Kazutoshi Yamamoto¹, Ana Opina², Keita Saito³, Ronja M Malinowski⁴, Tomohiro Seki¹, Nobu Oshima¹, Deepak Sail², Jeffrey R Brender³, Shun Kishimoto³, Nallathamby Devasahayam¹, Jan H Ardenkjær-Larsen⁴, James B Mitchell⁵, Rolf E Swenson², and Murali C Krishna^1
1National Cancer Institute, National Institutes of Health, Bethesda, MD, United States, ²Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, MD, United States, ³National Institutes of Health, Bethesda, MD, United States, ⁴Department of Electrical Engineering, Technical University of Denmark, Lyngby, Denmark, ⁵NCI/RBB, National Institutes of Health, Bethesda, MD, United States

N-acetyl cysteine (NAC) is a widely used therapeutic and involved to stimulate glutathione synthesis. Glutathione elevates detoxification and works directly as a free radical scavenger.  Here, we synthesized and demonstrated [1-¹³C]NAC as a promising novel probe for hyperpolarized ¹³C MRI methodologies, which has limitations in available number of probes.  In vivo hyperpolarized NAC was broadly distributed throughout the body.  The chemical conversions into products were observed in pancreatic tumor xenografts, Hs766t, and SU.86.86, with various conversion efficiencies depending on metabolic characteristics and status.  Hyperpolarized NAC can provide insights into redox status, metabolic profile, and enzymatic activities.

Julia Traechtler¹, Valery Vishnevskiy¹, Maximilian Fuetterer¹, Andreas Dounas¹, and Sebastian Kozerke^1
1Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland

An advanced signal model-based reconstruction jointly estimating image and field map from multi-echo, multi-coil acquisition of hyperpolarized metabolic data was developed and validated using synthetic and in-vivo data. Relative to standard multi-echo reconstruction methods, reconstruction accuracy improved  by up to 30% for synthetic data considering realistic noise levels and field map gradients. Geometric distortion correction resulted in less than 20% error. For in-vivo data, the average improvement was 15%. Depending on the direction of the field gradients present, multi-coil reconstruction was found to be beneficial for addressing signal folding issues.

James A Bankson¹, Keith A Michel¹, Zhan Xu¹, Collin J Harlan¹, Gary Martinez ¹, and Christopher M Walker^1
1Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Imaging tumor metabolism using hyperpolarized (HP) pyruvate shows tremendous potential for new insight into disease and response to therapy, but these technically challenging measurements must be carefully designed to maximize accuracy and reproducibility.  In this work, we explore the temporal filtering effects of signal excitations on observed HP MRI magnetization.  The signal flow diagram and its associated transfer function confirm a low-pass filtering effect that can be controlled by the prescribed excitation angle and sampling interval.  Low excitation angles promote temporal averaging but reduce sensitivity to higher frequency content.  We explore the effects of signal excitation on quantification.

Ting Sun^1,2, Renuka Sriram¹, Kathy Giacomini¹, James Chien¹, Sook Wah Yee¹, Shubhangi Agarwal¹, Joao Piraquive Agudelo¹, Cornelius Von Morze³, John Kurhanewicz¹, Huadan Xue², and Michael Ohliger^1
1University of California, San Francisco, San Francisco, San Francisco, CA, United States, ²Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China, ³Washington University, Seattle, WA, United States

This study demonstrated that hyperpolarized ¹³C metabolic signals arising from intracellular and extracellular ¹³C metabolites can be selectively suppressed by the intracellular liver-specific gadolinium contrast agent. This data further elucidates how targeted relaxation agents affect observed hyperpolarized ¹³C signals, expanding the way these agents can be used to distinguish between specific cell types in vivo.
 

Rie B Olin¹, Juan D Sánchez-Heredia¹, Mary A McLean², Christoffer Laustsen³, Adam E Hansen⁴, Lars G Hanson^1,5, and Jan H Ardenkjær-Larsen^1,6
1Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark, ²Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom, ³MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, ⁴Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark, ⁵Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark, ⁶GE Healthcare, Brøndby, Denmark

We propose a new quality assurance (QA) protocol for signal to noise ratio (SNR) evaluation of ¹³C receive coils to both guide coil developments and assist the choice of the best suited coil for a given hyperpolarized ¹³C MR experiment. The protocol allows fair comparison of coils with different number of elements and comparison across scanner vendors. The protocol was used to test and compare seven different coils at three different MR sites, which provided insights into coil performance, trade-offs, and malfunctions. All data and source code are shared publicly online.

Martin Grashei¹, Sandra Sühnel¹, Geoffrey Topping¹, Elisabeth Bliemsrieder¹, Stephan Düwel¹, Christian Hundshammer¹, and Franz Schilling^1
1Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Here, we demonstrate multi-compartment in vivo pH imaging in healthy and EL4-tumor bearing mice using deuterated hyperpolarized [1,5‑¹³C₂, 3,6,6,6-D₄]zymonic acid. Three pH-compartments of the healthy kidney (pH_ureter = 6.53±0.16, pH_medulla = 7.06±0.06 and pH_cortex = 7.38±0.03) could be reliably detected using PRESS-voxel spectroscopy and chemical shift imaging. pH-imaging in mice bearing subcutaneous EL4-tumors allowed to identify one physiologic (pH_phys = 7.39±0.05) and two acidic pH-compartments in the tumour (pH_ac,1 =  6.96±0.17, n=5), with the second pH-compartment being only present in subregions (pH_ac,2 =  6.62±0.10, n=5).

Junjie Ma¹ and Jae Mo Park^1,2,3
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ³Electrical Engineering, UT Dallas, Richardson, TX, United States

In this study, a patch-based super-resolution algorithm is proposed, which uses prior knowledge from high-resolution ¹H MRI to guide the reconstruction of hyperpolarized ¹³C images. The algorithm was validated with simulation and phantom, and the results show enhanced spatial resolution, SNR and contrast as well as comparable quantification accuracy to the upsampled images from nearest-neighbor, bilinear and spline interpolation methods. Finally, the proposed algorithm was applied to metabolic imaging of human brain with hyperpolarized [1-¹³C]pyruvate injection, which significantly improve the image resolution, SNR and contrast while keeping the quantification accuracy.

Pavithra Viswanath¹, Georgios Batsios¹, Anne Marie Gillespie¹, Peng Cao¹, Peder E Z Larson¹, Russell O Pieper², and Sabrina M Ronen^1
1Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, ²Neurological Surgery, University of California San Francisco, San Francisco, CA, United States

Telomerase reverse transcriptase (TERT) expression is a fundamental hallmark of tumor proliferation, including in low-grade oligodendrogliomas. Inhibiting TERT expression is also a therapeutic strategy for gliomas. In this study, we show, for the first time, that metabolism of hyperpolarized [U-¹³C,U-²H]-glucose to 6-phosphogluconate via the pentose phosphate pathway and hyperpolarized [1-¹³C]-alanine flux to lactate can serve to non-invasively detect TERT expression in orthotopic low-grade oligodendrogliomas in vivo. Our imaging biomarkers will allow non-invasive, longitudinal detection of a molecular hallmark of tumor proliferation and have the potential to enhance imaging of glioma burden and response to emerging TERT therapies in the clinic.

Claudia C Zanella¹, Andrea Capozzi¹, Hikari A I Yoshihara¹, Alice Radaelli¹, Lionel P Arn^2,3, Rolf Gruetter¹, and Jessica A M Bastiaansen^2,3
1Laboratory for Functional and Metabolic Imaging (LIFMET), EPFL, Lausanne, Switzerland, ²Department of Diagnostic and Interventional Radiology, CHUV, Lausanne, Switzerland, ³Department of Diagnostic and Interventional Radiology, UNIL, Lausanne, Switzerland

Using nonpersistent radicals generated by UV-irradiation of endogenous metabolite precursors for dissolution DNP avoids the need for radical filtration and may potentially lengthen the measurement window of hyperpolarized MRI measurements. Here, the endogenous pyruvate-analogues alpha-ketobutyrate and alpha-ketovalerate were proposed as nonpersistent radical precursors. Radical yields were characterized along with their performance as polarizing agents for in vitro and in vivo dDNP experiments. A ¹³C-glucose liquid state polarization of 26.4% was attained using alpha-ketobutyrate-derived radical, while pyruvate-derived radical yielded 21.7% (compared to 18.9% reported with the persistent trityl radical). Alpha-ketobutyrate was used to hyperpolarize [1-¹³C]butyrate and measure cardiac metabolism in vivo.

