Benjamin J. Geraghty^1,2, Justin Y. C. Lau^1,2, Albert P. Chen³, and Charles H. Cunningham^1,2
1Dept. of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ²Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada

Simultaneous acquisition of multiple hyperpolarized 13C metabolites within a single-shot is possible through jointly sampling k-t space with a spiral trajectory that oversamples the field-of-view, and has been demonstrated on a small animal scanner. Due to limited gradient performance in conventional clinical scanners, achieving large oversampling rates while maintaining adequate resolution within a single readout is unfeasible. We relax the oversampling requirement by selectively exciting only two metabolites using a dual-band spectral-spatial pulse. Images are recovered through a model based least squares reconstruction. In vivo feasibility of simultaneous acquisition of hyperpolarized [1-13C]pyruvate and lactate is demonstrated on a healthy rat.

Elena Nasonova¹, Markus Durst^2,3, Concetta Gringeri³, Eliane V. Farrell⁴, Michael Friebe¹, Axel Haase², Markus Schwaiger⁴, and Rolf F. Schulte^3
1Chair of Computer Aided Medical Procedures, TU München, Munich, Germany, ²Zentralinstitut für Medizintechnik (IMETUM), Munich, Germany, ³GE Global Research, Munich, Germany, ⁴Department for Nuclear Medicine, TU München, Munich, Germany

Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) is a fast and efficient method for separation of 13C species. However, the underlying least squares chemical shift imaging (LSCSI) technique makes use of assumption of constant signal contributions from metabolites within several acquisitions and, therefore, is not consistent with the fast-changing metabolic signal. We attempted to compensate this non-valid assumption in our method. It uses time-dependent correcting factors, obtained from the computed metabolic time courses and inserted into a spectral encoding matrix. Resulting images are then obtained by conventional inversion of this modified matrix and gridding reconstruction.

Christine Leon Swisher^1,2, Jason C. Crane¹, Marram P. Olson¹, Cornelius Von Morze¹, Daniel B. Vigneron^1,2, and Sarah J. Nelson^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

Considerable attention has been dedicated to investigating the dynamics of hyperpolarized signals to detect the underlining pathophysiology4-8. Derivation of kinetics from HP substrates often requires complex, multi-compartment models, which are prone to misinterpretation. Moreover, as the technology moves into the clinic, there is a clear need for standardization, simplification of complicated workflows, and a format compatible with PACS. The SIVIC package processes and quantifies dynamic HP spectroscopic data in two simple steps producing multiple parameters including quantification of dynamics, perfusion, and metabolic reaction rate kinetics. These can then be displayed with ease in SIVIC, a free, open-source software package.

Elena Nasonova¹, Markus Durst², Concetta Gringeri³, Eliane V. Farrell⁴, Michael Friebe¹, Axel Haase², Markus Schwaiger⁴, and Rolf F. Schulte^3
1Chair of Computer Aided Medical Procedures, TU München, Munich, Germany, ²Zentralinstitut für Medizintechnik (IMETUM), Munich, Germany, ³GE Global Research, Munich, Germany, ⁴Department for Nuclear Medicine, TU München, Munich, Germany

MR spectroscopy with hyperpolarised [1-13C] agents is a novel functional imaging modality that examines natural metabolic reactions. Due to rapid signal decay and challenging experimental settings reconstructed images exhibit low signal-to-noise ratio (SNR) and artifacts. In this work the SNR improvement by 20% at least was achieved with iterative reconstruction with included Tikhonov, total variation (TV), total generalised variation (TGV) regularisation terms as well as anatomy-based support mask. The proposed methods were validated in mathematical simulations and in vivo studies and proved to be advantageous for reconstruction of functional metabolic images.

Gopal Varma¹, Xiaoen Wang¹, and Aaron K Grant^1
1Radiology, Division of MR Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Balanced steady-state free precession (bSSFP) offers potential advantages for imaging of hyperpolarized ¹³C, including high signal-to-noise ratio (SNR) and efficient use of magnetization. Several variants of bSSFP provide spectroscopically selective images, including multi-echo methods and techniques that use a variable RF phase advance. Both approaches have undesirable sensitivity to off-resonance, and poor conditioning of the reconstruction can degrade SNR. Here we describe a multi-echo variable phase advance method that may provide more robust imaging. The technique is applied to phantoms and in vivo imaging of pyruvate and its metabolites, yielding images with 1mm² in-plane resolution, 4mm slice, and peak lactate SNR~30.

Jeremy W Gordon¹, Sean B Fain^1,2, David J Niles¹, and Kevin M Johnson^1,2
1Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, ²Radiology, University of Wisconsin-Madison, Madison, WI, United States

Joint spatial-spectral reconstruction enables highly accelerated ¹³C spectroscopic imaging but requires high performance gradients to optimally sample k-t space. However, temporal correlations between adjacent timeframes can be exploited by permuting or shifting the TE to reduce gradient requirements while still sampling k-t space sufficiently. Simulations and in-vivo results indicate that by permuting the k-t trajectory via pseudorandom TEs and incorporating low-rank regularization, temporal correlations across timeframes can be incorporated to improve the conditioning of the encoding matrix and reduce noise in low signal metabolite images. The proposed framework reduces gradient requirements and may enable k-t spiral sampling on clinical platforms.

