Zheng-Rong Lu¹, Amita Vaidya¹, Nadia Ayat¹, Helen Wang¹, and Megan Buford^1
1Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States

Non-invasive active surveillance and risk-stratification of drug-resistant colon cancer is imperative, in order to facilitate disease management and tailor therapeutic interventions. This research demonstrates that acquired drug resistance in colon cancer is associated with enhanced expression of extracellular matrix oncoprotein extradomain-B fibronectin (EDB-FN). MR molecular imaging of EDB-FN at a subclinical dose of macrocyclic ZD2-targeted contrast agent ZD2-N₃-Gd(HP-DO3A) facilitates effective assessment of drug-resistant colon cancer in two independent models, highlighting the potential of EDB-FN as a diagnostic molecular marker for invasive colon cancer.

Daniel Andrzej Szulc^1,2, Mohammadali Ahmadipour^1,3, Fabio Gava Aoki^3,4, Thomas K. Waddell^1,3,5, Golnaz of Karoubi^5,6,7, and Hai-Ling Margaret Cheng^1,2,7,8,9
1Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada, ²Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada, ³Latner Thoracic Surgery Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada, ⁴Biomedical Engineering Laboratory, University of Sao Paulo, Sao Paulo, Brazil, ⁵Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada, ⁶Latner Thoracic Surgery Laboratories, University of Toronto, Toronto, ON, Canada, ⁷Ontario Institute for Regenerative Medicine, Toronto, ON, Canada, ⁸Heart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, Toronto, ON, Canada, ⁹Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, ON, Canada

Extracellular matrix (ECM) forms the underlying complex structure of bodily tissues, for this reason, ECM has been greatly explored as an ideal scaffold for tissue engineering. To better understand and optimize scaffold-based therapies we require sensitive and non-invasive imaging techniques. In this study, a novel and facile method for labelling and imaging decellularized ECM scaffolds is presented.  A series of tissue-specific (bladder, lung, and tracheal smooth muscle and cartilage) dECM scaffolds are labelled with a small molecule manganese porphyrin, MnPNH₂. The labelled scaffolds are biocompatible and exhibit significant and sustained signal in vitro and in vivo.

Nikorn Pothayee¹, Deepak Sail², Stephen Dodd¹, Rolf Swenson², and Alan Koretsky^1
1Laboratory of Functional and Molecular Imaging, National Institutes of Health, Bethesda, MD, United States, ²Imaging Probe Development Center, National Institutes of Health, Rockville, MD, United States

One of the most important goals of brain imaging is to define the anatomical connections within the brain. In addition to revealing normal circuitry, studies of neural connections and their transports can show rewiring and outgrowth during degeneration following brain injury and diseases. Ultrasensitive agents that can reveal neuroconnectivity and axonal transport dynamics in vivo will be very useful and allow for the interrogation of changes in brain connections and circuitry. In this work, we report two novel MR-visible neural tracers that can be used to visualize neuroconnectivity in vivo. 

Pengpeng Sun¹, Yunfei Zhang², Kaicheng Li¹, Cong Wang³, Feng Zeng³, Jinyu Zhu¹, Yongming Dai², Xiaofeng Tao¹, and Yinwei Wu^1
1Shanghai Ninth People’s Hospital, Shanghai, China, ²United Imaging Healthcare, Shanghai, China, ³Fudan University, Shanghai, China

Accurately defining infiltrative tumor margin is extremely crucial for complete resection and avoiding mistaken removal of normal tissue. Currently, pre-operative MRI imaging is the most widely-used strategy for defining tumor margin. However, there are plenty of insurmountable disadvantages in terms of accuracy, low resolution, mismatch and so on. This research aims to develop one targeting MRI-Raman nanoprobe able to pre-operatively and intra-operatively evaluate infiltrative margin of head and neck carcinoma (HNSCC) and real-timely guide tumor resection. The results showed that the nanoprobe greatly benefits the complete resection of HNSCC. As a result, the prognosis of tumor-bearing rabbits were considerably improved.

