Lindsay Kathleen Hill^1,2, Stewart Russell^3,4, Dung Minh Hoang¹, and Youssef Zaim Wadghiri^1
1Radiology, NYU School of Medicine, New York, NY, United States, ²Biomedical Engineering, SUNY Downstate Medical Center, Brooklyn, NY, United States, ³Thayer School of Engineering, Dartmouth College, Hanover, NH, United States, ⁴Department of Mechanical Engineering, The City College of New York, New York, NY, United States

Advancement in the field of Gadolinium-bound contrast agent discovery is reliant on the development and characterization of novel constructs made in-house. However, the assessment of physicochemical properties and in vivo pharmacokinetics, requiring highly sensitive measurements, is often impeded by the lack of analytical techniques that are simultaneously sensitive, affordable, and accessible. Here we demonstrate that Carbostyril 124-sensitized DTPA can be incorporated into a lipid-based microparticle, allowing for rapid quantification of Gadolinium concentration with nanomolar sensitivity using a readily available fluorescence plate reader. This sensitive and convenient technique could rapidly propel the characterization of novel MR contrast agents. 

Nutte Teraphongphom¹, Peter Chhour², John Eisenbrey³, Pratap Chandra Naha², Walter Witschey², Borirak Opasanont⁴, Lauren Jablonowski¹, David Peter Cormode², and Margaret Wheatley^1
1Biomedical Engineering, Drexel University, Philadelphia, PA, United States, ²Radiology, University of Pennsylvania, Philadelphia, PA, United States, ³Radiology, Thomas Jefferson University, Philadelphia, PA, United States, ⁴Chemical and Biological Engineering, Drexel University, Philadelphia, PA, United States

To create multimodal contrast agents, we hypothesized that the shell of polymeric microbubbles could accommodate additional payloads. We therefore modified microbubbles by encapsulating nanoparticles including quantum dots, magnetic iron oxide nanoparticles, or gold nanoparticles to create bi-modality platforms in a manner that minimally compromised the performance for each individual imaging technique (ultrasound, fluorescence imaging, computed tomography and MRI). 

Zhuxian Zhou^1,2, Zheng Han¹, and Zheng-Rong Lu^1
1Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States, ²Chemical and Biological Engineering, Zhejiang University, Hangzhou, China, People's Republic of

To produce MRI detectable signal enhancement for the biomarker on cancer cell surface, we developed a targeted host-guest nanosized contrast agent cRGD-POSS-βCD-(DOTA-Gd)-Cy5. The nanosized host-guest systems are preferable for facile synthesis of customized and functionalized imaging agent. Here, a cyclic peptide cRGD targeting to cancer cell α_vβ₃-integrin, a macrocyclic Gd(III) chelate and Cy5 fluorescent probes were loaded on the nanosized carrier by host-guest interaction. cRGD-POSS-βCD-(DOTA-Gd)-Cy5 can provide strong contrast enhancement to delineate malignant tumors during molecular MR and fluorescent imaging in a mouse 4T1 breast cancer model.

Eric A Tanifum^1,2, Chandresh Patel¹, Robia Pautler², and Ananth Annapragada^1,2
1Texas Children's Hospital, Houston, TX, United States, ²Baylor College of Medicine, Houston, TX, United States

Perfluorocarbons and perfluoropolyethers are currently the major molecules of choice in ¹⁹F MRI contrast agents. These molecules generally have magnetically diverse ¹⁹F atoms and are very hydrophobic. The later characteristic greatly hinders easy access to stable formulations for broad usage and the former generates chemical shift artifacts which result in blurred images. We have synthesized several hydrophilic organofluorine molecules all bearing magnetically equivalent ¹⁹F atoms and demonstrated that they are amenable to facile liposome nanoparticle formulation protocols. The resulting particles are highly stable and present a great potential for diverse applications as ¹⁹F MRI molecular imaging probes. 

Tanja Savic¹, Serhat Gündüz², Rolf Pohmann³, Nikos Logothetis⁴, Klaus Scheffler³, and Goran Angelovski^1
1Research group "MR Neuroimaging agents", Max Planck Institute for Biological Cybernetics, Tübingen, Germany, ²Research Group "MR Neuroimaging agents", Max Planck Institute for Biological Cybernetics, Tübingen, Germany, ³High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Tübingen, Germany, ⁴Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Tübingen, Germany

A number of bioresponsive MRI contrast agents have been developed, with the aim of producing the maximal signal difference for a given biological event. This paper introduces an approach which substantially improves the detection of physiological events with fast kinetics. A nanosized, calcium-sensitive dendrimeric probe was developed and characterized by means of a balanced steady-state free precession imaging protocol. Results show an almost four times greater contrast gain per unit of time as compared to conventional T1-weighted imaging with small sized contrast agents. Consequently, this ratiometric methodology has a profound significance for future studies of biological dynamic processes by means of MRI.

