All Publications

  • Detection of Metabolic Changes using Hyperpolarized C-13 MRI in a Negative F-18-FDG PET Rat Brain Cancer Model Lauritzen, M., Datta, K., Merchant, M., Jang, T., Hurd, R., Liu, S., Recht, L., Spielman, D. SOC NUCLEAR MEDICINE INC. 2019
  • Methodological consensus on clinical proton MRS of the brain: Review and recommendations. Magnetic resonance in medicine Wilson, M., Andronesi, O., Barker, P. B., Bartha, R., Bizzi, A., Bolan, P. J., Brindle, K. M., Choi, I., Cudalbu, C., Dydak, U., Emir, U. E., Gonzalez, R. G., Gruber, S., Gruetter, R., Gupta, R. K., Heerschap, A., Henning, A., Hetherington, H. P., Huppi, P. S., Hurd, R. E., Kantarci, K., Kauppinen, R. A., Klomp, D. W., Kreis, R., Kruiskamp, M. J., Leach, M. O., Lin, A. P., Luijten, P. R., Marjanska, M., Maudsley, A. A., Meyerhoff, D. J., Mountford, C. E., Mullins, P. G., Murdoch, J. B., Nelson, S. J., Noeske, R., Oz, G., Pan, J. W., Peet, A. C., Poptani, H., Posse, S., Ratai, E., Salibi, N., Scheenen, T. W., Smith, I. C., Soher, B. J., Tkac, I., Vigneron, D. B., Howe, F. A. 2019


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

    View details for DOI 10.1002/mrm.27742

    View details for PubMedID 30919510

  • Pulse sequence considerations for quantification of pyruvate-to-lactate conversion kPL in hyperpolarized 13 C imaging. NMR in biomedicine Chen, H., Gordon, J. W., Bok, R. A., Cao, P., von Morze, C., van Criekinge, M., Milshteyn, E., Carvajal, L., Hurd, R. E., Kurhanewicz, J., Vigneron, D. B., Larson, P. E. 2019: e4052


    Hyperpolarized 13 C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, kPL , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID-Delay,Crush /kPL,FID-Delay =1.37±0.33, P<0.01, N=6), which agrees with simulation outcomes (12.5% kPL error with Deltav=40cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum-TE version (kPL,FID-Delay /kPL,FID =0.67±0.09, P<0.01, N=5), and the lactate peak had broader linewidth than pyruvate (Deltaomegalactate /Deltaomegapyruvate =1.32±0.07, P<0.000 01, N=13). This illustrated that lactate's T2 *, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin-echo sequence that includes spin-echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE /kPL,FID =2.40±0.98, P<0.0001, N=7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL . The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies.

    View details for PubMedID 30664305

  • PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose ONCOTARGET Tee, S., Park, J., Hurd, R. E., Brimacombe, K. R., Boxer, M. B., Massoud, T. F., Rutt, B. K., Spielman, D. M. 2017; 8 (53): 90959–68
  • C]Alanine. Magnetic resonance in medicine Park, J. M., Khemtong, C., Liu, S., Hurd, R. E., Spielman, D. M. 2017; 77 (5): 1741-1748


    The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD(+) ]. In this study, we assessed the use of hyperpolarized [1-(13) C]alanine and the subsequent detection of the intracellular products of [1-(13) C]pyruvate and [1-(13) C]lactate as a useful substrate for assessing redox levels in the liver in vivo.Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1-(13) C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of (13) C MRS spectra.In vivo rat liver spectra showed peaks from [1-(13) C] alanine and the products of [1-(13) C]lactate, [1-(13) C]pyruvate, and (13) C-bicarbonate. A significantly increased (13) C-lactate/(13) C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in (13) C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes.A method to measure in vivo tissue redox using hyperpolarized [1-(13) C]alanine is presented, with the validity of the proposed (13) C-pyruvate/(13) C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

    View details for DOI 10.1002/mrm.26662

    View details for PubMedID 28261868

  • In vivo assessment of intracellular redox state in rat liver using hyperpolarized [1-C-13]Alanine MAGNETIC RESONANCE IN MEDICINE Park, J. M., Khemtong, C., Liu, S., Hurd, R. E., Spielman, D. M. 2017; 77 (5): 1741-1748


    The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD(+) ]. In this study, we assessed the use of hyperpolarized [1-(13) C]alanine and the subsequent detection of the intracellular products of [1-(13) C]pyruvate and [1-(13) C]lactate as a useful substrate for assessing redox levels in the liver in vivo.Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1-(13) C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of (13) C MRS spectra.In vivo rat liver spectra showed peaks from [1-(13) C] alanine and the products of [1-(13) C]lactate, [1-(13) C]pyruvate, and (13) C-bicarbonate. A significantly increased (13) C-lactate/(13) C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in (13) C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes.A method to measure in vivo tissue redox using hyperpolarized [1-(13) C]alanine is presented, with the validity of the proposed (13) C-pyruvate/(13) C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

    View details for DOI 10.1002/mrm.26662

    View details for Web of Science ID 000399666400002

  • GABA editing with macromolecule suppression using an improved MEGA-SPECIAL sequence. Magnetic resonance in medicine Gu, M., Hurd, R., Noeske, R., Baltusis, L., Hancock, R., Sacchet, M. D., Gotlib, I. H., Chin, F. T., Spielman, D. M. 2017


    The most common γ-aminobutyric-acid (GABA) editing approach, MEGA-PRESS, uses J-editing to measure GABA distinct from larger overlapping metabolites, but suffers contamination from coedited macromolecules (MMs) comprising 40 to 60% of the observed signal. MEGA-SPECIAL is an alternative method with better MM suppression, but is not widely used primarily because of its relatively poor spatial localization. Our goal was to develop an improved MM-suppressed GABA editing sequence at 3 Tesla.We modified a single-voxel MEGA-SPECIAL sequence with an oscillating readout gradient for improved spatial localization, and used very selective 30-ms editing pulses for improved suppression of coedited MMs.Simulation and in vivo experiments confirmed excellent MM suppression, insensitive to the range of B0 frequency drifts typically encountered in vivo. Both intersubject and intrasubject studies showed that MMs, when suppressed by the improved MEGA-SPECIAL method, contributed approximately 40% to the corresponding MEGA-PRESS measurements. From the intersubject study, the coefficient of variation for GABA+/Cre (MEGA-PRESS) was 11.2% versus 7% for GABA/Cre (improved MEGA-SPECIAL), demonstrating significantly reduced variance (P = 0.005), likely coming from coedited MMs.This improved MEGA-SPECIAL sequence provides unbiased GABA measurements with reduced variance as compared with conventional MEGA-PRESS. This approach is also relatively insensitive to the range of B0 drifts typically observed in in vivo human studies. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

    View details for DOI 10.1002/mrm.26691

    View details for PubMedID 28370458

  • PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose. Oncotarget Tee, S. S., Park, J. M., Hurd, R. E., Brimacombe, K. R., Boxer, M. B., Massoud, T. F., Rutt, B. K., Spielman, D. M. 2017; 8 (53): 90959–68


    Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated in vivo on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate 13C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.

    View details for PubMedID 29207616

  • Hyperpolarized (13) C-lactate to (13) C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment. NMR in biomedicine Park, J. M., Spielman, D. M., Josan, S., Jang, T., Merchant, M., Hurd, R. E., Mayer, D., Recht, L. D. 2016; 29 (5): 650-659


    Hyperpolarized [1-(13) C]pyruvate MRS provides a unique imaging opportunity to study the reaction kinetics and enzyme activities of in vivo metabolism because of its favorable imaging characteristics and critical position in the cellular metabolic pathway, where it can either be reduced to lactate (reflecting glycolysis) or converted to acetyl-coenzyme A and bicarbonate (reflecting oxidative phosphorylation). Cancer tissue metabolism is altered in such a way as to result in a relative preponderance of glycolysis relative to oxidative phosphorylation (i.e. Warburg effect). Although there is a strong theoretical basis for presuming that readjustment of the metabolic balance towards normal could alter tumor growth, a robust noninvasive in vivo tool with which to measure the balance between these two metabolic processes has yet to be developed. Until recently, hyperpolarized (13) C-pyruvate imaging studies had focused solely on [1-(13) C]lactate production because of its strong signal. However, without a concomitant measure of pyruvate entry into the mitochondria, the lactate signal provides no information on the balance between the glycolytic and oxidative metabolic pathways. Consistent measurement of (13) C-bicarbonate in cancer tissue, which does provide such information, has proven difficult, however. In this study, we report the reliable measurement of (13) C-bicarbonate production in both the healthy brain and a highly glycolytic experimental glioblastoma model using an optimized (13) C MRS imaging protocol. With the capacity to obtain signal in all tumors, we also confirm for the first time that the ratio of (13) C-lactate to (13) C-bicarbonate provides a more robust metric relative to (13) C-lactate for the assessment of the metabolic effects of anti-angiogenic therapy. Our data suggest a potential application of this ratio as an early biomarker to assess therapeutic effectiveness. Furthermore, although further study is needed, the results suggest that anti-angiogenic treatment results in a rapid normalization in the relative tissue utilization of glycolytic and oxidative phosphorylation by tumor tissue. Copyright © 2016 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.3509

    View details for PubMedID 26990457

  • Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model. Magnetic resonance in medicine Park, J. M., Josan, S., Jang, T., Merchant, M., Watkins, R., Hurd, R. E., Recht, L. D., Mayer, D., Spielman, D. M. 2016; 75 (3): 973-984


    MRS of hyperpolarized [2-(13) C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13) C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13) C]pyruvate in glioma-bearing brain.Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13) C]pyruvate, [2-(13) C]lactate, and [5-(13) C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13) C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13) C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity.The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13) C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain.Robust volumetric imaging with hyperpolarized [2-(13) C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/mrm.25766

    View details for PubMedID 25946547

  • Handheld Electromagnet Carrier for Transfer of Hyperpolarized Carbon-13 Samples MAGNETIC RESONANCE IN MEDICINE Shang, H., Skloss, T., Von Morze, C., Carvajal, L., Van Criekinge, M., Milshteyn, E., Larson, P. E., Hurd, R. E., Vigneron, D. B. 2016; 75 (2): 917-922


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

    View details for DOI 10.1002/mrm.25657

    View details for Web of Science ID 000370597000046

    View details for PubMedID 25765516

  • Assessing inflammatory liver injury in an acute CCl4 model using dynamic 3D metabolic imaging of hyperpolarized [1-C-13]pyruvate NMR IN BIOMEDICINE Josan, S., Billingsley, K., Orduna, J., Park, J. M., Luong, R., Yu, L., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2015; 28 (12): 1671-1677


    To facilitate diagnosis and staging of liver disease, sensitive and non-invasive methods for the measurement of liver metabolism are needed. This study used hyperpolarized (13) C-pyruvate to assess metabolic parameters in a CCl4 model of liver damage in rats. Dynamic 3D (13) C chemical shift imaging data from a volume covering kidney and liver were acquired from 8 control and 10 CCl4 -treated rats. At 12 time points at 5 s temporal resolution, we quantified the signal intensities and established time courses for pyruvate, alanine, and lactate. These measurements were compared with standard liver histology and an alanine transaminase (ALT) enzyme assay using liver tissue from the same animals. All CCl4 -treated but none of the control animals showed histological liver damage and elevated ALT enzyme levels. In agreement with these results, metabolic imaging revealed an increased alanine/pyruvate ratio in liver of CCl4 -treated rats, which is indicative of elevated ALT activity. Similarly, lactate/pyruvate ratios were higher in CCl4 -treated compared with control animals, demonstrating the presence of inflammation. No significant differences in metabolite ratios were observed in kidney or vasculature. Thus this work shows that metabolic imaging using (13) C-pyruvate can be a successful tool to non-invasively assess liver damage in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.3431

    View details for Web of Science ID 000367315100007

  • Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle. journal of experimental biology Park, J. M., Josan, S., Mayer, D., Hurd, R. E., Chung, Y., Bendahan, D., Spielman, D. M., Jue, T. 2015; 218: 3308-3318


    The production of glycolytic end products, such as lactate, usually evokes the concept of a cellular shift from aerobic to anaerobic ATP generation and O2 insufficiency. In the classical view, muscle lactate must export to liver for clearance. Studies, however, indicate that lactate also forms under well-oxygenated conditions and have led investigators to postulate lactate shuttling from non-oxidative to oxidative muscle fiber, where it can serve as a precursor. Indeed, the intracellular lactate shuttle and the glycogen shunt hypotheses expand the vision to include a dynamic mobilization and utilization of lactate during a muscle contraction cycle. Testing the tenability of these provocative ideas during a rapid contraction cycle has posed a technical challenge. The present study herein reports the use of hyperpolarized [1-(13)C]lactate and [2-(13)C]pyruvate in dynamic nuclear polarization (DNP) NMR experiments to measure the rapid pyruvate and lactate kinetics in rat muscle. With a 2-s temporal resolution, (13)C DNP NMR detects both [1-(13)C]lactate and [2-(13)C]pyruvate kinetics in muscle. Infusing dichloroacetate to stimulate pyruvate dehydrogenase activity and shifts the kinetics toward oxidative metabolism. Bicarbonate formation increases sharply from [1-(13)C]lactate. Acetyl-L-carnitine, acetoacetate, and glutamate levels rise. Such a quick mobilization of pyruvate and lactate toward oxidative metabolism supports the postulated role of lactate in the glycogen shunt and the intracellular lactate shuttle models. The study introduces then an innovative DNP approach to measure metabolite transients, which will help delineate the cellular and physiological role of lactate and glycolytic end products.

    View details for DOI 10.1242/jeb.123141

    View details for PubMedID 26347554

  • Assessing inflammatory liver injury in an acute CCl4 model using dynamic 3D metabolic imaging of hyperpolarized [1-(13) C]pyruvate. NMR in biomedicine Josan, S., Billingsley, K., Orduna, J., Park, J. M., Luong, R., Yu, L., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2015


    To facilitate diagnosis and staging of liver disease, sensitive and non-invasive methods for the measurement of liver metabolism are needed. This study used hyperpolarized (13) C-pyruvate to assess metabolic parameters in a CCl4 model of liver damage in rats. Dynamic 3D (13) C chemical shift imaging data from a volume covering kidney and liver were acquired from 8 control and 10 CCl4 -treated rats. At 12 time points at 5 s temporal resolution, we quantified the signal intensities and established time courses for pyruvate, alanine, and lactate. These measurements were compared with standard liver histology and an alanine transaminase (ALT) enzyme assay using liver tissue from the same animals. All CCl4 -treated but none of the control animals showed histological liver damage and elevated ALT enzyme levels. In agreement with these results, metabolic imaging revealed an increased alanine/pyruvate ratio in liver of CCl4 -treated rats, which is indicative of elevated ALT activity. Similarly, lactate/pyruvate ratios were higher in CCl4 -treated compared with control animals, demonstrating the presence of inflammation. No significant differences in metabolite ratios were observed in kidney or vasculature. Thus this work shows that metabolic imaging using (13) C-pyruvate can be a successful tool to non-invasively assess liver damage in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

    View details for PubMedID 26474216

  • The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate. Magnetic resonance imaging Billingsley, K. L., Park, J. M., Josan, S., Hurd, R., Mayer, D., Spielman-Sun, E., Nishimura, D. G., Brooks, J. D., Spielman, D. 2014; 32 (7): 791-795


    Recent advancements in the field of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) have yielded powerful techniques capable of real-time analysis of metabolic pathways. These non-invasive methods have increasingly shown application in impacting disease diagnosis and have further been employed in mechanistic studies of disease onset and progression. Our goals were to investigate branched-chain aminotransferase (BCAT) activity in prostate cancer with a novel molecular probe, hyperpolarized [1-(13)C]-2-ketoisocaproate ([1-(13)C]-KIC), and explore the potential of branched-chain amino acid (BCAA) metabolism to serve as a biomarker. Using traditional spectrophotometric assays, BCAT enzymatic activities were determined in vitro for various sources of prostate cancer (human, transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse and human cell lines). These preliminary studies indicated that low levels of BCAT activity were present in all models of prostate cancer but enzymatic levels are altered significantly in prostate cancer relative to healthy tissue. The MR spectroscopic studies were conducted with two cellular models (PC-3 and DU-145) that exhibited levels of BCAA metabolism comparable to the human disease state. Hyperpolarized [1-(13)C]-KIC was administered to prostate cancer cell lines, and the conversion of [1-(13)C]-KIC to the metabolic product, [1-(13)C]-leucine ([1-(13)C]-Leu), could be monitored via hyperpolarized (13)C MRS.

