Studies of Metabolism Using Hyperpolarized 13C
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Tuesday 8 May 2012
Room 212-213  13:30 - 15:30 Moderators: Rolf Gruetter, David M. Wilson

13:30 0265.   Nuclear hyperpolarization in 1H and 19F rich fluids induced by photon beams endowed with Orbital Angular Momentum
Remus Albu1, Daniel Elgort1, Khalid shahzad1, Ramon Erkamp1, Shiwei Zhou1, and Jean-Luc Robert1
1Philips Research N.A., Briarcliff Manor, NY, United States

A novel hyperpolarization approach is presented that uses a photon beam endowed with orbital angular momentum (OAM) to induce nuclear hyperpolarization in liquids at room temperature. The feasibility of this hyperpolarization method was verified experimentally by irradiating small volumes of 1H and 19F – rich liquid samples with a focused OAM beam endowed with OAM charges of 0 to ±20. The NMR signal level for “light off” and OAM=0 conditions were comparable, while the NMR signal level increased with the absolute value of the OAM charge. The nuclear magnetic polarization of the fluid sample inside the focal spot of the OAM beam was estimated to be between ~1.5% and 5%.

13:42 0266.   
Exploiting spatiotemporal correlations for accelerating dynamic 2D spectroscopic imaging of hyperpolarized pyruvate in the heart
Kilian Weiss1, Andreas Sigfridsson1, Georgios Batsios1, Marcin Krajewski1, Michael Batel2, and Sebastian Kozerke1
1Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, 2Physical Chemistry, ETH Zurich, Zurich, Switzerland

The investigation of real-time metabolic processes using hyperpolarized compounds requires efficient sampling schedules for sufficient spatiotemporal resolutions. Dynamic hyperpolarized 13C signals in the heart are inherently sparse and their dynamics may be represented by few temporal basis functions. To this end, spatiotemporal acceleration techniques are particularly suited to speed up acquisitions. In this work k-t PCA was implemented and tested based on simulated and hyperpolarized in-vivo data of the rat heart. Accurate reconstructions from up to 8-fold k-t undersampled data have been achieved demonstrating the potential of k-t undersampling approaches for dynamic hyperpolarized imaging of the heart.

13:54 0267.   
Monitoring urea transport in rat kidney in vivo using hyperpolarized 13C MRI
Cornelius von Morze1, Robert A Bok1, Jeff M Sands2, John Kurhanewicz1, and Daniel B Vigneron1
1Department of Radiology and Biomedical Imaging, UCSF, San Francisco, California, United States, 2Department of Medicine, Emory University, Atlanta, Georgia, United States

Urea functions as a key osmolyte in the urinary concentrating mechanism of the renal inner medulla. The urea transporter UT-A1 is upregulated by antidiuretic hormone, facilitating faster equilibration of urea between the lumen and interstitium of the inner medullary collecting duct, resulting in the formation of more highly concentrated urine. New methods in dynamic nuclear polarization, providing ~50,000-fold enhancement of NMR signals in the liquid state, offer a novel means to monitor this process in vivo using MRI. In this study, we detected significant signal differences in the rat kidney between acute diuretic and antidiuretic states, using dynamic 13C MRI following a bolus infusion of hyperpolarized [13C]urea. More rapid medullary enhancement was observed under antidiuresis, consistent with known upregulation of UT-A1.

14:06 0268.   
In vivo reduction of Hyperpolarized [1-13C]-Dehydroascorbic Acid is affected by glucose transporter expression
Sarah E Bohndiek1,2, Mikko I Kettunen1,2, David Lewis2, Tiago B Rodrigues1,2, Ferdia A Gallagher1,2, Dmitry Soloviev2, and Kevin M Brindle1,2
1Department of Biochemistry, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom, 2Cambridge Research Institute, Cancer Research UK, Cambridge, Cambridgeshire, United Kingdom

Hyperpolarized [1-13C]-Dehydroascorbic Acid (DHA) has recently been demonstrated as a novel imaging biomarker of tumor redox status in vivo. We show here that the rate of [1-13C]-DHA reduction is also influenced by glucose transporter expression, so care should be taken to assess the effect of DHA transport on imaging studies performed with this promising hyperpolarized probe.