Andrea Galisova¹, Daniel Jirak¹, Marketa Jiratova¹, Martin Hruby², Maria Rabyk², Aneta Pospisilova², and Milan Hajek^1
1MR Unit, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, ²Academy of Sciences, Institute of Macromolecular Chemistry, Prague, Czech Republic

An effective cancer diagnostic and therapeutic contrast agent with suitable properties including high specificity and safety is on high demand. In this study, accumulation of a biocompatible and biodegradable glycogen-based nanoprobe (GG-Gd-DOTA-Dy) was tested and compared to a commercially available contrast agent (gadoterate meglumine). Relaxivity and MR imaging of the probe was performed on the phantoms. The uptake of the agents was measured on the tumor-bearing rats at several time points after the contrast agent administration by MRI and fluorescence imaging. We found out that the novel probe is superior to a commercially available contrast agent regarding the relaxivity and accumulation in the tumor tissue.

Begona Lavin Plaza¹, Alkystis Phinikaridou¹, Marcelo Andia², Silvia Lorrio Gonzalez¹, and Rene Botnar^1
1Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom, ²Pontificia Universidad Catolica de Chile, Santiago de Chile, Chile

Despite the beneficial effect of percutaneous transluminal coronary angioplasty and stent implantation, negative vascular remodeling remains as one of the most important complications of interventional cardiology. These procedures may damage the vessel wall, particularly the endothelium, leading to a dysfunctional state characterized by impaired vasodilation, increased leukocyte adhesion and permeability that constitute the initial steps of atherosclerosis. The arterial tree can be divided in either “athero-susceptible” areas, e.g. arterial branches and curvatures, where blood flow is turbulent and shear stress is multidirectional or “athero-resistant” areas, e.g. abdominal aorta, where blood flow is laminar and shear stress is low. In this study, we investigated (1) whether an “atherosclerotic-resistant” segment of the vascular tree, like the aorta, can be switched into an “atherosclerotic-susceptible” area following endothelial injury and (2) whether such a switch in vessel wall remodeling is associated with changes in vascular permeability that can be assessed in-vivo using the albumin binding MR contrast agent, gadofosveset.

Sudath Hapuarachchige¹, Robert Ivkov², and Dmitri Artemov^1
1Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Bionized nanoferrites are magnetic nanoparticles, which can be used as contrast agents and therapeutic platforms for alternating magnetic field (AMF) induced hyperthermia. One important application is enhancing of vascular permeability in tumors for delivery of nanodrugs. We studied BNF nanoparticles specifically targeted to the tumor vasculature via VEGF receptors ligands. Targeted BNF particles were visualized by intravital multiphoton and MR imaging, and increased accumulation of targeted BNF was detected in breast cancer models.

Danting Cui¹, Xiaodan Lu¹, Chenggong Yan¹, Xiang Liu¹, Yingjie Mei², Meirong Hou¹, Yikai Xu¹, and Ruiying Liu^3
1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China, People's Republic of, ²Philips Healthcare, Guangzhou, China, People's Republic of, ³School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China, People's Republic of

Bombesin (BBN) is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPr), To develop a BBN-assembled nanoprobe based on Gd2O3 was efficent for earlier tumor detection. Gd2O3 was conjugated with 5(6)-carboxyfluorescein and bombesin for MR/optical bimodal imaging of GRPr positive tumor. Gd2O3-FI-PEG NPs without bombesin-modified NPs were tested as non-targeted control.  MRI and opitical  imaging in vitro and vivo confirmed BBN-assembled Gd2O3 nanoprobe exhibited better binding affinity to GRPr positive tumor than the control group. The nanoprobe may provide opportunities to further biomedical application.

Yuqi Yang¹, Shizhen Chen¹, Sha Li¹, Lianhua Liu¹, and Xin Zhou^1
1Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China, People's Republic of

Two types of water-insoluble texphyrins (TP), anticancer drug Gd-TP and photosensitizer Lu-TP, were synthesized and loaded onto RGD-functionalized graphene quantum dots (GQDs) via π-π stacking. The obtained complex could be used as a MRI-fluorecent imaging multi-model probe for cancer therapy. Compared with conventional photodynamic therapy (PDT), our method demonstrated better therapy efficiency for deeper tissue, because a laser with longer wavelength was applied to active the photosensitizer Lu-TP. Furthermore, reactive oxygen species resulted from the reaction between redox active drug Gd-TP and cellular reducing metabolites and photothermal effect from GQDs led cancer cells more impressionable to PDT from Lu-TP. 

Ghulam Muhammad^1,2, Jiadi Xu³, Jeff W.M. Bulte¹, Anna Jablonska¹, Piotr Walczak^1,4, and Miroslaw Janowski^5
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States, ²Stem Cell Laboratory, University of the Punjab, Lahore, Pakistan, ³F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, MD, United States, ⁴Department of Radiology, University of Warmia and Mazury, Olsztyn, Poland, ⁵Johns Hopkins University, Baltimore, MD, United States

Incidence of acid burns due to accidents and attacks is on the rise and mesenchymal stem cell transplantation is a promising therapeutic strategy. Cell tracking makes treatment more precise. We have compared two MRI tracking strategies: SPIO nanoparticles-based 1H MRI and 19F nanoemulsion “hot-spot” MRI. Bioluminescence imaging was used as a reference standard for monitoring cell survival. Susceptibility artifacts due to skin injury compromised the interpretation of 1H imaging, while 19F MRI was capable of providing information on cell location and survival. The SPIO nanoparticles and fluorine nanoemulsion had no detrimental effect on the therapeutic activity and survival of MSCs.