    View details for DOI 10.1016/j.mri.2014.04.015

    View details for PubMedID 24907854

    View details for PubMedCentralID PMC4099288

  • Dynamic metabolic imaging of hyperpolarized [2-(13) C]pyruvate using spiral chemical shift imaging with alternating spectral band excitation. Magnetic resonance in medicine Josan, S., Hurd, R., Park, J. M., Yen, Y., Watkins, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2014; 71 (6): 2051-2058


    In contrast to [1-(13) C]pyruvate, hyperpolarized [2-(13) C]pyruvate permits the ability to follow the (13) C label beyond flux through pyruvate dehydrogenase complex and investigate the incorporation of acetyl-coenzyme A into different metabolic pathways. However, chemical shift imaging (CSI) with [2-(13) C]pyruvate is challenging owing to the large spectral dispersion of the resonances, which also leads to severe chemical shift displacement artifacts for slice-selective acquisitions.This study introduces a sequence for three-dimensional CSI of [2-(13) C]pyruvate using spectrally selective excitation of limited frequency bands containing a subset of metabolites. Dynamic CSI data were acquired alternately from multiple frequency bands in phantoms for sequence testing and in vivo in rat heart.Phantom experiments verified the radiofrequency pulse design and demonstrated that the signal behavior of each group of resonances was unaffected by excitation of the other frequency bands. Dynamic three-dimensional (13) C CSI data demonstrated the sequence capability to image pyruvate, lactate, acetylcarnitine, glutamate, and acetoacetate, enabling the analysis of organ-specific spectra and metabolite time courses.The presented method allows CSI of widely separated resonances without chemical shift displacement artifact, acquiring multiple frequency bands alternately to obtain dynamic time-course information. This approach enables robust imaging of downstream metabolic products of acetyl-coenzyme A with hyperpolarized [2-(13) C]pyruvate. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/mrm.24871

    View details for PubMedID 23878057

  • Hyperpolarized [1,4-C-13]-diethylsuccinate: a potential DNP substrate for in vivo metabolic imaging NMR IN BIOMEDICINE Billingsley, K. L., Josan, S., Park, J. M., Tee, S. S., Spielman-Sun, E., Hurd, R., Mayer, D., Spielman, D. 2014; 27 (3): 356-362


    The tricarboxylic acid (TCA) cycle performs an essential role in the regulation of energy and metabolism, and deficiencies in this pathway are commonly correlated with various diseases. However, the development of non-invasive techniques for the assessment of the cycle in vivo has remained challenging. In this work, the applicability of a novel imaging agent, [1,4-(13) C]-diethylsuccinate, for hyperpolarized (13) C metabolic imaging of the TCA cycle was explored. In vivo spectroscopic studies were conducted in conjunction with in vitro analyses to determine the metabolic fate of the imaging agent. Contrary to previous reports (Zacharias NM et al. J. Am. Chem. Soc. 2012; 134: 934-943), [(13) C]-labeled diethylsuccinate was primarily metabolized to succinate-derived products not originating from TCA cycle metabolism. These results illustrate potential issues of utilizing dialkyl ester analogs of TCA cycle intermediates as molecular probes for hyperpolarized (13) C metabolic imaging. Copyright © 2014 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.3071

    View details for Web of Science ID 000330798100013

    View details for PubMedID 24421249

  • Clinical Proton MR Spectroscopy in Central Nervous System Disorders RADIOLOGY Oz, G., Alger, J. R., Barker, P. B., Bartha, R., Bizzi, A., Boesch, C., Bolan, P. J., Brindle, K. M., Cudalbu, C., Dincer, A., Dydak, U., Emir, U. E., Frahm, J., Gonzalez, R. G., Gruber, S., Gruetter, R., Gupta, R. K., Heerschap, A., Henning, A., Hetherington, H. P., Howe, F. A., Hueppi, P. S., Hurd, R. E. 2014; 270 (3): 658-679


    A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

    View details for DOI 10.1148/radiol.13130531

    View details for Web of Science ID 000335136800005

    View details for PubMedID 24568703

  • Frequency correction method for improved spatial correlation of hyperpolarized C-13 metabolites and anatomy NMR IN BIOMEDICINE Cunningham, C. H., Viqueira, W. D., Hurd, R. E., Chen, A. P. 2014; 27 (2): 212-218

    View details for DOI 10.1002/nbm.3055

    View details for Web of Science ID 000329986900011

  • In vivo investigation of cardiac metabolism in the rat using MRS of hyperpolarized [1-(13) C] and [2-(13) C]pyruvate. NMR in biomedicine Josan, S., Park, J. M., Hurd, R., Yen, Y., Pfefferbaum, A., Spielman, D., Mayer, D. 2013; 26 (12): 1680-1687


    Hyperpolarized (13) C MRS allows the in vivo assessment of pyruvate dehydrogenase complex (PDC) flux, which converts pyruvate to acetyl-coenzyme A (acetyl-CoA). [1-(13) C]pyruvate has been used to measure changes in cardiac PDC flux, with demonstrated increase in (13) C-bicarbonate production after dichloroacetate (DCA) administration. With [1-(13) C]pyruvate, the (13) C label is released as (13) CO2 /(13) C-bicarbonate, and, hence, does not allow us to follow the fate of acetyl-CoA. Pyruvate labeled in the C2 position has been used to track the (13) C label into the TCA (tricarboxylic acid) cycle and measure [5-(13) C]glutamate as well as study changes in [1-(13) C]acetylcarnitine with DCA and dobutamine. This work investigates changes in the metabolic fate of acetyl-CoA in response to metabolic interventions of DCA-induced increased PDC flux in the fed and fasted state, and increased cardiac workload with dobutamine in vivo in rat heart at two different pyruvate doses. DCA led to a modest increase in the (13) C labeling of [5-(13) C]glutamate, and a considerable increase in [1-(13) C]acetylcarnitine and [1,3-(13) C]acetoacetate peaks. Dobutamine resulted in an increased labeling of [2-(13) C]lactate, [2-(13) C]alanine and [5-(13) C]glutamate. The change in glutamate with dobutamine was observed using a high pyruvate dose but not with a low dose. The relative changes in the different metabolic products provide information about the relationship between PDC-mediated oxidation of pyruvate and its subsequent incorporation into the TCA cycle compared with other metabolic pathways. Using a high dose of pyruvate may provide an improved ability to observe changes in glutamate. Copyright © 2013 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.3003

    View details for PubMedID 23904148

    View details for PubMedCentralID PMC3838505

  • Effects of isoflurane anesthesia on hyperpolarized (13)C metabolic measurements in rat brain. Magnetic resonance in medicine Josan, S., Hurd, R., Billingsley, K., Senadheera, L., Park, J. M., Yen, Y., Pfefferbaum, A., Spielman, D., Mayer, D. 2013; 70 (4): 1117-1124


    PURPOSE: Commonly used anesthetic agents such as isoflurane are known to be potent cerebral vasodilators, with reported dose-dependent increase in cerebral blood flow and cerebral blood volume. Despite the widespread use of isoflurane in hyperpolarized (13) C preclinical research studies, a quantitative assessment of its effect on metabolic measurements is limited. This work investigates the effect of isoflurane anesthesia dose on hyperpolarized (13) C MR metabolic measurements in rat brain for [1-(13) C]pyruvate and 2-keto[1-(13) C]isocaproate. METHODS: Dynamic 2D and 3D spiral chemical shift imaging was used to acquire metabolic images of rat brain as well as kidney and liver following bolus injections of hyperpolarized [1-(13) C]pyruvate or 2-keto[1-(13) C]isocaproate. The impact of a "low dose" vs. a "high dose" of isoflurane on cerebral metabolite levels and apparent conversion rates was examined. RESULTS: The cerebral substrate signal levels, and hence the metabolite-to-substrate ratios and apparent conversion rates, were found to depend markedly on isoflurane dose, while signal levels of metabolic products and their ratios, e.g. bicarbonate/lactate, were largely insensitive to isoflurane levels. No obvious dependence on isoflurane was observed in kidney or liver for pyruvate. CONCLUSION: This study highlights the importance of careful attention to the effects of anesthesia on the metabolic measures for hyperpolarized (13) C metabolic imaging in brain. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

    View details for DOI 10.1002/mrm.24532

    View details for PubMedID 23086864

  • Effects of Isoflurane Anesthesia on Hyperpolarized C-13 Metabolic Measurements in Rat Brain MAGNETIC RESONANCE IN MEDICINE Josan, S., Hurd, R., Billingsley, K., Senadheera, L., Park, J. M., Yen, Y., Pfefferbaum, A., Spielman, D., Mayer, D. 2013; 70 (4): 1117-1124

    View details for DOI 10.1002/mrm.24532

    View details for Web of Science ID 000325136300023

  • Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-(13) C]pyruvate. NMR in biomedicine Park, J. M., Josan, S., Grafendorfer, T., Yen, Y., Hurd, R. E., Spielman, D. M., Mayer, D. 2013; 26 (10): 1197-1203


    Hyperpolarized [1-(13) C]pyruvate ([1-(13) C]Pyr) has been used to assess metabolism in healthy and diseased states, focusing on the downstream labeling of lactate (Lac), bicarbonate and alanine. Although hyperpolarized [2-(13) C]Pyr, which retains the labeled carbon when Pyr is converted to acetyl-coenzyme A, has been used successfully to assess mitochondrial metabolism in the heart, the application of [2-(13) C]Pyr in the study of brain metabolism has been limited to date, with Lac being the only downstream metabolic product reported previously. In this study, single-time-point chemical shift imaging data were acquired from rat brain in vivo. [5-(13) C]Glutamate, [1-(13) C]acetylcarnitine and [1-(13) C]citrate were detected in addition to resonances from [2-(13) C]Pyr and [2-(13) C]Lac. Brain metabolism was further investigated by infusing dichloroacetate, which upregulates Pyr flux to acetyl-coenzyme A. After dichloroacetate administration, a 40% increase in [5-(13) C]glutamate from 0.014 ± 0.004 to 0.020 ± 0.006 (p = 0.02), primarily from brain, and a trend to higher citrate (0.002 ± 0.001 to 0.004 ± 0.002) were detected, whereas [1-(13) C]acetylcarnitine was increased in peripheral tissues. This study demonstrates, for the first time, that hyperpolarized [2-(13) C]Pyr can be used for the in vivo investigation of mitochondrial function and tricarboxylic acid cycle metabolism in brain. Copyright © 2013 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.2935

    View details for PubMedID 23553852

  • Exchange-Linked Dissolution Agents in Dissolution-DNP C-13 Metabolic Imaging MAGNETIC RESONANCE IN MEDICINE Hurd, R. E., Spielman, D., Josan, S., Yen, Y., Pfefferbaum, A., Mayer, D. 2013; 70 (4): 936-942

    View details for DOI 10.1002/mrm.24544

    View details for Web of Science ID 000325136300005

  • Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-C-13]Pyruvate SCIENCE TRANSLATIONAL MEDICINE Nelson, S. J., Kurhanewicz, J., Vigneron, D. B., Larson, P. E., Harzstark, A. L., Ferrone, M., Van Criekinge, M., Chang, J. W., Bok, R., Park, I., Reed, G., Carvajal, L., Small, E. J., Munster, P., Weinberg, V. K., Ardenkjaer-Larsen, J. H., Chen, A. P., Hurd, R. E., Odegardstuen, L., Robb, F. J., Tropp, J., Murray, J. A. 2013; 5 (198)


    This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

    View details for DOI 10.1126/scitranslmed.3006070

    View details for Web of Science ID 000323132200008

    View details for PubMedID 23946197

  • Perfusion and diffusion sensitive C-13 stimulated-echo MRSI for metabolic imaging of cancer MAGNETIC RESONANCE IMAGING Larson, P. E., Hurd, R. E., Kerr, A. B., Pauly, J. M., Bok, R. A., Kurhanewicz, J., Vigneron, D. B. 2013; 31 (5): 635-642


    Metabolic imaging with hyperpolarized [1-(13)C]-pyruvate can rapidly probe tissue metabolic profiles in vivo and has been shown to provide cancer imaging biomarkers for tumor detection, progression, and response to therapy. This technique uses a bolus injection followed by imaging within 1-2 minutes. The observed metabolites include vascular components and their generation is also influenced by cellular transport. These factors complicate image interpretation, especially since [1-(13)C]lactate, a metabolic product that is a biomarker of cancer, is also produced by red blood cells. It would be valuable to understand the distribution of metabolites between the vasculature, interstitial space, and intracellular compartments. The purpose of this study was to better understand this compartmentalization by using a perfusion and diffusion-sensitive stimulated-echo acquisition mode (STEAM) MRSI acquisition method tailored to hyperpolarized substrates. Our results in mouse models showed that among metabolites, the injected substrate (13)C-pyruvate had the largest vascular fraction overall while (13)C-alanine had the smallest vascular fraction. We observed a larger vascular fraction of pyruvate and lactate in the kidneys and liver when compared to back muscle and prostate tumor tissue. Our data suggests that (13)C-lactate in prostate tumor tissue voxels was the most abundant labeled metabolite intracellularly. This was shown in STEAM images that highlighted abnormal cancer cell metabolism and suppressed vascular (13)C metabolite signals.