Jun Chen¹, Richard Martin¹, Lloyd Lumata², Zoltan Kovacs¹, and Jae Mo Park^1,3
1AIRC, UT Southwestern Medical Center at Dallas, Dallas, TX, United States, ²Physics, University of Texas at Dallas, Richardson, TX, United States, ³Electrical Engineering, University of Texas at Dallas, Richardson, TX, United States

Yttrium-89 in the form of diamagnetic ⁸⁹Y complexes is an attractive nucleus for the design of responsive magnetic resonance spectroscopy and imaging probes the ⁸⁹Y NMR chemical shift is quite sensitive to the coordination environment of the Y³⁺ ion.  ⁸⁹Y has a great potential for in vivo hyperpolarized NMR due to its extremely long T¹ relaxation time.  In this study, we developed an RF coil for imaging ⁸⁹Y signal in vivo, tested it with phantoms containing thermally polarized and hyperpolarized yttrium compounds, and demonstrated the feasibility of using hyperpolarized ⁸⁹Y complexes for in vivo studies in a rat.

Yu Saida¹, Shun Kishimoto¹, Yasunori Otowa¹, Kazutoshi Yamamoto¹, Jeffery R. Brender¹, Nallathamby Devasahayam¹, and Murali C. Krishna^1
1National Cancer Institute, Bethesda, MD, United States

The purpose of this study is to detect physiologic and metabolic changes in tumor-bearing mouse model in response to immune checkpoint blockade therapy by using multi-modal imaging methods including hyperpolarized ¹³C-MRI with [1-¹³C] pyruvate, with [1,4-¹³C₂] fumarate, and DCE-MRI. Lactate/Pyruvate ratio tended to decrease in αPD-L1 Ab + αCTLA-4 Ab treated tumor in mouse model although not statistically significant. Significantly increased Malate/Fumarate ratio and higher permeability were observed in treated tumor. We will investigate capability of detecting early response to immune checkpoint blockade therapy using multi-modal imaging.

Nadia D. Bragagnolo^1,2, Benjamin J. Geraghty^1,2, Casey Y. Lee^1,2, Albert P. Chen³, and Charles H. Cunningham^1,2
1Medical Biophysics, University of Toronto, Toronto, ON, Canada, ²Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada, ³GE Healthcare Technologies, Toronto, ON, Canada

This project aims to minimize the B₁⁺ field inhomogeneities that arise when using a flexible transmit coil system in multi-organ hyperpolarized ¹³C MRI. A method for rapid B₁⁺ measurement of several locations immediately prior to image acquisition was developed to determine scaling factors for the power input of slices over a large field-of-view. These scaling factors ensure that the desired flip angle is achieved across multiple organs. The rapid B₁⁺ measurement technique has been tested in in vivo scans, giving values accurate within ±1μT. This method will be used to minimize the variability in multi-organ thoracic and abdominal imaging.

Jason Graham Skinner¹, Geoffrey Topping¹, Irina Heid², Maximilian Aigner¹, Martin Grashei¹, Christian Hundshammer¹, Lukas Kritzner², Frits Hendrik Anton van Heijster¹, Tim Wartewig^3,4, Erik Hameister^3,4, Jürgen Ruland^3,4,5,6, Rickmer Braren², and Franz Schilling^1
1Nuclear Medicine, Klinikum rechts der Isar, The Technical University of Munich, Munich, Germany, ²Institute of Radiology, Klinikum rechts der Isar, The Technical University of Munich, Munich, Germany, ³Institute for Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, The Technical University of Munich, Munich, Germany, ⁴TranslaTUM, Center for Translational Cancer Research, The Technical University of Munich, Munich, Germany, ⁵German Cancer Consortium (DKTK), Heidelberg, Germany, ⁶German Center for Infection Research (DZIF), Munich, Germany

A fast, spectrally selective 3D bSSFP sequence was developed for preclinical metabolic imaging of hyperpolarized ¹³C agents at 7 T. High spatiotemporal resolution 3D images of metabolism were produced in healthy mice and in two endogenous models of cancer: pancreatic ductal adenocarcinoma (PDAC) and T-cell lymphoma. Using 900 Hz FHWM pulses, 1.75 mm³ isotropic whole-body images were obtained with a scantime of 1.212 s per image. A significant difference between 3D bSSFP derived AUC ratios in healthy and high-glycolytic-phenotype T-cell lymphoma mice was found, and AUC ratios correlated with PET measurements. Potential tumour heterogeneity was detected in PDAC mice.

Liam A J Young^1,2, Jack JJJ Miller^1,3, Ladislav Valkovic^1,4, Esben SS Hansen⁵, Mary A McLean^6,7, Ferdia A Gallagher⁷, Christoffer Laustsen⁵, Damian J Tyler^1,3, Christopher T Rodgers^1,2, and Justin YC Lau^1,3
1Oxford Centre for Clinical Magnetic Resonance Research (OCMR), University of Oxford, Oxford, United Kingdom, ²Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom, ³Department of Anatomy and Physiology, University of Oxford, Oxford, United Kingdom, ⁴Department of Imaging Methods, Institute of Measurement Science, Slovak Academy of Sciences, Bratislava, Slovakia, ⁵Department of Clinical Medicine, the MR Research Centre, Aarhus University, Aarhus N, Denmark, ⁶CRUK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom, ⁷Department of Radiology, University of Cambridge, Cambridge, United Kingdom

As dissolution dynamic nuclear polarization (d-DNP) hyperpolarised ¹³C  magnetic resonance imaging progresses towards multi-centre clinical trials, a reproducible, scalable in vitro testing platform is required that allows quality assurance, multi-centre validation, and further technical development. We present a method to exploit the inherent pH dependence of the hydrate-to-keto ratio of pyruvic acid to generate a simple, inexpensive, and reproducible non-enzymatic dynamic phantom to address this need. The method was validated at three different sites with a variety of hardware produced by different vendors.

Nicholas Dwork¹, Jeremy Gordon¹, Shuyu Tang¹, Daniel O'Connor², and Peder E.Z. Larson^1
1Radiology and Biomedical Imaging, University of California in San Francisco, San Francisco, CA, United States, ²Mathematics and Statistics, University of San Francisco, San Francisco, CA, United States

We present a method for using a high-resolution proton image to inform the interpolation of a low-resolution metabolic image. An observer is able to better localize the metabolic activity in the interpolated imagery.

Keith A Michel¹, Christopher M Walker¹, Matthew E Merritt², and James A Bankson^1
1Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States, ²Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States

Imaging of hyperpolarized (HP) agents permits real-time non-invasive measurement of metabolic flux, however these experiments require specialized techniques for rapidly encoding chemical shift in a way that is sensitive metabolic signals that are often low SNR. The SNR performance of two chemical shift encoding methods commonly used for HP ¹³C MRI, IDEAL and spectral-spatial excitation pulses, were compared for a typical preclinical experiment imaging [1-¹³C]pyruvate at 7 T. The SNR of these two techniques were found to be equivalent in numerical simulation, while the SNR measured for IDEAL was ~30% greater than for spectral-spatial pulses in a thermal phantom experiment.

Keshav Datta¹ and Daniel Mark Spielman^1
1Department of Radiology, Stanford University, Stanford, CA, United States

Magnetic resonance spectroscopic imaging of hyperpolarized [2-¹³C] Pyruvate and its metabolic products enables real-time assessment of in vivo glycolysis and oxidative phosphorylation simultaneously. However, significant technical difficulties arising from the widely dispersed spectrum and the J-coupling of the ¹³C labeled carbon with its chemically bonded proton limit its practical use for imaging. We propose a narrowband radiofrequency excitation based-method for eliminating the J-modulated artifacts in imaging [2-¹³C] Lactate. Results from simulations, phantoms and rat brain demonstrate the utility of this method, and highlight its potential role in the real-time simultaneous assessment of GLY and OXPHOS in vivo. 