Sonal Josan^1,2, Kelvin Billingsley^1,3, Juan Orduna², Jae Mo Park¹, Richard Luong⁴, Srinevas Reddy⁵, Ralph Hurd⁶, Adolf Pfefferbaum^2,7, Daniel Spielman¹, and Dirk Mayer^1,8
1Radiology, Stanford University, Stanford, CA, United States, ²SRI International, Menlo Park, CA, United States, ³Chemistry and Biochemistry, San Francisco State University, San Francisco, CA, United States, ⁴Comparative Medicine, Stanford University, Stanford, CA, United States, ⁵Surgery, University of Maryland, Baltimore, MD, United States, ⁶GE Healthcare, CA, United States, ⁷Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States, ⁸Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, United States

Numerous studies using hyperpolarized pyruvate (Pyr) have been applied to investigate cancer and heart disease, but very few reports have been published on applications in diseased liver other than cancer. As several liver pathologies are associated with elevated alanine transaminase (ALT) activity, the aim of this work was to investigate the use of dynamic metabolic imaging of hyperpolarized [1-13C]Pyr for the assessment of liver damage induced by administration of carbon tetrachloride (CCl4).

Daniel Spielman¹, Keshav Datta², Sonal Josan³, Stephen Lynch⁴, and Ralph Hurd^5
1Radiology, Stanford University, Stanord, CA, United States, ²Electrical Engineering, Stanford University, CA, United States, ³Radiology, Stanford University, CA, United States, ⁴Chemistry, Stanford University, CA, United States, ⁵GE Healthcare, CA, United States

Polarization transfer methods provide improved detection of 13C nuclei directly bonded to protons. However, efficient in vivo measurements are difficult due to SAR-intensive decoupling requirements. Here we present a modification to the conventional INEPT sequence that eliminates splitting due to short-range 13C-1H J-coupling, while providing a √2 SNR gain, without the need for proton decoupling. The targeted application is enhanced imaging and spectroscopy of [2-13C]Lac and [2-13C]Ala (metabolic products generated by hyperpolarized [2-13C]Pyr), however the approach may also be applicable to detecting C2, C3, and C4 glutamate and glutamine resonances following infusion of thermally polarized 13C-substrates.

Leo L Tsai¹, Xiaoen Wang¹, Gopal Varma¹, Benjamin Edelstein¹, Rupal Bhatt², David C Alsop¹, and Aaron K Grant^1
1Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, United States, ²Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

Hyperpolarized C-13-tert-butanol (hC13-tert-butanol) provides a robust and rapid method of tumor perfusion quantification with high SNR, with high translational potential for clinical monitoring of antiangiogenics. Here we show excellent correlation of hC13-tert-butanol perfusion quantification as compared to ASL and direct immunostaining with CD34.

Mor Mishkovsky^1,2, Emine Can³, Tim Eichhorn⁴, Denis Mario⁵, Ivan Radovanovic⁵, Rolf Gruetter^1,6, Virginie Clément-Schatlo⁵, and Arnaud Comment^3
1Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ²Department of radiology, Univesity of Lausanne, Lausanne, Switzerland, ³Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ⁴Paul Scherrer Institute (PSI), Villigen, Switzerland, ⁵Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland,⁶Department of radiology, Univesity of Lausanne and Geneva, Switzerland

Hyperpolarized [1-13C]pyruvate solutions prepared without persistent radicals were used to study brain metabolism in rat model of human glioblastoma. Real time in vivo pyruvate metabolism was acquired with large signal-to-noise ratio that allows studying the kinetic of the LDH-mediated conversion of pyruvate to lactate in the tumor. The use of completely endogenous sample compositions through all the steps of the dissolution DNP experiment can facilitate the clinical application of hyperpolarized pyruvate for tumor diagnostic and treatment response as the filtration step is eliminated.

Keshav Datta¹, Sonal Josan², and Daniel Spielman^2
1Dept. of Electrical Engineering, Stanford University, Stanford, CA, United States, ²Department of Radiology, Stanford University, Stanford, CA, United States

Knowledge of the liquid-state polarization is necessary for absolute quantitation of in vivo hyperpolarized MRS data. In contrast to earlier work suggesting asymmetry of the C2 doublet (aC2) of [1,2-13C]Pyr (1% naturally abundant in a hyperpolarized [1-13C]Pyr sample) can directly be used to compute the instantaneous polarization, we present both analytic expressions and experimental results demonstrating a single measurement of aC2 is insufficient, and polarization calculations also depend on both the delay between the sample exiting the polarizer and the time of measurement as well as knowledge of the T1 decay rates of the individual peaks in the doublet resonance.

Sonal Josan¹, Jae Mo Park¹, Ralph Hurd², Daniel Spielman¹, and Dirk Mayer^1,3
1Radiology, Stanford University, Stanford, CA, United States, ²GE Healthcare, CA, United States, ³Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, United States

There has been growing interest recently in using hyperpolarized [2-13C]pyruvate, to follow the 13C label into metabolic products including glutamate (in exchange with α-ketoglutarate in the TCA cycle), citrate, and acetylcarnitine as well as lactate and alanine. CSI with [2-13C]Pyr is challenging given the wide spectral dispersion of the resonances. This work presents an improved design for 3D CSI with [2-13C]Pyr using spectrally selective excitation of limited frequency bands containing a subset of metabolites, and interleaving different bands to acquire dynamic metabolic data in vivo in rat liver.

Albert P Chen¹ and Charles H Cunningham^2,3
1GE Healthcare, Toronto, ON, Canada, ²Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, ³Medical Biophysics, University of Toronto, Toronto, ON, Canada

PRESS technique has been widely used to achieve voxel localization for in vivo 1H MRS acquisitions, but for dynamic hyperpolarized 13C MRS experiments, the transition bands of the refocusing pulses may prematurely saturate the pre-polarized substrate spins moving into the voxel. This limitation may be overcame by designing refocusing pulses that do not perturb the resonance of the hyperpolarized substrate but refocuses the spins of the metabolic products. In this study, a PRESS pulse sequence incorporating spectral-spatial refocusing pulses that have a stop band (‘notch’) at the substrate resonance is tested in vivo using hyperpolarized [1-13C]pyruvate.