    View details for DOI 10.1016/j.mri.2012.10.020

    View details for Web of Science ID 000319103000001

    View details for PubMedID 23260391

    View details for PubMedCentralID PMC3626756

  • In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-(13) C]pyruvate. NMR in biomedicine Josan, S., Xu, T., Yen, Y., Hurd, R., Ferreira, J., Chen, C., Mochly-Rosen, D., Pfefferbaum, A., Mayer, D., Spielman, D. 2013; 26 (6): 607-612


    To date, measurements of the activity of aldehyde dehydrogenase-2 (ALDH2), a critical mitochondrial enzyme for the elimination of certain cytotoxic aldehydes in the body and a promising target for drug development, have been largely limited to in vitro methods. Recent advancements in MRS of hyperpolarized (13) C-labeled substrates have provided a method to detect and image in vivo metabolic pathways with signal-to-noise ratio gains greater than 10 000-fold over conventional MRS techniques. However aldehydes, because of their toxicity and short T1 relaxation times, are generally poor targets for such (13) C-labeled studies. In this work, we show that dynamic MRSI of hyperpolarized [1-(13) C]pyruvate and its conversion to [1-(13) C]lactate can provide an indirect in vivo measurement of ALDH2 activity via the concentration of NADH (nicotinamide adenine dinucleotide, reduced form), a co-factor common to both the reduction of pyruvate to lactate and the oxidation of acetaldehyde to acetate. Results from a rat liver ethanol model (n = 9) show that changes in (13) C-lactate labeling following the bolus injection of hyperpolarized pyruvate are highly correlated with changes in ALDH2 activity (R(2)  = 0.76). Copyright © 2012 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/nbm.2897

    View details for PubMedID 23225495

    View details for PubMedCentralID PMC3634870

  • Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized C-13 magnetic resonance spectroscopic imaging NEURO-ONCOLOGY Park, J. M., Recht, L. D., Josan, S., Merchant, M., Jang, T., Yen, Y., Hurd, R. E., Spielman, D. M., Mayer, D. 2013; 15 (4): 433-441


    The metabolic phenotype that derives disproportionate energy via glycolysis in solid tumors, including glioma, leads to elevated lactate labeling in metabolic imaging using hyperpolarized [1-(13)C]pyruvate. Although the pyruvate dehydrogenase (PDH)-mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 ((13)C)-labeled bicarbonate, it has proven difficult to visualize (13)C-bicarbonate at high enough levels from injected [1-(13)C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of (13)C-labeled metabolites, in particular bicarbonate, in glioma and normal brain in vivo and to measure the metabolic response to dichloroacetate, which upregulates PDH activity.An optimized protocol for chemical shift imaging and high concentration of hyperpolarized [1-(13)C]pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1-(13)C]pyruvate was injected before and 45 min after dichloroacetate infusion. Metabolite ratios of lactate to bicarbonate were calculated to provide improved metrics for characterizing tumor metabolism.Glioma and normal brain were well differentiated by lactate-to-bicarbonate ratio (P = .002, n = 5) as well as bicarbonate (P = .0002) and lactate (P = .001), and a stronger response to dichloroacetate was observed in glioma than in normal brain.Our results clearly demonstrate for the first time the feasibility of quantitatively detecting (13)C-bicarbonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDH flux. The simultaneous detection of lactate and bicarbonate provides a tool for a more comprehensive analysis of glioma metabolism and the assessment of metabolic agents as anti-brain cancer drugs.

    View details for DOI 10.1093/neuonc/nos319

    View details for Web of Science ID 000316965600005

    View details for PubMedID 23328814

    View details for PubMedCentralID PMC3607261

  • Hyperpolarized 13C metabolic imaging using dissolution dynamic nuclear polarization JOURNAL OF MAGNETIC RESONANCE IMAGING Hurd, R. E., Yen, Y., Chen, A., Ardenkjaer-Larsen, J. H. 2012; 36 (6): 1314-1328


    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.

    View details for DOI 10.1002/jmri.23753

    View details for Web of Science ID 000311381900005

    View details for PubMedID 23165733

  • Metabolite kinetics in C6 rat glioma model using magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate MAGNETIC RESONANCE IN MEDICINE Park, J. M., Josan, S., Jang, T., Merchant, M., Yen, Y., Hurd, R. E., Recht, L., Spielman, D. M., Mayer, D. 2012; 68 (6): 1886-1893


    In addition to an increased lactate-to-pyruvate ratio, altered metabolism of a malignant glioma can be further characterized by its kinetics. Spatially resolved dynamic data of pyruvate and lactate from C6-implanted female Sprague-Dawley rat brain were acquired using a spiral chemical shift imaging sequence after a bolus injection of a hyperpolarized [1-(13)C]pyruvate. Apparent rate constants for the conversion of pyruvate to lactate in three different regions (glioma, normal appearing brain, and vasculature) were estimated based on a two-site exchange model. The apparent conversion rate constant was 0.018 ± 0.004 s(-1) (mean ± standard deviation, n = 6) for glioma, 0.009 ± 0.003 s(-1) for normal brain, and 0.005 ± 0.001 s(-1) for vasculature, whereas the lactate-to-pyruvate ratio, the metabolic marker used to date to identify tumor regions, was 0.36 ± 0.07 (mean ± SD), 0.24 ± 0.07, and 0.12 ± 0.02 for glioma, normal brain, and vasculature, respectively. The data suggest that the apparent conversion rate better differentiate glioma from normal brain (P = 0.001, n = 6) than the lactate-to-pyruvate ratio (P = 0.02).

    View details for DOI 10.1002/mrm.24181

    View details for Web of Science ID 000311398600022

    View details for PubMedID 22334279

    View details for PubMedCentralID PMC3376665

  • Application of hyperpolarized [1-13C]lactate for the in vivo investigation of cardiac metabolism NMR IN BIOMEDICINE Mayer, D., Yen, Y., Josan, S., Park, J. M., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2012; 25 (10): 1119-1124


    In addition to cancer imaging, (13) C-MRS of hyperpolarized pyruvate has also demonstrated utility for the investigation of cardiac metabolism and ischemic heart disease. Although no adverse effects have yet been reported for doses commonly used in vivo, high substrate concentrations have lead to supraphysiological pyruvate levels that can affect the underlying metabolism and should be considered when interpreting results. With lactate serving as an important energy source for the heart and physiological lactate levels one to two orders of magnitude higher than for pyruvate, hyperpolarized lactate could potentially be used as an alternative to pyruvate for probing cardiac metabolism. In this study, hyperpolarized [1-(13) C]lactate was used to acquire time-resolved spectra from the healthy rat heart in vivo and to measure dichloroacetate (DCA)-modulated changes in flux through pyruvate dehydrogenase (PDH). Both primary oxidation of lactate to pyruvate and subsequent conversion of pyruvate to alanine and bicarbonate could reliably be detected. Since DCA stimulates the activity of PDH through inhibition of PDH kinase, a more than 2.5-fold increase in bicarbonate-to-substrate ratio was found after administration of DCA, similar to the effect when using [1-(13) C]pyruvate as the substrate.

    View details for DOI 10.1002/nbm.2778

    View details for Web of Science ID 000308710400003

    View details for PubMedID 22278751

    View details for PubMedCentralID PMC3357452

  • Fast volumetric imaging of ethanol metabolism in rat liver with hyperpolarized [1-13C]pyruvate NMR IN BIOMEDICINE Josan, S., Spielman, D., Yen, Y., Hurd, R., Pfefferbaum, A., Mayer, D. 2012; 25 (8): 993-999


    Rapid volumetric imaging of hyperpolarized (13) C compounds allows the real-time measurement of metabolic activity and can be useful in distinguishing between normal and diseased tissues. This work extends a fast two-dimensional undersampled spiral MRSI sequence to provide volumetric coverage, acquiring a 16 × 16 × 12 matrix with a nominal isotropic resolution of 5 mm in 4.5 s. The rapid acquisition enables a high temporal resolution for dynamic imaging. This dynamic three-dimensional MRSI method was used to investigate hyperpolarized [1-(13) C]pyruvate metabolism modulated by the administration of ethanol in rat liver. A significant increase in the pyruvate to lactate conversion was observed in the liver as a result of the greater availability of NADH (nicotinamide adenine dinucleotide, reduced form) from ethanol metabolism.

    View details for DOI 10.1002/nbm.2762

    View details for Web of Science ID 000306178400005

    View details for PubMedID 22331837

    View details for PubMedCentralID PMC3366020

  • Generating Super Stimulated-Echoes in MRI and Their Application to Hyperpolarized C-13 Diffusion Metabolic Imaging IEEE TRANSACTIONS ON MEDICAL IMAGING Larson, P. E., Kerr, A. B., Reed, G. D., Hurd, R. E., Kurhanewicz, J., Pauly, J. M., Vigneron, D. B. 2012; 31 (2): 265-275


    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.

    View details for DOI 10.1109/TMI.2011.2168235

    View details for Web of Science ID 000300197500010

    View details for PubMedID 22027366

    View details for PubMedCentralID PMC3274664

  • Simultaneous investigation of cardiac pyruvate dehydrogenase flux, Krebs cycle metabolism and pH, using hyperpolarized [1,2-C-13(2)]pyruvate in vivo NMR IN BIOMEDICINE Chen, A. P., Hurd, R. E., Schroeder, M. A., Lau, A. Z., Gu, Y., Lam, W. W., Barry, J., Tropp, J., Cunningham, C. H. 2012; 25 (2): 305-311


    (13)C MR spectroscopy studies performed on hearts ex vivo and in vivo following perfusion of prepolarized [1-(13)C]pyruvate have shown that changes in pyruvate dehydrogenase (PDH) flux may be monitored non-invasively. However, to allow investigation of Krebs cycle metabolism, the (13)C 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 ((13)CO(2) and H(13)CO(3)(-)) and Krebs cycle flux ([5-(13)C]glutamate) with a single dose of the agent. Cardiac pH could also be monitored in the same experiment, but adequate SNR of the (13)CO(2) resonance may be difficult to obtain in vivo. Using an interleaved selective RF pulse acquisition scheme to improve (13)CO(2) detection, the feasibility of using dual-labeled hyperpolarized [1,2-(13)C(2)]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.

    View details for DOI 10.1002/nbm.1749

    View details for Web of Science ID 000301597300014

    View details for PubMedID 21774012

  • Spin tagging for hyperpolarized C-13 metabolic studies JOURNAL OF MAGNETIC RESONANCE Chen, A. P., Hurd, R. E., Cunningham, C. H. 2012; 214: 319-323


    In studies utilizing pre-polarized (13)C substrates to investigate metabolic activities in vivo, the metabolite signals observed in a region or a voxel contains a mixture of intracellular and extracellular components. This extracellular component arriving via perfusion may confound the measurements of metabolic flux or exchange rates. But if spin tagging is performed on the magnetization of the substrate, it may be possible to measure the signals of the metabolic products in the intracellular space that were derived from the tagged substrate spins locally. In this study, a spin tagging pulse sequence designed for acquiring data from spatially tagged longitudinal magnetization in hyperpolarized (13)C metabolic studies was presented and tested. Using a spectral-spatial RF pulse during the tagging preparation enabled the observation of metabolite signals derived exclusively from the tagged substrate in vivo.

    View details for DOI 10.1016/j.jmr.2011.10.007

    View details for Web of Science ID 000299656400041

    View details for PubMedID 22050921

  • Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic C-13 MRSI NMR IN BIOMEDICINE Xu, T., Mayer, D., Gu, M., Yen, Y., Josan, S., Tropp, J., Pfefferbaum, A., Hurd, R., Spielman, D. 2011; 24 (8): 997-1005


    With signal-to-noise ratio enhancements on the order of 10,000-fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1-(13)C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1-(13)C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time-to-peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small-flip-angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral-based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo (13)C labeling of lactate and alanine after a bolus injection of [1-(13)C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis-Menten-like formulation, with the resulting estimated apparent maximal reaction velocity V(max) and apparent Michaelis constant K(M) being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis-Menten kinetics, it is conceptually different. In this study, we focus on the (13)C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process.

    View details for DOI 10.1002/nbm.1719

    View details for Web of Science ID 000295293900009

    View details for PubMedID 21538639

    View details for PubMedCentralID PMC3169748

  • Spectral-spatial excitation for rapid imaging of DNP compounds NMR IN BIOMEDICINE Lau, A. Z., Chen, A. P., Hurd, R. E., Cunningham, C. H. 2011; 24 (8): 988-996


    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 (13)C metabolic imaging in cardiac and cancer applications are explored. Spiral pulse sequences for multislice imaging of [1-(13)C]pyruvate in the heart were developed, as well as time-resolved, three-dimensional, echo-planar imaging sequences for the imaging of [1-(13)C]pyruvate-lactate exchange in cancer. The advantages and challenges associated with these sequences were determined by testing in pig and rat models.

    View details for DOI 10.1002/nbm.1743

    View details for Web of Science ID 000295293900008

    View details for PubMedID 21751271

  • C-13 MR reporter probe system using dynamic nuclear polarization NMR IN BIOMEDICINE Chen, A. P., Hurd, R. E., Gu, Y., Wilson, D. M., Cunningham, C. H. 2011; 24 (5): 514-520


    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 (13) C MR reporter system, using the aminoacylase-1 reporter gene (Acy-1) and prepolarized [1-(13) C]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 (13) C-labeled substrate by the aminoacylase-1 enzyme was demonstrated with purified protein in solution by dynamic (13) C MRS and two-dimensional MRSI experiments. The potential to perform targeted MRI of cells using this system was also demonstrated by (13) C 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.

    View details for DOI 10.1002/nbm.1618

    View details for Web of Science ID 000291597200010

    View details for PubMedID 21674653

  • In vivo MRSI of hyperpolarized [1-C-13]pyruvate metabolism in rat hepatocellular carcinoma NMR IN BIOMEDICINE Darpolor, M. M., Yen, Y., Chua, M., Xing, L., Clarke-Katzenberg, R. H., Shi, W., Mayer, D., Josan, S., Hurd, R. E., Pfefferbaum, A., Senadheera, L., So, S., Hofmann, L. V., Glazer, G. M., Spielman, D. M. 2011; 24 (5): 506-513


    Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1-(13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1-(13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors.

    View details for DOI 10.1002/nbm.1616

    View details for Web of Science ID 000291597200009

    View details for PubMedID 21674652

    View details for PubMedCentralID PMC3073155

  • Dynamic and High-Resolution Metabolic Imaging of Hyperpolarized [1-C-13]-Pyruvate in the Rat Brain Using a High-Performance Gradient Insert MAGNETIC RESONANCE IN MEDICINE Mayer, D., Yen, Y., Takahashi, A., Josan, S., Tropp, J., Rutt, B. K., Hurd, R. E., Spielman, D. M., Pfefferbaum, A. 2011; 65 (5): 1228-1233


    Fast chemical shift imaging (CSI) techniques are advantageous in metabolic imaging of hyperpolarized compounds due to the limited duration of the signal amplification. At the same time, reducing the acquisition time in hyperpolarized imaging does not necessarily lead to the conventional penalty in signal-to-noise ratio that occurs in imaging at thermal equilibrium polarization levels. Here a high-performance gradient insert was used in combination with undersampled spiral CSI to increase either the imaging speed or the spatial resolution of hyperpolarized (13)C metabolic imaging on a clinical 3T MR scanner. Both a single-shot sequence with a total acquisition time of 125 ms and a three-shot sequence with a nominal in-plane resolution of 1.5 mm were implemented. The k-space trajectories were measured and then used during image reconstruction. The technique was applied to metabolic imaging of the rat brain in vivo after the injection of hyperpolarized [1-(13)C]-pyruvate. Dynamic imaging afforded the measurement of region-of-interest-specific time courses of pyruvate and its metabolic products, while imaging at high spatial resolution was used to better characterize the spatial distribution of the metabolite signals.

