Animal Models 1

Monday 22 April 2013

Nicolas Coquery^1,2, Clément S. Debacker^3,4, Régine Farion^2,5, Chantal Rémy^1,2, Olivier Francois^6,7, and Emmanuel Luc Barbier^2,8
1U836, INSERM, Grenoble, France, ²Université Joseph Fourier, grenoble, France, ³Université Joseph Fourier, Grenoble, France, ⁴Bruker Biospin MRI, Ettlingen, Germany, ⁵Grenoble MRI Facility IRMaGe, Grenoble, France, ⁶TIMC-IMAG laboratory, UMR5525, CNRS, La Tronche, France, ⁷Université Joseph Fourier, La Tronche, France, ⁸INSERM U836, Grenoble, France

Multiple parameters of tumor microvasculature can be assessed with MRI. The accumulation of physiologically linked information might not be readily interpretable. To address this concern, we propose a cluster-based approach to highlight independent microvasular features within tumor. This strategy could distinguish two glioma models based on their cluster composition. This approach might be useful for solid tumor diagnosis as well as for the localization of pathological areas within the tumor that might become resistant to treatment.

James A. Goodman¹, Peter Cheng-Te Chou¹, Zhiyong Xie¹, and Kelly R. Bales^2
1Precision Medicine, Pfizer Inc, Groton, CT, United States, ²Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, United States

Theƒn4 allele of the apolipoprotein E (ApoE) gene is associated with increased risk of Alzheimer¡¦s disease (AD) combined with an earlier age of disease onset. Little is known about how the 4 allele confers disease susceptibility, so mouse models expressing human ApoE alleles in the place of endogenous mouse ApoE protein by targeted replacement serve as ideal in vivo models to investigate how the 4 allele may influence normal brain function. We utilized structural, functional, and metabolic MRI techniques to characterize mice that are homozygous for human Apo2, 3, and 4, at 14 and 20 months of age.

Ulysse Gimenez¹, Florence Appaix¹, Teodora-Adriana Perles-Barbacaru¹, Franck Mauconduit¹, Marie-France Nissou¹, Emilie Langard¹, Laurent Pelletier¹, Francois Berger¹, Didier Wion¹, Boudewijn van der Sanden¹, and Hana Lahrech^1
1Grenoble Institute of Neurosciences, La Tronche, France

A microscopic 3D-DTI is applied on a mouse glioma model using GFP transfected Glio6 cells to detect tumor cell migration. Two-photon microscopy is used for validation. Monte-Carlo simulations of water diffusion in numerical models of cerebral tissue geometry with micro-architecture changes are developed. FA decrease is observed in the corpus callosum where tumor cell invasion is particularly detected by microscopy. Typical elongated tumor cells indicate migration along the fibers. FA changes simulations versus extra / intracellular and white-matter / grey-matter show similar tendency as detected experimentally. The Glio6 model and 3D-DTI constitute a powerful tool to study tumor cell migration.

X. Jiang¹, John A. Engelbach², Jeremy Cates³, Dinesh K. Thotala⁴, RE Drzymala⁴, D.E. Hallahan⁴, JJH J.H. Ackerman⁵, and Joel R. Garbow^6
1Chemistry, Washington Univ. in st. louis, st louis, MO, United States, ²Radiology, Washington Univ. in st. louis, st louis, MO, United States, ³Radiation Oncology, Washington University in Saint Louis, st louis, MO, United States, ⁴Radiation Oncology, Washington Univ. in st. louis, st louis, MO, United States, ⁵Chemistry, Washington University in St. Louis, st louis, MO, United States, ⁶Radiology, Washington University in Saint Louis, st louis, MO, United States

Bevacizumab, is a powerful anti-angiogenic used in the treatment of tumors. Radiation necrosis, a severe but late occurring injury to normal tissue within and surrounding a radiation treatment field, has been suggested resulting from increases in vascular permeability (“leakiness”). Bevacizumab may help to repair “leaky” capillaries and thereby mitigate radiation necrosis. We have recently developed a novel mouse model of radiation necrosis using Gamma Knife irradiation. Here, we use small-animal MRI to monitor the therapeutic effect of bevacizumab and of mouse bevacizumab (B20-4.1.1), which is capable of high-affinity binding to both human and murine VEGF-A.

Roger J. Mullins^1,2, Su Xu¹, Joseph D. Pescrille³, Jacek Mamczarz³, Edna Pereira³, Edson X. Albuquerque³, and Rao P. Gullapalli^1
1Diagnostic Radiology & Nuclear Medicine, Core for Translational Research in Imaging @ University of Maryland, Baltimore, Maryland, United States, ²Program in Neuroscience, University of Maryland, Baltimore, Maryland, United States, ³Division of Toxicology, Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States

The offspring of guinea pigs exposed during pregnancy to the organophosphorus pesticide chlorpyrifos were examined using MR imaging and behavioral methods. Guinea pigs were given either a dose of chlorpyrifos or peanut oil during pregnancy. Morris water maze, T2-weighted anatomicals, and diffusion-weighted imaging was administered to the offspring at PND 70. The chlorpyrifos group showed significant decreases in performance on the Morris Water Maze test as well as a decrease in fractional anisotropy and mean diffusivity in several areas. These results underscore the extent of genetic changes that are possible with low levels of commonly used organophosphorus compounds during pregnancy that lead to neurodevelopmental changes.

