A pharmacokinetic model for hyperpolarized 13C-pyruvate MRI when using metabolite-specific bSSFP sequences.

PURPOSE: Metabolite-specific balanced SSFP (MS-bSSFP) sequences are increasingly used in hyperpolarized [1-13C]Pyruvate (HP 13C) MRI studies as they improve SNR by refocusing the magnetization each TR. Currently, pharmacokinetic models used to fit conversion rate constants, kPL and kPB, and rate constant maps do not account for differences in the signal evolution of MS-bSSFP acquisitions. METHODS: In this work, a flexible MS-bSSFP model was built that can be used to fit conversion rate constants for these experiments. The model was validated in vivo using paired animal (healthy rat kidneys n = 8, transgenic adenocarcinoma of the mouse prostate n = 3) and human renal cell carcinoma (n = 3) datasets. Gradient echo (GRE) acquisitions were used with a previous GRE model to compare to the results of the proposed GRE-bSSFP model. RESULTS: Within simulations, the proposed GRE-bSSFP model fits the simulated data well, whereas a GRE model shows bias because of model mismatch. For the in vivo datasets, the estimated conversion rate constants using the proposed GRE-bSSFP model are consistent with a previous GRE model. Jointly fitting the lactate T2 with kPL resulted in less precise kPL estimates. CONCLUSION: The proposed GRE-bSSFP model provides a method to estimate conversion rate constants, kPL and kPB, for MS-bSSFP HP 13C experiments. This model may also be modified and used for other applications, for example, estimating rate constants with other hyperpolarized reagents or multi-echo bSSFP.

A Simulation of the Effects of Diffusion on Hyperpolarized [1-13C]-Pyruvate Signal Evolution.

OBJECTIVE: Hyperpolarized [1-13C]-pyruvate magnetic resonance imaging is an emerging metabolic imaging method that offers unprecedented spatiotemporal resolution for monitoring tumor metabolism in vivo. To establish robust imaging biomarkers of metabolism, we must characterize phenomena that may modulate the apparent pyruvate-to-lactate conversion rate (kPL). Here, we investigate the potential effect of diffusion on pyruvate-to-lactate conversion, as failure to account for diffusion in pharmacokinetic analysis may obscure true intracellular chemical conversion rates. METHODS: Changes in hyperpolarized pyruvate and lactate signal were calculated using a finite-difference time domain simulation of a two-dimensional tissue model. Signal evolution curves with intracellular kPL values from 0.02 to 1.00 s-1 were analyzed using spatially invariant one-compartment and two-compartment pharmacokinetic models. A second spatially variant simulation incorporating compartmental instantaneous mixing was fit with the same one-compartment model. RESULTS: When fitting with the one-compartment model, apparent kPL underestimated intracellular kPL by approximately 50% at an intracellular kPL of 0.02 s-1. This underestimation increased for larger kPL values. However, fitting the instantaneous mixing curves showed that diffusion accounted for only a small part of this underestimation. Fitting with the two-compartment model yielded more accurate intracellular kPL values. SIGNIFICANCE: This work suggests diffusion is not a significant rate-limiting factor in pyruvate-to-lactate conversion given that our model assumptions hold true. In higher order models, diffusion effects may be accounted for by a term characterizing metabolite transport. Pharmacokinetic models used to analyze hyperpolarized pyruvate signal evolution should focus on carefully selecting the analytical model for fitting rather than accounting for diffusion effects.

Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP-Epac-CREB Signaling Pathway.

Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP-Epac-CREB signaling pathway to upregulate FGF21 expression in hepatocytes.

Pharmacodynamics and pharmacokinetics of hyperpolarized [1-13 C]-pyruvate in a translational oncologic model.

This study investigates the in vivo pharmacokinetics and pharmacodynamics of hyperpolarized [1-13 C]-pyruvate in a translational cancer model in order to inform the application of dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI) as a tool for imaging liver cancer. Intratumoral metabolism within autochthonous hepatocellular carcinomas in male Wistar rats was analyzed by MRSI following hyperpolarized [1-13 C]-pyruvate injections with 80 mM (low dose [LD]) or 160 mM (high dose [HD]) pyruvate. Rats received (i) LD followed by HD injection, (ii) sequential LD injections with or without an interposed lactate dehydrogenase inhibitor (LDHi) injection, or (iii) a single LD injection. A subset of rats in (ii) were sacrificed immediately after imaging, permitting measurement of active LDH concentrations in tumor extracts. Urine and serum were collected before and after injections for rats in (iii). Comparison of LD and HD injections confirmed concentration-dependent variation of intratumoral metabolite fractions and intermetabolite ratios. In addition, quantification of the lactate-to-pyruvate ratio was sensitive to pharmacologic inhibition with intermetabolite ratios correlating with active LDH concentrations in tumor extracts. Finally, comparison of pre- and post-DNP urine collections revealed that pyruvate and the radical source are renally excreted after injection. These data demonstrate that DNP-MRSI facilitates real-time quantification of intratumoral metabolism that is repeatable and reflective of intracellular processes. A translational model system confirmed that interpretation requires consideration of probe dose, administration frequency and excretion.

