|Sensitivity Enhancement Through Hyperpolarization of Carbon & Other Nuclei|
Use of Hyperpolarized13C MR to Monitor Cardiiac
Metabolism In Vito in Type 1 Diabetes
Marie Allen Schroeder1, Lowri Elizabeth Cochlin1, Kieran Clarke1, George K. Radda1, Damian J. Tyler1
1University of Oxford, Oxford, UK
Hyperpolarized 13C MR provides the signal necessary to visualize in vivo substrate uptake and metabolism in real time. This study used hyperpolarized 1-13C-pyruvate as a metabolic tracer to detect changes in cardiac metabolism characteristic of type 1 diabetes. Specifically, a reduction in the activity of pyruvate dehydrogenase (PDH) was observed. This work represents the first instance in which PDH activity has been detected in vivo non-invasively. The ability to monitor PDH activity in vivo should provide a powerful tool for the study of disease progression and treatment in type 1 diabetes.
NMR Detection of 13CO2 and [13C]Bicarbonate is
Sensitive to the Duration of Reperfusion After Brief Myocardial Ischemia
Matthew Merritt1, Crystal Harrison1, Charles Storey1, A. Dean Sherry1, 2, Craig Malloy1, 3
1University of Texas Southwestern Medical Center, Dallas, Texas, USA; 2University of Texas at Dallas, Richardson, Texas, USA; 3VA North Texas Healthcare System, Dallas, Texas, USA
13CO2 and [13C]bicarbonate from hyperpolarized [1-13C]pyruvate were monitored by 13C NMR in the isolated rat hearts immediately and 20 minutes after brief global ischemia. 31P NMR spectra for detecting ATP, phosphocreatine and pH were obtained every 3 minutes in parallel experiments. Immediately after ischemia, 13CO2 and [13C]bicarbonatewere not observed although the [ATP] and [phosphocreatine] were nearly normal. Twenty minutes later, the appearance of 13CO2 and [13C]bicarbonate recovered. Using multinuclear NMR, during the first 90 seconds of reperfusion pyruvate oxidation is essentially zero but recovers quickly in reversibly-injured myocardium. 13C NMR is sensitive to the duration of reperfusion.
Serial Hyperpolarized 13C 3D-MRSI Following
Therapy in a Mouse Model of Prostate Cancer
Albert P. Chen1, Robert Bok1, Vickie Zhang1, duan Xu1, Srivathsa Veeraraghavan1, Ralph E. Hurd2, Sarah J. Nelson1, John Kurhanewicz1, Daniel B. Vigneron1
1UCSF, San Francisco, California , USA; 2GE Healthcare, Menlo Park, California , USA
Using hyperpolarized 13C substrates, it has been demonstrated that tumor progression in an animal model and tumor cells response to chemo-therapy ex vivo can be monitored by MRSI/MRS studies. In this study, a transgenic mouse model of prostate cancer mice were studied serially prior and after androgen deprivation therapy using 13C MRSI with hyperpolarized 13C pyruvate as a substrate. From the preliminary results, lower tumor Lac/Pyr ratios at baseline were associated with a reduction in Lac/Pyr after therapy and a positive response to therapy. More studies are required to understand this possible correlation.
Imaging PH in Vivo Using Hyperpolarized 13C-Labeled
Ferdia Aidan Gallagher1, 2, Mikko I. Kettunen1, 2, Sam E. Day1, 2, De-en Hu1, 2, René in ‘t Zandt3, Pernille R. Jensen3, Magnus Karlsson3, Klaes Golman4, Mathilde H. Lerche3, Kevin M. Brindle1, 2
1University of Cambridge, Cambridge, UK; 2CRUK Cambridge Research Institute, Cambridge, UK; 3Imagnia, Malmö, Sweden; 4Imagnia, Sweden
Alterations in pH underlie many pathological processes and therefore there is a pressing need for techniques that could be used to measure tissue pH in the clinic. We show here that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized H13CO3- and 13CO2 following injection of hyperpolarized H13CO3-. The technique has shown that the average pH of a mouse tumor was significantly lower than the surrounding tissue in keeping with an acidic extracellular environment.
Signal Enhancement in Low-Dose
Hyperpolarized 13C Imaging Using Multi-Slice FSEPSI Sequence
Yi-Fen Yen1, Patrick Le Roux2, Rober Bok3, Jim Tropp1, Albert Chen3, Matthew Zierhut3, 4, Ilwoo Park3, 4, Mark Albers3, 4, Hubert Dirven5, Tim Skloss6, Jan Wolber7, Vickie Zhang3, Simon Hu3, 4, Dan Vigneron3, John Kurhanewicz3, Sarah Nelson3, Ralph Hurd1
1GE Healthcare, Menlo Park, California , USA; 2GE Healthcare, France; 3University of California, San Francisco, California , USA; 4Berkeley, California , USA; 5GE Healthcare, Oslo, Norway; 6GE Healthcare, Waukesha, USA; 7GE Healthcare, Amersham, UK
We explored the application of an FSEPSI sequence for low-dose, hyperpolarized 13C metabolic imaging. The sequence utilized a CPMG echo train to sustain the transverse magnetization of the imaging slice. The longitudinal magnetization outside of the imaging slice was remained undisturbed. A symmetric EPSI waveform centered at each spin echo was used for spectroscopic imaging. Multiple slices were acquired, each with a single-shot FSEPSI acquisition. The SNR advantage of the FSEPSI sequence was demonstrated in dog prostate spectroscopic imaging following an injection of low-dose hyperpolarized 13C-pyruvate solution.
|11:30||891.|| How Does Dose of Hyperpolarized 13C1-Pyruvate
Affect Metabolic Results in Dog Prostate?
