Joint Annual Meeting ISMRM-ESMRMB 2014 10-16 May 2014 Milan, Italy

Hyperpolarized Contrast Agents

Friday 16 May 2014
Silver  08:00 - 10:00 Moderators: Kevin M. Bennett, Ph.D., Arnaud Comment, Ph.D.

08:00 0981.   
Simultaneous multi-slice imaging of multiple metabolites using spectral-spatial excitation for hyperpolarized 13C experiments
Angus Z. Lau1,2, William Dominguez-Viqueira3, Albert P. Chen4, Charles H. Cunningham3,5, Matthew D. Robson1, and Damian J. Tyler1,2
1Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom, 2Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom, 3Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 4GE Healthcare, Toronto, ON, Canada, 5Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

DNP-dissolution MRI is a novel method for imaging in vivo metabolism in real-time. Spectral-spatial excitation can be used to obtain full 3D volumes rapidly in a multi-slice mode, but for substrates with many downstream metabolites or multiple polarized substrates, excitation of metabolic resonances one at a time becomes challenging due to limited available scan time. In this abstract, we combine simultaneous multi-slice (SMS) acceleration with spectral-spatial excitation. We demonstrate the method in a water/acetone phantom (7-fold acceleration) and in retrospectively aliased 13C cardiac images (2-fold acceleration). We anticipate the scan time reduction will enable new applications in hyperpolarized 13C MRI.

08:12 0982.   
Dynamic Ultrafast 2D Exchange Spectroscopy (EXSY) of Hyperpolarized Substrates
Christine Leon Swisher1,2, Peder E.Z. Larson1,2, Bertram L. Koelsch1,2, Subramaniam Sukumar1, Renuka Sriram1, Justin Delos Santos1, Adam B. Kerr3, John M. Pauly3, John Kurhanewicz1,2, and Daniel B. Vigneron1,2
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 2UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA, United States, 3Magnetic Resonance Systems Research Laboratory, Department of Electrical Engineering, Stanford University, Stanford, CA, United States

We present for the first time a simple ultrafast method for acquiring dynamic 2D Exchange Spectroscopy (EXSY) using MAD-STEAM. This technique reconstructs 2D EXSY spectra from 1D spectra based on phase accrual during the echo time. Utilizing single-step encoding and single-shot acquisition, it is ideal for dynamic imaging of many exchange pathways and applicable to hyperpolarized substrates. We have validated this method in simulations, hyperpolarized hydration experiments, and cell studies where forward and backward exchange of pyruvate-lactate and pyruvate-hydrate were resolved in real-time. This new approach could improve specificity to cancer metabolism via isolation of directionality of metabolic pathways.

08:24 0983.   In vivo assessment of diabetes-induced renal oxidative stress and response to therapy using hyperpolarized 13C dehydroascorbate magnetic resonance imaging
Kayvan R Keshari1, David M Wilson2, Victor Sai2, Robert Bok2, Kuang-Yu Jen3, Peder Larson2, Mark Van Criekinge2, John Kurhanewicz2, and Zhen Jane Wang2
1Radiology and Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States, 2Radiology, UCSF Medical Center, San Francisco, CA, United States, 3Pathology, UCSF Medical Center, San Francisco, CA, United States

Oxidative stress is proposed as a unifying cause for diabetic nephropathy. We apply an endogenous redox sensor, HP 13C-dehydroascorbate (DHA), to interrogate the renal redox capacity in a mouse diabetes model. The diabetic mice demonstrate decreased redox capacity, with lower 13C-DHA reduction to the antioxidant Vitamin C. This correlates to lower reduced glutathione (GSH) concentration and higher Nox4 expression, consistent with increased generation of superoxide and oxidative stress. ACE inhibition normalizes 13C-DHA reduction to Vitamin C, GSH concentration, and Nox4 expression. HP 13C DHA enables rapid in vivo assessment of altered redox capacity in diabetic nephropathy and following successful treatment.