Tomohiro Seki¹, Kazutoshi Yamamoto², Nobu Oshima¹, Marino Itoda³, Yohei Kondo³, Yutaro Saito³, Yoichi Takakusagi⁴, Shun Kishimoto¹, Jeffrey R Brender¹, Ronja M Malinowski⁵, Jan Henrik Ardenkjær-Larsen⁶, Hiroshi Nonaka³, Murali C Krishna¹, and Shinsuke Sando^3
1National Institutes of Health, Bethesda, MD, United States, ²National Cancer Institute, National Institutes of Health, Bethesda, MD, United States, ³University of Tokyo, Bunkyo ku, Japan, ⁴Quantum Medical Science, Chiba, Japan, ⁵Technical University of Denmark, Lyngby, Denmark, ⁶Department of Electrical Engineering, Technical University of Denmark, Lyngby, Denmark

It is well known that dysregulation of γ-glutamyl transferase (GGT) activities in malignant cells leads to more aggressive phenotypes by producing reactive oxygen species.  GGT is important for glutathione homeostasis, and has also been used as a diagnostic marker for various pathologies in the liver, biliary system, and pancreas.   Here, for the first time, a novel hyperpolarized 13C probe, γ-Glu-[1-¹³C]Gly, was demonstrated in in vivo tumor xenografts, including human pancreatic ductal adenocarcinoma and ovarian adenocarcinoma, to detect real-time γ-glutamyl transferase activities as a prospective biomarker for monitoring the tumor progression and prognosis with/without various cancer therapeutic approaches.

Jasmine Y. Graham^1,2, Peder E.Z. Larson², Daniel B. Vigneron², and Jeremy W. Gordon^2
1Bioengineering, UC San Francisco, UC Berkeley, San Francisco, CA, United States, ²Radiology and Biomedical Imaging, UC San Francisco, San Francisco, CA, United States

Downstream metabolic products from hyperpolarized pyruvate, such as lactate and bicarbonate, are acquired with coarse resolution for adequate SNR. However, the injected pyruvate exhibits high signal and can be acquired with higher resolution. A simulation framework has been developed to perform multi-resolution acquisitions of hyperpolarized [1-¹³C]pyruvate, which analyzes SNR and kinetic rate fits for differing resolution schemes. Utilizing the multi-resolution acquisition, lactate and bicarbonate have respective SNR improvement of 3.3-fold and 5.7-fold compared to high resolution images. Kinetic fits for multi-resolution images accurately estimated ground truth values. This simulation framework performed and analyzed variable resolution acquisitions to improve metabolic quantification.

Shubhangi Agarwal¹, Jinny Sun¹, Robert A Bok¹, Romelyn Delos Santos¹, Mark van Criekinge¹, Rahul Aggarwal², Daniel B Vigneron¹, John Kurhanewicz¹, and Renuka Sriram^1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²2Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States

The study of prostate patient derived xenografts in kidney, bone and liver demonstrated the impact of microenvironment on metabolic characteristics of the metastatic prostate cancer and how it differs with respect to the host organ’s characteristics. Hyperpolarized ¹³C MRI was able to identify the modifications in the pyruvate metabolism between the kidney, bone and liver tumors before and after therapeutic intervention. This study demonstrates that Hyperpolarized ¹³C MRI can be used to monitor the real time changes in metabolic profile of prostate cancer and its metastases.

Frederike Euchner¹, Christian Bruns¹, Johannes Bernarding¹, and Markus Plaumann^1
1Institute of Biometrics and Medical Informatics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Fluorinated aromatic substrates are of high interest in biomedical and pharmaceutical applications.  To increase the low ¹⁹F MR signal intensity in aqueous solutions, the hyperpolarization technique photo-Chemical Induced Dynamic Nuclear Polarization (photo-CIDNP) can be used. Compounds such as 2-fluoro-tyrosine, 3-fluoro-tyrosine or 3-fluoro-4-hydroxyphenylacetic acid were hyperpolarized repeatable inside the detection field (7T). Strong ¹⁹F signal enhancements could be detected for aromatic systems, which were fluorinated in meta-position. The simultaneous hyperpolarization of different substrates allows e.g. the study of molecule-molecule interactions and their binding behavior.

Philip M Lee¹, Hsin-Yu Chen², Jeremy W Gordon², Peder EZ Larson², Mark Van Criekinge², Michael A Ohliger², Duan Xu², John Kurhanewicz², Robert A Bok², Rahul Aggarwal³, Pamela N Munster³, and Daniel B Vigneron^2
1Department of Radiology & Biomedical Imaging, University of California, San Francisco, Berkeley, CA, United States, ²Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ³Department of Medicine, University of California, San Francisco, San Francisco, CA, United States

The inhomogeneous B₁ excitation profile of ¹³C surface transmit/receive coils results in a decreasing gradient of flip angles for voxels increasingly farther away from the coil. For accurately quantifying the pyruvate to lactate conversion rate (k_PL), the flip angle needs to be corrected based on the B₁ excitation profile. A voxel-wise B₁ excitation field correction method for hyperpolarized ¹³C MRSI scans of human patients was developed and applied, yielding an improved quantitative accuracy of k_PL values in metastatic cancer patients. The corrected k_PL estimations agree with simulations where over-flip leads to an underestimation of k_PL, whereas under-flip leads to overestimation.

Jeffrey R. Brender¹, Shun Kishimoto¹, Gareth R. Eaton², Sandra S. Eaton², Yu Saida¹, and Murali C. Krishna^1
1Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, MD, United States, ²Department of Chemistry & Biochemistry, University of Denver, Denver, CO, United States

Glassing agents are essential in DNP studies but have the potential to perturb the metabolic measurements that are being studied. Glycerol, the glassing agent of choice for in vivo DNP studies, is effective at reducing ice crystal formation during freezing but is rapidly metabolized, potentially altering the redox and ATP balance of the system. As a biologically inert alternative to glycerol, we show here that 15-20 wt % trehalose yields a glass that polarizes samples more rapidly than the commonly used 60% wt formulation of glycerol and yields similar polarization levels within clinically relevant timeframes. 

Mehrdad Pourfathi¹, Hooman Hamedani^1,2, Yi Xin^1,2, Stephen J Kadlecek¹, Ian Duncan¹, Maurizio Cereda^1,3, Sarmad Siddiqui¹, Harrilla Profka¹, Luis Loza¹, Faraz Amzajerdian ^1,2, Tahmina Achekzai¹, Kai Ruppert¹, Michael Rosalino¹, Federico Sertic^1,4, Ryan Baron¹, Jon Snow¹, Yiwen Qian^1,2, Gabriel Unger¹, Shampa Chatterjee⁵, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Bioengineering, University of Pennsylvania, Philadelphia, PA, United States, ³Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United States, ⁴Surgery, University of Pennsylvania, Philadelphia, PA, United States, ⁵Physiology, University of Pennsylvania, Philadelphia, PA, United States

Hyperpolarized ¹³C and ¹²⁹Xe MRI are novel imaging methods that have been used to characterize tissue metabolism and lung function, respectively. In this study, we demonstrate the use of these techniques in tandem in order to characterize lung injury in a porcine model of aspiration pneumonitis. 

Aneurin J Kennerley¹, Marie-Christine BD Labarthe¹, Elizabeth J Fear¹, Peter J Rayner¹, and Simon B Duckett^1
1Chemistry, University of York, York, United Kingdom

We demonstrate that signal amplification by reversible exchange (SABRE) presents as a promising and fast route to hyperpolarising a wide range of biologically relevant contrast agents, including nicotinamide (a precursor for NAD+ a mediator of metabolism) and pyruvate (for mapping anaerobic metabolism) for in-vivo preclinical magnetic resonance imaging and spectroscopic detection. Images recorded in a rat model at 7 Tesla (Bruker BioSpec 70/30) are presented. We highlight necessary chemical preparation steps to ensure that the SABRE agents are bio-compatible following exposure to high pressure para-hydrogen gas and the heavy metal Iridium catalyst required for SABRE hyperpolarisation.  

Xiaobo Qu¹, Yihui Huang¹, Hengfa Lu¹, Tianyu Qiu¹, Di Guo², Tatiana Agback³, Vladislav Orekhov⁴, and Zhong Chen^1
1Department of Electronic Science, Xiamen University, Xiamen, China, ²School of Computer and Information Engineering, Xiamen University of Technology, Xiamen, China, ³Department of Molecular Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden, ⁴Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden

Nuclear magnetic resonance (NMR) spectroscopy serves as an indispensable tool in chemistry and biology but often suffers from long experimental time. In this work, we present a proof-of-concept of application of deep learning and neural network for high-quality, reliable, and very fast NMR spectra reconstruction from limited experimental data. Experimental results show that the neural network training can be achieved using solely synthetic NMR signal with exponential functions, which lifts the prohibiting demand for a large volume of realistic training data usually required in the deep learning approach.