Slice profile effects on quantitative analysis of hyperpolarized pyruvate.

Magnetic resonance imaging of hyperpolarized pyruvate provides a new imaging biomarker for cancer metabolism, based on the dynamic in vivo conversion of hyperpolarized pyruvate to lactate. Methods for quantification of signal evolution need to be robust and reproducible across a range of experimental conditions. Pharmacokinetic analysis of dynamic spectroscopic imaging data from hyperpolarized pyruvate and its metabolites generally assumes that signal arises from ideal rectangular slice excitation profiles. In this study, we examined whether this assumption could lead to bias in kinetic analysis of hyperpolarized pyruvate and, if so, whether such a bias can be corrected. A Bloch-McConnell simulator was used to generate synthetic data using a known set of "ground truth" pharmacokinetic parameter values. Signal evolution was then analyzed using analysis software that either assumed a uniform slice profile, or incorporated information about the slice profile into the analysis. To correct for slice profile effects, the expected slice profile was subdivided into multiple sub-slices to account for variable excitation angles along the slice dimension. An ensemble of sub-slices was then used to fit the measured signal evolution. A mismatch between slice profiles used for data acquisition and those assumed during kinetic analysis was identified as a source of quantification bias. Results indicate that imperfect slice profiles preferentially increase detected lactate signal, leading to an overestimation of the apparent metabolic exchange rate. The slice profile-correction algorithm was tested in simulation, in phantom measurements, and applied to data acquired from a patient with prostate cancer. The results demonstrated that slice profile-induced biases can be minimized by accounting for the slice profile during pharmacokinetic analysis. This algorithm can be used to correct data from either single or multislice acquisitions.

Kinetic Modeling of Hyperpolarized Carbon-13 Pyruvate Metabolism in the Human Brain.

Kinetic modeling of the in vivo pyruvate-to-lactate conversion is crucial to investigating aberrant cancer metabolism that demonstrates Warburg effect modifications. Non-invasive detection of alterations to metabolic flux might offer prognostic value and improve the monitoring of response to treatment. In this clinical research project, hyperpolarized [1-13C] pyruvate was intravenously injected in a total of 10 brain tumor patients to measure its rate of conversion to lactate ( kPL ) and bicarbonate ( kPB ) via echo-planar imaging. Our aim was to investigate new methods to provide kPL and kPB maps with whole-brain coverage. The approach was data-driven and addressed two main issues: selecting the optimal model for fitting our data and determining an appropriate goodness-of-fit metric. The statistical analysis suggested that an input-less model had the best agreement with the data. It was also found that selecting voxels based on post-fitting error criteria provided improved precision and wider spatial coverage compared to using signal-to-noise cutoffs alone.

Using a local low rank plus sparse reconstruction to accelerate dynamic hyperpolarized 13C imaging using the bSSFP sequence.

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.

Influence of parameter accuracy on pharmacokinetic analysis of hyperpolarized pyruvate.

PURPOSE: To explore the effects of noise and error on kinetic analyses of tumor metabolism using hyperpolarized [1-13 C] pyruvate. METHODS: Numerical simulations were performed to systematically investigate the effects of noise, the number of unknowns, and error in kinetic parameter estimates on kinetic analysis of the apparent rate of chemical conversion from hyperpolarized pyruvate to lactate (kPL ). A pharmacokinetic model with two physical and two chemical pools of hyperpolarized spins was used to generate and analyze the synthetic data. RESULTS: The reproducibility of kPL estimates worsened quickly when peak signal-to-noise ratio for hyperpolarized pyruvate was below approximately 20. The accuracy of kPL estimates was most sensitive to errors in high excitation angles, the vascular blood volume fraction (vb ), and the rate of pyruvate extravasation (kve ), and was least sensitive to errors in the T1 of pyruvate. When vb and/or kve were fit as additional unknowns, the accuracy of kPL estimates suffered, and when the vascular input function of pyruvate was also fit, the reproducibility of kPL estimates worsened. CONCLUSIONS: The accuracy and precision of kPL estimates improve substantially for peak signal-to-noise ratio above approximately 20. Accurate estimates of perfusion parameters (combinations of vb , kve , and the pyruvate vascular input function) and transmit calibration at high excitation angles have the greatest effect on the accuracy of kinetic analyses. Magn Reson Med 79:3239-3248, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors.