Hoora Shaghaghi¹, Stephen J. Kadlecek¹, Sarmad Siddiqui¹, Mehrdad Pourfathi¹, Profka Harrilla¹, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Ascorbic acid is a first line pulmonary defense mechanism against endogenous and exogenous oxygen reactive species. As such, we investigated the effect of ascorbate on lung metabolic activity using hyperpolarized [1-13C] pyruvate. The bicarbonate signal significantly increased in the presence of ascorbate. Addition of N,N,N′,N′-tetramethyl-p-phenylenediamine(TMPD), a well-known compound used in electron transfer chain investigations, into the ascorbate-containing perfusate amplifies this enhancement. Since the reaction rate of ascorbate plus TMPD is 30 times faster than that of ascorbate alone, we concluded that the effect of ascorbate on PDH flux is a mitochondrial membrane linked effect.

Justin Y. C. Lau^1,2, Albert P. Chen³, Jennifer Barry², William Dominguez-Viqueira², and Charles H. Cunningham^1,2
1Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, ²Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada, ³GE Healthcare, Toronto, Ontario, Canada

The feasibility of interleaved imaging and selective spectroscopic acquisition for hyperpolarized ¹³C is demonstrated in vivo. The asymmetry of the pyruvate C₂ doublet has been shown to correlate with the instantaneous polarization. Combined with a calibration-based interpretation of measured C₂asymmetry, this investigation is a promising step toward hyperpolarized signal intensity normalization for quantitative in vivo metabolic image analysis.

Steven Reynolds¹, Tooba Alizadeh², Stephen Metcalf², Adriana Bucur¹, Samira Kazan², Becky Bibby², Martyn Paley¹, and Gillian M Tozer^2
1Academic unit of radiology, University of Sheffield, Sheffield, South Yorkshire, United Kingdom, ²Tumor microcirculation group, University of Sheffield, Sheffield, South Yorkshire, United Kingdom

Hyperpolarized ¹³C-pyruvate MRS/MRI was used to study the effect of dichloroacetate (DCA), which disrupts pyruvate dehydrogenase kinase, on tumor metabolism. We used acute DCA dosing (30 minutes prior to scanning) and chronic DCA dosing (up to 10 daily doses) in P22 sarcoma-bearing BDIX rats. MR data showed no significant difference between treated and control groups for the pyruvate to lactate rate constant k_pl in either the acute or chronic cohorts. There were also no significant differences in tumor growth rate or percentage cell necrosis. However, pyruvate concentration was decreased in tumors treated chronically with DCA versus control.

Michael S Dodd¹, Andrew J Lewis¹, Vicky Ball¹, and Damain J Tyler^1
1Oxford Metabolic Imaging Group, University of Oxford, Oxford, OXON, United Kingdom

Carnitine performs several vital roles in cellular metabolism including facilitating the transport of fatty acids into the mitochondria and buffering acetyl groups from excess acetyl-CoA. Carnitine supplementation has been proposed as a treatment for conditions such as heart failure. In this study, short-term carnitine supplementation in control animals did not alter the metabolism of pyruvate under normal situations. However, during a time of increased acetyl group availability, caused by dichloroacetate infusion, there was evidence of a carnitine reserve which was able to buffer excess acetyl groups into acetylcarnitine, allowing recycling of CoA back into β-oxidation or the TCA cycle.

Tsen-Hsuan Lin¹, Joong Hee Kim², Carlos Perez-Torres², Chia-Wen Chiang², Kathryn Trinkaus³, Anne H. Cross^4,5, and Sheng-Kwei Song^2,5
1Physics, Washington University, St. Louis, MO, United States, ²Radiology, Washington University School of Medicine, St. Louis, MO, United States,³Biostatistics, Washington University School of Medicine, St. Louis, MO, United States, ⁴Neurology, Washington University School of Medicine, St. Louis, MO, United States, ⁵The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Axonal transport plays a crucial role in neurodegenerative diseases. However, few reports have assessed axonal transport rate in MS or in experimental autoimmune encephalomyelitis (EAE). To assess the integrity of axonal transport in EAE, we employed the widely used manganese-enhanced MRI (MEMRI) on EAE mice at the onset of optic neuritis. Our results reveal that the axonal transport rate in EAE mice at the optic neuritis onset was significant decreased compared with the sham mice and correlated well with severity of impaired visual function. Postmortem immunohistochemistry was performed to assess optic nerve pathologies, including axonal injury, demyelination, and inflammation.

Kamila U Szulc^1,2, Jason P Lerch³, Brian J Nieman³, Benjamin B Bartelle^1,4, Edward J Houston¹, Giselle A Suero-Abreu^1,2, Miriam Friedel³, Charles Watson⁵, Alexandra L Joyner⁶, and Daniel H Turnbull^1,7
1Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY, United States,²Biomedical Imaging Graduate Program, NYU School of Medicine, New York, NY, United States, ³Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada, ⁴Molecular Biophysics Graduate Program, NYU School of Medicine, New York, NY, United States, ⁵The Australian Mouse Brain Mapping Consortium, The University of Queensland, Brisbane, QLD, Australia, ⁶Developmental Biology Program, Sloan-Kettering Institute, New York, NY, United States, ⁷Departments of Radiology and Pathology, NYU School of Medicine, New York, NY, United States

Lacking among the currently available set of MRI techniques has been an imaging approach that would allow for 3D noninvasive, longitudinal studies of brain development in individual mice. The goal of this project was to develop and optimize a Mn-enhanced MRI (MEMRI) imaging approach and to create a comprehensive database of normal mouse brain development to serve as a reference for future studies of mouse models of neurodevelopmental disorders. Through this work we were able to show that different brain regions are characterized by unique growth rates and patterns, which are accompanied by brain-region specific changes in MEMRI signal intensity.