Donghyun Hong¹, Georgios Batsios¹, Pavithra Viswanath¹, Elavarasan Subramani¹, Marina Radoul¹, and Sabrina M. Ronen^1
1Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

Although the hyperpolarized (HP) spectroscopy shows significant SNR enhancement, quantification of the HP in-vivo spectrum can sometimes be challenging due to low metabolite levels, rapid signal relaxation, short acquisition time, and signal overlap. This study describes a quantification pipeline which includes spectral denoising and automatic fitting using LCModel in order to monitor dynamic HP in-vivo brain metabolism. HP [2-¹³C] Pyruvate in-vivo data was acquired from healthy rats. Proposed quantification pipeline revealed low concentration metabolites which were not clearly visible before denoising and allowed for improved metabolic kinetic information.
 

Gaurav Sharma¹, Alexander Funk¹, Xiaodong Wen¹, Crystal Harrison¹, Nesmine Maptue¹, Craig R. Malloy^1,2,3, A. Dean Sherry^1,3,4, and Chalermchai Khemtong^1,3
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States, ³Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ⁴Chemistry, The University of Texas at Dallas, Richardson, TX, United States

Heart failure due to ischemic coronary artery disease is a leading cause of morbidity and mortality. Metabolic assessment of myocardium could be important for assessing myocardial ischemia in patients. This study evaluated in vivo metabolism of hyperpolarized ¹³C-pyruvate in ischemia rat hearts under normal and elevated workload by dobutamine stimulation. Decreased production of bicarbonate was observed in hearts with ischemic myocardium compared to control hearts. Dobutamine stimulation lowered bicarbonate production in control hearts but did not change the appearance of bicarbonate signals in ischemic group.

Seong-Eun Kim¹, J Scott McNally¹, Matthew Alexander ¹, Dennis L Parker¹, and Ronald Day^2
1UCAIR, Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, United States, ²Department of Pediatrics, University of Utah, Salt Lake City, UT, United States

There are increasing concerns about Gadolinium based contrasts safety. One potential alternative agent is endogenous intracellular methemoglobin(MrtHb), a paramagnetic molecule in small amounts in our blood cells. Intracellular levels of MetHb can be increased by exposing blood to nitric oxide or sodium nitrite. The previous in vitro studies suggest that an intracellular MetHb level less than 10% sufficiently increases the T1 signal of blood to be an effective contrast agent. The purpose of this work is to evaluate the change of T1 of blood according to a transient increase in intracellular MetHb in an in vivo animal model.

Dengfeng Li¹, Xiaohong Ma¹, Chengyan Dong², and Xinming Zhao^1
1Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, ²GE Healthcare, Beijing, China

Integrin α_vβ₆ is considered a promising molecular imaging target because it is significantly up-regulated in various types of cancers and correlates with the survival time of patients. MR imaging has advantages of non-invasive, non-radioactive, high soft-tissue contrast, and multiparameter imaging. Therefore, this study synthesized an integrin α_vβ₆-targeted nanoparticle probe for MR molecular imaging. Our experiments showed that novel targeted nanoparticles can specifically bind with integrin α_vβ₆ overexpressed cells in vitro and in vivo, presenting potential applications in the fields of α_vβ₆-positive tumor targeted MR molecular imaging.

Yuancheng Li¹, Yaolin Xu¹, Kecheng Lei², Bing Ji¹, Seong Kang², Keqiang Ye², and Hui Mao^1
1Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, United States, ²Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States

Sub-5 nm ultrafine iron oxide nanoparticles (uIONP) is capable of entering intracranial U87 brain tumors in mice, leading to T1-contrast enhancement in the tumor similar to the clinically used gadolinium chelate contrast agents. The intra-tumoral accumulation of uIONP was supported by in vivo and ex vivo NIR imaging of NIR830-labeled uIONP and histological analysis. The developed uIONPs demonstrated faster clearance via kidney and liver comparing to conventional IONPs with larger sizes. Further development of uIONP-based MRI probes and drug carriers can provide a theranostic platform for precision medicine in brain tumors.

Fan Lin^1
1The First Affiliated Hospital of Shenzhen University, Shenzhen, China

Moat chemotherapeutic drugs failed to effectively treat glioblastoma (GBM) on account of the existence of blood-brain barrier, which play a role in GBM. In this study, we constructed an integrated nanoprobe based on albumin nanoparticles for targeted diagnosis and treatment of GBM. The nanoprobe consists of albumin-coated superparamagnetic iron oxide, Carmustine and indocyanine green to achieve bimodal imaging and drug delivery. And the surface-coupled Angiopep-2 can specifically bind to LRP, which is overexpressed in BBB and GBM cells. This novel targeting imaging and drug delivery system provides an efficient strategy for targeted therapy and intraoperative localization of GBM.

Nadia Ayat¹, Sarah Roelle¹, Songqi Gao¹, Yajuan Li¹, and Zheng-Rong Lu^1
1Case Western Reserve University, Cleveland, OH, United States

This research highlights the potential of a targeted contrast agent specific to the extra-domain B (EDB-FN) to be utilized in the diagnosis of prostate cancer at reduced dosages.  EDB-FN specific MR contrast agent MT218 produced robust tumor enhancement at dosages as low as 0.02 mmol Gd/kg.

Violaine Hubert¹, Ines Hristovska², Szilvia Karpati³, Frederic Lerouge³, Maelle Monteil⁴, Emmanuel Brun⁵, Naura Chounlamountri², Chantal Watrin², Fabien Chauveau⁶, Yves Berthezene⁷, Marc Lecouvey⁴, Stephane Parola³, Olivier Pascual², and Marlene Wiart^1
1Université Lyon, CarMeN laboratory, Inserm U1060, Lyon, France, ²Université Lyon Institut Neuromyogène CNRS UMR 5310, INSERM U1217, Lyon, France, ³Université de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR 5182, Université Lyon 1, Laboratoire de Chimie, Lyon, France, ⁴Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS UMR 7244, Paris, France, ⁵STROBE team, European Synchrotron Radiation Facility, Grenoble, France, ⁶Université Lyon, Lyon Neuroscience Research Center, CNRS UMR5292, Inserm U1028, Lyon, France, ⁷Université Lyon, CREATIS CNRS UMR 5220-INSERM U1206, Lyon, France

We here report the first quantitative study using MRI and intravital two-photon microscopy back-to-back to image inflammation in a mouse model of permanent middle cerebral artery occlusion, thanks to NanoGd, a new multimodal nanoparticle. Overall, our data suggest that NanoGd is safe and does not induce inflammation. NanoGd is phagocytosed by Macrophages/Microglia both in-vitro and in-vivo. In permanent ischemic stroke, NanoGd-enhanced MRI allows to visualize inflamed areas within the ischemic lesion and thus appears as a promising tool for the evaluation of anti-inflammatory treatments.

Natalia Ziółkowska^1,2, Martin Hrubý³, Martin Vít^1,4, Zdislava Pechrová^3,5, and Daniel Jirák^1,2
1Department of Computed Tomography, Magnetic Resonance and Clinical Experimental Spectroscopy, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, ²First Faculty of Medicine, Institute of Biophysics and Informatics, Charles University, Prague, Czech Republic, ³Supramolecular polymer systems department, Institute of Macromolecular Chemistry, Prague, Czech Republic, ⁴Faculty of Mechatronics Informatics and Interdisciplinary Studies, Technical University of Liberec, Liberec, Czech Republic, ⁵Faculty of Sciences, Department of Physical and Macromolecular Chemistry, Charles University, Prague, Czech Republic

We present a new class of biodegradable responsive ³¹P phosphorus–containing contrast agent for dual ¹H/³¹P MRI. Both ¹H and ³¹P MR imaging modalities offer complementary information and can be easily combined at the same experiment. The switch to phosphorus MR signal can reflect biochemical changes in the organism. An implementation for ¹H/³¹P MR at 4.7 T is presented and its properties are investigated.

Alyssa C Pollard^1,2, Aikaterini Kotrotsou², Jorge de la Cerda², F William Schuler², Federica Pisaneschi², Seth T Gammon², and Mark D Pagel^1,2
1Chemistry, Rice University, Houston, TX, United States, ²Cancer Systems Imaging, MD Anderson Cancer Center, Houston, TX, United States

Extracellular pH (pHe) in the tumor microenvironment is a biomarker that is used to assess tumor acidosis, which is caused by upregulated aerobic glycolysis in cancer cells. A PET/MRI contrast agent has developed consisting of a pH-responsive MRI co-agent, and a PET co-agent with matching pharmacokinetics to report on the concentration of the MRI co-agent. Using our simultaneous PET/MRI methodology, the pHe of a MIA PaCa-2 pancreatic tumor mouse model was found to be 6.76. These in vivo pH measurements can be used to detect a response to therapy or identify tumor vs. non-tumor tissue.