Hyperpolarized [1-(13)C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison with alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly undersampled imaging data from tumor-bearing animals. Compared with naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements.

Simultaneous Hyperpolarized 13C-Pyruvate MRI and 18F-FDG PET (HyperPET) in 10 Dogs with Cancer.

UNLABELLED: With the introduction of combined PET/MR spectroscopic (MRS) imaging, it is now possible to directly and indirectly image the Warburg effect with hyperpolarized (13)C-pyruvate and (18)F-FDG PET imaging, respectively, via a technique we have named hyperPET. The main purpose of this present study was to establish a practical workflow for performing (18)F-FDG PET and hyperpolarized (13)C-pyruvate MRS imaging simultaneously for tumor tissue characterization and on a larger scale test its feasibility. In addition, we evaluated the correlation between (18)F-FDG uptake and (13)C-lactate production. METHODS: Ten dogs with biopsy-verified spontaneous malignant tumors were included for imaging. All dogs underwent a protocol of simultaneous (18)F-FDG PET, anatomic MR, and hyperpolarized dynamic nuclear polarization with (13)C-pyruvate imaging. The data were acquired using a combined clinical PET/MR imaging scanner. RESULTS: We found that combined (18)F-FDG PET and (13)C-pyruvate MRS imaging was possible in a single session of approximately 2 h. A continuous workflow was obtained with the injection of (18)F-FDG when the dogs was placed in the PET/MR scanner. (13)C-MRS dynamic acquisition demonstrated in an axial slab increased (13)C-lactate production in 9 of 10 dogs. For the 9 dogs, the (13)C-lactate was detected after a mean of 25 s (range, 17-33 s), with a mean to peak of (13)C-lactate at 49 s (range, 40-62 s). (13)C-pyruvate could be detected on average after 13 s (range, 5-26 s) and peaked on average after 25 s (range, 13-42 s). We noticed concordance of (18)F-FDG uptake and production of (13)C-lactate in most, but not all, axial slices. CONCLUSION: In this study, we have shown in a series of dogs with cancer that hyperPET can easily be performed within 2 h. We showed mostly correspondence between (13)C-lactate production and (18)F-FDG uptake and expect the combined modalities to reveal additional metabolic information to improve prognostic value and improve response monitoring.

Comparison of acquisition schemes for hyperpolarised ¹³C imaging.

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

Monitoring mammary tumor progression and effect of tamoxifen treatment in MMTV-PymT using MRI and magnetic resonance spectroscopy with hyperpolarized [1-13C]pyruvate.

PURPOSE: To use dynamic magnetic resonance spectroscopy (MRS) of hyperpolarized (13)C-pyruvate to follow the progress over time in vivo of breast cancer metabolism in the MMTV-PymT model, and to follow the response to the anti-estrogen drug tamoxifen. METHODS: Tumor growth was monitored by anatomical MRI by measuring tumor volumes. Dynamic MRS of hyperpolarized (13)C was used to measure an "apparent" pyruvate-to-lactate rate constant (kp) of lactate dehydrogenase (LDH) in vivo. Further, ex vivo pathology and in vitro LDH initial reaction velocity were evaluated. RESULTS: Tamoxifen significantly halted the tumor growth measured as tumor volume by MRI. In the untreated animals, kp correlated with tumor growth. The kP was somewhat but not significantly lower in the treated group. Studies in vitro confirmed the effects of tamoxifen on tumor growth, and here the LDH reaction velocity was reduced significantly in the treated group. CONCLUSION: These hyperpolarized (13)C MRS findings indicate that tumor metabolic changes affects kP. The measured kp did not relate to treatment response to the same extent as did tumor growth, histological evaluation, and in vitro determination of LDH activity.

Longitudinal anatomical and metabolic MRI characterization of orthotopic xenograft prostate tumors in nude mice.

PURPOSE: To assess anatomic and functional magnetic resonance imaging (MRI) for monitoring of tumor volume and metabolism of orthotopic xenograft prostate cancer tumors. MATERIALS AND METHODS: Human-derived PC-3M cells were implanted into the prostate in 22 nude mice. Tumor volume and MRI appearance were monitored for up to 29 days. Histology was performed to detect metastases. Hyperpolarized [1-(13) C]pyruvate MRI was used to measure tumor metabolism on day 22. RESULTS: Tumors were visible by MRI 9 days after tumor cell implantation. Tumor volume increased to 720 ± 190 mm(3) on day 29 of imaging. Metastasis was seen in the iliac lymph nodes at all timepoints, and in more distant lymph nodes at later timepoints, but was not detectable by MRI. Regions with low pyruvate uptake corresponded to regions with necrosis and had a higher lactate/pyruvate ratio (0.98 ± 0.4 vs. 1.6 ± 1.1). CONCLUSION: MRI using the balanced steady-state free precession (bSSFP) sequence can be used to monitor tumor growth in orthotopic PC-3M tumors as early as 9 days post-injection. Hyperpolarized pyruvate MRI has potential to assess tumor metabolism and necrosis.

Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized (13)C-pyruvate.

RATIONALE AND OBJECTIVES: Cancer cells generate more lactate than normal cells under both aerobic and hypoxic conditions-exhibiting the so-called Warburg effect. However, the relationship between the Warburg effect and tumor metastatic potential remains controversial. We intend to investigate whether the higher lactate reflects higher tumor metastatic potential. MATERIALS AND METHODS: We used hyperpolarized (13)C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate (13)C-labeling in vivo in mouse xenografts of the highly metastatic (MDA-MB-231) and the relatively indolent (MCF-7) human breast cancer cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of data analysis including the differential equation fit, q-ratio fit, and ratio fit methods. RESULTS: Consistent results from the three methods showed that the highly metastatic tumors exhibited a smaller apparent forward rate constant (k(+) = 0.060 ± 0.004 s(-1)) than the relatively indolent tumors (k(+) = 0.097 ± 0.013 s(-1)). The ratio fit generated the greatest statistical significance for the difference (P = .02). No significant difference in the reverse rate constant was found between the two tumor lines. CONCLUSIONS: The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected (13)C-pyruvate and supports the notion that breast tumor metastatic risk is not necessarily associated with the high levels of glycolysis and lactate production. More studies are needed to confirm whether and how much the measured apparent rate constants are affected by the membrane transporter activity and whether they are primarily determined by the LDH activity.

Radial spectroscopic MRI of hyperpolarized [1-(13) C] pyruvate at 7 tesla.

PURPOSE: The transient and nonrenewable signal from hyperpolarized metabolites necessitates extensive sequence optimization for encoding spatial, spectral, and dynamic information. In this work, we evaluate the utility of radial single-timepoint and cumulative spectroscopic MRI of hyperpolarized [1-(13) C] pyruvate and its metabolic products at 7 Tesla (T). METHODS: Simulations of radial echo planar spectroscopic imaging (EPSI) and multiband frequency encoding (MBFE) acquisitions were performed to confirm feasibility and evaluate performance for HP (13) C imaging. Corresponding sequences were implemented on a 7T small-animal MRI system, tested in phantom, and demonstrated in a murine model of anaplastic thyroid cancer. RESULTS: MBFE provides excellent spectral separation but is susceptible to blurring and T2 * signal loss inherent to using low readout gradients. The higher readout gradients and more flexible spectral encoding for EPSI result in good spatial resolution and spectral separation. Radial acquisition throughout HP signal evolution offers the flexibility for reconstructing spatial maps of mean metabolite distribution and global dynamic time courses of multiple metabolites. CONCLUSION: Radial EPSI and MBFE acquisitions are well-suited for hyperpolarized (13) C MRI over short and long durations. Advantages to this approach include robustness to nonstationary magnetization, insensitivity to precise acquisition timing, and versatility for reconstructing dynamically acquired spectroscopic data.

Kinetic modeling of hyperpolarized (13)C pyruvate metabolism in tumors using a measured arterial input function.

Mathematical models are required to estimate kinetic parameters of [1-(13)C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. One- or two-way exchange models utilizing a hypothetical approximation to the true arterial input function (AIF), (e.g. an ideal 'box-car' function) have been used previously. We present a method for direct measurement of the AIF in the rat. The hyperpolarized [1-(13)C] pyruvate signal was measured in arterial blood as it was continuously withdrawn through a small chamber. The measured signal was corrected for T1 relaxation of pyruvate, RF pulses and dispersion of blood in the chamber to allow for the estimation of the direct AIF. Using direct AIF, rather than the commonly used box-car AIF, provided realistic estimates of the rate constant of conversion of pyruvate to lactate, kpl, the rate constant of conversion of lactate to pyruvate klp, the clearance rate constant of pyruvate from blood to tissue, Kip, and the relaxation rate of lactate T1la. Since no lactate signal was present in blood, it was possible to use a simple precursor-product relationship, with the tumor tissue pyruvate time-course as the input for the lactate time-course. This provided a robust estimate of kpl, similar to that obtained using a directly measured AIF.