08:36 0984.   
Quantified pH imaging with hyperpolarized 13C-Bicarbonate
David Johannes Scholz1, Martin A. Janich2, Annette Frank3, Ulrich Köllisch1, Jan H. Ardenkjaer-Larsen4,5, Rolf F. Schulte2, Markus Schwaiger3, Axel Haase1, and Marion I. Menzel2
1IMETUM, Technische Universität München, Munich, Germany, 2GE Global Research, Munich, Germany, 3Nuclear Medicine, Technische Universität München, Munich, Germany, 4Technical University of Denmark, Copenhagen, Denmark, 5GE Healthcare, Copenhagen, Denmark

Hyperpolarized 13C-Bicarbonate pH mapping enables the opportunity to investigate a key parameter in many biochemical processes, the pH, which is relevant for a broad range of disease characterization such like cancer, inflammatory diseases (e.g. Alzheimer disease, multiple sclerosis and osteoarthritis), hypoxia and many others. In vitro and in vivo quantification of pH, acquired spatially and time resolved helps to reveal the potential and the limits of the method. pH mapping was applied in vivo using tailor-made spectral-spatial pulse design and acquisition techniques on rats, investigating induced metabolic alkalosis in kidneys and sterile inflammation.

08:48 0985.   
Imaging of tumor metabolism: a longitudinal study of tumor response to therapies using hyperpolarized [1-13C]pyruvate.
Heeseung Lim1, Kundan Thind1, Timothy Pok Chi Yeung1,2, Francisco M Martinez-Santiesteban1, Eugene Wong2,3, Paula J Foster1,4, and Timothy J Scholl1,4
1Medical Biophysics, Western University, London, Ontario, Canada, 2London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada, 3Physics and Astronomy, Western University, London, Ontario, Canada, 4Robarts Research Institute, Western University, London, Ontario, Canada

This longitudinal study uses hyperpolarized 13C MRSI to image and quantify metabolic changes in brain tumor in response to therapies. Wistar rats showed significant changes in tumour metabolism within a day or two after therapy measured by the ratio of lactate to pyruvate after injection of hyperpolarized [1-13C]pyruvate. This work establishes evidence for the capability of hyperpolarized 13C MRSI to detect early metabolic changes in brain tumors in response to radio- and chemotherapies and the ratio of lactate to pyruvate as a longitudinal non-invasive biomarker for therapeutic response.

09:00 0986.   
Reduction of (1-13C)-dehydroascorbic acid to (1-13C)-ascorbic acid is not correlated to glutathione in a treatment response model of murine lymphoma in vivo
Kerstin N Timm1,2, Mikko I Kettunen1,2, De E Hu1,2, Tiago B Rodrigues1,2, Timothy J Larkin1,2, Irene Marco-Rius1,2, and Kevin M Brindle1,2
1Department of Biochemistry, University of Cambridge, Cambridge, Cambridgshire, United Kingdom, 2Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, Cambridgshire, United Kingdom

Hyperpolarized [1-13C]-dehydroascorbic acid (DHA), the oxidized form of vitamin C, can be used as a magnetic resonance marker of redox state in vitro and in vivo. What limits the reduction of hyperpolarized [1-13C]-DHA to [1-13C]-ascorbic acid (AA) in vivo and hence which metabolic process it directly reports on is still poorly understood. We treated EL4 tumor bearing mice with the topoisomerase inhibitor etoposide and showed that the reduction rate of hyperpolarized [1-13C]-DHA in vivo is highly variable, which was not correlated with intracellular glutathione levels. This suggests contribution of other factors such as NADPH from the pentose phosphate pathway.

09:12 0987.   
Measuring In Vivo Myocardial Substrate Competition Using Hyperpolarized 13C Magnetic Resonance
Jessica A.M. Bastiaansen1, Matthew E. Merritt2, and Arnaud Comment3
1Laboratory of Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland, 2Advanced Imaging Research Center,Department of Radiology,Molecular Biophysics,Biomedical Engineering, UTSW Medical Center, Texas, United States, 3Institute of Physics of Biological Systems, EPFL, Lausanne, Switzerland

Cardiac dysfunction is often associated with a shift in substrate preference, while current in vivo techniques only provide direct information on substrate uptake. To study substrate competition in the rat heart in vivo, hyperpolarized [1-13C]pyruvate and [1-13C]butyrate were co-administrated as surrogates for carbohydrate and fatty acid metabolism respectively. The appearance of downstream metabolites allowed for independent monitoring of oxidation of both substrates uniquely in a single experiment. A simple metabolic intervention led to significant changes in substrate preference. Combining hyperpolarized 13C technology and co-administration of two separate imaging agents enabled the simultaneous monitoring of both fatty acid and carbohydrate oxidation in the heart in vivo.

