Animal Models of Neurodegeneration
Wednesday 22 April 2009
Room 311 16:00-18:00


Louise van der Weerd and Ruth Vreys

16:00 538. Young Investigator Award Finalist:  Magnetic Resonance Imaging and Histological Analysis of Beta-Amyloid Plaques in Both Human Alzheimer’s Disease and APP/PS1 Transgenic Mice
    Mark David Meadowcroft1,2, James R. Connor3, Michael B. Smith1, Qing X. Yang1,3
Radiology, Pennsylvania State University - College of Medicine, Hershey, PA, USA; 2Neural and Behavioral Sciences, Pennsylvania State University - College of Medicine, Hershey, PA, USA; 3Neurosurgery, Pennsylvania State University - College of Medicine, Hershey, PA, USA
    The histo-pathological basis of image contrast associated with Aβ plaques and the connected relaxation mechanism has not been well-understood. T2*-weighted images and R2* parametric maps were compared to histology stains from the same set of AD and APP/PS1 tissue slices. The electronic microscopy and histology images revealed differences in plaque morphology and associated iron concentration between APP/PS1 mice and AD tissue. T2* contrast of Aβ-plaques was associated with the gradation of iron concentration and plaque morphology. These data suggested a duality in the relaxation mechanism where both focal iron concentration and highly compact fibrillar Aβ masses cause rapid proton transverse magnetization decay.
16:20 539. Imaging Biophysics of Axonal Transport with MEMRI: Optic Tract Transport Is Altered in Mouse Model of Alzheimer's Disease
    Elaine L. Bearer1, Xiaowei Zhang2, Octavian Biris1, Russell E. Jacobs2
Pathology and Laboratory Medicine, Brown University, Providence, RI, USA; 2Biology, California Institute of Technology, Pasadena, CA, USA
    Alterations in transport dynamics are implicated in neurodegenerative diseases. We are using MEMRI to image the biophysics of intra-neuronal axonal transport and correlate rates of MR intensity changes with genetic/molecular differences in transport mechanics. Here we compare Mn++ transport dynamics observed by capturing 6-min time-lapse MR images in the polarized neural processes of the optic track between aged mice expressing an APP mutant correlated with Alzheimer' disease in humans (swAPP) and their wild-type age-matched counterparts. Our findings show that transport dynamics in the optic track are altered in the swAPP mouse, an Alzheimer's disease model.
16:32 540. Early Impaired Axonal Transport in a Triple Transgenic Mouse Model of Alzheimer’s Disease
    Jieun Kim1, In-Young Choi1,2, Mary L. Michaelis3, Sang-Pil Lee1,4
Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, KS, USA; 2Department of Neurology, Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA; 3Department of Pharmacology and Toxocology, University of Kansas, Lawrence, KS, USA; 4Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
    Axonal transport deficit has been implicated as a common mechanism of Alzheimer’s disease (AD) pathology. We used MEMRI to measure fast axonal transport rates in olfactory bulbs and olfactory cortex of a triple transgenic mouse model of AD (3xTg). Our results indicate that axonal transport deficit starts as early as 3 months of age and precedes Aβ plaque and neuro-fibrillary tangle pathology.
16:44 541. Longitudinal Assessment of Neurodegeneration in a Spinocerebellar Ataxia Type 1 (SCA1) Mouse Model by 1H MRS at 9.4 Tesla: Correlation with Histopathology
    Gulin Oz1, H. Brent Clark1, Christopher D. Nelson1, Dee M. Koski1, Pierre-Gilles Henry1, Malgorzata Marjanska1, Dinesh K. Deelchand1, Harry T. Orr1
University of Minnesota, Minneapolis, MN, USA
    To assess the sensitivity of high field 1H MRS to disease onset and progression in neurodegenerative diseases, we measured cerebellar neurochemical profiles of a mouse model of spinocerebellar ataxia 1 (SCA1) and controls at 3 different ages at 9.4T using short-echo LASER. Multiple biomarkers clearly distinguished the mutant animals from controls at all ages. Multiple MRS measures were significantly different in the mutant animals already at 6 weeks, prior to significant pathological and neurological changes. These data demonstrate the ability of MRS to non-invasively detect pre-clinical disease, as well as its sensitivity to disease progression.