Marios Georgiadis^1,2,3, Els Fieremans², Aileen Schroeter³, Manuel Guizar-Sicairos⁴, Zirui Gao⁴, Aleezah Balolia⁵, Piotr Walczak^6,7, Lin Yang⁸, Gergely David⁹, Jiangyang Zhang², Dmitry S. Novikov¹⁰, Markus Rudin^3,11, and Michael Zeineh^1
1Radiology, Stanford University, Stanford, CA, United States, ²NYU School of Medicine, New York, NY, United States, ³Institute for Biomedical Engineering, ETH Zurich, Zurich, Switzerland, ⁴Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland, ⁵Psychology, University of Colorado Denver, Denver, CO, United States, ⁶Radiology, Johns Hopkins Medicine, Baltimore, MD, United States, ⁷Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States, ⁸National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY, United States, ⁹Balgrist University Hospital, University of Zurich, Zurich, Switzerland, ¹⁰Center for Biomedical Imaging, NYU School of Medicine, New York, NY, United States, ¹¹Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

Axonal myelination is an important indicator of brain development and is implicated in many neurologic diseases. However, MRI methods to probe myelin are sensitive but not specific. Small-angle X-ray scattering (SAXS) produces signal specific to myelin’s nanostructural periodicity. Here we apply the recently developed SAXS tensor tomography (SAXS-TT) to non-invasively retrieve myelin levels in mouse brains, and compare them to myelin-sensitive MRI methods. We demonstrate SAXS-TT myelin specificity i) using myelin histology, ii) on a dysmyelination model and iii) by selectively probing central and peripheral nervous system myelin. We propose SAXS-TT as quantitative tomographic method for validating MRI myelin-sensitive sequences.

Ravichandran Rajkumar^1,2,3, Claudia Régio Brambilla^1,2,3, Christine Wyss^1,4, Shukti Ramkiran^1,2, Linda Orth^1,2, Joshua Lewis Bierbrier^1,5, Elena Rota Kops¹, Jürgen Scheins¹, Bernd Neumaier⁶, Johannes Ermert⁶, Hans Herzog¹, Karl Joseph Langen^1,3,7, Christoph Lerche¹, N. Jon Shah^1,3,8,9, and Irene Neuner^1,2,3
1Institute of Neuroscience and Medicine 4 (INM-4), Forschungszentrum Jülich, Jülich, Germany, ²Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany, ³JARA – BRAIN – Translational Medicine, Aachen, Germany, ⁴Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Zürich, Switzerland, ⁵Department of Electrical and Computer Engineering, McMaster University, Hamilton, ON, Canada, ⁶Institute of Neuroscience and Medicine 5 (INM-5), Forschungszentrum Jülich, Jülich, Germany, ⁷Department of Nuclear Medicine, RWTH Aachen University, Aachen, Germany, ⁸Institute of Neuroscience and Medicine 11 (INM-11), Forschungszentrum Jülich, Jülich, Germany, ⁹Department of Neurology, RWTH Aachen University, Aachen, Germany

  fMRI-BOLD signals reflect the synaptic activity and glucose energy metabolism in the brain. This study investigated the association between excitatory (mGLUR5), inhibitory (GABA_A) neuroreceptors, and glucose metabolism using PET imaging with resting-state fMRI for the first time. The significantly higher mGLUR5 and GABA_A neuroreceptor availability and glucose metabolism within the DMN and its correlations show a possible association between increased energy requirements and neuronal activity in the DMN. Further correlations with fMRI measurements show that higher energy demand is utilised for higher functional connectivity, and consecutively higher connectivity within the DMN is more strongly associated with inhibitory receptors.

Li Liu¹, Stephen Dodd¹, Ryan Hunt¹, Nikorn Pothayee¹, Nadia Bouraoud¹, Dragan Maric¹, E Ashley Moseman¹, Dorian B McGavern¹, and Alan P Koretsky^1
1National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States

A method to label non-phagocytic CD8 T cells with a micron-sized iron oxide particle (MPIO) has been developed which enables MRI single cell detection. Adoptive transfer of T cells showed therapeutic effects in mice causing less bleeding after intranasal virus infection. MPIO-labeled CD8 T cells entered the brain and the combination of labeled T cells and blood made sites of microbleeds easily detectable by MRI. The ability to track individual immune cells by MRI should open new possibilities for early detection of inflammation as well as to monitor the rapidly expanding field of immune cell therapies.