Muhammad Jamal Afridi¹, Arun Ross², and Erik M Shapiro^3
1Department of Radiology, Department of Computer Science, Michigan State University, East Lansing, MI, United States, ²Department of Computer Science, Michigan State University, East Lansing, MI, United States,³Department of Radiology, Michigan State University, East Lansing, MI, United States

We describe an image analysis strategy for quantifying the location and number of transplanted stem cells from MRI images. MRI-based single cell detection facilitates the use of machine learning algorithms for spot detection. Using convolutional neural networks, automatic and intelligent cell enumeration was first developed on in vitro agarose samples containing a known number of labeled cell mimics. Then, the validated image analysis approach was used to quantify stem cell transplants in rodent brains. An accuracy of 99.8% was achieved on in vitro samples and 94.6% on in vivo examples.

Muhammad Jamal Afridi¹, Arun Ross², Steven Hoffman², and Erik M Shapiro^3
1Department of Radiology and Department of Computer Science, Michigan State University, East Lansing, MI, United States, ²Department of Computer Science, Michigan State University, East Lansing, MI, United States, ³Department of Radiology, Michigan State University, East Lansing, MI, United States

Despite advances in machine learning and computer-vision, many MRI studies rely on tedious manual procedures for quantifying imaging features, i.e. cell numbers, contrast area etc. Development of intelligent, automatic tools for quantifying imaging data requires large scale data for their training and tuning, which in the clinical arena is challenging to obtain.  Here, we present an approach that obviates the need for large scale data collection to develop an intelligent and automatic tool for single cell detection in MRI. Our strategy achieves 91.3% accuracy for in vivo cell detection in MRI despite using only 40% of the data for training.

Kai D. Ludwig¹, Benjamin L. Cox^1,2,3, Myriam N. Bouchlaka^4,5, Stephen A. Graves¹, Justin J. Jeffery⁵, R. Jerry Nickles¹, Bryan P. Bednarz^1,6, Christian M. Capitini^4,5, and Sean B. Fain^1,6,7
1Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, ²Morgridge Institute for Research, Madison, WI, United States, ³Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI, United States, ⁴Pediatrics, University of Wisconsin-Madison, Madison, WI, United States, ⁵Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States,⁶Radiology, University of Wisconsin-Madison, Madison, WI, United States, ⁷Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States

Methods for non-invasive cell tracking may greatly enhance the ability to assess efficacy of cellular-based therapies. A dual-labeled (⁸⁹Zr and ¹⁹F) cell labeling approach could inform and potentially improve in vivo cell tracking sensitivity and clinical adoption. Here, we show longitudinal detection of localized cell injections with ¹⁹F MRI and the ability to quantify the number of cells within a voxel. Additionally, ⁸⁹Zr cell tracking results shows a high sensitivity for intravenous delivery of cells with longitudinal signal detection. Future work aims to combine both cell tracking approaches utilizing the dual-modality imaging platform on a PET/MRI system.

Chien-Lin Yeh¹, Carlos J. Perez-Torres¹, and Ulrike Dydak^1,2
1School of Health Sciences, Purdue University, West lafayette, IN, United States, ²Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States

Being able to use MRI to estimate brain Mn accumulation is of high interest in occupational Mn exposure settings. As a first step towards absolute quantification of brain Mn concentration in exposed humans using MRI, the interaction between Mn and Fe and their combined effect to R1 need to be explored. Our results suggest that a model only assuming independent linear contributions of Mn and Fe already explains the R1 data well. However introducing a cross term of Mn and Fe in the equation improves the fits, suggesting a Mn-Fe interaction.   

Amit Kumar Srivastava^1,2, Jiadi Xu³, Peter C.M. van Zijl^2,3, Nicholas J Maragakis⁴, and Jeff W.M. Bulte^1,2,3
1Cellular Imaging Section, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, United States, ²Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States, ³F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, ⁴Neurology, Johns Hopkins University, Baltimore, MD, United States

Amyotrophic lateral sclerosis (ALS) is characterized by selective loss of motor neurons. ALS treatment is very difficult because disease manifestation and diagnosis often happen much later than when ALS pathology occurs in the patient. In this study, we developed two non-invasive MRI biomarkers for the early detection of disease pathology and its progression thereafter. A newly developed Glutamate-sensitive CEST showed higher signal intensity in the spinal cord level of ALS at pre-symptomatic stage, an indicator of initiation of ALS pathology. Manganese-enhanced MRI showed higher T1-weighted signal in the ALS spinal cord at post-symptomatic stage suggesting activation of astrocytes.          

Harikrishna Rallapalli¹, Eugenia Rafaela Volkova¹, I-Li Tan², Alexandre Wojcinski², Alexandra L Joyner², and Daniel H Turnbull^1
1Skirball Institute and Radiology, New York University School of Medicine, New York, NY, United States, ²Developmental Biology, Sloan Kettering Institute, New York, NY, United States

In this work, we describe a powerful longitudinal Manganese-enhanced magnetic resonance imaging (MEMRI) strategy to characterize a novel mouse medulloblastoma model. An activated Smoothened mutation was engineered to induce proliferative growth in the cerebellum. Lesions were monitored using MEMRI up to postnatal day P100, and 3D tumors were segmented for quantitative volumetric analysis. Qualitative analysis has shown a ~50% chance of regression overall (n=21), and preliminary quantitation has suggested a combined progression/regression growth model. With this model, we aim to guide diagnostic decisions from early timepoints and quantify therapeutic efficacy.