Chiao-Yun Chen^1,2, Twei-Shiun Jaw^1,2, Deng-Chyang Wu^2,3, Yun-Ming Wang⁴, Gin-Chung Liu^1,2, Kazunari K. Yokoyama², and Yaw-Bin Huang^2
1Kaohsiung Medical University Hospital, Kaohsiung, TAIWAN, Taiwan, ²Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TAIWAN, Taiwan, ³Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, TAIWAN, Taiwan, ⁴National Chiao Tung University, Hsinchu, TAIWAN, Taiwan

We established a high penetration, high sensitivity infrared-fluorescent protein(IFP) for fluorescent imaging and synthesized the relatively high temporal and spatial resolution MR sensing contrast agent (SCA):£]-galactosidase(£]-gal) MR probe for producing the MR molecular imaging with a dual-imaging reporter animal model. The modality was used to verify the role of HOXA gene subfamily in gastric cancer development .It might also be useful in evaluating the effects of various therapeutic approaches. Because of the advantages offered by a combination of optical and MR images, it is hopeful that this technique will move quickly from in vitro and animal study to clinical trials.

Piotr Dzien¹, Sui-Seng Tee¹, Mikko Kettunen¹, Timothy Larkin¹, Scott Lyons¹, Kerstin Timm¹, De-En Hu¹, Tiago Rodrigues¹, Eva Serrao¹, Elizabeth Mannion¹, Paula D'Santos¹, and Kevin Brindle^1
1Biochemistry, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom

A reporter gene that could be used with MRI would allow exploitation of the advantages of this imaging technique - spatial and temporal resolution and the penetration depth necessary for in vivo imaging. DNP increases the signal-to-noise ratio sufficiently to allow direct detection of the 13C tracer in real time and presents a novel approach for developing MR reporter genes. Here we report a proof of concept study in which we use inducible expression of a bacterial gene encoding the enzyme, pyruvate decarboxylase (PDC), as a marker for DNP MRSI.

Dian R. Arifin^1,2, Deepak Kadayakkara^1,2, and Jeff W.M. Bulte^1,2
1Russell H. Morgan Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

We developed fluorine-labeled alginate microcapsules (fluorocapsules) for protection of transplanted pancreatic cells against immunorejection. Our goal is to assess the feasibility of ¹⁹F MRI to non-invasively visualize the degradation of fluoroencapsulated cell grafts, and therefore the impending failure of cell therapy in the case of capsule rupture. We successfully demonstrated that the release and dissipation of the fluorine agent upon capsule rupture could be detected as a reduction in ¹⁹F MR signal. This corresponded to a decrease in cell viability, indicating that ¹⁹F MRI can be used as a surrogate marker to predict therapeutic success or failure.

Yuki Mori^1,2, Ting Chen¹, Koji Ohno³, Shinichi Yoshida⁴, Yoshiyuki Tago⁴, Tetsuya Fujisawa⁵, Yuuto Kashiwagi¹, Masaki Fukunaga^1,2, Yutaka Komai⁶, Yutaka Hata⁵, and Yoshichika Yoshioka^1,2
1Biofunctional Imaging, Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan, ²Center for Information and Neural Networks (CiNet), National Institute of Information and Communications Technology (NICT) and Osaka University, Suita, Osaka, Japan, ³Institute for Chemical Research, Kyoto University, Uji, Kyoto, Japan, ⁴Frontier Biochemical and Medical Research Laboratories, Kaneka Corporation, Takasago, Hyogo, Japan, ⁵Graduate School of Engineering, University of Hyogo, Himeji, Hyogo, Japan, ⁶Single Molecule Imaging, IFReC, Osaka University, Suita, Osaka, Japan

Combination of MRI and nanoparticles has a possibility for visualizing the dynamics of cells in mouse brain. In this study, we focused on peripheral macrophages and attempted to track them noninvasively. We also attempted to monitor dynamic behaviors of cell migration with time-lapse MRI movie. MRI can successfully monitor the recruitment of peripheral macrophages into CNS even in normal as well as abnormal condition such as systemic inflammation or brain ischemia. Time-lapse MRI movie may reveal critical insights into cell behaviors that are not readily evident by microscopy. Our technique could contribute to reveal the mechanisms of neuro-immune crosstalk.

Jeff M Gaudet^1,2, Emeline J Ribot³, Yuhua Chen¹, Kyle Gilbert⁴, and Paula Foster^1,2
1Imaging Research Laboratories, Robarts Research Institute, London, Ontario, Canada, ²Medical Biophysics, University of Western Ontario, London, Ontario, Canada, ³Centre de Resonance Magnetique des Systemes Biologiques, Universite Bordeaux, France, ⁴Centre for Functional and Metabolic Mapping, Robarts Research Institute, London, Ontario, Canada

Stem cell therapy has the potential to revolutionize modern medicine and clinical trials are already underway. Still, questions persist concerning which parameters (implantation method, size of transplant, timing) produce the best clinical outcomes. Fluorine-19 (¹⁹F) MRI provides an excellent tool to address these issues because of the potential for unambiguous detection and accurate quantification. In this study we correlate the change in ¹⁹F-signal quantification over time with fluorescence microscopy and immunohistochemistry. Our results indicate that accurate quantification of the cellular number is possible under some conditions and that ¹⁹F –labeling of bystander macrophages can confuse interpretation in certain cases.

