

The advantages of using a 3 Tesla (T) scanner for MR spectroscopic imaging (MRSI) of brain tissue include improved spectral resolution and increased sensitivity. Very selective saturation (VSS) pulses are important for maximizing selectivity for PRESS MRSI and minimizing chemical shift misregistration by saturating signals from outside the selected region. Although three-dimensional (3D) PRESS MRSI is able to provide excellent quality metabolic data for patients with brain tumors and has been shown to be important for defining tumor burden, the method is currently limited by how much of the anatomic lesion can be covered within a single examination. In this study we designed and implemented cosine modulated VSS pulses that were optimized for 3T MRSI acquisitions. This provided improved coverage and suppression of unwanted lipid signals with a smaller number of pulses. The use of the improved pulse sequence was validated in volunteer studies, and in clinical 3D MRSI exams of brain tumors.

To compare peak enhancement (PE), determined from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and the magnetic resonance (MR) directionally-averaged apparent diffusion coefficient (D) in glandular versus stromal prostatic tissues and, with this comparison, to infer if the hypothesis that gadolinium-DTPA (Gd-DTPA) does not enter healthy glands or ducts is plausible.MRI, MR spectroscopic imaging, DCE MRI and MR diffusion were evaluated in 17 untreated subjects with suspected or proven prostate cancer. PE andDwere compared in glandular-ductal tissues [normal peripheral zone and glandular benign prostatic hyperplasia (BPH)] and stromal-low ductal tissues (central gland/mixed BPH and stromal BPH).The glandular-ductal tissues had lower PE [125+/-6.4 (% baseline)] and higherD[1.57+/-0.15 (s/10(-3) mm2)] than the stromal-low ductal tissues [PE=132+/-5.5 (% baseline) (P.0008),D=1.18+/-0.20 (s/10(-3) mm2) (P1 x 10(-8))]. A statistical model based upon stepwise regression was generated and completely separated the tissue types: ductal Measure = 448+669 xD(s/10(-3) mm2)-10.7 x PE (1/%), R2=1.0 and P8 x 10(-10).The very different MR results in the glandular-ductal versus stromal-low ductal tissues suggest that these tissues have different underlying structure. These results support the hypothesis that Gd-DTPA does not enter healthy prostatic glands or ducts. This may explain the higher PE and lowerDthat previously have been reported in prostate cancer versus healthy tissue.

The development of dynamic nuclear polarization (DNP) in solution has enabled in vivo 13C MR studies at high signal to noise ratio (SNR) following injection of pre-polarized 13C substrates. While prior studies have demonstrated the ability to observe metabolism following injection of hyperpolarized 13C-pyruvate, the goal of this study was to develop and test a new hyperpolarized agent for investigating in vivo metabolism, [1-13C] lactate. A preparation for pre-polarized 13C-lactate and the requisite dissolution media were developed to investigate the feasibility for in vivo 13C MRS/MRSI studies following injection of this hyperpolarized agent. This study demonstrated, for the first time, not only the ability to detect hyperpolarized [1-13C] lactate in vivo, but also the metabolic products 13C pyruvate, 13C alanine and 13C bicarbonate following injection in normal rats. Using 13C-lactate as a substrate provided the ability to study the conversion of lactate to pyruvate in vivo and to detect the secondary conversions to alanine and bicarbonate through pyruvate. This study also demonstrated the potential value of this hyperpolarized agent to investigate in vivo lactate uptake and metabolism in pre-clinical animal models.

The purpose of this study was to assess the benefits of a 3 T scanner and an eight-channel phased-array head coil for acquiring three-dimensional PRESS (Point REsolved Spectral Selection) proton (H-1) magnetic resonance spectroscopic imaging (MRSI) data from the brains of volunteers and patients with brain tumors relative to previous studies that used a 1.5 T scanner and a quadrature head coil. Issues that were of concern included differences in chemical shift artifacts, line broadening due to increased susceptibility at higher field strengths, changes in relaxation times and the increased complexity of the postprocessing software due to the need for combining signals from the multichannel data. Simulated and phantom spectra showed that very selective suppression pulses with a thickness of 40 mm and an overpress factor of at least 1.2 are needed to reduce chemical shift artifact and lipid contamination at higher field strengths. Spectral data from a phantom and those from six volunteers demonstrated that the signal-to-noise ratio (SNR) in the eight-channel coil was more than 50% higher than that in the quadrature head coil. For healthy volunteers and eight patients with brain tumors, the SNR at 3 T with the eight-channel coil was on average 1.5 times higher relative to the eight-channel coil at 1.5 T in voxels from normal-appearing brains. In combination with the effect of a higher field strength, the use of the eight-channel coil was able to provide an increase in the SNR of more than 2.33 times the corresponding acquisition at 1.5 T with a quadrature head coil. This is expected to be critical for clinical applications of MRSI in patients with brain tumors because it can be used to either decrease acquisition time or improve spatial resolution.

A 3 T MLEV-point-resolved spectroscopy (PRESS) sequence employing optimized spectral–spatial and very selective outer-voxel suppression pulses was tested in 25 prostate cancer patients. At an echo time of 85 ms, the MLEV-PRESS sequence resulted in maximally upright inner resonances and minimal outer resonances of the citrate doublet of doublets. Magnetic resonance spectroscopic imaging (MRSI) exams performed at both 3 and 1.5 T for 10 patients demonstrated a 2.08±0.36-fold increase in signal-to-noise ratio (SNR) at 3 T as compared with 1.5 T for the center citrate resonances. This permitted the acquisition of MRSI data with a nominal spatial resolution of 0.16 cm 3 at 3 T with similar SNR as the 0.34-cm 3 data acquired at 1.5 T. Due to the twofold increase in spectral resolution at 3 T and the improved magnetic field homogeneity provided by susceptibility-matched endorectal coils, the choline resonance was better resolved from polyamine and creatine resonances as compared with 1.5 T spectra. In prostate cancer patients, the elevation of choline and the reduction of polyamines were more clearly observed at 3 T, as compared with 1.5 T MRSI. The increased SNR and corresponding spatial resolution obtainable at 3 T reduced partial volume effects and allowed improved detection of the presence and extent of abnormal metabolite levels in prostate cancer patients, as compared with 1.5 T MRSI.