16:56 542. Assessment of Neurodegeneration Reversal in a Spinocerebellar Ataxia Type 1 (SCA1) Mouse Model by 1H MRS at 9.4 Tesla
    Gulin Oz1, H. Brent Clark1, Christopher D. Nelson1, Dee M. Koski1, Manda L. Vollmers1, Harry T. Orr1
University of Minnesota, Minneapolis, MN, USA
    To assess the sensitivity of high field 1H MRS to reversal of neurodegeneration, we utilized a conditional mouse model of SCA1. We turned off the mutated gene from 12-24 weeks and measured cerebellar neurochemical profiles of treated and untreated conditional mice and controls at 9.4T using short echo LASER and LCModel. The altered levels of multiple biomarkers partially reversed to control values at 24 weeks in the treated mice, in agreement with partial reversal of Purkinje cell pathology. These data demonstrate the ability of MRS to non-invasively detect disease reversal and its potential utility in future pre-clinical and clinical trials.
17:08 543. Increased VEGF Expression Correlates with Severely Reduced Cerebral Perfusion in Glutaric Acidemia Type I (GA-1) Mouse Model of Diet Induced Encephalopathy
    Jelena Lazovic1, William J. Zinnanti1,2, Ellen Wolpert3, David A. Antonetti3, Russell E. Jacobs1
Biology, California Institute of Technology, Pasadena, CA, USA; 2Biochemistry, Pennsylvania State University, Hershey, PA, USA; 3Physiology, Pennsylvania State University, Hershey, PA, USA
    The neuroprotective role of vascular endothelial factor (VEGF) following cerebral ischemia remains highly controversial. The inborn error of metabolism glutaric acidemia type-1 (GA-1) is frequently associated with cerebral and retinal hemorrhages, and affected individuals often experience ischemic injury involving basal ganglia. To investigate the relationship between VEGF expression and ischemic injury we measured cerebral blood flow using arterial spin labeling method, and VEGF protein levels in mouse model of GA-1. Significantly increased levels of VEGF correlated with severely reduced perfusion, and were found in encephalopathic mice.
17:20 544. Deformation-Based Morphometry in the R6/2 Huntington's Disease Mouse Brain
    Stephen J. Sawiak1, Nigel I. Wood2, G B. Williams1, A J. Morton3, T A. Carpenter1
Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK; 2Department of Pharmacology, University of Cambridge; 3Department of Pharmacology, University of Cambridge, UK
    With the relative ease of creating transgenic mouse models of disease, mice are increasingly used for studying pathology. Automated analysis techniques are of increasing importance to deal with overwhelming amounts of data. Having previously examined the phenotype of the R6/2 Huntington's model with voxel-based morphometry (VBM) here we present our findings with an increased dataset of 116 images, using deformation-based morphometry (DBM), showing it to be more sensitive in finding differences within the same tissue classes.
17:32 545. Tract Based Spatial Statistics in Mouse Model of Neurodegerative Unverricht-Lundborg (EPM1) Disease
    Otto Heikki Henrikki Manninen1, Kimmo K. Lehtimäki2, Teemu Laitinen3, Tarja Joensuu1, Outi Kopra1, Anna-Elina Lehesjoki1, Olli Gröhn3
Folkhälsan Inst. of Genetics and Neuroscience Center, University of Helsinki, Helsinki, Finland; 2Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland; 3Dept. of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
    We implemented a recently introduced whole brain voxelwise statistical analysis method, tract based spatial statistics (TBSS), into a mouse model of neurodegenerative disease, introducing TBSS in mice. Doing black box statistical comparison of diffusion tensor imaging (DTI) parameters between controls and affected animals, TBSS revealed areas of significantly redused FA compared to controls in both brain regions known to be associated with mouse model of Unverricht-Lundborg disease as well as regions not earlier connected with the disease, promising great potential to serve as a robust screening method to guide histological analysis to novel target areas in the brain.
17:44 546. In Vivo Brain Phenotypes of the Reeler Mutant Mouse by Using DT-MRI and MEMRI
    Laura-Adela Harsan1, Csaba David2, Dominik Paul1, Susanne Schnell1, Jürgen Hennig1, Jochen F. Staiger2, Dominik von Elverfeldt1
Diagnostic Radiology, Medical Physics, University Hospital, Freiburg, Germany; 2Department of Neuroanatomy, Institute for Anatomy and Cell Biology, Center for Neuroscience, Freiburg, Germany
    In the present study, the brain cytoarchitecture of the Reeler mutant mouse was visualized by using MEMRI while the neural connectivity was depicted in-vivo and non-invasively by DT-MRI. Disorganization of the neuronal layers was clearly visible in cortical structures of the Reeler brain. In-vivo DT-MRI and fiber tracking showed distorted axonal pathways when compared to wild type brain. Particularly, Reeler mice have poorly compacted thalamic axonal bundles that project abnormally into the cortical structures. Furthermore, color-coded maps evidenced abnormalities at the level of the cingulum structure in Reeler mice and depicted the failure in the cerebellar cortex lamination.