    View details for DOI 10.1002/mrm.22707

    View details for Web of Science ID 000289760800003

    View details for PubMedID 21500253

    View details for PubMedCentralID PMC3126907

  • Detection of Inflammatory Arthritis by Using Hyperpolarized C-13-Pyruvate with MR Imaging and Spectroscopy RADIOLOGY MacKenzie, J. D., Yen, Y., Mayer, D., Tropp, J. S., Hurd, R. E., Spielman, D. M. 2011; 259 (2): 414-420


    To examine the feasibility of using magnetic resonance (MR) spectroscopy with hyperpolarized carbon 13 ((13)C)-labeled pyruvate to detect inflammation.The animal care and use committee approved all work with animals. Arthritis was induced in the right hind paw of six rats; the left hind paw served as an internal control. The lactate dehydrogenase-catalyzed conversion of pyruvate to lactate was measured in inflamed and control paws by using (13)C MR spectroscopy. Clinical and histologic data were obtained to confirm the presence and severity of arthritis. Hyperpolarized (13)C-pyruvate was intravenously injected into the rats before simultaneous imaging of both paws with (13)C MR spectroscopy. The Wilcoxon signed rank test was used to test for differences in metabolites between the control and arthritic paws.All animals showed findings of inflammation in the affected paws and no signs of arthritis in the control paws at both visible inspection (clinical index of 3 for arthritic paws and 0 for control paws) and histologic examination (histologic score of 3-5 for arthritic paws and 0 for control paws). Analysis of the spectroscopic profiles of (13)C-pyruvate and converted (13)C-lactate showed an increase in the amount of (13)C-lactate in inflamed paws (median lactate-to-pyruvate ratio, 0.50; mean lactate-to-pyruvate ratio ± standard deviation, 0.52 ± 0.16) versus control paws (median lactate-to-pyruvate ratio, 0.27; mean lactate-to-pyruvate ratio, 0.32 ± 0.11) (P < .03). The ratio of (13)C-lactate to total (13)C was also significantly increased in inflamed paws compared with control paws (P < .03).These results suggest that alterations in the conversion of pyruvate to lactate as detected with (13)C-MR spectroscopy may be indicative of the presence of inflammatory arthritis.

    View details for DOI 10.1148/radiol.10101921

    View details for Web of Science ID 000289667300013

    View details for PubMedID 21406626

    View details for PubMedCentralID PMC3079121

  • Application of double spin echo spiral chemical shift imaging to rapid metabolic mapping of hyperpolarized [1-C-13]-pyruvate JOURNAL OF MAGNETIC RESONANCE Josan, S., Yen, Y., Hurd, R., Pfefferbaum, A., Spielman, D., Mayer, D. 2011; 209 (2): 332-336


    Undersampled spiral CSI (spCSI) using a free induction decay (FID) acquisition allows sub-second metabolic imaging of hyperpolarized ¹³C. Phase correction of the FID acquisition can be difficult, especially with contributions from aliased out-of-phase peaks. This work extends the spCSI sequence by incorporating double spin echo radiofrequency (RF) pulses to eliminate the need for phase correction and obtain high quality spectra in magnitude mode. The sequence also provides an added benefit of attenuating signal from flowing spins, which can otherwise contaminate signal in the organ of interest. The refocusing pulses can potentially lead to a loss of hyperpolarized magnetization in dynamic imaging due to flow of spins through the fringe field of the RF coil, where the refocusing pulses fail to provide complete refocusing. Care must be taken for dynamic imaging to ensure that the spins remain within the B₁-homogeneous sensitive volume of the RF coil.

    View details for DOI 10.1016/j.jmr.2011.01.010

    View details for Web of Science ID 000289270900030

    View details for PubMedID 21316280

    View details for PubMedCentralID PMC3072043

  • Multi-channel metabolic imaging, with SENSE reconstruction, of hyperpolarized [1-C-13] pyruvate in a live rat at 3.0 tesla on a clinical MR scanner JOURNAL OF MAGNETIC RESONANCE Tropp, J., Lupo, J. M., Chen, A., Calderon, P., McCune, D., Grafendorfer, T., Ozturk-Isik, E., Larson, P. E., Hu, S., Yen, Y., Robb, F., Bok, R., Schulte, R., Xu, D., Hurd, R., Vigneron, D., Nelson, S. 2011; 208 (1): 171-177


    We report metabolic images of (13)C, following injection of a bolus of hyperpolarized [1-(13)C] pyruvate in a live rat. The data were acquired on a clinical scanner, using custom coils for volume transmission and array reception. Proton blocking of all carbon resonators enabled proton anatomic imaging with the system body coil, to allow for registration of anatomic and metabolic images, for which good correlation was achieved, with some anatomic features (kidney and heart) clearly visible in a carbon image, without reference to the corresponding proton image. Parallel imaging with sensitivity encoding was used to increase the spatial resolution in the SI direction of the rat. The signal to noise ratio in was in some instances unexpectedly high in the parallel images; variability of the polarization among different trials, plus partial volume effects, are noted as a possible cause of this.

    View details for DOI 10.1016/j.jmr.2010.10.007

    View details for Web of Science ID 000286774300022

    View details for PubMedID 21130012

    View details for PubMedCentralID PMC3387549

  • Cerebral dynamics and metabolism of hyperpolarized [1-C-13]pyruvate using time-resolved MR spectroscopic imaging JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Hurd, R. E., Yen, Y., Tropp, J., Pfefferbaum, A., Spielman, D. M., Mayer, D. 2010; 30 (10): 1734-1741


    Dynamic hyperpolarized [1-(13)C]pyruvate metabolic imaging in the normal anesthetized rat brain is demonstrated on a clinical 3-T magnetic resonance imaging scanner. A 12-second bolus injection of hyperpolarized [1-(13)C]pyruvate is imaged at a 3-second temporal resolution. The observed dynamics are evaluated with regard to cerebral blood volume (CBV), flow, transport, and metabolic exchange with the cerebral lactate pool. A model for brain [1-(13)C]lactate, based on blood-brain transport kinetics, CBV, and the observed pyruvate dynamics is described.

    View details for DOI 10.1038/jcbfm.2010.93

    View details for Web of Science ID 000282382200007

    View details for PubMedID 20588318

    View details for PubMedCentralID PMC2975615

  • In vivo application of sub-second spiral chemical shift imaging (CSI) to hyperpolarized C-13 metabolic imaging: Comparison with phase-encoded CSI JOURNAL OF MAGNETIC RESONANCE Mayer, D., Yen, Y., Levin, Y. S., Tropp, J., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2010; 204 (2): 340-345


    A fast spiral chemical shift imaging (CSI) has been developed to address the challenge of the limited acquisition window in hyperpolarized (13)C metabolic imaging. The sequence exploits the sparsity of the spectra and prior knowledge of resonance frequencies to reduce the measurement time by undersampling the data in the spectral domain. As a consequence, multiple reconstructions are necessary for any given data set as only frequency components within a selected bandwidth are reconstructed "in-focus" while components outside that band are severely blurred ("spectral tomosynthesis"). A variable-flip-angle scheme was used for optimal use of the longitudinal magnetization. The sequence was applied to sub-second metabolic imaging of the rat in vivo after injection of hyperpolarized [1-(13)C]-pyruvate on a clinical 3T MR scanner. The comparison with conventional CSI based on phase encoding showed similar signal-to-noise ratio (SNR) and spatial resolution in metabolic maps for the substrate and its metabolic products lactate, alanine, and bicarbonate, despite a 50-fold reduction in scan time for the spiral CSI acquisition. The presented results demonstrate that dramatic reductions in scan time are feasible in hyperpolarized (13)C metabolic imaging without a penalty in SNR or spatial resolution.

    View details for DOI 10.1016/j.jmr.2010.03.005

    View details for Web of Science ID 000278162300021

    View details for PubMedID 20346717

    View details for PubMedCentralID PMC2893149

  • Metabolic Imaging in the Anesthetized Rat Brain Using Hyperpolarized [1-C-13] Pyruvate and [1-C-13] Ethyl Pyruvate MAGNETIC RESONANCE IN MEDICINE Hurd, R. E., Yen, Y., Mayer, D., Chen, A., Wilson, D., Kohler, S., Bok, R., Vigneron, D., Kurhanewicz, J., Tropp, J., Spielman, D., Pfefferbaum, A. 2010; 63 (5): 1137-1143


    Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1-(13)C]-ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and (13)C spectroscopic imaging was used to compare the uptake of hyperpolarized [1-(13)C]-ethyl pyruvate relative to hyperpolarized [1-(13)C]-pyruvate into anesthetized rat brain. Hyperpolarized [1-(13)C]-ethyl pyruvate and [1-(13)C]-pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range-finding study.

    View details for DOI 10.1002/mrm.22364

    View details for Web of Science ID 000277098100001

    View details for PubMedID 20432284

    View details for PubMedCentralID PMC2890241

  • T-2 relaxation times of C-13 metabolites in a rat hepatocellular carcinoma model measured in vivo using C-13-MRS of hyperpolarized [1-C-13]pyruvate NMR IN BIOMEDICINE Yen, Y., Le Roux, P., Mayer, D., King, R., Spielman, D., Tropp, J., Pauly, K. B., Pfefferbaum, A., Vasanawala, S., Hurd, R. 2010; 23 (4): 414-423


    A single-voxel Carr-Purcell-Meibloom-Gill sequence was developed to measure localized T(2) relaxation times of (13)C-labeled metabolites in vivo for the first time. Following hyperpolarized [1-(13)C]pyruvate injections, pyruvate and its metabolic products, alanine and lactate, were observed in the liver of five rats with hepatocellular carcinoma and five healthy control rats. The T(2) relaxation times of alanine and lactate were both significantly longer in HCC tumors than in normal livers (p < 0.002). The HCC tumors also showed significantly higher alanine signal relative to the total (13)C signal than normal livers (p < 0.006). The intra- and inter-subject variations of the alanine T(2) relaxation time were 11% and 13%, respectively. The intra- and inter-subject variations of the lactate T(2) relaxation time were 6% and 7%, respectively. The intra-subject variability of alanine to total carbon ratio was 16% and the inter-subject variability 28%. The intra-subject variability of lactate to total carbon ratio was 14% and the inter-subject variability 20%. The study results show that the signal level and relaxivity of [1-(13)C]alanine may be promising biomarkers for HCC tumors. Its diagnostic values in HCC staging and treatment monitoring are yet to be explored.

    View details for DOI 10.1002/nbm.1481

    View details for Web of Science ID 000277525800011

    View details for PubMedID 20175135

    View details for PubMedCentralID PMC2891253

  • Kinetic modeling of hyperpolarized C-13(1)-pyruvate metabolism in normal rats and TRAMP mice JOURNAL OF MAGNETIC RESONANCE Zierhut, M. L., Yen, Y., Chen, A. P., Bok, R., Albers, M. J., Zhang, V., Tropp, J., Park, I., Vigneron, D. B., Kurhanewicz, J., Hurd, R. E., Nelson, S. J. 2010; 202 (1): 85-92


    To investigate metabolic exchange between (13)C(1)-pyruvate, (13)C(1)-lactate, and (13)C(1)-alanine in pre-clinical model systems using kinetic modeling of dynamic hyperpolarized (13)C spectroscopic data and to examine the relationship between fitted parameters and dose-response.Dynamic (13)C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice.The kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis-Menten kinetics were able to describe the dose-response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for k(pyr-->lac) and k(pyr-->ala), respectively. In TRAMP mice, k(pyr-->lac) increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic (13)C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice.The metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

    View details for DOI 10.1016/j.jmr.2009.10.003

    View details for Web of Science ID 000273526800012

    View details for PubMedID 19884027

  • In Vivo Carbon-13 Dynamic MRS and MRSI of Normal and Fasted Rat Liver with Hyperpolarized C-13-Pyruvate MOLECULAR IMAGING AND BIOLOGY Hu, S., Chen, A. P., Zierhut, M. L., Bok, R., Yen, Y., Schroeder, M. A., Hurd, R. E., Nelson, S. J., Kurhanewicz, J., Vigneron, D. B. 2009; 11 (6): 399-407


    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.[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).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.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.

    View details for DOI 10.1007/s11307-009-0218-z

    View details for Web of Science ID 000270882900003

    View details for PubMedID 19424761

  • Design of spectral-spatial outer volume suppression RF pulses for tissue specific metabolic characterization with hyperpolarized C-13 pyruvate JOURNAL OF MAGNETIC RESONANCE Chen, A. P., Leung, K., Lam, W., Hurd, R. E., Vigneron, D. B., Cunningham, C. H. 2009; 200 (2): 344-348


    [1-(13)C] pyruvate pre-polarized via DNP has been used in animal models to probe changes in metabolic enzyme activities in vivo. To more accurately assess the metabolic state and its change from disease progression or therapy in a specific region or tissue in vivo, it may be desirable to separate the downstream (13)C metabolite signals resulting from the metabolic activity within the tissue of interest and those brought into the tissue by perfusion. In this study, a spectral-spatial saturation pulse that selectively saturates the signal from the metabolic products [1-(13)C] lactate and [1-(13)C] alanine was designed and implemented as outer volume suppression for localized MRSI acquisition. Preliminary in vivo results showed that the suppression pulse did not prevent the pre-polarized pyruvate from being delivered throughout the animal while it saturated the metabolites within the targeted saturation region.

    View details for DOI 10.1016/j.jmr.2009.06.021

    View details for Web of Science ID 000272260900024

    View details for PubMedID 19616981

  • Application of Subsecond Spiral Chemical Shift Imaging to Real-Time Multislice Metabolic Imaging of the Rat In Vivo after Injection of Hyperpolarized C-13(1)-Pyruvate MAGNETIC RESONANCE IN MEDICINE Mayer, D., Yen, Y., Tropp, J., Pfefferbaum, A., Hurd, R. E., Spielman, D. M. 2009; 62 (3): 557-564


    Dynamic nuclear polarization can create hyperpolarized compounds with MR signal-to-noise ratio enhancements on the order of 10,000-fold. Both exogenous and normally occurring endogenous compounds can be polarized, and their initial concentration and downstream metabolic products can be assessed using MR spectroscopy. Given the transient nature of the hyperpolarized signal enhancement, fast imaging techniques are a critical requirement for real-time metabolic imaging. We report on the development of an ultrafast, multislice, spiral chemical shift imaging sequence, with subsecond acquisition time, achieved on a clinical MR scanner. The technique was used for dynamic metabolic imaging in rats, with measurement of time-resolved spatial distributions of hyperpolarized (13)C(1)-pyruvate and metabolic products (13)C(1)-lactate and (13)C(1)-alanine, with a temporal resolution of as fast as 1 s. Metabolic imaging revealed different signal time courses in liver from kidney. These results demonstrate the feasibility of real-time, hyperpolarized metabolic imaging and highlight its potential in assessing organ-specific kinetic parameters.

    View details for DOI 10.1002/mrm.22041

    View details for Web of Science ID 000269404900001

    View details for PubMedID 19585607

    View details for PubMedCentralID PMC2782691

  • In Vivo Measurement of Ethanol Metabolism in the Rat Liver Using Magnetic Resonance Spectroscopy of Hyperpolarized [1-C-13]Pyruvate MAGNETIC RESONANCE IN MEDICINE Spielman, D. M., Mayer, D., Yen, Y., Tropp, J., Hurd, R. E., Pfefferbaum, A. 2009; 62 (2): 307-313


    [1-(13)C]pyruvate is a readily polarizable substrate that has been the subject of numerous magnetic resonance spectroscopy (MRS) studies of in vivo metabolism. In this work (13)C-MRS of hyperpolarized [1-(13)C]pyruvate was used to interrogate a metabolic pathway involved in neither aerobic nor anaerobic metabolism. In particular, ethanol consumption leads to altered liver metabolism, which when excessive is associated with adverse medical conditions including fatty liver disease, hepatitis, cirrhosis, and cancer. Here we present a method for noninvasively monitoring this important process in vivo. Following the bolus injection of hyperpolarized [1-(13)C]pyruvate, we demonstrate a significantly increased rat liver lactate production rate with the coadministration of ethanol (P = 0.0016 unpaired t-test). The affect is attributable to increased liver nicotinamide adenine dinucleotide (NADH) associated with ethanol metabolism in combination with NADH's role as a coenzyme in pyruvate-to-lactate conversion. Beyond studies of liver metabolism, this novel in vivo assay of changes in NADH levels makes hyperpolarized [1-(13)C]pyruvate a potentially viable substrate for studying the multiple in vivo metabolic pathways that use NADH (or NAD(+)) as a coenzyme, thus broadening the range of applications that have been discussed in the literature to date.