Alexia Daoust¹, Stephen Dodd¹, and Alan Koretsky^1
1NINDS, LFMI, NIH, Bethesda, MD, United States

MEMRI can be used for different applications such as tracing neuronal connections or functional imaging. However, Mn cellular uptake is still unclear. We studied this mechanism by the use of MEMRI in a hippocampal organotypic slice culture. After added Mn to the medium for 2h, we obtained an optimal MR contrast that was affected by Ca channel manipulation. Mn cellular uptake was also affected by the presence of other metals that use divalent metal transporters (DMT-1). Our results suggest a strong capacity of our technique to study the cellular mechanisms related to MEMRI.

Bashar Issa^1
1Physics, UAE University, Al-Ain, United Arab Emirates

Theories describing 1/T2 enhancement due to the presence of superparamagnetic particles agree well with experimental and Monte Carlo (MC) simulation data under the condition that the particles are monodisperse both in size and magnetization. We present a 1/T2 distributed model that takes into account the particle size and magnetization distributions. We average the individual 1/T2 components exhibited by each group of particle with a uniform particle size. MC simulations of the model successfully predict 1/T2 within the MAR regime confirming the implicit assumption that the spins are able to sample all the particles’ radii and magnetizations within the echo time.

Sergey Korchak¹, Wolfgang Kilian¹, Leif Schröder², and Lorenz Mitschang^1
1Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Germany, ²Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany

The reversible binding of xenon to host structures is fundamental to the development of novel contrast agents employing hyperpolarized xenon and chemical exchange saturation transfer (HyperCEST) for molecular imaging. The rates for entering and leaving the host depend on atomic details and affect the obtainable contrast rendering them pivotal for the selection of hosts and optimization of imaging methods. However, different exchange processes may apply whose contributions are difficult to assign. Exchange spectroscopy experiments are proposed which enable straightforward disentanglement of the exchange kinetics and quantification of individual contributions. The approaches are exemplified for the cryptophane-xenon host-guest system.

Eleni Demetriou¹, Mohamed Tachrount¹, Marilena Rega², Franscisco Torrealdea¹, Karin Shmueli³, Mark Farrow⁴, and Xavier Golay^1
1Brain Repair and Rehabilitation, Institute of Neurology, London, United Kingdom, ²Institute of Neurology, London, United Kingdom, ³Medical Physics and Biomedical Engineering, University College of London, London, United Kingdom, ⁴MRC prion unit, Institute of Neurology, London, United Kingdom

Prion diseases are fatal neurodegenerative disorders which are caused by abnormal conformational changes of cellular prion protein. Chemical Exchange Saturation Transfer (CEST) imaging of NOE effects has been proposed as a new imaging mechanism to monitor protein folding by MRI. In this study, prion-infected mice were imaged at three stages of prion disease (asymptomatic, early-stage and late-stage) to investigate whether prion propagation could be detected in their brains. We concluded that NOE values at different stages of prion disease provide additional evidence of prion protein misfolding occurring in the brains of diseased mice. 

Ferdinand Seith¹, Holger Schmidt¹, Sergios Gatidis¹, Ilja Bezrukov², Christina Schraml¹, Christina Pfannenberg¹, Christian la Fougère³, Konstanin Nikolaou¹, and Nina Schwenzer^1
1Radiology, Universitätsklinikum Tübingen, Tübingen, Germany, ²Max-Planck-Institut, Tübingen, Germany, ³Nuclear Medicine, Universitätsklinikum Tübingen, Tübingen, Germany

Attenuation correction (AC) plays a key role in the quantification of tracer uptake in positron emission tomography (PET), expressed as standardized uptake value (SUV). The segmentation method is the standard approach for AC in whole-body PET/magnetic resonance imaging (MRI) that has been implemented into the software of most vendors. However, this method is neglecting bone and applies only one single patient-independent attenuation coefficient for the whole lung. Our study could demonstrate that both, differences lung density and surrounding bone tissue can have significant influence on SUV measurement of physiological lung tissue, mostly affecting the posterior regions.

Ina Vernikouskaya^1,2, Alexander Pochert³, Mika Lindén³, and Volker Rasche^1,2
1Internal Medicine II, University Hospital of Ulm, Ulm, Germany, ²Small Animal MRI, University of Ulm, Ulm, Germany, ³Inorganic Chemistry II, University of Ulm, Ulm, Germany

Quantification of ¹H MR contrast agents (CA) is limited by the only indirect visualization of the changes of the relaxation properties of the surrounding tissue. Using alternative nuclei such as fluorine (¹⁹F) as CA enables direct and quantifiable readout of local CA aggregations, since the ¹⁹F signal linearly correlates with its local concentration. However non-uniformity of the transmit/receive radiofrequency fields impact the resulting absolute signal, leading to wrong quantification results. Application of an easy-to-use time-efficient B₁⁺/B₁^--mapping technique for correction of the ¹⁹F signal in vivo is presented in this work.