Di Chang^1
1Department of Radiology, Jiangsu Key Laboratory of Molecular and Functional Imaging, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China

Angiogenesis is defined as blood vessel formation from a pre-existing vasculature, the formation of which can promote the recovery of cardiac blood flow after myocardial infarction. Proliferating endothelial cells highly express a number of integrins associated with angiogenesis, of which ¦Á¦Í¦Â3 has been shown to be particularly important. Cyclic peptide containing an arginine-glycine-aspartic acid (cyclic RGD) sequence has a high affinity to ¦Á¦Í¦Â3 integrin. The objective of this study was to design and develop a novel cyclic RGD probe based multi-modality imaging for evaluation of angiogenesis in myocardial infarction model.

Shruti Kanakia¹, Dung Minh Hoang², Jimmy Toussaint¹, Sayan Mullick Chowdhury¹, Stephen Lee¹, Kenneth R Shroyer³, William Moore⁴, Balaji Sitharaman¹, and Youssef Zaim Wadghiri^2
1Biomedical Engineering, Stony Brook University, Stony Brook, NY, United States, ²Radiology, Bernard & Irene Schwartz Center for Biomedical Imaging, NYU School of Medicine, New York, NY, United States, ³Pathology, Stony Brook University, Stony Brook, NY, United States, ⁴Radiology, Stony Brook University, Stony Brook, NY, United States

We report pre-clinical in vivo small animal safety and efficacy studies of a novel graphene-based blood pool MRI CA. The formulation called Mn-GNP-Dex (disk-shaped, thickness=3-4 nm, diameter ~100 nm) consists of graphene nanoparticles intercalated with manganese Mn2+ ions, are water-solubilized with dextran and have r1 relaxivity 92 mM-1S-1. The results show that the Mn-GNP-Dex formulation is safe, does not show any toxic effect in the animals with renal insufficiency, remains in blood for up to 2 hours and is more efficacious than clinical blood pool CA Ablavar®. Hence, Mn-GNP-Dex has great potential for development as high performance T1 blood pool MRI CA.

Céline Boutin¹, Estelle Léonce², Thierry Brotin³, Alexej Jerschow⁴, and Patrick Berthault^2
1IRAMIS, SIS2M, UMR CEA/CNRS 3299, CEA Saclay, Gif-sur-Yvette, Gif sur Yvette, France, ²IRAMIS, SIS2M, UMR CEA/CNRS 3299, CEA Saclay, Gif sur Yvette, France, ³Laboratoire de Chimie, CNRS, Ecole Normale Supérieure de Lyon, Lyon, France, ⁴Chemistry Department, New York University, New York, NY, United States

129Xe biosensors have been demonstrated to provide sensitive probes of biological events. Very sensitive detection thresholds can be reached with the HyperCEST approach. We report herein the use of ultra-fast Z-spectroscopy as a powerful means to detect low concentrations of 129Xe NMR-based sensors in a single shot. This experiment enables a multiplexed detection of several sensors, as well as the extraction of the exchange buildup rate constant in a single-shot fashion. The ultrafast method makes it possible to provide ultra-fast and high-throughput sampling of biomarker mixtures.

Benedicte Descamps¹, Sara Neyt², Caroline Dumolyn², Elke Decrock³, Julie Bolcaen^4,5, Ingeborg Goethals^4,5, Tom Boterberg^6,7, Filip De Vos², Christian Vanhove^1,8, and Karel Deblaere^4,9
1Infinity - Medisip - iMinds, Ghent University, Ghent, Belgium, ²Radiopharmacy, Ghent University, Ghent, Belgium, ³Basic Medical Sciences, Ghent University, Ghent, Belgium, ⁴Radiology and Nuclear Medicine, Ghent University, Ghent, Belgium, ⁵Nuclear Medicine, Ghent University Hospital, Ghent, Belgium, ⁶Radiotherapy and Experimental Cancer Research, Ghent University, Ghent, Belgium, ⁷Radiotherapy, Ghent University Hospital, Ghent, Belgium, ⁸GROUP-ID, Ghent University, Ghent, Belgium, ⁹Radiology and Medical Imaging, Ghent University Hospital, Ghent, Belgium

Iron oxide-based contrast agents can be labeled with antibodies to image selectively targeted molecular processes using MRI. Intercellular adhesion molecule (ICAM1) plays a key role in the early inflammatory cascade following brain irradiation. This protein mostly expresses on the luminal surface of the endothelium of brain venules and capillaries and promotes the recruitment and migration of leukocytes. We show that micron-sized particles of iron oxide (MPIO) labeled with anti-ICAM1 antibodies are a useful tool to selectively image the local upregulation of endothelial ICAM1 expression in an animal model of early radiation injury using T2*w MRI.

Zhuoli Zhang¹, Andrew Christian Gordon¹, Weiguo Li¹, Yang Guo¹, Elias Gounaris¹, Alexander Sheu¹, Jodi Robin Nicolai¹, Daniele Procissi¹, and Andrew Larson^1
1Radiology, Northwestern University, Chicago, Illinois, United States

In this work we demonstrate that iron-oxide labeled Dendritic Cells (DC), loaded with antigens, can be effectively tracked as they “home in” on the lymph nodes using MRI. We also correlate therapeutic response to successful targeting of DC as measured with MRI. The potential of the methods described can provide additional tools to develop DC based cancer vaccines.