    View details for DOI 10.1002/mrm.21998

    View details for Web of Science ID 000268432400005

    View details for PubMedID 19526498

    View details for PubMedCentralID PMC2780439

  • Imaging Considerations for In Vivo C-13 Metabolic Mapping Using Hyperpolarized C-13-Pyruvate MAGNETIC RESONANCE IN MEDICINE Yen, Y., Kohler, S. J., CHEN, A. P., Tropp, J., Bok, R., Wolber, J., Albers, M. J., Gram, K. A., Zierhut, M. L., Park, I., Zhang, V., Hu, S., Nelson, S. J., Vigneron, D. B., Kurhanewicz, J., Dirven, H. A., Hurd, R. E. 2009; 62 (1): 1-10


    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.

    View details for DOI 10.1002/mrm.21987

    View details for Web of Science ID 000267404300001

    View details for PubMedID 19319902

  • Generation of hyperpolarized substrates by secondary labeling with [1,1-C-13] acetic anhydride PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wilson, D. M., Hurd, R. E., Keshari, K., Van Criekinge, M., Chen, A. P., Nelson, S. J., Vigneron, D. B., Kurhanewicz, J. 2009; 106 (14): 5503-5507


    In this manuscript, the remarkable NMR signal enhancement that can be provided by dynamic nuclear polarization (DNP) was combined with the reactivity of acetic anhydride with amines to perform rapid, high SNR analyses of amino acid mixtures and to hyperpolarize new biomolecules of interest. [1,1-(13)C] acetic anhydride is an excellent substrate for DNP hyperpolarization because it can be well polarized in only 30 min and has a relatively long T(1) relaxation time (33.9 s at 11.7 T and 37 degrees C). The secondary hyperpolarization approach developed in this project takes advantage of the preferential reaction of acetic anhydride with amine nucleophiles, which occurs much more rapidly than hydrolysis to produce hyperpolarized N-acetyl adducts. This new approach was used to reproducibly and near-quantitatively (mean yield - 89.8%) resolve a mixture of amino acids Gly, Ser, Val, Leu, and Ala in a single acquisition (3 s) with a signal enhancement of up to 1,400-fold as compared with thermal equilibrium. Secondary hyperpolarization was performed for several small peptides and N-acetylcysteine, a drug administered intravenously to treat acetaminophen overdose. Although, in general the T(1) of the N-acetyl adducts decreased with increasing molecular weight of the biomolecules, the T(1) values were still on the order of 10 s, and the correlation of T(1) with molecular weight was not exact suggesting the potential of secondarily polarizing relatively large biomolecules. This study demonstrates the feasibility of using prepolarized [1,1-(13)C] acetic anhydride and rapid chemical reactions to provide high SNR NMR spectra of amino acid derivatives and other biomolecules.

    View details for DOI 10.1073/pnas.0810190106

    View details for Web of Science ID 000264967500011

    View details for PubMedID 19276112

  • In vivo hyperpolarized C-13 MR spectroscopic imaging with H-1 decoupling JOURNAL OF MAGNETIC RESONANCE Chen, A. P., Tropp, J., Hurd, R. E., Van Criekinge, M., Carvajal, L. G., Xu, D., Kurhanewicz, J., Vigneron, D. B. 2009; 197 (1): 100-106


    Application of (13)C MRS in vivo on whole body MR system has been limited due to the low static field (and consequent low signal to noise ratio-SNR) of these scanners; thus there have been few reports of (1)H decoupled (13)C MRS in vivo using a clinical MR platform. The recent development of techniques to retain highly polarized spins in solution following DNP in a solid matrix has provided a mechanism to use endogenous pre-polarized (13)C labeled substrates to study real time cellular metabolism in vivo with high SNR. In a recent in vivo hyperpolarized metabolic imaging study using (13)C pyruvate, it has been demonstrated that the line shape (signal decay) of the resonances observed are greatly affected by J(CH) coupling in addition to inhomogeneous broadening. This study demonstrates the feasibility of improving hyperpolarized (13)C metabolic imaging in vivo by incorporating (1)H decoupling on a clinical whole body 3T MR scanner. No reduction of T1 of a pre-polarized (13)C substrate ([1-(13)C] lactate) in solution was observed when (1)H decoupling was applied with WALTZ16 sequence. Narrower linewidth for the [1-(13)C] lactate resonance was observed in hyperpolarized (13)C MRSI data in vivo with (1)H decoupling.

    View details for DOI 10.1016/j.jmr.2008.12.004

    View details for Web of Science ID 000263987500016

    View details for PubMedID 19112035

  • Blood flow and metabolic regulation in seal muscle during apnea JOURNAL OF EXPERIMENTAL BIOLOGY Ponganis, P. J., Kreutzer, U., Stockard, T. K., Lin, P., Sailasuta, N., Tran, T., Hurd, R., Jue, T. 2008; 211 (20): 3323-3332


    In order to examine myoglobin (Mb) function and metabolic responses of seal muscle during progressive ischemia and hypoxemia, Mb saturation and high-energy phosphate levels were monitored with NMR spectroscopy during sleep apnea in elephant seals (Mirounga angustirostris). Muscle blood flow (MBF) was measured with laser-Doppler flowmetry (LDF). During six, spontaneous, 8-12 min apneas of an unrestrained juvenile seal, apneic MBF decreased to 46+/-10% of the mean eupneic MBF. By the end of apnea, MBF reached 31+/-8% of the eupneic value. The t(1/2) for 90% decline in apneic MBF was 1.9+/-1.2 min. The initial post-apneic peak in MBF occurred within 0.20+/-0.04 min after the start of eupnea. NMR measurements revealed that Mb desaturated rapidly from its eupenic resting level to a lower steady state value within 4 min after the onset of apnea at rates between 1.7+/-1.0 and 3.8+/-1.5% min(-1), which corresponded to a muscle O(2) depletion rate of 1-2.3 ml O(2) kg(-1) min(-1). High-energy phosphate levels did not change with apnea. During the transition from apnea to eupnea, Mb resaturated to 95% of its resting level within the first minute. Despite the high Mb concentration in seal muscle, experiments detected Mb diffusing with a translational diffusion coefficient of 4.5 x 10(-7) cm(2) s(-1), consistent with the value observed in rat myocardium. Equipoise P(O(2)) analysis revealed that Mb is the predominant intracellular O(2) transporter in elephant seals during eupnea and apnea.

    View details for DOI 10.1242/jeb.018887

    View details for Web of Science ID 000259866400017

    View details for PubMedID 18840667

  • Hyperpolarized C-13 Lactate, Pyruvate, and Alanine: Noninvasive Biomarkers for Prostate Cancer Detection and Grading CANCER RESEARCH Albers, M. J., Bok, R., Chen, A. P., Cunningham, C. H., Zierhut, M. L., Zhang, V. Y., Kohler, S. J., Tropp, J., Hurd, R. E., Yen, Y., Nelson, S. J., Vigneron, D. B., Kurhanewicz, J. 2008; 68 (20): 8607-8615


    An extraordinary new technique using hyperpolarized (13)C-labeled pyruvate and taking advantage of increased glycolysis in cancer has the potential to improve the way magnetic resonance imaging is used for detection and characterization of prostate cancer. The aim of this study was to quantify, for the first time, differences in hyperpolarized [1-(13)C] pyruvate and its metabolic products between the various histologic grades of prostate cancer using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Fast spectroscopic imaging techniques were used to image lactate, alanine, and total hyperpolarized carbon (THC = lactate + pyruvate + alanine) from the entire abdomen of normal mice and TRAMP mice with low- and high-grade prostate tumors in 14 s. Within 1 week, the mice were dissected and the tumors were histologically analyzed. Hyperpolarized lactate SNR levels significantly increased (P < 0.05) with cancer development and progression (41 +/- 11, 74 +/- 17, and 154 +/- 24 in normal prostates, low-grade primary tumors, and high-grade primary tumors, respectively) and had a correlation coefficient of 0.95 with the histologic grade. In addition, there was minimal overlap in the lactate levels between the three groups with only one of the seven normal prostates overlapping with the low-grade primary tumors. The amount of THC, a possible measure of substrate uptake, and hyperpolarized alanine also increased with tumor grade but showed more overlap between the groups. In summary, elevated hyperpolarized lactate and potentially THC and alanine are noninvasive biomarkers of prostate cancer presence and histologic grade that could be used in future three-dimensional (13)C spectroscopic imaging studies of prostate cancer patients.

    View details for DOI 10.1158/0008-5472.CAN-08-0749

    View details for Web of Science ID 000260323400049

    View details for PubMedID 18922937

  • DNP-hyperpolarized C-13 magnetic resonance metabolic imaging for cancer applications APPLIED MAGNETIC RESONANCE Nelson, S. J., Vigneron, D., Kurhanewicz, J., Chen, A., Bok, R., Hurd, R. 2008; 34 (3-4): 533-544


    Critical factors in characterizing the aggressiveness and response to therapy for tumors are the availability of noninvasive biomarkers that can be combined with other clinical parameters to tailor treatment regimens to each individual patient. While conventional magnetic resonance (MR) images are widely used to estimate changes in tumor size, they do not provide the rapid readout that is required to make an early decision on whether a change in therapy is required. The use of hyperpolarized (13)C agents to obtain metabolic imaging data is of great interest for in vivo assessment of tumors. One of the first agents being considered for in vivo studies with dynamic nuclear polarization (DNP) is 1-(13)C-labeled pyruvate, which is converted to lactate or alanine, dependent upon the needs of the tissue in question. The development of this new technology and its implementation in preclinical cancer model systems has clearly demonstrated the potential for highlighting tumor aggressiveness and for monitoring changes associated with disease progression. While there is further work to do in terms of studying new agents, improving the DNP process itself and developing efficient MR methods for acquiring and analyzing the data, the preliminary results are extremely promising and provide strong motivation for considering cancer as one of the first applications of the technology.

    View details for DOI 10.1007/s00723-008-0136-2

    View details for Web of Science ID 000259125200027

    View details for PubMedID 20198109

  • Pulse sequence for dynamic volumetric imaging of hyperpolarized metabolic products JOURNAL OF MAGNETIC RESONANCE Cunningham, C. H., Chen, A. P., Lustig, M., Hargreaves, B. A., Lupo, J., Xu, D., Kurhanewicz, J., Hurd, R. E., Pauly, J. M., Nelson, S. J., Vigneron, D. B. 2008; 193 (1): 139-146


    Dynamic nuclear polarization and dissolution of a (13)C-labeled substrate enables the dynamic imaging of cellular metabolism. Spectroscopic information is typically acquired, making the acquisition of dynamic volumetric data a challenge. To enable rapid volumetric imaging, a spectral-spatial excitation pulse was designed to excite a single line of the carbon spectrum. With only a single resonance present in the signal, an echo-planar readout trajectory could be used to resolve spatial information, giving full volume coverage of 32 x 32 x 16 voxels every 3.5s. This high frame rate was used to measure the different lactate dynamics in different tissues in a normal rat model and a mouse model of prostate cancer.

    View details for DOI 10.1016/j.jmr.2008.03.012

    View details for Web of Science ID 000256891700019

    View details for PubMedID 18424203

    View details for PubMedCentralID PMC3051833

  • Feasibility of using hyperpolarized [1-C-13]lactate as a substrate for in vivo metabolic C-13 MRSI studies MAGNETIC RESONANCE IMAGING Chen, A. P., Kurhanewicz, J., Bok, R., Xua, D., Joun, D., Zhang, V., Nelson, S. J., Hurd, R. E., Vigneron, D. B. 2008; 26 (6): 721-726


    The development of dynamic nuclear polarization in solution has enabled in vivo 13C MR studies at high signal-to-noise ratio following injection of prepolarized 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 prepolarized 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. The use of 13C lactate as a substrate provided the opportunity 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 preclinical animal models.

    View details for DOI 10.1016/j.mri.2008.01.002

    View details for Web of Science ID 000257777200001

    View details for PubMedID 18479878

  • Compressed sensing for resolution enhancement of hyperpolarized C-13 flyback 3D-MRSI JOURNAL OF MAGNETIC RESONANCE Hu, S., Lustig, M., Chen, A. P., Crane, J., Kerr, A., Kelley, D. A., Hurd, R., Kurhanewicz, J., Nelson, S. J., Pauly, J. M., Vigneron, D. B. 2008; 192 (2): 258-264


    High polarization of nuclear spins in liquid state through dynamic nuclear polarization has enabled the direct monitoring of 13C metabolites in vivo at very high signal-to-noise, allowing for rapid assessment of tissue metabolism. The abundant SNR afforded by this hyperpolarization technique makes high-resolution 13C 3D-MRSI feasible. However, the number of phase encodes that can be fit into the short acquisition time for hyperpolarized imaging limits spatial coverage and resolution. To take advantage of the high SNR available from hyperpolarization, we have applied compressed sensing to achieve a factor of 2 enhancement in spatial resolution without increasing acquisition time or decreasing coverage. In this paper, the design and testing of compressed sensing suited for a flyback 13C 3D-MRSI sequence are presented. The key to this design was the undersampling of spectral k-space using a novel blipped scheme, thus taking advantage of the considerable sparsity in typical hyperpolarized 13C spectra. Phantom tests validated the accuracy of the compressed sensing approach and initial mouse experiments demonstrated in vivo feasibility.

    View details for DOI 10.1016/j.jmr.2008.03.003

    View details for Web of Science ID 000256538300011

    View details for PubMedID 18367420

    View details for PubMedCentralID PMC2475338

  • Hyperpolarized c-13 spectroscopic imaging of the TRAMP mouse at 3T - Initial experience MAGNETIC RESONANCE IN MEDICINE Chen, A. P., Albers, M. J., Cunningham, C. H., Kohler, S. J., Yen, Y., Hurd, R. E., Tropp, J., Bok, R., Pauly, J. M., Nelson, S. J., Kurhanewicz, J., Vigneron, D. B. 2007; 58 (6): 1099-1106


    The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse is a well-studied murine model of prostate cancer with histopathology and disease progression that mimic the human disease. To investigate differences in cellular bioenergetics between normal prostate epithelial cells and prostate tumor cells, in vivo MR spectroscopic (MRS) studies with non-proton nuclei, such as (13)C, in the TRAMP model would be extremely useful. The recent development of a method for retaining dynamic nuclear polarization (DNP) in solution permits high signal-to-noise ratio (SNR) (13)C MRI or MRSI data to be obtained following injection of a hyperpolarized (13)C agent. In this transgenic mouse study, this method was applied using a double spin-echo (DSE) pulse sequence with a small-tip-angle excitation RF pulse, hyperbolic-secant refocusing pulses, and a flyback echo-planar readout trajectory for fast (10-14 s) MRSI of (13)C pyruvate (pyr) and its metabolic products at 0.135 cm(3) nominal spatial resolution. Elevated (13)C lactate (lac) was observed in both primary and metastatic tumors, demonstrating the feasibility of studying cellular bioenergetics in vivo with DNP hyperpolarized (13)C MRSI.