14:18 0269.   
In Vivo Imaging of Hyperpolarized 13C Labelled Choline and Monitoring of Metabolism
Trevor Wade1,2, Hyla Allouche-Arnon3,4, Lanette Friesen Waldner1,5, Charles A McKenzie1,5, Kundan Thind1,5, Alexei Ouriadov5, Albert Chen6, J. Moshe Gomori3, and Rachel Katz-Brull3,4
1Medical Biophysics, The University of Western Ontario, London, Ontario, Canada, 2XLR Imaging, London, Ontario, Canada, 3Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 4BrainWatch Ltd, Tel-Aviv, Israel, 5Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, 6GE Healthcare

The first noninvasive and nonradioactive imaging of choline labelled at position 1 with hyperpolarized 13C is presented as well as monitoring of its metabolism in a specific organ (the kidney) in the living rat. The chemical shift between choline and phosphocholine is sufficient to monitor the kinetics of choline metabolism using dynamic spectroscopy. Imaging and 2D CSI are also used to monitor regional choline uptake and the metabolic products.

14:30 0270.   
Non-invasive assessment of IDH status in glioblastoma using dynamic 13C MRS of hyperpolarized lower case Greek alpha-ketoglutarate
Myriam Marianne Chaumeil1, Sarah Woods1, Robert M Danforth1, Hikari Yoshihara1, Alessia Lodi1, Aaron Robinson2, Joanna J Philips2,3, and Sabrina M Ronen1
1Radiology, University of California, San Francisco, San Francisco, CA, United States, 2Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States, 3Pathology, University of California, San Francisco, San Francisco, CA, United States

The mutational status of isocitrate dehydrogenase (IDH1) was assessed using dynamic 13C MRS of hyperpolarized (HP) lower case Greek alpha-ketoglutarate in two glioblastoma cells lines: U87 transduced with IDH1 wild-type (U87IDHwt) or IDH mutant (U87IDHmut). Following injection of HP lower case Greek alpha-KG, HP 2-hydroxyglutarate and HP glutamate were detected in U87IDHmut lysates. Only HP glutamate was visible in U87IDHwt lysates. Injection of HP lower case Greek alpha-KG in live perfused U87IDHwt cells resulted in dynamic HP glutamate build-up whereas no HP glutamate was detected in perfused U87IDHmut cells. This pioneer study demonstrates that HP lower case Greek alpha-KG can inform on IDH mutational status through the dynamic assessment of its metabolism.

14:42 0271.   Imaging biomarkers: a comparison of hyperpolarized 13C MRS and diffusion-weighted MRI
XIAOMENG ZHANG1, Dutta Prasanta1, Gary Martinez1, N V Rajeshkumar2, A Le2, A Maitra2, C V Dang2, and Robert J Gillies1
1cancer imaging, Moffitt cancer center, TAMPA, FL - Florida, United States, 2School of Medicine, Johns Hopkins University, Baltimore, MD, United States

Development of novel targeted anti-cancer therapies is highly dependent on qualified in-vivo biomarkers for the therapeutic response. Small molecule drug FX11 that inhibits the lactate dehydrogenase A (LDHA) alters cellular energy metabolism, and reduces the tumor progression1. This procedure could be captured in-vivo by monitoring the metabolic conversion rate of 13C-labled substrates using dynamic nuclear polarization (DNP)2. This measurement could be compared with the most common imaging response biomarker: diffusion-weighted MRI (DW-MRI), which is a measure of tumor cellularity. The apparent diffusion coefficient (ADC) of tumors calculated from DW-MRI has been shown to be valuable for predicting early response to therapies in a variety of cancers3. The purpose of this study is to demonstrate the dynamics of metabolic conversion from 13C pyruvate to 13C lactate with FX11 treatment and compare the ability of two response biomarkers: hyperpolarized (HP) 13C-labled magnetic resonance spectroscopy (MRS) and DW-MRI in the drug sensitive tumor Panc253.