Marie Poirier-Quinot¹, Ludovic de Rochefort¹, Ingrid Leguerney^1,2, Sandra Robin^1,2, Xavier Violas³, Luc Darrasse¹, Rose-Marie Dubuisson¹, Stéphanie Pitre-Champagnat¹, Philippe Robert³, and Nathalie Lassau^1,2
1Univ Paris Sud, CNRS, UMR 8081, IR4M, Orsay, France, ²IRCIV Gustave Roussy, Villejuif, France, ³Guerbet, Research, Roissy CDG Cedex, France

Evaluation of the specificity of multimodal molecular protocol, with two different imaging techniques, US and MRI, involving contrast agents (µbubbles and iron oxide nanoemulsion) both of them functionalized to target the same integrin (ανβ3) in mouse xenograft tumor model of kidney cancer is presented here. The protocol allows to quantify the tumor size, the dynamic contrast-enhanced DCE-US, the diffusion, the dynamic susceptibility contrast DSC-MR during 1 hour after injection. This methodological study could be used to follow-up treatment response.

VIOLAS Xavier¹, ROBERT Philippe², NAIN DIT DUCRET Martine², ROBIC Caroline², BALLET Sebastien², and COROT Claire^2
1Guerbet, Aulnay sous bois, France, ²Guerbet, France

A new iron oxide nanoparticle based USPIO (P04000) is evaluated in terms of specificity and capacity to monitor antiangiogenic treatment in a brain tumor model in mice. The high affinity rgd vectored contrast agent who targets avb3 allows, with a basic Multi Gradient Echo sequence, to specifically enhance the tumor 2 hours post injection. The uptake of this agent is reduced to zero in the bevacizumab treated group before the tumor regression. This MR contrast agent is able to early demonstrate the effect of anti-angiogenic therapy with feasible MRI sequence and data post processing in humans.

Nevin McVicar^1,2, Alex X Li², Mojmir Suchy³, Robert H Hudson³, and Robert Bartha^1,2
1Medical Biophysics, University of Western Ontario, London, Ontario, Canada, ²Centre for Functional and Metabolic Mapping, Robarts Research Institute, London, Ontario, Canada, ³Chemistry, University of Western Ontario, London, Ontario, Canada

Tissue temperature is measured in-vivo in mouse leg muscle following intramuscular injection of a paraCEST contrast agent using magnetic resonance imaging (MRI). Tissue MRI properties including relaxation time constants, diffusion coefficients and magnetization transfer effects were measured before and after paraCEST injection. Significant changes in tissue MR properties were observed between pre- and post-injection data. Only apparent diffusion coefficient correlated with measured tissue temperature. The paraCEST tissue temperature measurements were in agreement with true tissue temperature. Therefore, in-vivo tissue temperature measurements made using paraCEST contrast agents following direct injection are accurate despite changes in tissue relaxation properties.

Yuguo Li^1,2, Kannie Chan^1,2, Yuan Qiao³, Jiadi Xu², Jeff Bulte¹, Bert Vogelstein³, Michael McMahon^1,2, Shibin Zhou³, Peter van Zijl^1,2, and Guanshu Liu^1,2
1Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²FM Kirby center, Kennedy Krieger Institute, Baltimore, MD, United States, ³Ludwig Center, Howard Hughes Medical Institute and Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Assessing tumor vascular permeability has important applications in clinical diagnosis and for the development of personalized nanoparticulate therapeutics. Here, we explored dextran as a potential Chemical Exchange Saturation Transfer (CEST) imaging agent by utilizing the CEST contrast originating from OH protons on the glucose units. Contrast was studied for particle sizes ranging from 4-60 nm. Dextrans of different molecular weights could be readily detected using CEST MRI. The differential permeability of an experimental tumor to dextrans sized at 4 and 14 nm was detected and renal clearance of the agents was also monitored.

Xiaodong Zhong¹, Liya Wang^2,3, Jing Huang^2,3, and Hui Mao^2,3
1MR R&D Collaborations, Siemens Healthcare, Atlanta, GA, United States, ²Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, United States, ³Center for Systems Imaging, Emory University School of Medicine, Atlanta, GA, United States

This study demonstrates a new method of SubShortTE, i.e. subtraction of a later echo signal from an earlier echo signal, with widely available SE/TSE sequences for generating positive contrast from magnetic nanoparticle contrast agents. This approach was evaluated with theoretical simulation and phantom imaging using iron oxide nanoparticles (IONP) with different sizes and concentrations. The results demonstrated that positive contrast could be obtained in IONP phantoms using this approach. SubShortTE could potentially provide a robust alternative method to the other positive contrast methods for molecular imaging and cell tracking applications without the need of any special sequences.

Andrea Protti¹, Xuebin Dong¹, Ajay Shah¹, and Rene Botnar^1
1King’s College London British Heart Foundation Centre of Excellence, London, UK, United Kingdom

Dynamic contrast-enhanced MRI (DCE-MRI) plays an increasingly important role in cardiac imaging . The dynamics of contrast agent uptake and distribution have shown high sensitivity and specificity for many pathological changes that are not detectable by anatomical imaging. Magnevist Gd-DTPA is one of the most used clinically approved contrast agents able to differentiate areas of burden from healthy after myocardial infarction (MI). Despite being an optimal tool to delineate the extent of infarction areas, Magnevist does not provide any insight about remodeling processes. For this reason, the albumin contrast agent gadofosveset, trade name Vasovist (from Ablavar), is used in this work to evaluate similarities and advantages to Magnevist in an MI mouse model at 7T.