Kai Qiao^1,2, Lydia Le Page^1,2, Celine Taglang^1,2, and Myriam M Chaumeil^1,2
1Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA, United States, ²Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States

The immune system plays an essential role in various diseases, and macrophage activation patterns can vary greatly - impacting intervention. We propose that ¹³C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-¹³C] Pyruvate and [1-¹³C] Dehydroascorbic acid (DHA) can differentiate between non-activated and M1 classically activated macrophages at the clinically-relevant field strength of 1.47T. In M1-activated macrophages we report increased HP Lactate from Pyruvate, and increased HP Ascorbic Acid from DHA compared to Control cells. This study is a first in differentiating between activated and non-activated macrophages with HP probes at this field strength and could become a powerful translational tool.

Emmanuelle Flatt¹, Bernard Lanz¹, Andrea Capozzi¹, Magnus Karlsson², Mathilde H.Lerche², Rolf Grütter^1,3, and Mor Mishkovsky^1
1LIFMET, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, ²Danmarks Tekniske Universitet, Lyngby, Denmark, ³CIBM, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Glucose is the primary fuel for the brain and its metabolism is linked with cerebral function. Isoflurane anesthesia is commonly employed in preclinical MRS but influences functional connectivity. The combination of isoflurane and medetomidine is regularly used in rodent fMRI and show similar functional connectivity as in awake animals. Here we compared the cerebral metabolism of hyperpolarized [²H₇,U-¹³C₆]-D-glucose under these two anesthetic conditions. When using the combination, the [1-¹³C]lactate signal and lactate-to-glucose ratio were more than doubled compared to isoflurane solely, showing that the change of anesthesia had a high impact on cerebral glucose uptake and glycolytic flux.

Jun Chen¹, Toral Patel², Crystal E Harrison¹, Galen D Reed³, Craig R Malloy¹, Bruce Mickey², and Jae Mo Park^1,4,5
1Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States, ²Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX, United States, ³GE Healthcare, GE Healthcare, Dallas, TX, United States, ⁴Radiology, University of Texas Southwestern Medical Center, Dallas, TX, United States, ⁵Electrical Engineering, University of Texas Dallas, Richardson, TX, United States

Noninvasive tumor characterization is extremely beneficial for brain tumor patients for establishing surgical procedure and treatment plans. In this study, we imaged newly diagnosed glioblastoma patients using hyperpolarized [1-¹³C]pyruvate few days prior to surgical procedures and compared the imaging and biopsy results to evaluate the diagnostic values of hyperpolarized pyruvate imaging. Brain regions with increased ¹³C-lactate production are confirmed as glioblastoma from stereotactic tissue-biopsy. This pilot study with treatment-naïve or newly diagnosed brain tumor patients suggest that preoperative metabolic imaging with hyperpolarized [1-¹³C]pyruvate may have strong diagnostic value with potential to be an alternative method for tissue biopsy.

Friederike Hesse¹, Vencel Somai^1,2, Flaviu Bulat¹, Felix Kreis¹, and Kevin Brindle^1,3
1Cancer Research UK Cambridge Institute, Cambridge, United Kingdom, ²Department of Radiology, University of Cambridge, Cambridge, United Kingdom, ³Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

Monitoring tumor responses to treatment using metabolic imaging can give an early indication of outcome. We show here that Deuterium Metabolic Imaging (DMI) with ²H-labelled fumarate can be used to detect early evidence of cell death following drug treatment in a pre-clinical murine lymphoma model. ²H spectra were acquired from tumors with a time resolution of 5 min, following a bolus injection of ²H-labelled fumarate. Within 48 h of etoposide treatment the rate of tumor malate production from the labelled fumarate increased significantly. Increased levels of labelled malate were also evident in spectroscopic images of the tumors.

Felix Kreis¹, Grzegorz Kwiatkowski¹, and Sebastian Kozerke^1
1Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland

We investigated whether deuterium MR spectroscopy using ²H-labeled glucose can be used to assess Krebs cycle metabolism in the in-vivo heart. Localized ²H spectra were acquired from a slice containing the whole heart and from a voxel containing only the left ventricle of the heart using a temporal resolution of ~12 min following a bolus injection of [6,6′-²H₂]glucose. Single voxel spectra show the production of labelled Glutamate/Glutamine (Glx) ˜36 min after the administration of the glucose. The Glx concentration reflects Krebs cycle activity which holds potential to probe various metabolic states of the heart.