14:54 0272.   Real-time Metabolic Probe into Non-Alcoholic Fatty Liver Disease with Hyperpolarized Carbon-13

Non-alcoholic fatty liver disease (NAFLD) induces changes in liver metabolism. In order to measure such functional aberration, we injected hyperpolarized carbon-13-labeled pyruvate into a mouse model of hepatic steatosis and followed its metabolism in real-time and in-vivo. Initial results showed elevation in malate and aspartate levels, suggesting an increase in pyruvate carboxylase flux. Glucose tolerance test reveals glucose intolerance, a harbinger of diabetes. Quantification of pyruvate carboxylase flux via hyperpolarized pyruvate, as well as measures of downstream malate and aspartate metabolite pools could serve as alternative biomarkers of hepatic steatosis.

15:06 0273.   
Hyperpolarized 13C imaging of metabolic remodeling in a porcine cardiac ischemia-reperfusion model
Angus Z. Lau1,2, Albert P. Chen3, William Dominguez-Viqueira2, Marie A. Schroeder2,4, Yiping Gu2, Jennifer Barry2, John Graham2,5, Nilesh Ghugre2, Graham A. Wright1,2, and Charles H. Cunningham1,2
1Dept. of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, 2Imaging Research, Sunnybrook Research Institute, Toronto, Ontario, Canada, 3GE Healthcare, Toronto, Ontario, Canada, 4Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom,5Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada

A dual respiratory and cardiac-gated, multi-slice, single-shot spiral frequency-specific 13C pulse sequence was used to characterize cardiac metabolic remodeling following acute myocardial infarction in vivo in a porcine ischemia-reperfusion model. We observed two distinct phenotypes, corresponding to myocardial stunning and infarction, with distinct metabolic remodeling patterns revealed by hyperpolarized 13C imaging. PDH flux was reduced following LAD occlusion, with recovery in stunned myocardium. Elevated myocardial lactate was observed in the peri-infarct region, presumably reflecting the potential viability of the myocardium in that area. This work may potentially enable a clinically feasible assessment of salvageable myocardium (the area-at-risk) in myocardial infarction.

15:18 0274.   Proof of Concept Clinical Trial of Hyperpolarized C-13 Pyruvate in Patients with Prostate Cancer
Sarah J. Nelson1,2, John Kurhanewicz3, Daniel B. Vigneron4, Peder Larson4, Andrea Harzstarck4, Marcus Ferrone4, Mark van Criekinge4, Jose Chang4, Robert Bok4, Ilwoo Park4, Galen Reed4, Lucas Carvajal4, Jason Crane4, Jan Henrik Ardenkjaer-Larsen5, Albert Chen6, Ralph Hurd7, Liv-Ingrid Odegardstuen8, and James Tropp7
1Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 2Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States, 3University of California, San Francisco, United States, 4University of California, San Francisco, 5General Electric Healthcare, Denmark, 6General Electric Healthcare, Toronto, Canada, 7General Electric Healthcare, Fremont, CA, USA, 8General Electric Healthcare, Oslo, Norway

The first clinical trial using C-13 MR metabolic imaging has been successfully performed in patients with biopsy proven prostate cancer. In this dose escalation study 31 patients received an injection of 250mM hyperpolarized C-13 pyruvate, followed by metabolic imaging at 3T. Dynamic data showed arrival of C-13 pyruvate approximately 20 seconds after injection and demonstrated that the T1 was long enough to detect uptake and conversion to lactate for 60+ seconds. There were no dose limiting toxicities observed. The highest dose of 0.43mL/Kg gave the best lactate SNR and contrast in lactate/pyruvate for tumor relative to normal prostate.