Matthew L. Zierhut1, 2, Yi-Fen Yen2, Albert P. Chen, Robert Bok, Mark Albers1, Vickie Zhang, James Tropp2, Ilwoo Park1, Daniel B. Vigneron1, John Kurhanewicz1, Ralph E. Hurd2, Sarah J. Nelson1
1UCB/UCSF, San Francisco, California , USA; 2GE Healthcare, California , USA
Varying dose levels of hyperpolarized 13C1-pyruvate were studied as a tool for investigating in-vivo 13C metabolism of dog prostate. Results suggest that pyruvate is converted into lactate at a higher rate with lower doses. Also, lactate SNR does not change significantly with 13C1-pyruvate dose.
|Acetyl-CoA and Acetyl-Carnitine Show
Organ Specific Distribution in Mice After Injection of DNP
Pernille Rose Jensen1, Rene in 't Zandt1, Magnus Karlsson1, Georg Hansson1, Sven Månsson1, Anna Gisselsson1, Mathilde Lerche1
1Imagnia AB, Malmö, Sweden
The metabolism of DNP hyperpolarized 13C1-acetate in mice reveals that acetate is a promising substrate to study metabolism in vivo. Two metabolites were identified; acetyl-CoA and acetyl-carnitine. Significant differences in the ratio between acetyl CoA and acetyl carnitine are observed by single aquisition spectra localized over the heart or liver regions. The acetyl-carnitine level is significantly higher in the heart. The conversion of acetate to acetyl carnitine via acetyl CoA can be visualized in vivo using 13C-DNP NMR, is organ specific and may be a valuable diagnostic tool for fatty acid metabolism under healthy and pathological conditions.
Imaging Cancer Gene Therapy Using 13C Hyperpolarised
Yann Jamin1, Steven Reynolds2, Lynette Smyth3, Cristina Gabellieri1, Simon P. Robinson1, Caroline J. Springer3, Martin O. Leach1, Geoffrey S. Payne1, Thomas R. Eykyn1
1Institute of Cancer research and Royal Marsden NHS trust, Sutton, UK; 2Oxford Instruments Molecular Biotools Ltd, Abingdon, UK; 3Institute of Cancer Research, Sutton, UK
We report the successful hyperpolarisation using dynamic nuclear polarization (DNP) of three 13C nuclei of 3,5-Difluorobenzoylglutamic acid (3,5-DFBGlu).3,5-DFBGlu is an in vivo reporter of the enzyme Carboxypeptidase G2 (CPG2). CPG2 is used in Gene Directed Enzyme Prodrug Therapy, a promising gene therapy strategy for cancer treatment to activate non toxic prodrugs into cytotoxic DNA alkylating agents. One of the 13C nuclei combines a consequent 13C NMR chemical shift upon CPG2-mediated cleavage of 3,5-DFBGlu into 3,5-DFBA and glutamic acid with a relatively long 13C T1. The successful hyperpolarisation of 3,5-DFBGlu demonstrates the potential of 13C MRS and hyperpolarised 3,5-DFBGlu to image CPG2 activity and transgene expression in vivo.
Therapeutic Target Metabolism Observed Using
Hyperpolarized 15N Choline
Cristina Gabellieri1, Steven Reynolds2, Arnon Lavie3, Geoffrey S. Payne1, Martin O. Leach1, Thomas R. Eykyn1
1The Institute of Cancer Research, Sutton, UK; 2Oxford Instruments Molecular Biotools Ltd, Abingdon, UK; 3University of Illinois, Chicago, USA
Choline is widely used as a diagnostic marker in oncology where malignant transformations are associated with altered phospholipid metabolism. Decrease in PCho level in cancer cells and in vivo is increasingly recognised as a positive response to treatments. Here we report the real-time metabolic conversion of 15N choline – hyperpolarized by Dynamic Nuclear Polarization - to hyperpolarized 15N phosphocholine catalyzed by choline kinase. The extraordinary long lifetime of the hyperpolarized signal of both parent and daughter compounds is of the order of many minutes and shows the potential of hyperpolarized 15N choline as a novel biomarker in oncology.
|Hyperpolarized 3He MRI Apparent Diffusion
Coefficients to Derive Non-Invasive Lung Pressure-Volume Curves
Andrea B. Evans1, David G. McCormack2, Roya Etemad-Rezai2, Giles E. Santyr1, Grace Parraga1
1Robarts Research Institute, London, Canada; 2The University of Western Ontario, London, Canada
Pressure-volume curves (PV-curves) of the lung reflect the global static mechanical properties of the respiratory system and yield information such as lung compliance, total lung capacity, and lung elasticity. Typically, PV-curves are generated experimentally in vivo by measuring transpulmonary pressure at various lung volumes while the patient is sedated and a volume of gas is administered to inflate the lung. This approach is invasive and uncomfortable for patients and as such, it is generally only performed on patients already mechanically ventilated which limits its use. We propose to noninvasively generate lung pressure volume-curves in patients using experimentally-derived hyperpolarized 3He magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC). Experimental ADC values are used to derive alveolar/acinar size and using established mathematical models of the lung transpulmonary pressure at various volumes is derived and PV-curves can be generated. The simulated PV-curves are in good agreement with previously published data from healthy subjects and those with COPD.