Spectral-spatial RF (SSRF) pulses allow simultaneous selection in both frequency and spatial domains. These pulses are particularly important for clinical and research MR spectroscopy (MRS) applications for suppression of large water and lipid resonances. Also, the high bandwidth of the subpulses (5-10 kHz) greatly reduces the spatial-shift errors associated with different chemical shifts. However, the use of high-bandwidth subpulses along with enough spectral bandwidth to measure a typical range of metabolite frequencies (e.g., 300 Hz at 3 T) can require RF amplitudes beyond the limits of the RF amplifier of a typical scanner. In this article, a new method is described for designing nonlinear-phase 180 degrees SSRF pulses that can be used for spectral editing. The novel feature of the pulses is that the spectral profile develops as a symmetric sweep, from the outside edges of the spectral window towards the middle, so that coupled components are tipped simultaneously and over a short interval. Pulses were designed for lactate editing at 1.5 T and 3 T. The spectral and spatial spin-echo profiles of the new pulses were measured experimentally. Spectra acquired in phantom experiments showed a well-resolved, edited lactate doublet, with 91% to 93% editing efficiency.

In vivo pH mapping in tissue using hyperpolarized hydrogencarbonate-13 C has been proposed as a method to study tumor growth and treatment and other pathological conditions related to pH changes. The finite spin-lattice relaxation times (T1 ) of hyperpolarized media are a significant limiting factor for in vivo imaging. Relaxation times can be measured at standard magnetic fields (1.5 T, 3.0 T etc.), but no such data are available at low fields, where T1 values can be significantly shorter. This information is required to determine the potential loss of polarization as the agent is dispensed and transported from the polarizer to the MRI scanner. The purpose of this study is to measure T1 dispersion from low to clinical magnetic fields (0.4 mT to 3.0 T) of different hyperpolarized hydrogencarbonate formulations previously proposed in the literature for in vivo pH measurements. 13 C-enriched cesium and sodium hydrogencarbonate preparations were hyperpolarized using dynamic nuclear polarization, and the T1 values of different samples were measured at different magnetic field strengths using a fast field-cycling relaxometer and a 3.0 T clinical MRI system. The effects of deuterium oxide as a dissolution medium for sodium hydrogencarbonate were also analyzed. This study finds that the cesium formulation has slightly shorter T1 values compared with the sodium preparation. However, the higher solubility of cesium hydrogencarbonate-13 C means it can be polarized at greater concentration, using less trityl radical than sodium hydrogencarbonate-13 C. This study also establishes that the preparation and handling of sodium hydrogencarbonate formulations in relation to cesium hydrogencarbonate is more difficult, due to the higher viscosity and lower achievable concentrations, and that deuterium oxide significantly increases the T1 of sodium hydrogencarbonate solutions. Finally, this work also investigates the influence of pH on the spin-lattice relaxation of cesium hydrogencarbonate-13 C measured over a pH range of 7 to 9 at 0.47 T.

This article describes the basic physics of dissolution dynamic nuclear polarization (dissolution-DNP), and the impact of the resulting highly nonequilibrium spin states, on the physics of magnetic resonance imaging (MRI) detection. The hardware requirements for clinical translation of this technology are also presented. For studies that allow the use of externally administered agents, hyperpolarization offers a way to overcome normal magnetic resonance sensitivity limitations, at least for a brief T(1)-dependent observation window. A 10,000-100,000-fold signal-to-noise advantage provides an avenue for real-time measurement of perfusion, metabolite transport, exchange, and metabolism. The principles behind these measurements, as well as the choice of agent, and progress toward the application of hyperpolarized (13)C metabolic imaging in oncology, cardiology, and neurology are reviewed.

BACKGROUND: The use of in vivo (13)C nuclear magnetic resonance spectroscopy in probing metabolic pathways to study normal metabolism and characterize disease physiology has been limited by its low sensitivity. However, recent technological advances have enabled greater than 50,000-fold enhancement of liquid-state polarization of metabolically active (13)C substrates, allowing for rapid assessment of (13)C metabolism in vivo. The present study applied hyperpolarized (13)C magnetic resonance spectroscopy to the investigation of liver metabolism, demonstrating for the first time the feasibility of applying this technology to detect differences in liver metabolic states. PROCEDURES: [1-(13)C]pyruvate was hyperpolarized with a dynamic nuclear polarization instrument and injected into normal and fasted rats. The uptake of pyruvate and its conversion to the metabolic products lactate and alanine were observed with slice-localized dynamic magnetic resonance spectroscopy and 3D magnetic resonance spectroscopic imaging (3D-MRSI). RESULTS: Significant differences in lactate to alanine ratio (P < 0.01) between normal and fasted rat liver slice dynamic spectra were observed. 3D-MRSI localized to the fasted livers demonstrated significantly decreased (13)C-alanine levels (P < 0.01) compared to normal. CONCLUSIONS: This study presents the initial demonstration of characterizing metabolic state differences in the liver with hyperpolarized (13)C spectroscopy and shows the ability to detect physiological perturbations in alanine aminotransferase activity, which is an encouraging result for future liver disease investigations with hyperpolarized magnetic resonance technology.