Animals in White Matter Diseases
Friday 24 April 2009
Room 311 10:30-12:30


Charles R.G. Guttmann and Victor Song

10:30 832. Deep Gray Matter T2 Hypointensity Correlates with Disability in a Murine Model of MS
    Istvan Pirko1, Aaron J. Johnson2, Anne K. Lohrey2, Jun Ying3, Diana Lindquist4, R. Scott Dunn4
Department of Neurology, University of Cincinnati, Cincinnati, OH, USA; 2Department of Neurology, University of Cincinnati, USA; 3Department of Biostatistics and Epidemiology, University of Cincinnati, USA; 4Imaging Research Center, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA
    Advanced MRI studies have demonstrated a variety of non-lesional pathology in MS. T2 weighted scans of deep gray matter nuclei often reveal hypointensity, which has been shown to correlate with cognitive, neuropsychiatric and motor dysfunction. In this abstract we demonstrate the first MS model of deep gray matter T2 hypointensity. In a TMEV induced MS model in SJL/J mice, gradual development of thalamic T2 hypointensity was observed. Quantitative intensity analysis demonstrated a strong correlation between the degree of hypointensity and disability. This novel model will allow us to study the pathogenesis and significance of deep gray T2 hypointensity in MS.
10:42 833. T2 Relaxation Parallels Progressive Clinical Symptoms of Demyelination in a Novel Transgenic Mouse Model
    Thomas Mueggler1, Hartmut Pohl2, Dieter Riethmacher3, Christof Baltes1, Ueli Suter2, Markus Rudin1,4
Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland; 2Institute for Cell Biology, ETH Zurich, Zurich, Switzerland; 3Human Genetics Division, Southampton University School of Medicine, Southampton, UK; 4Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    A novel mouse model of demyelination uses intrinsic triggering of oligodendrocyte cell death leading to progressive symptoms allowing to disentangle the role of apoptotic cell death from that of the immune system in Multiple Sclerosis. To evaluate the sensitivity of various MR readouts for monitoring the pathology we assessed T2, MTR and infiltration of macrophages in diseased and control mice. Whereas T2 hyper-intensities become apparent at a time-point of first clinical symptoms a MTR decrease is only present at progressed pathology stage. No infiltration of macrophages could be measured reflecting integrity of BBB and weak recruitment of blood-borne immune cells.
10:54 834. Neural Precursor Migration Following Intracerebroventricular Delivery During the Chronic Phase of Experimental Allergic Encephalomyelitis Is Reduced as Compared to the Acute Phase
    Naser Muja1,2, Mikhal Cohen3, Jiangyang Zhang1, Assaf A. Gilad1,2, Piotr Walczak1,2, Tamir Ben-Hur3, Jeff W.M. Bulte1,2
Radiology, Divivsion of MR Research, Johns Hopkins University, Baltimore, MD, USA; 2Institute for Cell Engineering, Johns Hopkins University, Baltimore , MD, USA; 3Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    Using experimental autoimmune encephalomyelitis (EAE) as a mouse model for multiple sclerosis, we used serial MR imaging of Feridex-labeled neural precursor cells (NPCs) to detect potential differences in the migratory response of ICV-transplanted NPCs between the acute inflammatory or the chronic demyelinated phase of the disease. We found that cell movements are determined by the phase of EAE, with a characteristic radial migration pattern of cells moving out from the ventricular spaces into and around blood vessels within the somatosensory cortex during the acute but not the chronic phase.
11:06 835. MRI Estimation of Sub-Clinical Disease in Japanese Macaque Encephalomyelitis
    William D. Rooney1, Steven G. Kohama, Paul Wang, Jeffrey M. Njus, Scott W. Wong, Lawrence S. Sherman, Michael K. Axthelm, Gail H. Marracci, Dennis N. Bourdette
1Advanded Imaging Research Center, Oregon Health and Science University, Portland, OR, USA
    A spontaneously occurring demyelinating disease has recently been characterized in Japanese macaques (Macaca fuscata) at the Oregon National Regional Primate Center (ONPRC); the disease has been named "Japanese macaque encephalomyelitis" (JME). JME bears many similarities to human multiple sclerosis (MS) but has a much greater incidence. Typically, JME has an acute onset with rapid progression and is readily detected in affected individuals as impaired ambulation or motor skills during routine observation. The major finding of this study suggests that JME occurs with an even higher incidence that previously appreciated and with a disease severity that ranges from benign to fulminant. These observations have important implications for the development of a non-human primate model of MS based on a naturally occurring disease.
11:18 836. Q-Space and Conventional DWI of Axonal and Myelin Damage in the Rat Spinal Cord After Axotomy
    Jonathan Andrew David Farrell1,2, Jiangyang Zhang2, Melina Jones3, Cynthia A. DeBoy3, Paul N. Hoffman3,4, Seth A. Smith1,2, Daniel S. Reich3,5, Peter A. Calabresi3, Peter C. van Zijl1,2
F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA; 2Neuroscience Section, Division of MR Research, Dept. of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Dept. of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4Dept. of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Division of Neuroradiology, Dept. of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Dorsal root axotomy causes axonal degeneration with subsequent delayed myelin damage in the dorsal column. We investigated water diffusion perpendicular and parallel to the rat spinal cord (3 and 30 days post-injury). We compared contrasts from q-space analysis to conventional anisotropy and diffusivity measurements and histological staining for axonal and myelin damage. Perpendicular diffusion was increased, and more Gaussian in lesions compared to contralateral white matter, but was not specific for myelin damage. Parallel diffusion was decreased, and less Gaussian, which may be specific for axonal damage. Q-space contrasts, including kurtosis excess, provide a comprehensive assessment of white matter damage.