H. Douglas Morris¹ and J. Andrew Derbyshire^2
1NIH Mouse Imaging Facility, National Institutes of Health, Bethesda, MD, United States, ²Functional MRI Facility, National Institutes of Health, Bethesda, MD, United States

Rapid imaging of endogenously labeled neuroprogenitor cells in the rat brain is shown using high-field MRI and efficient Steady-State Free Precession sequences.  A RF-phase cycle progression based on the Golden Angle is used to produce Linear Combination SSFP (LCSSFP) images without banding artifacts.  The method yields high resolution images with few global distortions suitable for cell tracking and calculating relaxation images.

Yesu Feng¹, Jeremy Gordon¹, Peter Shin¹, Cornelius von Morze¹, Michael Lustig², Peder E.Z. Larson¹, Michael A. Ohliger¹, Lucas Carvajal¹, James Tropp³, John M Pauly⁴, and Daniel B. Vigneron^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States, ²EECS, UC Berkeley, Berkeley, CA, United States, ³GE Healthcare, Fremont, CA, United States, ⁴Electrical Engineering, Stanford, Stanford, CA, United States

Hyperpolarized (HP) 13C imaging requires fast data acquisition due to the fast T1 relaxation. Parallel imaging methods are well suited for acceleration of data acquisition, yet conventional parallel imaging schemes require explicit calibration of coil sensitivity which presents significant challenge to HP 13C imaging. In this study, a calibrationless parallel imaging method was tested and applied to HP 13C MRI. A 2-fold acceleration was achieved when this technique was applied together with a 2D EPI readout. This strategy is being extended for 3D HP 13C EPI for improved volumetric coverage and better temporal resolution for future clinical studies. 

Eugene Milshteyn¹, Cornelius von Morze¹, Galen D Reed², Hong Shang¹, Peter J Shin¹, Peder EZ Larson¹, and Daniel B Vigneron^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States, ²HeartVista, Menlo Park, CA, United States

Hyperpolarized ¹³C MR can provide unique imaging assessments of metabolism and perfusion in various disease conditions in vivo. High spatiotemporal resolution is needed to best characterize these processes. This project used a low rank plus sparse reconstruction with the bSSFP acquisition to achieve high isotropic resolution dynamic 3D imaging with multiple hyperpolarized substrates.

Steven Reynolds¹, Stephen Metcalf², Rebecca Collins³, Edward Cochrane³, Simon Jones³, Martyn Paley¹, and Gillian Tozer^2
1Academic unit of radiology, University of Sheffield, Sheffield, United Kingdom, ²Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom, ³Department of Chemistry, University of Sheffield, Sheffield, United Kingdom

Hyperpolarizing drug candidates could allow insights into their mode of action and metabolic fate. However, administering drug molecules at high concentrations can lead to adverse effects in animals. We have developed a method for directly administering substrates to tumor tissue by infusion through a single supplying artery, thus maximizing tumor drug delivery and minimizing T1 relaxation and systemic toxicity. The net signal gain for arterially injected ¹³C-pyruvate was x54, compared with the systemically administered venous route. Hyperpolarized custom ¹³C-labeled CA1 was arterially administered and its parent peak observed, in vivo, at its expected chemical shift (58ppm).

Anja Bille Bohn¹, Nathalie Nielsen², Christoffer Laustsen², Hans Stødkilde-Jørgensen², and Lotte Bonde Bertelsen^2
1The department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark, ²MR Research Centre, Aarhus University, Aarhus University Hospital, Aarhus, Denmark

Synopsis: Studies of metabolism in stem cells have revealed a shift in the balance between glycolysis, mitochondrial oxidative phosphorylation and oxidative stress during the maturation of stem cells. In the stem cells, pyruvate from glycolysis will mainly be metabolized to lactate as a result of an uncoupling of the citric acid cycle and the oxidative phosphorylation pathway, thus the application of a novel metabolic cell culture tool could add valuable information to the studies of stem cell characterisation during development. In the present study we use hyperpolarised [1-13C] pyruvate to characterise mesenchymal stem cells harvested from adipose tissue.

Hikari A. I. Yoshihara¹, Jessica A. M. Bastiaansen², Corinne Berthonneche³, Arnaud Comment¹, and Juerg Schwitter^4
1Institute of Physics of Biological Systems, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland, ²Department of Radiology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland, ³Cardiovascular Assessment Facility, University Hospital Lausanne (CHUV), Lausanne, Switzerland, ⁴Division of Cardiology and Cardiac MR Center, University Hospital Lausanne (CHUV), Lausanne, Switzerland

In developing an intact rat model for myocardial ischemia using hyperpolarized ¹³C pyruvate, different compound formulations were evaluated. Infusion of 4-hydroxy-TEMPO-polarized sodium [1-¹³C]pyruvate was compared to an equivalent dose of buffered trityl radical-polarized [1-¹³C]pyruvic acid. Whereas higher levels of polarization and MRS signal were obtained with trityl radical, the metabolite signals normalized to total signal were lower. In particular, [1-¹³C]lactate signal relative to total signal was markedly higher using TEMPO-polarized pyruvate. [¹³C]bicarbonate and [1-¹³C]alanine signals were affected to a lesser degree. This study demonstrates the composition of the infused hyperpolarized pyruvate solution can significantly affect its metabolism in vivo.