    View details for DOI 10.1002/mrm.21256

    View details for Web of Science ID 000251346800004

    View details for PubMedID 17969006

  • Double spin-echo sequence for rapid spectroscopic imaging of hyperpolarized C-13 JOURNAL OF MAGNETIC RESONANCE Cunningham, C. H., Chen, A. P., Albers, M. J., Kurhanewicz, J., Hurd, R. E., Yen, Y., Pauly, J. M., Nelson, S. J., Vigneron, D. B. 2007; 187 (2): 357-362


    Dynamic nuclear polarization of metabolically active compounds labeled with (13)C has been introduced as a means for imaging metabolic processes in vivo. To differentiate between the injected compound and the various metabolic products, an imaging technique capable of separating the different chemical-shift species must be used. In this paper, the design and testing of a pulse sequence for rapid magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized (13)C is presented. The pulse sequence consists of a small-tip excitation followed by a double spin echo using adiabatic refocusing pulses and a "flyback" echo-planar readout gradient. Key elements of the sequence are insensitivity to calibration of the transmit gain, the formation of a spin echo giving high-quality spectral information, and a small effective tip angle that preserves the magnetization for a sufficient duration. Experiments in vivo showed three-dimensional coverage with excellent spectral quality and SNR.

    View details for DOI 10.1016/j.jmr.2007.05.014

    View details for Web of Science ID 000248462800022

    View details for PubMedID 17562376

  • Optimization of fast spiral chemical shift imaging using least squares reconstruction: Application for hyperpolarized C-13 metabolic imaging MAGNETIC RESONANCE IN MEDICINE Levin, Y. S., Mayer, D., Yen, Y., Hurd, R. E., Spielman, D. M. 2007; 58 (2): 245-252


    A least-squares-based optimization and reconstruction algorithm has been developed for rapid metabolic imaging in the context of hyperpolarized (13)C. The algorithm uses a priori knowledge of resonance frequencies, J-coupling constants, and T(2)* values to enable acquisition of high-quality metabolic images with imaging times of approximately 100 ms for an 8-cm field of view (FOV) and 0.5 cm isotropic resolution. A root-mean-square error (rMSE) analysis is introduced to optimize metabolic image quality by appropriate choice of pulse sequence parameters, echo times, and signal model. By performing the reconstruction in k-space, the algorithm also allows the inclusion of the effect of chemical shift evolution during the readout period. Single-interleaf multiecho spiral chemical shift imaging (spCSI) is analyzed in detail as an illustrative example for the use of the new reconstruction and optimization algorithm. Simulation of the in vivo spectrum following the bolus injection of hyperpolarized (13)C(1) pyruvate shows that single-interleaf spiral spectroscopic imaging can achieve image quality in 100 ms, comparable to the performance of a 13-s phase-encoded chemical shift imaging (FIDCSI) experiment. Single-interleaf spCSI was also tested at a 3-T MR scanner using a phantom containing approximately 0.5-M solutions of alanine, lactate, and a pyruvate-pyruvate hydrate C(1)-C(2) ester at thermal equilibrium polarization, all enriched to 99% (13)C in the C(1) carbonyl positions. Upon reconstruction using the k-space-based least-squares technique, metabolite ratios obtained using the spCSI method were comparable to those obtained using a reference FIDCSI acquisition.

    View details for DOI 10.1002/mrm.21327

    View details for Web of Science ID 000248488300006

    View details for PubMedID 17654596

  • In vivo (13)carbon metabolic imaging at 3T with hyperpolarized C-13-1-pyruvate MAGNETIC RESONANCE IN MEDICINE Kohler, S. J., Yen, Y., Wolber, J., CHEN, A. P., Albers, M. J., Bok, R., Zhang, V., Tropp, J., Nelson, S., Vigneron, D. B., Kurhanewicz, J., Hurd, R. E. 2007; 58 (1): 65-69


    We present for the first time dynamic spectra and spectroscopic images acquired in normal rats at 3T following the injection of (13)C-1-pyruvate that was hyperpolarized by the dynamic nuclear polarization (DNP) method. Spectroscopic sampling was optimized for signal-to-noise ratio (SNR) and for spectral resolution of (13)C-1-pyruvate and its metabolic products (13)C-1-alanine, (13)C-1-lactate, and (13)C-bicarbonate. Dynamic spectra in rats were collected with a temporal resolution of 3 s from a 90-mm axial slab using a dual (1)H-(13)C quadrature birdcage coil to observe the combined effects of metabolism, flow, and T(1) relaxation. In separate experiments, spectroscopic imaging data were obtained during a 17-s acquisition of a 20-mm axial slice centered on the rat kidney region to provide information on the spatial distribution of the metabolites. Conversion of pyruvate to lactate, alanine, and bicarbonate occurred within a minute of injection. Alanine was observed primarily in skeletal muscle and liver, while pyruvate, lactate, and bicarbonate concentrations were relatively high in the vasculature and kidneys. In contrast to earlier work at 1.5 T, bicarbonate was routinely observed in skeletal muscle as well as the kidney and vasculature.

    View details for DOI 10.1002/mrm.21253

    View details for Web of Science ID 000248488400008

    View details for PubMedID 17659629

  • High-speed 3T MR spectroscopic imaging of prostate with flyback echo-planar encoding JOURNAL OF MAGNETIC RESONANCE IMAGING Chen, A. P., Cunningham, C. H., Ozturk-Isik, E., Xu, D., Hurd, R. E., Kelley, D. A., Pauly, J. M., Kurhanewicz, J., Nelson, S. J., Vigneron, D. B. 2007; 25 (6): 1288-1292


    Prostate MR spectroscopic imaging (MRSI) at 3T may provide two-fold higher spatial resolution over 1.5T, but this can result in longer acquisition times to cover the entire gland using conventional phase-encoding. In this study, flyback echo-planar readout trajectories were incorporated into a Malcolm Levitt's composite-pulse decoupling sequence (MLEV)-point-resolved spectroscopy sequence (PRESS) to accelerate the acquisition of large array (16 x 16 x 8), high spatial (0.154 cm(3)) resolution MRSI data by eight-fold to just 8.5 minutes. Artifact free, high-quality MRSI data was obtained in nine prostate cancer patients. Easy data reconstruction and the robustness of the flyback echo-planar encoding make this technique particularly suitable for the clinical setting. The short acquisition time provided by this method reduces the 3T prostate MRI/MRSI exam time, allows longer repetition times, and/or allows the acquisition of additional MR acquisitions within the same exam.

    View details for DOI 10.1002/jmri.20916

    View details for Web of Science ID 000246824100025

    View details for PubMedID 17520729

  • Fast metabolic imaging of systems with sparse spectra: Application for hyperpolarized C-13 imaging MAGNETIC RESONANCE IN MEDICINE Mayer, D., Levin, Y. S., Hurd, R. E., Glover, G. H., Spielman, D. M. 2006; 56 (4): 932-937


    A fast spiral chemical shift imaging (spCSI) sequence was developed for application to hyperpolarized (13)C imaging. The sequence exploits sparse spectra, which can occur in such applications, and prior knowledge of resonance frequencies to reduce the measurement time by undersampling the data in the spectral domain. As a consequence, multiple reconstructions of a given data set have to be computed in which only components with frequencies within a certain bandwidth are reconstructed "in focus" while others are severely blurred ("spectral tomosynthesis"). The sequence was tested at 3 T on a phantom containing approximately 1.5-M solutions of alanine (Ala), lactate (Lac), and pyruvate-pyruvate hydrate C1-C2 ester (with two resonances, PPE1 and PPE2) at thermal equilibrium polarization, all enriched to 99% (13)C in the C1 carbonyl positions. Results from spCSI with a single spatial interleaf (single-shot spCSI) and three interleaves (three-shot spCSI) were compared with those obtained by phase-encoded free induction decay CSI (FIDCSI). The metabolic maps of all four resonances for three-shot spCSI, and of PPE1 and PPE2 for single-shot spCSI demonstrate resolution and localization properties similar to those of the FIDCSI images. The metabolic maps of Ala and Lac for single-shot spCSI contain minor artifacts due to signal overlap of aliased resonances.

    View details for DOI 10.1002/mrm.21025

    View details for Web of Science ID 000240897000028

    View details for PubMedID 16941617

  • High-resolution 3D MR spectroscopic imaging of the prostate at 3 T with the MLEV-PRESS sequence MAGNETIC RESONANCE IMAGING Chen, A. P., Cunningham, C. H., Kurhanewicz, J., Xu, D., Hurd, R. E., Pauly, J. M., Carvajal, L., Karpodinis, K., Vigneron, D. B. 2006; 24 (7): 825-832


    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 cm3 at 3 T with similar SNR as the 0.34-cm3 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.

    View details for DOI 10.1016/j.mri.2006.03.002

    View details for Web of Science ID 000240442800001

    View details for PubMedID 16916699

  • TE-averaged two-dimensional proton spectroscopic imaging of glutamate at 3 T NEUROIMAGE Srinivasan, R., Cunningham, C., Chen, A., Vigneron, D., Hurd, R., Nelson, S., Pelletier, D. 2006; 30 (4): 1171-1178


    Glutamate and glutamine are important neurochemicals in the central nervous system and the neurotoxic properties of excess glutamate have been associated with several neurodegenerative diseases. The TE-Averaged PRESS technique has been shown by our group to detect an unobstructed glutamate signal at 3 T that is resolved from glutamine and NAA at 2.35 ppm. TE-Averaged PRESS therefore provides an unambiguous measurement of glutamate as well as other metabolites such as NAA, choline, creatine, and myo-inositol. In this study, we extend the single voxel TE-Averaged PRESS technique for two-dimensional (2D) spectroscopic imaging (TE-Averaged MRSI) to generate 2D glutamate maps. To facilitate TE-Averaged MRSI within a reasonable time, a fast encoding trajectory was used. This enabled rapid acquisition of TE-Averaged spectral arrays with good spectral bandwidth (977 Hz) and resolution (approximately 2 Hz). MRSI data arrays of 10 x 16 were acquired with 1.8 cm3 spatial resolution over a approximately 110 cm3 volume in a scan time of approximately 21 min. Two-dimensional metabolite maps were obtained with good SNR and clear differentiation in glutamate levels was observed between gray and white matter with significantly higher glutamate in gray matter relative to white matter as anticipated.

    View details for DOI 10.1016/j.neuroimage.2005.10.048

    View details for Web of Science ID 000237601500010

    View details for PubMedID 16431138

  • Design of flyback echo-planar readout gradients for magnetic resonance spectroscopic imaging MAGNETIC RESONANCE IN MEDICINE Cunningham, C. H., Vigneron, D. B., CHEN, A. P., Xu, D., Nelson, S. J., Hurd, R. E., Kelley, D. A., Pauly, J. M. 2005; 54 (5): 1286-1289


    The spatial resolution of conventional magnetic resonance spectroscopic imaging-(MRSI) is typically coarse, mainly due to SNR limitations. The increased signal available with higher field scanners and new array coils now permits higher spatial resolution, but conventional chemical shift imaging (phase encoding) limits the spatial coverage possible in a patient-acceptable acquisition time. The "flyback" echo-planar trajectory is particularly insensitive to errors and provides data that are simple to process. In this study, high-efficiency gradient waveforms for flyback echo-planar MRSI were designed and implemented. Normal volunteer studies at 3 T showed the feasibility of acquiring high spatial resolution with large coverage in a short scan time (2048 voxels in 2.3 min and 4096 voxels in 8.5 min). The trajectories were insensitive to errors in timing and require only a modest (10 to 30%) penalty in SNR relative to conventional phase encoding using the same acquisition time.

    View details for DOI 10.1002/mrm.20663

    View details for Web of Science ID 000233099700030

    View details for PubMedID 16187273

  • Sequence design for magnetic resonance spectroscopic imaging of prostate cancer at 3T MAGNETIC RESONANCE IN MEDICINE Cunningham, C. H., Vigneron, D. B., Marjanska, M., CHEN, A. P., Xu, D., Hurd, R. E., Kurhanewicz, J., Garwood, M., Pauly, J. M. 2005; 53 (5): 1033-1039


    Magnetic resonance spectroscopic imaging (MRSI) has proven to be a powerful tool for the metabolic characterization of prostate cancer in patients before and following therapy. The metabolites that are of particular interest are citrate and choline because an increased choline-to-citrate ratio can be used as a marker for cancer. High-field systems offer the advantage of improved spectral resolution as well as increased magnetization. Initial attempts at extending MRSI methods to 3 T have been confounded by the J-modulation of the citrate resonances. A new pulse sequence is presented that controls the J-modulation of citrate at 3 T such that citrate is upright, with high amplitude, at a practical echo time. The design of short (14 ms) spectral-spatial refocusing pulses and trains of nonselective refocusing pulses are described. Phantom studies and simulations showed that upright citrate with negligible sidebands is observed at an echo time of 85 ms. Studies in a human subject verified that this behavior is reproduced in vivo and demonstrated that the water and lipid suppression of the new pulse sequence are sufficient for application in prostate cancer patients.

    View details for DOI 10.1002/mrm.20478

    View details for Web of Science ID 000228796900007

    View details for PubMedID 15844147

  • Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T BRAIN Srinivasan, R., Sailasuta, N., Hurd, R., Nelson, S., Pelletier, D. 2005; 128: 1016-1025


    Histopathological reports of multiple sclerosis and its animal models have shown evidence of a link between axonal injury in active lesions and impaired glutamate metabolism. Mature oligodendrocytes play a role in glutamate uptake to maintain glutamate homeostasis but in multiple sclerosis white matter the loss of expression of glutamate transporters in the lesion vicinity results in ineffective glutamate removal. Using a magnetic resonance spectroscopy technique that isolates the glutamate resonance at 3 T, we compared glutamate levels between normal subjects and multiple sclerosis patients in different brain areas. Metabolite concentrations (glutamate, glutamine, N-acetyl-aspartate, myo-inositol, choline, creatine) were derived from LCmodel and corrected for T1 relaxation time. Glutamate concentrations were found to be elevated in acute lesions (P = 0.02) and normal-appearing white matter (P = 0.03), with no significant elevation in chronic lesions (P = 0.77). The N-acetyl-aspartate level in chronic lesions was significantly lower (P < 0.001) than in acute lesions and normal-appearing white matter. The choline level in acute lesions was significantly higher (P < 0.001) than in chronic lesions. Evidence was also found for increased glial activity in multiple sclerosis, with significantly higher (P < 0.001) myo-inositol levels in acute lesions compared with control white matter. These in vivo results support the hypothesis that altered glutamate metabolism is present in brains of multiple sclerosis patients.

