Hyperpolarized Contrast Agents

Friday 16 May 2014

Angus Z. Lau^1,2, William Dominguez-Viqueira³, Albert P. Chen⁴, Charles H. Cunningham^3,5, Matthew D. Robson¹, and Damian J. Tyler^1,2
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.

Christine Leon Swisher^1,2, Peder E.Z. Larson^1,2, Bertram L. Koelsch^1,2, Subramaniam Sukumar¹, Renuka Sriram¹, Justin Delos Santos¹, Adam B. Kerr³, John M. Pauly³, John Kurhanewicz^1,2, and Daniel B. Vigneron^1,2
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.

Kayvan R Keshari¹, David M Wilson², Victor Sai², Robert Bok², Kuang-Yu Jen³, Peder Larson², Mark Van Criekinge², John Kurhanewicz², and Zhen Jane Wang^2
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.

David Johannes Scholz¹, Martin A. Janich², Annette Frank³, Ulrich Köllisch¹, Jan H. Ardenkjaer-Larsen^4,5, Rolf F. Schulte², Markus Schwaiger³, Axel Haase¹, and Marion I. Menzel^2
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.

Heeseung Lim¹, Kundan Thind¹, Timothy Pok Chi Yeung^1,2, Francisco M Martinez-Santiesteban¹, Eugene Wong^2,3, Paula J Foster^1,4, and Timothy J Scholl^1,4
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.

Kerstin N Timm^1,2, Mikko I Kettunen^1,2, De E Hu^1,2, Tiago B Rodrigues^1,2, Timothy J Larkin^1,2, Irene Marco-Rius^1,2, and Kevin M Brindle^1,2
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.

Jessica A.M. Bastiaansen¹, Matthew E. Merritt², and Arnaud Comment^3
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.

Ulrich Koellisch^1,2, Concetta V. Gringeri^2,3, Giaime Rancan⁴, Markus Durst^1,2, Markus Schwaiger³, Marion I. Menzel², Axel Haase¹, and Rolf F. Schulte^2
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.

Alessandra Flori¹, Matteo Liserani², Francesca Frijia³, Vincenzo Lionetti¹, Giulio Giovannetti^4,5, Giacomo Bianchi⁶, Anar Dushpanova¹, Jan Henrik Ardenkjaer-Larsen^7,8, Giovanni Donato Aquaro³, Vincenzo Positano⁹, Maria Filomena Santarelli^4,5, Luigi Landini^9,10, Massimo Lombardi³, and Luca Menichetti^3,4
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.

Lydia Le Page¹, Oliver Rider², Victoria Noden¹, Andrew Lewis², Latt Mansor¹, Lisa Heather¹, and Damian Tyler^1
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.