Badrul Alam Bony¹, Wenlong Xu¹, Tirusew Tegafaw Mengesha¹, Chorong Kim¹, Sung June Kim¹, Md. Wasi Ahmad¹, and Gang Ho Lee^1
1Chemistry, Kyungpook National University, Daegu, Korea

Biocompatible and water soluble D-glucuronic acid coated ultrasmall GdMnO₃ nanoparticles were synthesized through a straight forward one step route for the first time. In vivo and in vitro images confirmed that, this nanoparticles can be applicable as a potential MRI contrast agent.

Akshat C Pujara¹, Carolyn Wassong¹, Roy A Raad¹, James Babb¹, Linda Moy¹, and Amy Melsaether^1
1New York University School of Medicine, New York, NY, United States

Validation of MR attenuation correction (MRAC) is required for comparison of SUVs derived from PET/CT with those derived from PET/MRI. The current study demonstrates that SUVmax generated from MRAC correlates well with SUVmax generated from PET/CT for normal structures and breast cancer metastases, and can thus be used for quantification of FDG activity. Interestingly, the metabolic activity of breast cancer metastases during the interval between PET/CT and PET/MRI differed depending on the site of spread. Further investigation is needed to evaluate the potential role of SUV measurements in tailoring imaging protocols to the metabolic activity of organ-specific metastases.

Liya Wang^1,2, Jing Huang^1,2, Xiaodong Zhong³, Hui Wu^1,2, Lily Yang⁴, and Hui Mao^1,2
1Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, United States, ²Center for System Imaging, Emory University School of Medicine, Atlanta, Georgia, United States, ³MR R&D Collaborations, Siemens Healthcare, Atlanta, Georgia, United States, ⁴Surgery, Emory University School of Medicine, Atlanta, Georgia, United States

This study demonstrated the application of novel sub-5 nm ultra-fine iron oxide (UFIO) nanoparticles in imaging of xenograft tumors. The results showed higher tumor uptake of UFIO nanoparticles comparing to iron oxide nanoparticles (IONPs) with larger sizes, suggesting that the penetration and accumulation of IONPs in tumor tissue is size dependent. The transition from T1 contrast in the tumor vasculature in the early phase of post-injection to the T2 contrast at later phase, i.e., 24 hours after the injection of UFIO nanoparticles may provide a novel capability for following a dynamic process of delivery of UFIO probes to the tumor.

Ying-Ying Bai¹ and Shenghong Ju^1
1Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospita, Nanjing, Jiangsu, China

This study demonstrated that the neovasculature targeted nanoprobe can specifically evaluate angiogenesis in ischemic stroke. Molecular imaging demonstrated impaired angiogenesis in the diabetic mice and revealed the pro-angiogenic effects of EPC, the precursor cell of endothelial cell. While current clinical techniques for monitoring therapeutic efficacy, such as blood flow measurements, are capable of detecting large caliber vessels that form at the late stages of revascularization, molecular imaging with targeted contrast agents can map the early signatures of angiogenesis. In clinical practice, earlier detection of therapeutic response could be invaluable for guiding therapies, including determining effective drug doses and evaluating new treatment strategies.

Hsin-Jung Yang¹, Ke Cheng¹, Ryan middleton¹, Ivan Cokic¹, Avinash Kali¹, Louis Bouchard², Eduardo Marban¹, and Rohan Dharmakumar^1
1Cedars Sinai Medical Center, Los Angeles, California, United States, ²UCLA, Los Angeles, California, United States

Retention of cells within regions of interest following their delivery is a known obstacle in the field of regenerative medicine. Recent studies have demonstrated that magnetic field gradient of bar magnets can be used to couple with the dipole moment of the cells labeled with iron oxide can be used to enhance retention and therapeutic regeneration. In this work, we investigated whether a Maxwell coil, which can be positioned within the MR scanner, would be able to deliver sufficient one-dimensional force on USPIO particles and the effect of this resultant force can be captured on the basis of T2* MRI.

Simonetta Geninatti¹, Diego Alberti², Antonio Toppino², Annamaria Deagostino², Stefania Lanzardo², Nicoletta Protti³, Silva Bortulussi³, Saverio Altieri³, and Silvio Aime^2
1Molecular Biotechnology and health sciences, University of Torino, Torino, TO, Italy, ²University of Torino, TO, Italy, ³University of Pavia, PV, Italy

A new dual agent targeted to pulmunary metastasis via Low Density Lipoprotein transporters has been proposed as an efficient and selective carrier of Boron and Gadolinium for MRI guided Boron Neutron Capture Therapy.

Else Marie Huuse^1,2, Jana Cebulla², Dan E Meyer³, Karina Langseth⁴, Siver Andre Moestue², and Tone Frost Bathen^2
1Department of medical Imaging, St. Olavs University Hospital, Trondheim, Norway, ²MI lab and Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway, ³Biomedical Imaging & Physiology Laboratory, GE Global Research Center, Niskayuna, NY, United States, ⁴GE Healthcare AS, Oslo, Norway

Preclinical-phase iron oxide particles (GEH121333), with a relatively large diameter and a high r1/r2 rate was used for monitoring vascular response to bevacizumab treatment in ovarian xenografts. Changes in T2 and T2* relaxation rate was used for calculation marker for the blood vessel density Q=R2/(R2*^2/3) and post contrast tissue T1 after clearance of iron particles from the blood pool was used as a measure for changed tumor vessel permeability. The results suggest that the novel GEH121333 particles can be used to detect vascular changes after anti-angiogenic therapy and that their magnetic properties allow evaluation of changes both in T1 and susceptibility imaging, attributable to underlying changes in permeability and blood vessel density, respectively.