    View details for DOI 10.1093/brain/awh467

    View details for Web of Science ID 000228635300012

    View details for PubMedID 15758036

  • H-1 MR spectroscopy using TE averaged PRESS: A more sensitive technique to detect neuro degeneration associated with Alzheimer's disease MAGNETIC RESONANCE IN MEDICINE Hancu, I., Zimmerman, E. A., Sailasuta, N., Hurd, R. E. 2005; 53 (4): 777-782


    A sensitive proton magnetic resonance spectroscopy ((1)H MRS) acquisition scheme that is capable of discriminating between normal controls and a group of patients with early Alzheimer's disease (AD) is presented. The performance of this newly developed method, TE averaged PRESS (PRESS-J), in detecting neurodegeneration associated with early AD is compared with that of short echo time (TE) PRESS. A stepwise discriminant function analysis is used to construct discriminant functions for both pulse sequences. These functions are each composed of a single predictor: the N-acetyl aspartate (NAA)/creatine (Cr) ratio for PRESS-J, and the NAA/myoInositol (mI) ratio for PRESS. We observed lower P-values, higher areas under the receiver operating characteristic curves, and higher sensitivity at a given specificity for the PRESS-J discriminating function in comparison with the PRESS discriminating function. The higher sensitivity of PRESS-J is due to decreased variability when the singlets are fit in the spectra. This increased sensitivity enables new MR applications and, among other benefits, allows for smaller group sizes in drug trials, which can significantly reduce the cost of such trials.

    View details for DOI 10.1002/mrm.20419

    View details for Web of Science ID 000228068100005

    View details for PubMedID 15799041

  • Control of respiration and bioenergetics during muscle contraction AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY Chung, Y. R., Mole, P. A., Sailasuta, N., Tran, T. K., Hurd, R., Jue, T. 2005; 288 (3): C730-C738


    (1)H-NMR experiments have determined intracellular O(2) consumption (Vo(2)) with oxymyoglobin (MbO(2)) desaturation kinetics in human calf muscle during plantar flexion exercise at 0.75, 0.92, and 1.17 Hz with a constant load. At the onset of muscle contraction, myoglobin (Mb) desaturates rapidly. The desaturation rate constant of approximately 30 s reflects the intracellular Vo(2). Although Mb desaturates quickly with a similar time constant at all workload levels, its final steady-state level differs. As work increases, the final steady-state cellular Po(2) decreases progressively. After Mb desaturation has reached a steady state, however, Vo(2) continues to rise. On the basis of current respiratory control models, the analysis in the present report reveals two distinct Vo(2) phases: an ADP-independent phase at the onset of contraction and an ADP-dependent phase after Mb has reached a steady state. In contrast to the accepted view, the initial intracellular Vo(2) shows that oxidative phosphorylation can support up to 36% of the energy cost, a significantly higher fraction than expected. Partitioning of the energy flux shows that a 31% nonoxidative component exists and responds to the dynamic energy utilization-restoration cycle (which lasts for only milliseconds) as postulated in the glycogen shunt theory. The present study offers perspectives on the regulation of respiration, bioenergetics, and Mb function during muscle contraction.

    View details for DOI 10.1152/ajpcell.00138.2004

    View details for Web of Science ID 000226795100026

    View details for PubMedID 15537712

  • Design of symmetric-sweep spectral-spatial RF pulses for spectral editing MAGNETIC RESONANCE IN MEDICINE Cunningham, C. H., Vigneron, D. B., CHEN, A. P., Xu, D., Hurd, R. E., Sailasuta, N., Pauly, J. M. 2004; 52 (1): 147-153


    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.

    View details for DOI 10.1002/mrm.20116

    View details for Web of Science ID 000222491700020

    View details for PubMedID 15236378

  • In vivo 2D J-resolved magnetic resonance spectroscopy of rat brain with a 3-T clinical human scanner NEUROIMAGE Adalsteinsson, E., Hurd, R. E., Mayer, D., Sailasuta, N., SULLIVAN, E. V., Pfefferbaum, A. 2004; 22 (1): 381-386


    A clinical 3-T scanner equipped with a custom-made transmit/receive birdcage coil was used to collect 2D J-resolved single-voxel spectroscopy in vivo of rat brain. Four adult Wistar rats were scanned twice each, with a 2-week interval. Voxel size was approximately 5 x 10 x 5 mm(3). Total spectroscopic acquisition time was 14 min for collection of two 4:20 min water-suppressed acquisitions and one 4:20 min acquisition acquired in the absence of water suppression. The unsuppressed water data were used in post-processing to reduce residual water side bands, as well as for metabolite signal normalization to account for variations in coil loading and voxel size. Peak areas were estimated for resonances from N-acetyl aspartate (NAA), creatine, choline, taurine, glutamate, and combined glutamate and glutamine. T(2)-relaxation times were estimated for NAA and creatine. The average deviation from the mean of repeated measures for glutamate, combined glutamate and glutamine, and taurine ranged from 7.6% to 18.3%, while for NAA, creatine, and choline, the deviation was less than 3%. The estimated T(2) values for NAA (mean +/- SD = 330 +/- 57 ms) and creatine (174 +/- 27 ms) were similar to those reported previously for rat brain and for human gray and white matter. These results indicate that reliable, small animal brain MR spectroscopy can be performed on a human clinical 3-T scanner.

    View details for DOI 10.1016/j.neuroimage.2003.12.046

    View details for Web of Science ID 000221190200039

    View details for PubMedID 15110030

  • A comparative study of myo-inositol quantification using LCmodel at 1.5 T and 3.0 T with 3 D H-1 proton spectroscopic imaging of the human brain MAGNETIC RESONANCE IMAGING Srinivasan, R., Vigneron, D., Sailasuta, N., Hurd, R., Nelson, S. 2004; 22 (4): 523-528


    Myo-inositol is a strongly coupled system and resonates at four chemical shift positions. At 1.5 T, only the singlet component at 3.57 ppm is detected. However, at 3 T this resonance is resolved into its components at 3.55 ppm and 3.61 ppm. Due to the increased spectral resolution and signal-to-noise ratio, it is anticipated that the quantification of myo-inositol should improve at 3 T. Using data from normal controls and the LCmodel quantification procedure, we found that the quantification precision, reproducibility and detection sensitivity of myo-inositol is significantly better at 3 T relative to 1.5 T.

    View details for DOI 10.1016/j.mri.2004.01.028

    View details for Web of Science ID 000221292800011

    View details for PubMedID 15120172

  • Measurement of brain glutamate using TE-averaged PRESS at 3T MAGNETIC RESONANCE IN MEDICINE Hurd, R., Sailasuta, N., Srinivasan, R., Vigneron, D. B., Pelletier, D., Nelson, S. J. 2004; 51 (3): 435-440


    A method is introduced that provides improved in vivo spectroscopic measurements of glutamate (Glu), glutamine (Gln), choline (Cho), creatine (Cre), N-acetyl compounds (NAtot, NAA + NAAG), and the inositols (mI and sI). It was found that at 3T, TE averaging, the f1 = 0 slice of a 2D J-resolved spectrum, yielded unobstructed signals for Glu, Glu + Gln (Glx), mI, NA(tot), Cre, and Cho. The C4 protons of Glu at 2.35 ppm, and the C2 protons of Glx at 3.75 ppm were well resolved and yielded reliable measures of Glu/Gln stasis. Apparent T1/T2 values were obtained from the raw data, and metabolite tissue levels were determined relative to a readily available standard. A repeatibility error of <5%, and a coefficient of variation (CV) of <10% were observed for brain Glu levels in a study of six normal volunteers.

    View details for DOI 10.1002/mrm.20007

    View details for Web of Science ID 000220003200001

    View details for PubMedID 15004781

  • Proton HR-MAS spectroscopy and quantitative pathologic analysis of MRI/3D-MRSI-targeted postsurgical prostate tissues MAGNETIC RESONANCE IN MEDICINE Swanson, M. G., Vigneron, D. B., Tabatabai, Z. L., Males, R. G., Schmitt, L., Carroll, P. R., James, J. K., Hurd, R. E., Kurhanewicz, J. 2003; 50 (5): 944-954


    Proton high-resolution magic angle spinning ((1)H HR-MAS) NMR spectroscopy and quantitative histopathology were performed on the same 54 MRI/3D-MRSI-targeted postsurgical prostate tissue samples. Presurgical MRI/3D-MRSI targeted healthy and malignant prostate tissues with an accuracy of 81%. Even in the presence of substantial tissue heterogeneity, distinct (1)H HR-MAS spectral patterns were observed for different benign tissue types and prostate cancer. Specifically, healthy glandular tissue was discriminated from prostate cancer based on significantly higher levels of citrate (P = 0.04) and polyamines (P = 0.01), and lower (P = 0.02) levels of the choline-containing compounds choline, phosphocholine (PC), and glycerophosphocholine (GPC). Predominantly stromal tissue lacked both citrate and polyamines, but demonstrated significantly (P = 0.01) lower levels of choline compounds than cancer. In addition, taurine, myo-inositol, and scyllo-inositol were all higher in prostate cancer vs. healthy glandular and stromal tissues. Among cancer samples, larger increases in choline, and decreases in citrate and polyamines (P = 0.05) were observed with more aggressive cancers, and a MIB-1 labeling index correlated (r = 0.62, P = 0.01) with elevated choline. The elucidation of spectral patterns associated with mixtures of different prostate tissue types and cancer grades, and the inclusion of new metabolic markers for prostate cancer may significantly improve the clinical interpretation of in vivo prostate MRSI data.

    View details for DOI 10.1002/mrm.10614

    View details for Web of Science ID 000186326400008

    View details for PubMedID 14587005

  • Detection of myoglobin desaturation in Mirounga angustirostris during apnea AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Ponganis, P. J., Kreutzer, U., Sailasuta, N., Knower, T., Hurd, R., Jue, T. 2002; 282 (1): R267-R272


    1H NMR solution-state study of elephant seal (Mirounga angustirostris) myoglobin (Mb) and hemoglobin (Hb) establishes the temperature-dependent chemical shifts of the proximal histidyl N(delta)H signal, which reflects the respective intracellular and vascular PO2 in vivo. Both proteins exist predominantly in one major isoform and do not exhibit any conformational heterogeneity. The Mb and Hb signals are detectable in M. angustirostris tissue in vivo. During eupnea M. angustirostris muscle maintains a well-saturated MbO2. However, during apnea, the deoxymyoglobin proximal histidyl N(delta)H signal becomes visible, reflecting a declining tissue PO2. The study establishes a firm methodological basis for using NMR to investigate the metabolic responses during sleep apnea of the elephant seal and to secure insights into oxygen regulation in diving mammals.

    View details for Web of Science ID 000172722000032

    View details for PubMedID 11742847

  • N-acetylaspartate - A marker of neuronal integrity ANNALS OF NEUROLOGY SULLIVAN, E. V., Adalsteinsson, E., Spielman, D. M., Hurd, R. E., Pfefferbaum, A. 2001; 50 (6): 823-823

    View details for Web of Science ID 000172410900022

    View details for PubMedID 11761485

  • Single-voxel oversampled J-resolved spectroscopy of in vivo human prostate tissue MAGNETIC RESONANCE IN MEDICINE Swanson, M. G., Vigneron, D. B., Tran, T. K., Sailasuta, N., Hurd, R. E., Kurhanewicz, J. 2001; 45 (6): 973-980


    Single-voxel J-resolved spectroscopy with oversampling in the F1 dimension was used to obtain water unsuppressed 1H spectra of in situ human prostate tissue in 40 previously untreated prostate cancer patients. Based on T2-weighted MRI and previous biopsy information, voxels were placed in regions of benign or malignant peripheral zone tissue, or in regions of predominantly glandular or stromal benign prostatic hyperplasia (BPH) within the central gland. The addition of a second J-resolved dimension allowed for the observation of the J-modulation of citrate, as well as the resolution of polyamines from overlapping choline and creatine signals. Regions of healthy peripheral zone tissue and glandular BPH all demonstrated high levels of citrate and polyamines, with consistent coupling and J-modulation patterns. Conversely, regions of malignant peripheral zone tissue and stromal BPH demonstrated low levels of citrate and polyamines consistent with prior in vivo and ex vivo studies. Moreover, water T2 relaxation times determined for healthy peripheral zone tissue (mean 128 +/- 15.2 msec) were significantly different than for malignant peripheral zone tissue (mean 88.0 +/- 14.2 msec, P = 0.005), as well as for predominantly glandular (mean 92.4 +/- 12.2 msec, P = 0.009) and stromal BPH (mean 70.9 +/- 12.1 msec, P = 0.003). This preliminary study demonstrates that J-resolved spectroscopy of the in situ prostate can be acquired, and the information obtained from the second spectral dimension can provide additional physiologic information from human prostate tissue in a reasonable amount of time (< 10 min).

    View details for Web of Science ID 000168878900006

    View details for PubMedID 11378874

  • O-2 and respiration in exercising human muscle - The regulation of oxidative phosphorylation in vivo OXYGEN SENSING: MOLECULE TO MAN Jue, T., Chung, Y., Mole, P., Tran, T. K., Kreutzer, U., Sailasuta, N., Hurd, R. 2000; 475: 769-783

    View details for Web of Science ID 000088717700077

    View details for PubMedID 10849719

  • Very selective suppression pulses for clinical MRSI studies of brain and prostate cancer MAGNETIC RESONANCE IN MEDICINE Tran, T. K., Vigneron, D. B., Sailasuta, N., Tropp, J., Le Roux, P., Kurhanewicz, J., Nelson, S., Hurd, R. 2000; 43 (1): 23-33


    Focal three-dimensional magnetic resonance spectroscopic imaging (3D MRSI) methods based on conventional point resolved spectroscopy (PRESS) localization are compromised by the geometric restrictions in volume prescription and by chemical shift registration errors. Outer volume saturation (OVS) pulses have been applied to address the geometric limits, but conventional OVS pulses do little to overcome chemical shift registration error, are not particularly selective, and often leave substantial signals that can degrade the spectra of interest. In this paper, an optimized sequence of quadratic phase pulses is introduced to provide very selective spatial suppression with improved B1 and T1 insensitivity. This method was then validated in volunteer studies and in clinical 3D MRSI exams of brain tumors and prostate cancer.

    View details for Web of Science ID 000084538500004

    View details for PubMedID 10642728

  • Myoglobin desaturation with exercise intensity in human gastrocnemius muscle AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Mole, P. A., Chung, Y. R., Tran, T. K., Sailasuta, N., Hurd, R., Jue, T. 1999; 277 (1): R173-R180


    The present study evaluated whether intracellular partial pressure of O(2) (PO(2)) modulates the muscle O(2) uptake (VO(2)) as exercise intensity increased. Indirect calorimetry followed VO(2), whereas nuclear magnetic resonance (NMR) monitored the high-energy phosphate levels, intracellular pH, and intracellular PO(2) in the gastrocnemius muscle of four untrained subjects at rest, during plantar flexion exercise with a constant load at a repetition rate of 0.75, 0.92, and 1.17 Hz, and during postexercise recovery. VO(2) increased linearly with exercise intensity and peaked at 1.17 Hz (15. 1 +/- 0.37 watts), when the subjects could maintain the exercise for only 3 min. VO(2) reached a peak value of 13.0 +/- 1.59 ml O(2). min(-1). 100 ml leg volume(-1). The (31)P spectra indicated that phosphocreatine decreased to 32% of its resting value, whereas intracellular pH decreased linearly with power output, reaching 6.86. Muscle ATP concentration, however, remained constant throughout the exercise protocol. The (1)H NMR deoxymyoglobin signal, reflecting the cellular PO(2), decreased in proportion to increments in power output and VO(2). At the highest exercise intensity and peak VO(2), myoglobin was approximately 50% desaturated. These findings, taken together, suggest that the O(2) gradient from hemoglobin to the mitochondria can modulate the O(2) flux to meet the increased VO(2) in exercising muscle, but declining cellular PO(2) during enhanced mitochondrial respiration suggests that O(2) availability is not limiting VO(2) during exercise.