11:30 837. Diffusion Anisotropy Correlates Compound Action Potential in the Optic Nerve from Mice of Retina Ischemia
    Qing Wang1, Roman Vlkolinsky2, Sheng-Kwei Song3, Andre Obenaus4
Washington University, Saint Louis, MO, USA; 2Loma Linda University School of Medicine; 3Washington University School of Medicine; 4Loma Linda Unieristy School of Medicine, Loma Linda, CA, USA
    The compound action potential (CAP) amplitude was measured by the extracellular recording ex vivo on optic nerves from the control, and retinal ischemia mice at 3 and 7 days after injury. The axonal and myelin integrity of optic nerve from control and retinal ischemic mice as evaluated using diffusion tensor imaging (DTI). The correlation between DTI and CAP was established. The results suggest that the decreased diffusion anisotropy may reflect the function of optic nerve after retinal ischemia better despite the presence of axonal injury may be responsible for the long term disability of visual function. And the overall functional assessment would be best to be evaluated by diffusion anisotropy than axial or radial diffusivity alone.
11:42 838. White Matter Changes in a Model of Temporal Lobe Epileptogenesis: A Combined Diffusion Tensor Imaging and Histopathology Study
    Willem  Maarten Otte1,2, Pieter van Eijsden1, W. S. van der Hel1, O. van Nieuwenhuizen1, Rick M. Dijkhuizen2, R A. de Graaf3, Kees P.J. Braun1
Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht, Netherlands; 2Image Sciences Institute, UMC Utrecht, Utrecht, Netherlands; 3Department of Diagnostic Radiology, Magnetic Resonance Research Center, Yale School of Medicine, New Haven, CT, USA
    Although epilepsy is considered to be a grey matter disease, diffusion tensor imaging (DTI) studies have demonstrated that white matter is affected. However, interpretation of DTI findings is often complicated by the lack of histology. We characterized white matter changes longitudinally during epileptogenesis using DTI and histology in a rat model of temporal lobe epilepsy (TLE). Our analysis demonstrated significant reduction in Lambda1 of the corpus callosum at four weeks, before spontaneous seizures occur. Histology confirmed that myelin was affected at four weeks, but normalizes. Axonal integrity was not affected. Diffusion properties behave different during epipileptogenesis than in TLE.
11:54 839. Long-Term Treatment with Antipsychotics Affects NAA T1 in Normal Rat Brain
    Diana M. Lindquist1, R S. Dunn1
Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
    Multiple MRS studies have been reported comparing schizophrenic patients and normal subjects, with mixed results. Differences between normal subjects and patients may be due to changes in either water or metabolite relaxation times. Changes in relaxation times could result from the disease and/or the drugs used to treat it. In this 6-month study, we found that NAA T1 times in normal rat brain are significantly shorter for rats treated with either haloperidol or clozapine. Long term treatment with antipsychotics appears to decrease NAA T1 values, which may result in an overestimation of the NAA concentration in treated schizophrenic patients.
12:06 840. Imaging Model of Antidepressant Effects: A Pre-Clinical Investigation Using Pharmacological Magnetic Resonance Imaging
    Sakthivel Sekar1, Marleen Verhoye2, Johan Van Audekerke2, Greetje Vanhoutte2, Andrew M. Blamire3, Thomas Steckler4, Mohammed Shoaib1, Annemie Van der Linden2
Psychobiology Research Group, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK; 2Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium; 3Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne, UK; 4Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium
    Pharmacological MRI (phMRI) is a rapidly developing non-invasive advancement of functional Magnetic Resonance Imaging (fMRI) - phMRI signatures (neuroactivity maps) can be utilized to investigate the effects of psychotropic compoundís activity, thus serving as surrogate markers to screen for novel therapeutics. The study aims to map the key regions susceptible to acute and chronic exposure of the novel antidepressants: citalopram, reboxetine & bupropion in rodents there by to pharmacologically characterize the mechanisms underlying their clinical efficacy, using phMRI. This approach has also been extended to investigate the specific-receptor involvement by combining antidepressant with a highly receptor-selective antagonist, to obtain deeper insight felicitating translational research activities, to & from the clinic.
12:18 841. Pathological Correlates of the Decreased Axial Diffusivity in White Matter Injury
    Mingqiang Xie1, Matthew D. Budde2, Chin-I Chen2, Kathryn Trinkaus3, Regina C. Armstrong4, Anne H. Cross5, Sheng-Kwei Song2
Radiology, Washington University, St. Louis  , MO, USA; 2Radiology, Washington University, St. Louis, MO, USA; 3Biostatistics, Washington University, St. Louis, MO; 4Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 5Neurology and Neurosurgery, Washington University, St. Louis, MO, USA
    Decreased axial diffusivity from DTI has recently been used as a noninvasive biomarker for detecting axonal injury. The current study compared axial diffusivity with histology of YFP mouse corpus callosum (CC) throughout cuprizone-induced demyelination. Decreased axial diffusivity, axonal injury and increased microglia/macrophages at 4 weeks of cuprizone ingestion, and then they returned to the control level at 10 weeks of continuous treatment. In contrast, astrogliosis increased at 4 weeks and further increased at 10 weeks. The results demonstrate that decreased axial diffusivity mirrors the reversible nature of axonal injury and microglia/macrophage infiltration in cuprizone-treated mouse CC, and is not related to astrogliosis.