Cornelius von Morze¹, Irene Marco-Rius¹, Celine Baligand¹, Robert Bok¹, John Kurhanewicz¹, Daniel Vigneron¹, and Michael Abram Ohliger^1,2
1Radiology and Biomedial Imaging, University of California San Francisco, San Francisco, CA, United States, ²UCSF Liver Center, San Francisco, CA, United States

We investigate the rapid metabolic conversion of hyperpolarized (HP) [1-13C]α-ketobutyrate, a molecular analog of pyruvate, in mouse liver in vivo as compared to [1-13C]pyruvate.  Previously, it has been noted that in liver, there is relatively less conversion of [1-13C]α-ketobutyrate to its reduction product, [1-13C]hydroxybutyrate when compared to the conversion of [1-13C]pyruvate to [1-13C]lactate. This difference in conversion likely represents a different LDH activity in liver1. In this study, we examine the decarboxylation of ketobyrate into bicarbonate, which we have found to be unexpectedly elevated when compared to pyruvate, presumably also via PDH and/or a related enzyme.

Justin Y.C. Lau^1,2, Aws Abdul-Wahid³, Albert P. Chen⁴, Jean Gariépy^1,3, and Charles H. Cunningham^1,2
1Medical Biophysics, University of Toronto, Toronto, ON, Canada, ²Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada, ³Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada,⁴GE Healthcare, Toronto, ON, Canada

Conventionally, hyperpolarized ¹³C substrates are administered via intravenous injection. In this abstract, a novel route of hyperpolarized substrate delivery via intraperitoneal injection is demonstrated for observing metabolism in a mouse model of abdominal metastasis. 2D CSI revealed lactate signal in tumour-bearing mice, but only pyruvate signal in a control mouse. An extended time window of dynamic metabolic imaging may be possible with intraperitoneal administration due to the longer in vivo pyruvate T₁ of 54 s as measured by dynamic 3D EPI. Intraperitoneal administration of hyperpolarized ¹³C substrates is a promising complementary technique well suited for observing poorly vascularized metastatic nodules.

Mehrdad Pourfathi^1,2, David D. Aufhauser³, Douglas R. Murken³, Zhonglin Wang³, Stephen J. Kadlecek¹, Heather Gatens¹, Ali Naji³, Matthew H. Levine^3,4, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, PA, United States, ³Department of Surgery, Division of Transplant Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States, ⁴Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Renal ischemia repercussion injury (IRI) and its manifestation of acute kidney injury (AKI) is a significant source of morbidity in diverse medical and surgical scenarios, for which for which there is no current therapeutic modality. AKI contributes significantly to hospital stay, morbidity, and mortality. Despite the extensive metabolic derangements that accompany renal IRI, there is an absence of clinically useful markers to predict the clinical course following AKI in an expedient manner.  Here, we demonstrate the feasibility of using hyperpolarized carbon-13 MRI to image metabolic activity in the mice recovering from renal IRI.

Keshav Datta^1,2, Shie-Chau Liu¹, Stephen R Lynch³, Zixin Chen¹, Ralph Hurd⁴, Jianghong Rao¹, and Daniel Mark Spielman^1,2
1Dept. of Radiology, Stanford University, Stanford, CA, United States, ²Dept. of Electrical Engineering, Stanford University, Stanford, CA, United States, ³Dept. of Chemistry, Stanford University, Stanford, CA, United States, ⁴Applied Sciences Lab, GE Healthcare, Menlo Park, CA, United States

We evaluated the potential for the use of ([13C]-tert-butanol-bGal as hyperpolarizeable agent for in vivo imaging of senescent cells.   The chemical shift between [13C]-tert-butanol-bGal and bGal-cleaved [13C]-tert-butanol was found to be 7.4ppm, more than adequate for in vivo detection.  [13C]-tert-butanol-bGal was also found to polarize well(~30%) with [13C]-tert-butanol-bGal and [13C]-tert-butanol yielding T1 relaxation times of 22s and 34s respectively, very promising for in vivo studies.

Emine Can¹, Jessica A. M. Bastiaansen^2,3, Hikari A. I. Yoshihara^4,5, Rolf Gruetter^3,5,6, and Arnaud Comment^1
1Institute of Physics of Biological Systems, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ²Department of Radiology, University Hospital Lausanne (CHUV), Lausanne, Switzerland,³Department of Radiology, University of Lausanne (UNIL), Lausanne, Switzerland, ⁴Institute of Physics of Biological Systems, EPFL, Lausanne, Switzerland, ⁵Laboratory for Functional and Metabolic Imaging, EPFL, Lausanne, Switzerland, ⁶Department of Radiology, University of Geneva, Geneva, Switzerland

Hyperpolarized ¹³C-labeled pyruvate provides assessment of real-time liver mitochondrial enzymatic activities directly by labeling TCA cycle intermediates. However the technique is limited by the requirement of supraphysiological concentrations due to the low basal concentrations of metabolic intermediates. In this study we showed the feasibility of detecting liver metabolism in vivo with HP ¹³C pyruvate administered at plasma concentrations of at most 7-fold of the basal levels. Different metabolic response to the concentration change shows that the adaptation to supraphysiological levels can obscure feeding state-depending metabolic differences in liver.