Junjie Ma¹, Edward P. Hackett¹, and Jae Mo Park^1,2,3
1Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States, ²Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ³Electrical Engineering, UT Dallas, Richardson, TX, United States

Multi-echo ¹³C spiral imaging sequence combined with a spectral-spatial radiofrequency pulse is implemented for sequential imaging of hyperpolarized [¹³C]bicarbonate, [1-¹³C]lactate and [1-¹³C]pyruvate. From the multi-echo ¹³C images of each metabolite in vivo T₂* maps are generated. The pulse sequence was tested with a ¹³C-phantom and applied to measure T₂*s of hyperpolarized [1-¹³C]pyruvate and the products in rat heart in vivo. 

Joshua D Kaggie¹, Mary McLean¹, Rolf F Schulte², Dimitri A Kessler¹, Frances Henson³, Fiona J Gilbert¹, Martin J Graves¹, and Ferdia A Gallagher^1
1Radiology, University of Cambridge, Cambridge, United Kingdom, ²GE Healthcare, Munich, Germany, ³Veterinary Medicine and Divisino of Trauma and Orthopaedic Surgery, University of Cambridge, Cambridge, United Kingdom

We demonstrate natural abundance deuterium imaging of the normal human brain in vivo, without the requirement of an injected deuterated molecule, and within a 10-minute chemical shift imaging acquisition.

Naoya Hayashi^1,2, Junichi Hata^2,3, Tetsu Yoshida², Yawara Haga^1,2, Hideyuki Okano^2,4, Hirotaka James Okano³, and Akira Furukawa^1
1Department of Radiological Sciences, Human Health Sciences, Tokyo Metropolitan University Graduate School, Tokyo, Japan, ²Laboratory for Marmoset Neural Architecture, Center for Brain Science, RIKEN, Saitama, Japan, ³Division of Regenerative Medicine, The Jikei University School of Medicine, Tokyo, Japan, ⁴Department of Physiology, Keio University School of Medicine, Tokyo, Japan

We examined which gene we should transduce for genetic reporter for Magnetic Resonance Imaging (MRI) by comparing T1 or T2 values of the cells followed by exposure to MnCl₂ or Holo-transferrin. We identified the cell which has the shortest T1 or T2 values and it indicates that they can be useful genetic reporter for T1 Weighted Imaging (T1WI) or T2 Weighted Imaging (T2WI).

Asaduddin Muhammad¹, Wonsik Jung², Sangyong Jon², and Sung-Hong Park^1
1Bio and Brain Engineering, KAIST, Daejeon, Korea, Republic of, ²Biological Science, KAIST, Daejeon, Korea, Republic of

Common contrast enhanced MRI study relies on low retention and inert contrast. With the emerging trend of using paramagnetic metal for theragnostic study, few nanoparticles have been reported to have T1 enhancement property. In this research, we try to model the kinetics of such nanoparticles in mouse with A549 tumor. A novel three compartment model were introduced to explain the behavior of Mn-BRNP nanoparticles within mouse blood circulation system. This is the first study to explore reactive contrast agent with high retention, and successfully derived kinetic parameters that characterize the drug uptake behavior.

Mohammad Mehdi Khalighi¹, Mackenzie Carlson², Matthew Spangler-Bickell³, Timothy Deller⁴, Kristen Wangerin⁴, Dan Rettmann⁴, Tim Skloss⁴, Brian Burns⁴, Dawn Holley¹, Kim Halbert¹, Tyler N Toueg⁵, Phillip S DiGiacomo¹, Murat Aksoy⁶, Julian Maclaren⁶, Roland Bammer⁶, Floris Jansen⁴, Fred T. Chin¹, Michael Moseley¹, Greg Zaharchuk¹, Elizabeth Mormino⁵, and Michael Zeineh^1
1Radiology, Stanford Univ., Stanford, CA, United States, ²Bioengineering, Stanford Univ., Stanford, CA, United States, ³Was with: Nuclear Medicine, IRCCS Ospedale San Raffaele, Milan, Italy, ⁴GE Healthcare, Waukesha, WI, United States, ⁵Neurology, Stanford Univ., Stanford, CA, United States, ⁶HobbitView, San Jose, CA, United States

In a brain PET/MR scan, the PET acquisition is done during the entire exam which typically lasts between 30-60 min. Most subjects, especially patients with a motion disorder or AD, exhibit some degree of motion which results in image blurring, quantitative errors due to mismatched attenuation correction, and mis-registered PET and MR images which limits the advantages of PET reconstruction using anatomical priors. In this study, we describe the benefits of an optical motion tracking technique, which has been recently introduced for PET/MR, to acquire high resolution isotropic PET/MR images.

Yu Zhao¹, Daniel F. Gochberg², and Jianqi Li^1
1Shanghai Key Laboratory of Magnetic Resonance, Shanghai, China, ²Vanderbilt University Institute of Imaging Science, Nashville, TN, United States

The purpose of this study was to characterize the contribution of fat to the CEST signal when using a water-selective binomial-pulse excitation and the effects of multiple fat peaks and B₀ inhomogeneity. A CEST sequence with binomial-pulse excitation and a modified PRESS localization was applied to in vivo experiments to determine signal contributions of lipid resonances. Water excitation using a {1-3-3-1} pulse provided a broad signal suppression, which provided robustness against B₀ inhomogeneity. Significant fat signal contributions to CEST imaging of hydroxyl and amine were unavoidable, while much smaller contamination was seen when imaging amide sites, limited by B₀ inhomogeneity.

Mackenzie Leigh Carlson¹, Jun-Hyung Park², Tullia Lieb³, Bin Shen², Marc Stevens², Brian Mills², Nicole Mouchawar², Greg Zaharchuk², Michael Zeineh², and Michelle James^2,4
1Bioengineering, Stanford University, Stanford, CA, United States, ²Radiology, Stanford University, Stanford, CA, United States, ³Medicine, Stanford University, Stanford, CA, United States, ⁴Neurology, Stanford University, Stanford, CA, United States

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease affecting millions of people in the United States alone, but little is known about the underlying pathophysiology. We show that simultaneous TSPO-PET/MRI measurements using [¹¹C]DPA-713, including SUV, SUVr, QSM, R2*, and volume can uncover new information about this disease. We find that the putamen has significantly higher TSPO-PET signal in ME/CFS subjects compared to healthy controls, indicating an elevated inflammatory response in this area. This finding corresponds to previous fMRI and diffusion imaging findings and may help with future diagnosis and tracking of this chronic, widespread disease.

Mackenzie Leigh Carlson¹, Tyler Toueg², Mehdi Khalighi³, Jessa Castillo³, Bin Shen³, Carmen Azevedo³, Phillip DiGiacomo¹, Nicole Mouchawar³, Greg Zaharchuk³, Michelle James^2,3, Elizabeth Mormino², and Michael Zeineh^3
1Bioengineering, Stanford University, Stanford, CA, United States, ²Neurology, Stanford University, Stanford, CA, United States, ³Radiology, Stanford University, Stanford, CA, United States

We found structural changes and tau protein accumulation within the hippocampus that can be simultaneously assessed at the subfield level in Alzheimer’s Disease. We found more separation among AD, mild cognitive impairment (MCI), and control groups when considering subfields than whole hippocampal SUVr. This study highlights the potential of our combined subfield analysis technique in disentangling pathologic derangements accompanying AD in the hippocampus and for providing more nuanced imaging-based measures for tracking and staging disease in vivo.

Nicolas Kaulen^1,2, Claudia Régio Brambilla^1,3,4, Ravichandran Rajkumar^1,3,4, Shukti Ramkiran^1,3, Linda Orth^1,3, Hasan Sbaihat¹, Markus Lang⁵, Elena Rota Kops¹, Jürgen Scheins¹, Bernd Neumaier⁵, Johannes Ermert⁵, Hans Herzog¹, Karl-Josef Langen^1,4,6, Christoph Lerche¹, N. J. Shah^1,4,7,8, and Irene Neuner^1,3,4
1Institute of Neuroscience and Medicine 4, INM-4, Forschungszentrum Jülich, Jülich, Germany, ²Faculty of Physics, Technical University Dortmund, Dortmund, Germany, ³Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany, ⁴JARA – BRAIN – Translational Medicine, Aachen, Germany, ⁵Institute of Neuroscience and Medicine 5, INM-5, Forschungszentrum Jülich, Jülich, Germany, ⁶Department of Nuclear Medicine, RWTH Aachen University, Aachen, Germany, ⁷Institute of Neuroscience and Medicine 11, INM-4, Forschungszentrum Jülich, Jülich, Germany, ⁸Department of Neurology, RWTH Aachen University, Aachen, Germany

This project aims to create a standard space in vivo atlas of the mGluR5 distribution in the healthy brain using structural and metabolic information from simultaneously acquired [11C]ABP688-PET / MR data. The structural MRI scans served as an anatomical reference to create a parametric MNI space atlas of mGluR5 non-displaceable binding potential. Validation of the atlas was performed and global as well as local reductions of mGluR5 availability in healthy smokers and schizophrenic smokers that are in line with the results of previous studies could be shown. Preliminary investigation of schizophrenic non-smokers showed slight, though not conclusive, reductions of mGluR5.