    View details for Web of Science ID 000081259900021

    View details for PubMedID 10409271

  • Comparative analysis of NMR and NIRS measurements of intracellular PO2 in human skeletal muscle AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Tran, T. K., Sailasuta, N., Kreutzer, U., Hurd, R., Chung, Y. R., Mole, P., Kuno, S., Jue, T. 1999; 276 (6): R1682-R1690


    1H NMR has detected both the deoxygenated proximal histidyl NdeltaH signals of myoglobin (deoxyMb) and deoxygenated Hb (deoxyHb) from human gastrocnemius muscle. Exercising the muscle or pressure cuffing the leg to reduce blood flow elicits the appearance of the deoxyMb signal, which increases in intensity as cellular PO2 decreases. The deoxyMb signal is detected with a 45-s time resolution and reaches a steady-state level within 5 min of pressure cuffing. Its desaturation kinetics match those observed in the near-infrared spectroscopy (NIRS) experiments, implying that the NIRS signals are actually monitoring Mb desaturation. That interpretation is consistent with the signal intensity and desaturation of the deoxyHb proximal histidyl NdeltaH signal from the beta-subunit at 73 parts per million. The experimental results establish the feasibility and methodology to observe the deoxyMb and Hb signals in skeletal muscle, help clarify the origin of the NIRS signal, and set a stage for continuing study of O2 regulation in skeletal muscle.

    View details for Web of Science ID 000080695000018

    View details for PubMedID 10362748

  • Spatial distribution of deoxymyoglobin in human muscle: an index of local tissue oxygenation NMR IN BIOMEDICINE Tran, T. K., Sailasuta, N., Hurd, R., Jue, T. 1999; 12 (1): 26-30


    The proximal histidyl NdeltaH signal of myoglobin is detectable in 1H NMR spectra of myocardial and skeletal muscle, and its intensity reflects the intracellular oxygenation. At 1.5 Tesla (T), the typical field strength of clinical magnetic resonance imaging (MRI) magnets, the paramagnetic relaxation contribution decreases sufficiently to permit the implementation of chemical shift imaging technique to map the spatial distribution of the deoxy Mb NdeltaH signal from human gastrocnemius muscle. One and two-dimensional chemical shift imaging experiments reveal clearly the localized deoxy Mb signal in muscle and consequently the spatial distribution of the cellular oxygenation. The results indicate the feasibility to assess the pO2 in tissue regions and to directly study the regulation of oxidative metabolism in human tissue.

    View details for Web of Science ID 000079191200004

    View details for PubMedID 10195326

  • Myoglobin and O-2 consumption in exercising human gastrocnemius muscle OXYGEN TRANSPORT TO TISSUE XXI Jue, T., Tran, T. K., Mole, P., Chung, Y. R., Sailasuta, N., Hurd, R., Kreutzer, U., Kuno, S. 1999; 471: 289-294

    View details for Web of Science ID 000085570200035

    View details for PubMedID 10659159

  • Proton spectroscopy without water suppression: The oversampled J-resolved experiment MAGNETIC RESONANCE IN MEDICINE Hurd, R. E., Gurr, D., Sailasuta, N. 1998; 40 (3): 343-347


    A method is introduced for obtaining proton spectra in vivo with all the advantages of a full water signal. The method, based on F1 oversampled J-resolved spectroscopy, makes it possible to separate metabolite signals from unwanted baseline artifacts. The dominant water resonance is used as a 2D reference signal for the phase-sensitive reconstruction of the 2D J-resolved metabolite spectra. The powerful specificity of this method is demonstrated with model compound spectra, phantoms, and in vivo examples.

    View details for Web of Science ID 000075570500001

    View details for PubMedID 9727935

  • Decoupling theory and practice II. State of the art: In vivo applications of decoupling NMR IN BIOMEDICINE Freeman, D. M., Hurd, R. 1997; 10 (8): 381-393


    Current methods for broadband heteronuclear decoupling are reviewed from a historical perspective. The principal concern is that decoupling should be effective over a wide range of chemical shifts without undue radiofrequency heating of the sample, particularly when human patients are involved. Continuous-wave methods are the least efficient in this respect, followed by noise decoupling. Composite pulse schemes offer a more effective use of radiofrequency power, while adiabatic passage methods are the most efficient of all. Bi-level decoupling employs a low level of radiofrequency irradiation during the relaxation delay to maintain the nuclear Overhauser effect, with a higher level during signal acquisition in order to decouple over a wide frequency band. All decoupling sequences introduce cycling sidebands into the observed spectrum, and schemes are described to minimize the intensity of these artifacts. In part II, practical applications of decoupling methods are examined in the context of in vivo spectroscopy, where the improvements in sensitivity and resolution through broadband decoupling can be critical for solving clinical problems. Attention is focused on the regulatory limits on power deposition in these experiments. A tabulation of the existing work on decoupling in biological tissue is presented, mainly involving 31P and 13C spectroscopy in vivo or in vitro.

    View details for Web of Science ID 000072363400004

    View details for PubMedID 9542736

  • Automated shimming for deuterated solvents using field profiling JOURNAL OF MAGNETIC RESONANCE Sukumar, S., Johnson, M. O., Hurd, R. E., vanZijl, P. C. 1997; 125 (1): 159-162

    View details for Web of Science ID A1997WT45000021

    View details for PubMedID 9245373

  • Imaging of shifted stimulated echoes and multiple spin echoes MAGNETIC RESONANCE IN MEDICINE Mori, S., Hurd, R. E., vanZijl, P. C. 1997; 37 (3): 336-340


    It is shown that a repetitive pulse sequence consisting of two 90 degrees pulses and gradients in a 1:2 ratio around the second 90 degrees pulse generates interscan shifted stimulated echoes (SSTEs) and intrascan multiple spin echoes (MSEs). Separation of these two types of signals is accomplished using specific gradient crusher schemes. The intensity of the SSTEs is an order of magnitude larger than that of the MSEs and determines the signal contrast if both effects are selected simultaneously. The SSTE sequence generates improved contrast between gray and white matter, even at high field, which is explained in terms of increased inverse T1-weighting for the interscan echo. The MSE image has low signal to noise and no detectable contrast. The effect of interscan diffusion weighting is also discussed.

    View details for Web of Science ID A1997WJ66400004

    View details for PubMedID 9055221

  • Quantitation of automated single-voxel proton MRS using cerebral water as an internal reference MAGNETIC RESONANCE IN MEDICINE Soher, B. J., Hurd, R. E., Sailasuta, N., Barker, P. B. 1996; 36 (3): 335-339


    Data from a previously published, multi-site trial (P.G. Webb, N. Sailasuta, S.J. Kohler, T. Raidy, R.A. Moats, R.E. Hurd. Automated single-voxel proton MRS: technical development and multisite verification. Magn. Reson. Med. 31, 365-373 (1994)) of a fully automatic, single-voxel, proton spectroscopy package (PROBE/SV, GE Medical Systems) was re-analyzed in terms of absolute metabolite concentrations using the cerebral water signal as an internal reference. In 100 spectra from parietal white matter in normal volunteers ranging in age from 22 to 34 years at eight sites, overall concentrations of choline (Cho) creatine (Cr), and N-acetyl-aspartate (NAA) resonances were found to be 2.00 +/- 0.50, 8.43 +/- 1.28, and 12.55 +/- 1.76 mumol/g wet weight, respectively. These values are in good general agreement with previously published values from quantitative, single-voxel studies. Metabolite concentrations for NAA, Cr, and Cho across all sites had standard deviations of 14.1%, 14.9%, and 25.1%, respectively. Quantitation of PROBE data sets is routinely possible by using the cerebral water signal as an internal reference.

    View details for Web of Science ID A1996VE62700001

    View details for PubMedID 8875401

  • Impact of differential linearity in gradient-enhanced NMR JOURNAL OF MAGNETIC RESONANCE SERIES A Hurd, R. E., Deese, A., Johnson, M. O., Sukumar, S., Van zijl, P. C. 1996; 119 (2): 285-288
  • What do customers want? Discussion JOURNAL AMERICAN WATER WORKS ASSOCIATION STANFORD, M. J., Dearness, T., Schrieber, J., Hurd, R. E., Buckingham, A. M., Lam, B. N. 1996; 88 (3): 26-?


    In vivo phosphorus spectroscopy requires very short acquisition delays in order to capture the signal from components with short transverse relaxation times (T2). The echo time typical of standard slice selective spin-echo pulses are too long for this application, so hard pulse, free induction decay (FID) acquisitions have frequently been used instead. With FID, however, there is an interval between the time of coherence and data acquisition (acquisition delay), with resulting baseline distortions. In this paper we describe the design of a new short TE, slice-selective, composite spin-echo pulse with echo times as short as 2.5 ms. With a long TR, fully relaxed, multislice spectra can be collected. This technique will be useful for assessing in vivo, changes in brain phospholipid activity associated with psychiatric and neurological diseases.

    View details for Web of Science ID A1994NT73800012

    View details for PubMedID 8084242



    To improve clinical utility, an integrated method has been developed to automatically acquire and process single-voxel in vivo proton spectra on a 1.5 T clinical scanner. This method includes automated adjustment of linear shims using a very rapid modified simplex method, automated water suppression, and applies a water referencing scheme to correct for phase and residual eddy current effects. No operator intervention is required for the acquisition and processing of these pure-absorption spectra. This method was tested in a preliminary multisite trial to determine intersite and intrasite variability of metabolite ratio measurements. In a sample of over 100 examinations, the standard deviation of the ratios NAA:Cr, Cho:Cr, and ml:Cr were found to be under 15% when using this method, a substantially narrower range than has been found in studies relying on manual adjustment of the instrument and/or manual processing. This result indicates that automated setting of acquisition and processing parameters is of critical importance in the clinical application of in vivo spectroscopy.

    View details for Web of Science ID A1994ND21300003

    View details for PubMedID 8208111

  • PROTON-DETECTED N-15 NMR-SPECTROSCOPY AND IMAGING JOURNAL OF MAGNETIC RESONANCE SERIES B Freeman, D., Sailasuta, N., Sukumar, S., Hurd, R. E. 1993; 102 (2): 183-192


    Because of great inter-individual variability in the sizes and configurations of monkey brains, consistent intracerebral stereotaxic placements are not possible when a general brain atlas is relied upon to derive placement coordinates. We describe a procedure that allows the determination of brain atlases for individual monkeys using proton magnetic resonance imaging and the translation of image coordinates to stereotaxic coordinates. The latter is accomplished by chronically implanting glass beads filled with copper sulfate into the skull to establish a plane horizontal to the stereotaxic plane and to provide reference points for zeroing stereotaxic carriers during intracerebral implants. The efficacy of this procedure was confirmed experimentally.

    View details for Web of Science ID A1991GP16600001

    View details for PubMedID 1798341



    Highly specific NMR assays for the detection, quantitation and imaging of lactate in vivo are described. Applications in animals include tumor monitoring, the determination of hypoxic cell distribution and the demonstration of the efficacy of tumor-sensitizers. The methods (GE-DQCOSY and GE-HMQC) may be particularly useful in heteronuclear NMR in vivo.

    View details for Web of Science ID A1991FL48600007

    View details for PubMedID 1650243



    If proton nuclear magnetic resonance (1H NMR) spectroscopy is to provide a clinically useful modality for monitoring tumor growth and treatment, the technique must be able to unambiguously detect steady-state metabolite concentrations in human tumors and differentiate these from normal tissue levels. To address this problem, a two-dimensional double quantum coherence transfer spectroscopy (2DDQCT) method was developed and tested in a series of tumor cell lines implanted in mice. Lactate-edited proton NMR spectra were determined from a roughly 1-cm3 region of interest in EMT6, RIF-1, and fibroma. In two-dimensional data matrix representations of the 2DDQCT experiments (double quantum frequency on the vertical axis and chemical shift on the horizontal axis) the lactate signal (330 Hz with the transmitter set at the water resonance) was well-resolved from lipid (480 Hz, 600 Hz). The resolution in the double quantum dimension was also sufficient to conclude that a detectable level of alanine, which would reside at 358 Hz, was not present in the three tumor types. Following the NMR experiment, tumors were chemically assayed for lactate giving 8.17, 9.1, and 6.73 mumols/g wet wt for RIF-1, EMT6, and fibroma, respectively. This technique is likely to provide a noninvasive method for monitoring the steady-state lactic acid levels in small tumors before and after therapy, as well as in tissues with impaired oxygen delivery using clinical and research NMR systems.

    View details for Web of Science ID A1990DB71400016

    View details for PubMedID 2345512



    An imaging method is described that makes use of proton double quantum nuclear magnetic resonance (NMR) to construct images based on selected metabolites such as lactic acid. The optimization of the method is illustrated in vitro, followed by in vivo determination of lactic acid distribution in a solid tumor model. Water suppression and editing of lipid signals are such that two-dimensional spectra of lactic acid may be obtained from a radiation-induced fibrosarcoma (RIF-1) tumor in under 1 min and lactic acid images from the same tumor in under 1 hr at 2.0 T. This technique provides a fast and reproducible method at moderate magnetic field strength for mapping biologically relevant metabolites.

    View details for Web of Science ID A1989AB24900015

    View details for PubMedID 2734292

  • F-19 RELAXATION RATE ENHANCEMENT AND FREQUENCY-SHIFT WITH GD-DTPA INVESTIGATIVE RADIOLOGY RATNER, A. V., Quay, S., Muller, H. H., Simpson, B. B., Hurd, R., Young, S. W. 1989; 24 (3): 224-227

    View details for Web of Science ID A1989T670100008

    View details for PubMedID 2753638



    Previous 19F magnetic resonance imaging studies showed that the reticuloendothelial system can be imaged with an emulsion of perfluorooctyl bromide (PFOB). Similar techniques can be used to detect previously implanted RIF-1 tumors in mice after intravenous PFOB administration. Accumulation of PFOB within these neoplasms is due to egress of the emulsion through tumor capillary fenestrations. This is the first report in which 19F MRI and PFOB are used to detect tumors. This technique may allow clinical detection of cancer with 19F MRI.

    View details for Web of Science ID A1988N459200006

    View details for PubMedID 3384616



    In this study sequential 1H and 19F magnetic resonance imaging methods were used to map the distribution of fluorinated compounds in vivo. An intravenously administered emulsion of perfluorooctylbromide (PFOB), an agent known to localize in the reticuloendothelial system, was detected in the liver and spleen of all studied hamsters and mice using 19F MRI. Lungs and salivary glands were also affected in some animals. Using a G. E. NMR CSI 2-T spectroscopy/imaging system, projection 19F images were obtained in 4 to 8 min. Subsequent mouse studies using a thick-slice driven equilibrium pulse sequence produced 19F images with an improved signal-to-noise ratio in a shorter acquisition time. With PFOB, 19F MRI has the capability of detecting macrophages in the reticulo-endothelial system and in other sites where macrophages congregate. This is the first report where the reticuloendothelial system was specifically imaged in live animals and where driven equilibrium imaging techniques have been applied to 19F MRI.

    View details for Web of Science ID A1987L528600004

    View details for PubMedID 3437815