Cornelius von Morze¹, Peder E Larson¹, Michael A Ohliger¹, Ralph E Hurd², John Kurhanewicz¹, and Daniel B Vigneron^1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²GE Healthcare, Menlo Park, CA, United States

The purpose of this abstract was to investigate pool size effects in experiments with hyperpolarized [¹³C]α-ketobutyrate (αKB), a molecular analog of pyruvate which also has substantial activity with LDH. In contrast to pyruvate, formation of the reduction product [¹³C]α-hydroxybutyrate (αHB) necessarily reflects net metabolic flux as opposed to label exchange. We observed little change when co-injecting αHB but a large increase in the αHB-to-αKB ratio when co-injecting lactate. This suggests that the observed conversion of αKB to αHB only reflects net metabolic flux even in the presence of a large pool of reduction product.

Cornelius von Morze¹, Chloe Najac¹, Robert R Flavell¹, David E Korenchan¹, Pavithra Viswanath¹, Lucas Carvajal¹, John Kurhanewicz¹, Sabrina M Ronen¹, Daniel B Vigneron¹, and David M Wilson^1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

The purpose of this study was to show basic feasibility of non-invasively detecting small molecule thiols using hyperpolarized [¹³C]cyanate. We detected rapid formation of the expected hyperpolarized S-[¹³C]carbamyl thiol adduct after adding cysteine to liquid hyperpolarized [¹³C]cyanate samples. This work demonstrates a new non-enzymatic approach for detecting small molecule thiols such as reduced glutathione, which could be very useful for research on oxidative stress.

Nathalie Nielsen¹, Christoffer Laustsen¹, Hans Stødkilde-Jørgensen¹, and Lotte Bonde Bertelsen^1
1MR Research Centre, Department of Clinical Medicine, Aarhus University Hospital, Aarhus University, Aarhus, Denmark

This study aims to quantify the metabolic flux in EPCs in order to characterize the metabolic changes occurring during in-vitro culturing utilized for cell expansion, 3D scaffolds and suspension. [1-¹³C] hyperpolarized pyruvate is injected to a NMR compatible bioreactor system and the conversion is detected and measured as the lactate/pyruvate ratio. Activation assays and qPCR is performed to support the results. The lactate/pyruvate (6±1,07 fold) and LDH activity is increased in cell suspension culturing. Together with an elevated PDH expression in suspension cultures our conclusion is that adherent cells metabolically compensate in the suspension culture due to the environmental conditions.  

John Maidens¹, Jeremy W. Gordon², Murat Arcak¹, and Peder E. Z. Larson^2
1Electrical Engineering & Computer Sciences, University of California, Berkeley, Berkeley, CA, United States, ²Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

Hyperpolarized carbon-13 MRI experiments typically aim to distinguish between healthy and diseased tissues based on the rate at which they metabolize an injected substrate. Existing approaches to determine flip angle sequences for kinetic measurements have used metrics such as signal variation and signal-to-noise ratio, but are not optimized to provide the most reliable metabolic rate estimates. Here we present a flip angle sequence that maximizes the Fisher information about the metabolic rate. We demonstrate through numerical simulation that flip angle sequences optimized using the Fisher information lead to lower variance in metabolic rate estimates than existing sequences. We then validate this optimized sequence in vivo with experiments in a prostate cancer mouse model.

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

A novel dual echo EPI sequence is proposed for providing a built-in correction for off-resonance in time resolved, volumetric hyperpolarized ¹³C metabolic mapping with [1-¹³C]pyruvate. The phase evolution between two echoes was used to correct EPI distortion and improve spatial registration with the underlying anatomy. A correction term obtained from a fully phase encoded dual echo EPI proton reference scan was required to account for odd/even echo asymmetry in the ¹³C phase maps. Proof-of-concept dual echo EPI in vivo rat data was acquired on a clinical 3T MR scanner and corrected images are presented.

Hansol Lee¹, Joonsung Lee², Eunhae Joe¹, Seungwook Yang¹, Jae Eun Song¹, Young-suk Choi³, Eunkyung Wang³, Ho-Taek Song³, and Dong-Hyun Kim^1
1Department of Electrical & Electronic Engineering, Yonsei university, Seoul, Korea, Republic of, ²Center for Neuroscience Imaging Research, Institute for Basic Science, Sungkyunkwan University, Suwon, Korea, Republic of, ³Department of Radiology, Yonsei University College of Medicine, Seoul, Korea, Republic of

In hyperpolarized ¹³C MRI, high signal intensity of vasculature can cause errors in quantification of metabolites or conversion rate constants. The bipolar gradient was used to suppress vascular signal for accurate quantification. However, the velocity of vessel can vary depending on anesthetic level and pulsation. Furthermore, additional T₂* relaxation signal loss can be induced by delayed data acquisition in ultra-high field (9.4T) due to short T₂*. In this study, the bipolar gradient was optimized to minimize additional signal loss and mitigate variable velocity, then the optimized bipolar gradient was implemented for hyperpolarized ¹³C CSI and applied to mouse liver experiment.

Jeremy W Gordon¹, Eugene Milshteyn¹, Irene Marco-Rius¹, Michael Ohliger¹, Daniel B Vigneron¹, and Peder EZ Larson^1
1Radiology & Biomedical Imaging, University of California - San Francisco, San Francisco, CA, United States

Hyperpolarized diffusion weighted imaging has the potential to noninvasively assess transporter expression and probe specific metabolite microenvironments. However, the imperfect RF excitation profile and the transient, non-recoverable hyperpolarization lead to non-uniform depletion of M_z. After multiple RF pulses, this results in excess signal at later excitations, potentially biasing ADC estimation. Scaling the slice-select gradient can correct for this deviation, minimizing bias and providing more precise ADC measurements of hyperpolarized substrates.