Daehyun Yoon¹, Peter Cipriano¹, and Sandip Biswal^1
1Radiology, Stanford university, Stanford, CA, United States

Low back pain is a leading cause of job-related disability and missed workdays in the U.S. Unfortunately, the overall treatment effectiveness is significantly limited by our poor diagnostic capability, which fails to identify nociceptive sources in 80% to 90% of the cases. In this work, we introduce a PET/MRI approach for low back pain diagnosis using a novel radioligand to track the sigma-1 receptor, which is upregulated during nociceptive processes. Our early results demonstrate promise in achieving improved sensitivity and specificity to the local sources of low back pain.

Kelly T Smith¹, Akira Kawashima², Mark D Tyson³, Erik P Castle⁴, Alvin Silva¹, Yuxiang Zhou¹, Michael C Roarke¹, and Ming Yang^1
1Radiology, Mayo Clinic Arizona, PHOENIX, AZ, United States, ²Radiology, Mayo Clinic Arizona, Phoenix, AZ, United States, ³Urology, Mayo Clinic Arizona, PHOENIX, AZ, United States, ⁴Urology, Mayo Clinic Arizona, Phoenix, AZ, United States

The most prevalent malignancy in US men is prostate cancer. Appropriate treatment regimen is dependent on accurate tumor staging. Pelvic multiparametric MR (mpMRI) is the established modality for tumor and nodal staging. C-11 choline is FDA approved in diagnosis of recurrent prostate cancer.  Introduction of a hybrid time-of-flight PET/MR system affords the opportunity to perform a combined C-11 choline PET + mpMRI for prostate cancer staging.  We feel this system would be beneficial in staging of treatment naïve high risk prostate cancer.  

Xiaojun Luo¹, Chunwu Zhou², and Lizhi Xie^3
1Department of Radiology, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, China, ²National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, ³GE healthcare, China, Beijing, China

Superparamagnetic iron oxide nanoparticles (SPIONs) has been applied in diagnosis of different cancers, however its potential in breast cancer has not been fully explored. In this study, we research into the value of SPIONs conjugated with trastuzumab and indocyanine green (ICG) in becoming an effective multifunctional imaging agent and a tool for photothermal therapy for HER2-positive breast cancer. It was found that the biodistribution of dual-modality imaging agents has been observed by MRI and fluorescence imaging, which could provide effective technical assistance for HER2-positive breast cancer treatment.

Nikorn Pothayee¹, Stephen Dodd¹, Gary Zabow², and Alan Koretsky^1
1Laboratory of Functional and Molecular Imaging, National Institutes of Health, Bethesda, MD, United States, ²Magnetic Imaging Group, National Institute of Standards and Technology, Boulder, CO, United States

There is great potential if single cells can be tracked in vivo in the mammalian brain. Here, we demonstrate the applicability of microfabricated gold-coated iron particles for in vivo tracking of single-cell dynamics. These particles have a pure iron core as opposed to the more commonly used iron-oxide based particles. Following in situ labeling of neural precursor cells, we show that the migration of individual cells can be visualized in real-time.

Wenhui Huang^1,2, Kun Wang², Jie Tian², and Shuixing Zhang^1
1the First Affiliated Hospital,Jinan University, Guangdong, China, ²Institute of Automation, Chinese Academy of Sciences, Beijing, China

The accurate imaging hypoxia is especially vital for nasopharyngeal carcinoma (NPC) patients undergoing radiotherapy. Multimodality molecular imaging have great potential to acquire hypoxic imaging with high sensitivity and more accuracy. We propose a novel imaging strategy,which combined the hybrid fluorescence molecular tomography-computed tomography (FMT-CT) and the multispectral optoacoustic tomography (MSOT), for achieving three-dimensional (3D) quantitative evaluation of NPC hypoxia in small animal models.The results could not only detect the hypoxia in small sizes of NPCs and lymph nodes metatasis, but also visualize the heterogeneity of hypoxia in 3D. 

Mozhdeh Sojoodi¹, Ian Ramsay², Eric Gale², Peter Caravan^2,3, Kenneth Tanabe¹, and Veronica Clavijo Jordan ^2
1Division of Surgical Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States, ²Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, United States, ³Institute for Innovation in Imaging (i3), Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, United States

Zinc homeostasis is markedly dysregulated in pancreatic ductal adenocarcinoma (PDAC), and this dysregulation can be probed by selecting a secretagogue to stimulate the secretion of zinc and functional components from the exocrine pancreas. Here, we introduce the use of caerulein, a surrogate cholecystokinin agonist of pancreatic exocrine secretion, and a Gd-based zinc probe to monitor exocrine function in the healthy and PDAC mouse pancreas by MRI. Our results indicate that zinc dysregulation involves an increase in zinc accumulation in malignant tissue mediated by upregulation of zinc import transporters, and hypersecretory capacity as reported by caerulein-stimulated zinc secretion MRI in vivo.

Veronica Clavijo Jordan ¹, Andre Martins^2,3, Erica Dao⁴, Alia Al-Ebraheem⁴, Kalotina Geraki⁵, Xiaodong Wen³, Sara Chirayil³, Xiaojing Wang³, Mozhdeh Sojoodi⁶, Michael Farqhuarson⁴, and A.Dean Sherry^3,7
1Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, United States, ²Werner Siemens Imaging Center, Tuebingen, Germany, ³Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States, ⁴McMaster University, Hamilton, ON, Canada, ⁵Diamond Light Source, Harwell, United Kingdom, ⁶Division of Surgical Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States, ⁷Department of Chemistry, University of Texas at Dallas, Richardson, TX, United States

Zinc homeostasis is markedly dysregulated in prostate cancer (PCa), and this dysregulation can be detected with glucose-stimulated zinc secretion (GSZS) by MRI. Here we explore the use of GSZS MRI and synchrotron-radiation X-Ray fluorescence to interrogate the effect of dietary zinc on the healthy and malignant mouse prostate. Our results indicate that the lateral lobe of the healthy mouse is the only prostatic structure responsive to a variable zinc diet acting as the zinc “regulator” of the gland, and that in PCa this lobe no longer responds to changes in dietary zinc, highlighting the dysregulation of zinc transporters in PCa.  

Marie-Laurence Tremblay^1,2,3, Caitrin Sobey-Skelton^1,2, Hailey Wyatt^1,2, Victoria Gonzalez², Andrea Nuschke^1,4, Christa Davis¹, Alecia MacKay⁵, Kim Bobbitt⁵, Andrea West^2,5, Barbara Vanderhyden^6,7, Genevieve Weir⁵, Marianne Stanford⁵, and Kimberly Brewer^1,2
1Biomedical Translational Imaging Centre (BIOTIC), Halifax, NS, Canada, ²Dalhousie University, Halifax, NS, Canada, ³IWK Inc., Halifax, NS, Canada, ⁴Carleton University, Ottawa, ON, Canada, ⁵IMV Inc., Halifax, NS, Canada, ⁶Ottawa Hospital Research Institution, Ottawa, ON, Canada, ⁷University of Ottawa, Ottawa, ON, Canada

Epithelial ovarian cancers are highly aggressive tumor types making them a prime target for research using immunotherapies. Using simultaneous PET/MRI, we monitored an orthotopic ovarian cancer model to evaluate longitudinal tumor growth and metabolism in response to therapy while tracking immune cell subsets labeled with superparamagnetic iron oxide (SPIO). Treatment with the combination of immune therapies significantly decreased the volume of primary tumors and improved survival times. We quantified cytotoxic T lymphocytes (CTLs) and dendritic cells (DCs) recruited to the primary tumors and found treatment with the combination therapy increased recruitment of CTLs but resulted in decreased recruitment of DCs.