Rapid sequential injections of hyperpolarized [1-¹³C]pyruvate in vivo using a sub-kelvin, multi-sample DNP polarizer.

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

Saturation-recovery metabolic-exchange rate imaging with hyperpolarized [1-13C] pyruvate using spectral-spatial excitation.

Within the last decade hyperpolarized [1-13C] pyruvate chemical-shift imaging has demonstrated impressive potential for metabolic MR imaging for a wide range of applications in oncology, cardiology, and neurology. In this work, a highly efficient pulse sequence is described for time-resolved, multislice chemical shift imaging of the injected substrate and obtained downstream metabolites. Using spectral-spatial excitation in combination with single-shot spiral data acquisition, the overall encoding is evenly distributed between excitation and signal reception, allowing the encoding of one full two-dimensional metabolite image per excitation. The signal-to-noise ratio can be flexibly adjusted and optimized using lower flip angles for the pyruvate substrate and larger ones for the downstream metabolites. Selectively adjusting the excitation of the down-stream metabolites to 90° leads to a so-called "saturation-recovery" scheme with the detected signal content being determined by forward conversion of the available pyruvate. In case of repetitive excitations, the polarization is preserved using smaller flip angles for pyruvate. Metabolic exchange rates are determined spatially resolved from the metabolite images using a simplified two-site exchange model. This novel contrast is an important step toward more quantitative metabolic imaging. Goal of this work was to derive, analyze, and implement this "saturation-recovery metabolic exchange rate imaging" and demonstrate its capabilities in four rats bearing subcutaneous tumors.

Generating super stimulated-echoes in MRI and their application to hyperpolarized C-13 diffusion metabolic imaging.

Stimulated-echoes in MR can be used to provide high sensitivity to motion and flow, creating diffusion and perfusion weighting as well as T(1) contrast, but conventional approaches inherently suffer from a 50% signal loss. The super stimulated-echo, which uses a specialized radio-frequency (RF) pulse train, has been proposed in order to improve the signal while preserving motion and T(1) sensitivity. This paper presents a novel and straightforward method for designing the super stimulated-echo pulse train using inversion pulse design techniques. This method can also create adiabatic designs with an improved response to RF transmit field variations. The scheme was validated in phantom experiments and shown in vivo to improve signal-to-noise ratio (SNR). We have applied a super stimulated-echo to metabolic MRI with hyperpolarized (13)C-labeled molecules. For spectroscopic imaging of hyperpolarized agents, several repetition times are required but only a single stimulated-echo encoding is feasible, which can lead to unwanted motion blurring. To address this, a super stimulated-echo preparation scheme was used in which the diffusion weighting is terminated prior to the acquisition, and we observed a SNR increases of 60% in phantoms and 49% in vivo over a conventional stimulated-echo. Experiments following injection of hyperpolarized [1-(13)C] -pyruvate in murine transgenic cancer models have shown improved delineation for tumors since signals from metabolites within tumor tissues are retained while those from the vasculature are suppressed by the diffusion preparation scheme.

Fast dynamic 3D MR spectroscopic imaging with compressed sensing and multiband excitation pulses for hyperpolarized 13C studies.

Hyperpolarized 13C MR spectroscopic imaging can detect not only the uptake of the pre-polarized molecule but also its metabolic products in vivo, thus providing a powerful new method to study cellular metabolism. Imaging the dynamic perfusion and conversion of these metabolites provides additional tissue information but requires methods for efficient hyperpolarization usage and rapid acquisitions. In this work, we have developed a time-resolved 3D MR spectroscopic imaging method for acquiring hyperpolarized 13C data by combining compressed sensing methods for acceleration and multiband excitation pulses to efficiently use the magnetization. This method achieved a 2 sec temporal resolution with full volumetric coverage of a mouse, and metabolites were observed for up to 60 sec following injection of hyperpolarized [1-(13)C]-pyruvate. The compressed sensing acquisition used random phase encode gradient blips to create a novel random undersampling pattern tailored to dynamic MR spectroscopic imaging with sampling incoherency in four (time, frequency, and two spatial) dimensions. The reconstruction was also tailored to dynamic MR spectroscopic imaging by applying a temporal wavelet sparsifying transform to exploit the inherent temporal sparsity. Customized multiband excitation pulses were designed with a lower flip angle for the [1-(13)C]-pyruvate substrate given its higher concentration than its metabolic products ([1-(13)C]-lactate and [1-(13)C]-alanine), thus using less hyperpolarization per excitation. This approach has enabled the monitoring of perfusion and uptake of the pyruvate, and the conversion dynamics to lactate and alanine throughout a volume with high spatial and temporal resolution.