Nicolas Gargam¹, Luc Darrasse¹, Philippe Robert², Jean-Christophe Ginefri¹, Jean-Sébastien Raynaud², and Marie Poirier-Quinot^1
1IR4M - UMR 8081, Université Paris Sud XI, Orsay, France, ²Imaging and Biological Research, Guerbet, Paris, France

In this study, we introduce an in vitro set-up that allows to control the binding of a targeted CA to its receptor by micro-MRI. Experiments inspired by the BIAcore system were realized and allowed to know the kinetics of a CA towards its receptor. This new technique could help optimizing the in vivo protocols especially for the optimal time between the injection of the CA and the imaging acquisition.

Ludovic de Rochefort¹, Ingrid Leguerney¹, Marie Poirier-Quinot¹, Sandra Robin¹, Xavier Violas², Rose-Marie Dubuisson¹, Stéphanie Pitre-Champagnat¹, Luc Darrasse¹, Philippe Robert², and Nathalie Lassau^1
1IR4M, Univ. Paris-Sud, CNRS, UMR 8081, Orsay, France, ²Experimental Imaging, MRI unit, Research Division, Guerbet, Aulnay-sous-bois, France

A multimodal molecular MRI and DCE-US protocol was applied in kidney tumor xenograft in mice to follow up the response to anti-angiogenic treatments. Imaging was performed at D0 and D3 after monoclonal anti-body, tyrosine kinase inhibitor and m-Tor inhibitor administration. Tumor growth, perfusion (US), diffusion, first pass enhancement (1 min) and late enhancement (1 hour) of a targeted áíâ3 contrast agent (MRI) were quantified. Tumor growth was reduced with treatments. Differences were observed in apparent diffusion coefficient, targeted contrast agent clearance and fixation in the different groups after treatment.

Viviana Negri^1,2, Daniel Calle³, Piedad Ros⁴, Sebastian Cerdán³, and Paloma Ballesteros^2
1CSIC, Instituto de Investigaciones Biomédicas "A.Sols"-CSIC, Madrid, Madrid, Spain, ²Laboratorio de Síntesis Orgánica e Imagen Molecular por Resonancia Magnética, Facultad de Ciencia, UNED, Madrid, Madrid, Spain, ³Departamento de Modelos Experimentales de Enfermedades Humanas, CSIC, Instituto de Investigaciones Biomédicas "A.Sols"-CSIC, Madrid, Madrid, Spain, ⁴Departamento de Farmacia y Biotecnología, Universidad Europea de Madrid, Madrid, Madrid, Spain

We describe a new generation of highly soluble, paramagnetically labeled multiwall CNTs (MWCNTs) with Gd(III)DOTA monoamide-like functionalized with a pyrene moiety, linked to the CNT through - stacking interactions. In particular, we report on the synthesis, MRI studies (ADC, T1, T2) and fluorescence emission spectra of these - stacking MWCNTs-pyrene DOTAma adducts. We synthesized two different - stacking adducts MWNTs-Gd(III)DOTAmaPyrene and MWNTs-Gd(III)DOTAmaEtDiaminePyrene, shown to be highly water soluble and to induce anisotropic diffusion of water, due to alignment of the magnetic nanotubes along the B0 axis. These derivatives are also potential fluorescence probes yielding a novel multimodal imaging platform.

Sung June Kim¹, Wenlong Xu¹, and Gang Ho Lee^1
1Chemistry, Kyungpook National University, Daegu, Korea

We demonstrated that mixed lanthanide oxide nanoparticles should be potential dual T₂ MRI-FI agents by using three systems of ultrasmall mixed lanthanide (Dy/Eu, Ho/Eu, and Ho/Tb) oxide nanoparticles. Appreciable r₂ values at 1.5 tesla MR fields and appreciable fluorescence in visible region were observed in all samples.

Vít Herynek¹, Marie Martinisková², Andrea Gálisová¹, Jan Kotek², Daniel Jirák¹, and Milan Hájek^1
1Institute for Clinical and Experimental Medicine, Prague, Czech Republic, ²Faculty of Science, Charles University, Prague, Czech Republic

19F MRI is potentially an interesting tool for diffusion or perfusion measurements, and for cell tracking. It requires biocompatible and non-toxic contrast agents with high fluorine ion concentration with suitable relaxation times. We synthesized and tested both in vitro and in vivo probes based on DOTP chelates with 12 equivalent fluorine ions and a lanthanoid ion, which substantially shortens relaxation times. Measuring sequences were optimized for each chelated lanthanoid.

Lindsey Alexandra Crowe¹, Nicolas Kunz², Iris Friedli¹, Azza Gramoun¹, Kerstin Grosdemange¹, Lionel Maurizi³, Geraldine Coullerez³, Marie-Gabrielle Beuzelin³, Rolf Gruetter², Heinrich Hofmann³, and Jean-Paul Vallée^1
1Radiology, Geneva University Hospitals, Geneva, Switzerland, ²Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, ³Powder Technology Laboratory, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

The use of iron oxide nanoparticles in MRI is leading development of image acquisition and analysis techniques to accurately localize uptake and persistence of such contrast agents. Detailed localization of the SPION and its contrast to other structures that are also hypointense is important. We explore the advantages of high field and high resolution MRI to assess inflammation, macrophage uptake and bone erosion in an antigen-induced arthritis (AIA) model.