Lawrence M Lechuga¹, Matthew H Forsberg², Kai D Ludwig¹, Christian M Capitini^2,3, and Sean B Fain^1,4,5
1Medical Physics, University of Wisconsin, Madison, Madison, WI, United States, ²Pediatrics, University of Wisconsin, Madison, Madison, WI, United States, ³Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Madison, WI, United States, ⁴Biomedical Engineering, University of Wisconsin, Madison, Madison, WI, United States, ⁵Radiology, University of Wisconsin, Madison, Madison, WI, United States

Flourine-19 (¹⁹F) MRI has demonstrated the ability to monitor immune cell populations in vivo. Murine green fluorescent protein natural killer (NK) cells were labeled with perfluoropolyether (PFPE-red) and injected intratumorally into lymphoma-bearing mice. In this work, we demonstrate the ability to track and quantify NK cells up to 5 days in vivo, via 19F MRI. In vivo quantification indicated that 88% of the initially detected NK cells remained at the tumor site on day 5. Flow cytometry analysis provided validation that the cellular label remains colocalized within a significant portion of the NK cells at day 5. 

Mohammad Mehdi Khalighi¹, Timothy Deller², Matthew Spangler-Bickell³, Kristen Wangerin², Dawn Holley¹, Kim Halbert¹, Michael Zeineh¹, Greg Zaharchuk¹, Elizabeth Mormino⁴, Andrei Iagaru⁵, and Michael Moseley^1
1Radiology, Stanford University, Stanford, CA, United States, ²PET/MR Engineering, GE Healthcare, Waukesha, WI, United States, ³Was with: Nuclear Medicine, IRCCS Ospedale San Raffaele, Milan, Italy, ⁴Neurology, Stanford University, Stanford, CA, United States, ⁵Nuclear Medicine, Stanford University, Stanford, CA, United States

The current spatial resolution of PET images is ~4mm for whole body PET/MR. Anatomical MR images with higher resolution and superior SNR, have been used in PET reconstruction to improve the image quality and spatial resolution. However, these methods are generally vulnerable to mismatches between the anatomical image and the true activity distribution. To address this concern, we propose a feature based approach to incorporate anatomical priors in PET image reconstruction, where the location of a voxel or its neighbors doesn't play a direct role and both functional and anatomical images are used to construct the feature space.

Paola Scifo¹, Maurizio Barbera², Federico Fallanca¹, Antonella Castellano², Paola Mapelli¹, Valentino Bettinardi¹, Annarita Savi¹, Riccardo Rigamonti¹, Andrea Falini², Luigi Gianolli¹, Maria Picchio^1,3, and Nicoletta Anzalone^2
1Nuclear Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy, ²Neuroradiology and CERMAC, VIta-Salute University, IRCCS San Raffaele Scientific Institute, Milan, Italy, ³Vita-Salute San Raffaele University, Milan, Italy

Simultaneous PET/MRI offers a unique opportunity to investigate the relationship between concurrent phenomena measured by MET-PET and PWI-MR at the same physiological condition. Although 11C-Methionine uptake and perfusion are tightly coupled, it is not clear whether tumor regions (VOIs) defined by PWI and MET are overlapped and how the values of the corresponding parametric maps are distributed within each VOI. This preliminary work aims at studying the spatial relationship between PWI-MRI maps and MET-PET in brain tumors using a fully integrated PET/MRI system.

Timothy J Allen¹, Leah C Henze Bancroft², Manoj Kumar², Tyler Bradshaw², Roberta M Strigel^1,2,3, Alan McMillan^1,2, and Amy M Fowler^1,2,3
1Medical Physics, University of Wisconsin-Madison, Madison, WI, United States, ²Radiology, University of Wisconsin-Madison, Madison, WI, United States, ³Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States

The effect of gadolinium-based contrast agents (GBCAs) on dynamic PET quantification was investigated. Simultaneous PET/MRI was performed in patients with biopsy confirmed invasive breast cancer. Subjects received an injection of a GBCA as part of standard clinical dynamic contrast enhanced breast MRI exam. SUV_mean and SUV_max were calculated for the biopsy-proven breast cancer, aorta, liver, and benign fibroglandular tissue prior to and following GBCA injection. No significant difference in SUV_mean or SUV_max was measured suggesting GBCAs are unlikely to affect PET quantification in combined breast PET/MRI.   

wan tang¹, ting ouyang¹, and yan lin^1
1radiology, Second Affiliated Hospital, Shantou University Medical College, China, shantou, China

Breast multi-parametric magnetic resonance imaging (mp-MRI) is a well-established technique in breast cancer for tumor characterization, treatment strategies and post operative predicting, owing to its non-invasive nature of excellent soft-tissue contrast. Our preliminary work demonstrated that MK showed promise in characterizing breast lesions as well as predicting prognostic factors. However, due to the small samples in our previous research and few research relating to the correlation between MK and molecular subtypes, further study with larger cohort is needed to verify our initial results and explore more potential of MK in other clinical applications (assessing therapeutic response to MWA in BBLs).

Samuel Anthony Hurley¹, Matthew G Spangler-Bickell², Timothy Deller³, Timothy W Skloss³, Floris P Jansen³, Tyler J Bradshaw¹, and Alan B McMillan^1
1Radiology, University of Wisconsin, Madison, WI, United States, ²Nuclear Medicine Unit, IRCCS Ospedale San Raffaele, Milan, Italy, ³GE Healthcare, Waukesha, WI, United States

Motion during PET acquisition will result in blurring, which may reduce the diagnostic value of the images and cause inaccurate quantitation. Motion during an MR exam results in image replicates and ghosting along the phase encoding direction and other effects due to inconstant phase, rendering images non-diagnostic. In this work, we evaluate the ability of an optical motion tracking system to simultaneously enable prospective correction in MR and retrospective correction in PET of rigid body head motion.

Nevein Ibrahim¹, Minnie Kieler¹, Elizabeth A Sadowski¹, Steve Cho¹, Emmanuel Sampene¹, Alan McMillan^1,2, and Joanna E Kusmirek^1
1Diagnostic radiology, University of Wisconsin School of Medicine and Public health, Madison, WI, United States, ²Medical physics, University of Wisconsin School of Medicine and Public health, Madison, WI, United States

One of the limitations of PET/MRI is poor evaluation of lung parenchyma with free breathing sequences. In this study, 41 patients with gynecological malignancies underwent PET/MRI with rapid single breath hold lung acquisition after PET/CT. The CT and MRI of the lungs were reviewed blindly for detection of pulmonary nodules 4mm or larger. The study showed that there was no significant difference between the CT and single breath hold MRI using Chi square test. Improved detection of small pulmonary nodules using single breath hold sequence would increase the feasibility of stand-alone PET/MR imaging for clinical staging in oncologic patients.

Daehyun Yoon¹, Angela Fast², Peter Cipriano¹, Bin Shen¹, Michelle James¹, Deirdre Lum³, and Sandip Biswal^1
1Radiology, Stanford university, Stanford, CA, United States, ²Diagnostic, Molecular and Interventional Radiology, The Mount Sinai Hospital, New York, NY, United States, ³Gynecology, Stanford university, Palo Alto, CA, United States

Chronic pelvic pain is a highly prevalent pain condition among women, but it is quite challenging to determine the exact cause of pain. MRI is currently the imaging modality of choice, but even the most common etiology is very difficult to identify. In this abstract, we introduce a novel PET/MRI approach for chronic pelvic pain diagnosis to achieve improved sensitivity by enabling image tracking of sigma-1 receptor, a chaperone protein modulating ion channels for activating nociceptive processes. Our early results present promising results in identifying potential pain generators of chronic pelvic pain, which could not be detected in MRI alone. 

Haiyan Gao¹, Yan Bai¹, Lijuan Chen¹, and Meiyun Wang^1
1Henan Provincial People's Hospital, Zhengzhou, China

Glioblastoma is one of the most lethal cancers with few available therapeutic options.  Herein, we report a in situ self-assembled nanoplatform formed by RGD peptide-modified Bisulfite-ZincII-Dipicolylamine-Arg-Gly-Asp (Bis(DPA-Zn)-RGD) and ultrasmall Au-ICG nanoparticles. Taking advantage of RGD-mediated neovascular targeting, the Bis(DPA-Zn)-RGD selectively navigates to the tumor site, and then assembles into large nanoclusters with subsequently administered Au-ICG nanoclusters which can successfully cross the BBB due to ultrasmall particle size (~7 nm). This study demonstrates that such in situ self-assembly metal–organic nanosystems are ideal to overcome the BBB and BBTB, which promise a new way for orthotopic brain tumors imaging and therapy.