09:24 0988.   
Hyperpolarized 13C-acetate for the detection of metabolic response of the heart to a stress protocol
Ulrich Koellisch1,2, Concetta V. Gringeri2,3, Giaime Rancan4, Markus Durst1,2, Markus Schwaiger3, Marion I. Menzel2, Axel Haase1, and Rolf F. Schulte2
1IMETUM, Technical University München, Munich, Germany, 2GE Global Research, Munich, Germany, 3Nuclear Medicine, Technical University München, Munich, Germany, 4Technical University München, Munich, Germany

Acetate metabolism plays an important role particularly in myocardial cells where acetate gets converted to acetyl-carnitine (ALCAR) via Acetyl-CoA. Hyperpolarized MRS using [1-13C]acetate offers the possibility to investigate its conversion to [1-13C]ALCAR, which could be a marker for changes of myocardial fatty-acid metabolism. However the low SNR of ALCAR is the bottleneck of the proposed method. Adresing this problem a stress protocol using dobutamine was combined with an optimized spectrospatial pulse sequence in order to increase the SNR of ALCAR. The results show a significant increase of the ALCAR to acetate after dobutamine administration.

09:36 0989.   Hyperpolarized [1-13C]acetate kinetics and metabolism in translational animal model: cardiac real-time detection of metabolic flux of [13C]acetyl-carnitine in pigs
Alessandra Flori1, Matteo Liserani2, Francesca Frijia3, Vincenzo Lionetti1, Giulio Giovannetti4,5, Giacomo Bianchi6, Anar Dushpanova1, Jan Henrik Ardenkjaer-Larsen7,8, Giovanni Donato Aquaro3, Vincenzo Positano9, Maria Filomena Santarelli4,5, Luigi Landini9,10, Massimo Lombardi3, and Luca Menichetti3,4
1Scuola Superiore Sant'Anna, Institute of Life Sciences, Pisa, Italy, 2Department of Physics, University of Pisa, Pisa, Italy, 3Fondazione CNR/Regione Toscana G. Monasterio, Pisa, Italy, 4Institute of Clinical Physiology, National Council of Research, Pisa, Italy, 5MRI Unit, Fondazione CNR/Regione Toscana G. Monasterio, Pisa, Italy, 6Cardiac Surgery Department, Ospedale del Cuore "G. Pasquinucci", Fondazione CNR/Regione Toscana G. Monasterio, Massa, Italy, 7GE Healthcare, Denmark, 8Department of Electrical Engineering, Technical University of Denmark, Denmark, 9MRI Lab, Fondazione CNR/Regione Toscana G. Monasterio, Pisa, Italy, 10Department of Information Engineering, University of Pisa, Pisa, Italy

We present an analysis based on the ratio of total areas under the curve (AUC), for real-time detection of metabolic flux and enzymatic reactions using [1-13C]acetate dissolution-DNP and MRS. Hyperpolarized sodium [1-13C]acetate (150 mM) was administered in pigs at rest and during inotropic stress with dobutamine: [1-13C]acetate and [1-13C]acetyl-carnitine were detected in a selected heart slice. [1-13C]acetate kinetics displayed a typical biphasic shape and the ratio of [1-13C]Acetyl-carnitine/[1-13C]acetate AUC showed a good correlation with Rate Pressure Product. We proved the feasibility of cardiac metabolic studies with hyperpolarized [1-13C]acetate using an approach alternative to kinetic model-based analysis, relevant for clinical translation.

09:48 0990.   
Real-time assessment of the effect of acute and chronic hypoxia on cardiac metabolism in the control and diabetic rat: an in vivo study
Lydia Le Page1, Oliver Rider2, Victoria Noden1, Andrew Lewis2, Latt Mansor1, Lisa Heather1, and Damian Tyler1
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom, 2Oxford Centre for Clinical Magnetic Resonance Research, Oxford, United Kingdom

Diabetes is associated with a high risk of cardiovascular disease and hypoxia is potentially an important component of this risk. Here, we investigated thein vivo, real-time metabolic response of the diabetic rat heart to acute and chronic hypoxia. Acute hypoxia reduced pyruvate dehydrogenase (PDH) flux and increased lactate production in control hearts but this did not occur in diabetic hearts. Following chronic hypoxia, neither group showed alterations in cardiac PDH flux or lactate production. We have shown an acute metabolic inflexibility in the in vivo diabetic heart, which is possibly overcome over a longer hypoxic period by physiological adaptations.