William E. Wu¹, Ke Zhang¹, Assaf Tal¹, Eva-Maria Ratai², Ramon Gilberto Gonzalez², and Oded Gonen^3
1Radiology, New York University School of Medicine, New York, NY, United States, ²Neuroradiology, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States, ³Radiology, New York University, New York, NY, United States

It is not known in HIV-associated neurocognitive disorders whether subcortical injury is characterized by damage to neurons, glia, or both. These may be monitored via proton MR spectroscopy (1H-MRS) observed markers: N-acetylaspartate (NAA) for neurons, myo-inositol (mI) for glia, creatine (Cr) and choline (Cho). We test in simian immunodeficiency virus-infected rhesus macaques, an excellent model system, whether infection produces: (a) decreases in NAA; and/or (b) increases in mI, Cho, and Cr by performing multivoxel 1H-MRS (0.125 cm3 spatial resolution) in five macaques before and after infection. We found glial activation in subcortical regions, but overall neuronal health was not compromised.

Shu-Juan J. Fan^1,2, Wenwen A. Han^1,2, Frank Y. Lee^1,2, Kevin C. Chan^1,2, Samantha J. Ma^1,2, and Ed X. Wu^1,2
1Laboratory of Biomedical Imaging and Signal Processing, The University of Hong Kong, Hong Kong, Hong Kong, China, ²Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, Hong Kong, China

Manganese enhanced MRI (MEMRI) is capable of detecting layer specific interhemispheric somatosensory connections. In this study, Mn2+ was injected into the right visual cortex for tracing interhemispheric visual connections in normal and monocularly enucleated rats. In consistent with classic histological tracing studies, Mn2+ enhancement in the left hemisphere was concentrated within a narrow bi-laminar stripe. Upon left eye enucleation, which making the right cortex largely deprived of visual stimulation, the Mn2+ transfer dropped by 18.5%. These results for the first time demonstrated that MEMRI is capable of tracing layer-specific transcallosal connectivity of visual cortex and is sensitive to activity modulation.

Kaundinya Gopinath¹, Kevin Murnane², and Leonard Howell^2
1Department of Radiology & Imaging Sciences, Emory University, Atlanta, GA, United States, ²Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States

Non-human primates afford distinct advantages in translational neuroimaging studies of drug addiction. To date, fcMRI studies in non-human primates have been exclusively conducted in subjects under anesthesia. In this study, resting state functional connectivity in these networks were assessed in three awake nonhuman primates, before and after acute cocaine administration. Primates exhibited a marked decrease in functional connectivity between frontal and striatal regions after acute cocaine administration, indicating impairment of neurocircuitry underlying drug addiction. Results demonstrate the feasibility of acquiring resting state functional connectivity data from awake monkeys, and provide a translational model for studying the changes induced by cocaine.

Mathieu David Santin^1,2, Thomas Debeir³, Thierry Delzescaux^2,4, Anne-Sophie Herard^2,4, Caroline Cohen³, Laurent Pradier³, Thomas Rooney³, and Marc Dhenain^2,4
1Centre de Neuroimagerie de Recherche – CENIR, Institut du Cerveau et de la Moelle épinière – ICM, Paris, France, ²URA 2210 CEA/CNRS, Fontenay-aux-Roses, France, ³Therapeutic Strategy Unit Aging, Sanofi, Chilly-Mazarin, France, ⁴MIRCen, CEA / I2BM, Fontenay-aux-Roses, France

This work describes the use of Gd-Staining MRI to quantify the efficacy of an immunotherapy in a mouse model of cerebral amyloidosis. We showed that this technique is suitable for longitudinal studies and provided age-associated increase of amyloid plaques in transgenic mice.

Lisa M. Gazdzinski¹, Richard J. Alsop¹, and Brian J. Nieman^1
1Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada

Cranial irradiation for the treatment of paediatric cancer leads to the development of progressive neurocognitive deficits. Younger age at the time of irradiation, female sex, and the dose delivered are considered risk factors for the development of these deficits. Using longitudinal in vivo MRI, this study shows that the dose response following cranial irradiation at a young age varies with structure in the developing mouse brain. Knowledge of the dose sensitivity of different brain structures in children may help in treatment planning for paediatric cancer patients and in identifying the mechanisms leading to cognitive deficits.