Jia-Xiang Xin¹, Yi Li¹, Jian-Qi Li¹, Guang Yang¹, Jia-Chen Wang¹, Da-Xiu Wei¹, and Ye-Feng Prof. Yao^1
1East China Normal University, Shanghai, China

In this work, we report a novel method for obtaining an exact molecular targeted MRI and MRS. This method uses the nuclear spin singlet state to select the signals from a specific molecule. Several endogenetic molecules in living organism such as N-acetylaspartate and dopamine have been imaged and probed as the targeted molecules in the MRI and MRS experiments, demonstrating the unique molecular selectivity of the developed method.
 

Camryn Jayne Newman¹, Yurii Shepelytskyi^2,3, Ashvin Fernando⁴, Paul T Cesana⁴, Tao Li⁵, Alanna Wade⁵, Vira Grynko³, Adriana M Mendieta⁴, Francis T Hane^2,5, Brenton DeBoef⁴, and Mitchell S Albert^2,5,6
1Biology, Lakehead University, Thunder Bay, ON, Canada, ²Thunder Bay Regional Research Institute, Thunder Bay, ON, Canada, ³Chemistry and Material Science, Lakehead University, Thunder Bay, ON, Canada, ⁴Chemistry, University of Rhode Island, Kingston, RI, United States, ⁵Chemistry, Lakehead University, Thunder Bay, ON, Canada, ⁶Northern Ontario School of Medicine, Thunder Bay, ON, Canada

Hyperpolarized (HP) 129Xe molecular imaging technology has been working towards the detection of biochemically inactive supramolecular cage-molecules within a living mammalian model.  The issue originates from the non-specific natural biodistribution of the biosensor molecules, which makes it difficult to precisely localize them within a living mammalian body using HP 129Xe MRI.  We have previously identified cyclodextrin-based pseudorotaxanes and benzene-appended CB6 as conjugatable scaffolds for xenon biosensors; in this work, we introduce a third class of conjugatable scaffolds, with the hyperCEST detection of pillar[5]arene, a potential precursor to a large variety of targeted molecular imaging probes.

Camryn Jayne Newman¹, Yurii Shepelytskyi^2,3, Michael Campbell^2,4, Vira Grynko^2,3, Francis Theodor Hane^3,4, and Mitchell Scott Albert^4,5
1Biology, Lakehead University, Thunder Bay, ON, Canada, ²Thunder Bay Regional Research Institute, Thunder Bay, ON, Canada, ³Chemistry and Material Science, Lakehead University, Thunder Bay, ON, Canada, ⁴Chemistry, Lakehead University, Thunder Bay, ON, Canada, ⁵Northern Ontario School of Medicine, Thunder Bay, ON, Canada

The selective nature of the blood-brain barrier (BBB) is highly regarded when evaluating the permeability of a molecule such as Cucurbit[6]uril (CB6).  CB6 has previously demonstrated a strong hyperCEST effect, which makes it a valid candidate for detecting low concentrations of biomarkers of neurodegenerative pathologies.  However, CB6 must be permeable to the BBB to use the hyperCEST technique for neurological biomarkers.  Therefore, this work evaluates the permeability of CB6 across an artificial BBB based on diffusion.  It was found that CB6 can cross the brain sphingomyelin powder (BSM) based artificial BBB. 

Timothy W. Deller¹, Nicholas Mathew², Samuel Hurley², Chad Bobb¹, and Alan McMillan^2
1GE Healthcare, Waukesha, WI, United States, ²University of Wisconsin-Madison, Madison, WI, United States

Floating surface coils, such as the anterior array coil, are ignored in PET attenuation correction for PET/MR because their position is difficult to determine. This leads to quantitative bias in reconstructed PET images. This study investigates the potential to improve quantitative accuracy in PET when using a new lightweight "AIR Technology" anterior array coil, as compared to the traditional anterior array coil. Metrics of quantification accuracy and error variation were explored with a phantom and clinical study.

Eugene Milshteyn^1,2, Bastien Guerin^1,2, and Lawrence L. Wald^1,2,3
1Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States, ²Harvard Medical School, Boston, MA, United States, ³Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States

The current standard methods for magnetic resonance imaging of superparamagnetic iron oxide nanoparticles (SPIONs) can be subject to “1/f” physiological fluctuations that can confound pre/post comparisons. We present a method to combine Block Design contrast Modulations and statistical analysis with the bSSFP sequence (BDM-bSSFP) in order to mitigate this effect. To do this, we leverage the frequency response of the bSSFP sequence to the local fields created by SPIONs. We show the ability of this method to detect SPIONs down to 10 μg/mL through simulations and in-vitro acquisitions.

Vera Flocke¹, Pascal Bouvain¹, Sebastian Temme¹, and Uli Flögel^1
1Molecular Cardiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

There is increasing evidence that inflammatory diseases go along with substantial changes in intermediatory metabolism. Also it is known that metabolic syndrome is characterized by chronic low-grade inflammation in multiple organs^[1,2]. In this context, the metabolism of glucose is of major interest, since in particular in the initial phase of an inflammation infiltrating immune cells mainly rely on glycolysis to cover their energy demand. 

The present study demonstrates that ²H MRI can be successfully used for monitoring metabolic alterations in an inflammatory environment with a switch to a more anaerobic glucose utilization in the initial phase of immune cell recruitment. 

Wang Ting¹, Ma Lin¹, and Lou Xin^1
1Chinese PLA General Hospital, Beijing, China

An αvβ3-specific Fe3O4-RGD nanoprobe was prepared for MR imaging of the collaterals during AIC. The MCAO rat models were constructed for imaging studies on 7.0-T MRI. To show the binding specificity to the collaterals, the imaging results acquired with the Fe3O4-RGD nanoprobe, Fe3O4 mother nanoparticles and RGD blocking experiment. Cerebral ischemia-reperfusion studies were also performed to show the collateral dynamics upon reperfusion. The studies have the first-time enabled the direct observation of collaterals in a quasi-real time fashion and further disclosed that the antegrade flow upon reperfusion dominates the blood supply of primary ischemic tissue during early stage of infarction.

Lawrence M Lechuga¹, Alexa R Barres², Montira Tangsangasaksri³, Paul Begovatz¹, Sandro Mecozzi^3,4, and Sean B Fain^1,5,6
1Medical Physics, University of Wisconsin, Madison, Madison, WI, United States, ²Morgridge Institute for Research, Madison, WI, United States, ³Pharmacy, University of Wisconsin, Madison, Madison, WI, United States, ⁴Chemistry, University of Wisconsin, Madison, Madison, WI, United States, ⁵Biomedical Engineering, University of Wisconsin, Madison, Madison, WI, United States, ⁶Radiology, University of Wisconsin, Madison, Madison, WI, United States

Fluorine-19 MRI is a method that can utilize biocompatible perfluorocarbons to detect cancer. Implementation of a novel nanoemulsion has allowed for improved particle stability and PFC loading. Tumor-bearing mice were injected with perfluoro-[15-crown-5]-ether (PFCE) loaded nanoemulsion (NE) to explore the passive tumor targeting across 14 days. ¹⁹F MRI and subsequent ROI-image analysis suggested that there was a preferential retention of NE particles due to the enhanced permeability and retention (EPR) effect. This work demonstrates repeatable ¹⁹F imaging of a novel nanoemulsion that passively targets a fast growing tumor with improved stability and PFCE loading.

Cornelius von Morze¹, James D Quirk¹, John A Engelbach¹, Galen D Reed², Albert P Chen², Craig R Malloy³, Joel R Garbow¹, and Matthew E Merritt^4
1Department of Radiology, Washington University, St Louis, MO, United States, ²GE Healthcare, Dallas, TX, United States, ³Advanced Imaging Research Center, UT Southwestern, Dallas, TX, United States, ⁴Department of Biochemistry and Molecular Cell Biology, University of Florida, Gainesville, Gainesville, FL, United States

¹³C hyperpolarization has opened the door for real-time MR metabolic imaging but remains limited by T₁'s of approximately one minute or less. ¹⁵N offers potentially much longer T₁'s, but suffers from poor intrinsic sensitivity and small chemical-shift separation. We have hyperpolarized L-[¹⁵N]carnitine-d₉, a novel metabolic imaging probe, and found ultra-long T₁'s of 210s (in H₂O) / 160s (in vivo). We also demonstrate successful ¹⁵N->¹H hyperpolarization transfer for enhanced sensitivity of detection as well as larger chemical-shift separation among metabolites. The long signal lifetime and excellent safety profile of [¹⁵N]carnitine suggest great potential for metabolic imaging investigations and future clinical translation.