Omar Rutledge¹, Tiffany Kwak¹, Peng Cao¹, and Xiaoliang Zhang^1
1Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

RF coil operation at 7T is fraught with technical challenges, making expansion of 7T into clinical imaging difficult. In this work, a microstrip transmission line and a wire loop coil were combined to form a double-nuclear RF coil array for proton magnetic resonance imaging and carbon magnetic resonance spectroscopy at the ultrahigh magnetic field strength of 7T. Network analysis revealed a high Q-factor and excellent decoupling between the coils. Proton images and carbon spectra were acquired with high sensitivity. The successful testing of this novel double-coil array demonstrates the feasibility of this design for multi-nuclear studies at 7T.

Mor Mishkovsky¹, Lara Buscemi², Ximena Castillo², Mario Lepore³, Arnaud Comment⁴, Lorenz Hirt², and Jean-Noël Hyacinthe^5,6
1Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ²Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, ³Centre d'Imagerie Biomédicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ⁴Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ⁵School of Health Sciences - Geneva, University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland, ⁶Image Guided Intervention Laboratory, University of Geneva, Geneva, Switzerland

Stroke is a major public health challenge in the context of the current demographic changes. Among a wide range of applications, hyperpolarized magnetic resonance enables in vivo real-time measurement of biochemical transformations of hyperpolarized ¹³C-labeled precursors, including lactate, a known neuroprotectant in stroke at the preclinical level. This study shows the feasibility of measuring lactate metabolism in vivo in a mouse model of stroke (MCAO) following intravenous injection of hyperpolarized L-[1-¹³C]lactate. Calculated pyruvate-to-lactate ratio shows an increased labeling of the pyruvate pool in MCAO when compared to sham. This feasibility study suggests new perspectives to understand lactate biodistribution and its neuroprotective effect in stroke.

Peder Eric Zufall Larson¹, Jeremy Gordon¹, John Maidens², Murat Arcak², Hsin-Yu Chen¹, Galen Reed¹, Ilwoo Park¹, Rahul Aggarwal³, Robert Bok¹, Sarah J Nelson¹, John Kurhanewicz¹, and Daniel B Vigneron^1
1Radiology and Biomedical Imaging, University of California - San Francisco, San Francisco, CA, United States, ²Electrical Engineering & Computer Sciences, University of California - Berkeley, Berkeley, CA, United States, ³Medicine, University of California - San Francisco, San Francisco, CA, United States

Clinical evaluation of metabolic MRI using hyperpolarized C-13 agents has begun in earnest at multiple sites with the availability of the SpinLab commercial polarizer.  For this technology to succeed, robust imaging and analysis methods for quantification of metabolic activity are required.  We have developed and are applying efficient dynamic imaging methods, robust kinetic models, and specialized calibration schemes to enable accurate and reproducible quantification in clinical hyperpolarized MR studies.

Qianni Guo¹, Qingbin Zeng¹, Weiping Jiang¹, Xiaoxiao Zhang¹, Qing Luo¹, and Xin Zhou^1
1Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China, People's Republic of

Mercury contamination is widespread and arises from a variety of natural sources.We propose the use of hyperpolarized ¹²⁹Xe nuclear magnetic resonance (NMR) spectroscopy for the sensitive detection of Hg²⁺ions in aqueous solution.We develop a biosensor whose molecular structure is like a clamp. When interact with Hg²⁺ in aqueous solution, the molecular structure of the biosensor could be changed as a clamp from “open” to “closed”. This molecular structure change causes the distance between the two cryptophane cages of the biosensor become closer, and the electron cloud of them overlapped. As a result, comparing with normal downfield chemical shifts of the reported xenon biosensors formetallic ions, the Xe caged in the cryptophane moiety shows a upfield chemical shift change from 66.5 ppm to 66.1 ppm. Images were obtained using a CSI method preciously used for clinical MRI.

Eugene Milshteyn¹, Cornelius von Morze¹, Hong Shang¹, Galen D Reed², and Daniel B Vigneron^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States, ²HeartVista, Menlo Park, CA, United States

Hyperpolarized ¹³C MR imaging can provide simultaneous assessments of metabolism and perfusion to study disease processes. High resolution dynamic imaging is needed to fully understand these processes, but is challenging, especially on clinically relevant systems. This project investigated new methods for spectral selectivity with SNR-efficient bSSFP sequences to provide improved high resolution 3D dynamic in vivo HP ¹³C MR imaging at 3T. 

Gopal Varma¹, Patricia Coutinho de Souza¹, Leo Tsai¹, Rupal Bhatt², and Aaron Grant^1
1Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States, ²Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

Balanced steady-state free-precession (bSSFP) offers high sensitivity and good temporal resolution, and makes efficient use of hyperpolarized magnetization.  Several strategies for spectroscopically selective imaging with bSSFP have been proposed [1-5].  Here we investigate the use of simple binomial excitation pulses to selectively null the signals from either pyruvate or lactate, the two dominant metabolites in tumors, thereby obtaining images that are dominated by either lactate or pyruvate, respectively.  The method is robust to off-resonance effects, and can be used to augment existing spectroscopic bSSFP techniques.