Animal Models of White Matter Disease & Neurodegeneration
Wednesday 5 May 2010
Room A6 16:00-18:00 Moderators: Matthew D. Budde and Victor Song

16:00 462.  

Magnetic Resonance Microscopic Angiography Visualization of Abnormal Microvasculature in a Transgenic Mouse Model of Huntington’s Disease
Chien-Yuan Lin1, Chien-Hsiang Huang1,2, Ming-Huang Lin1, Yi-Hua Hsu1, Chung-Ru Tsai1, Hui-Mei Chen1, Yijuang Chern1, Chen Chang1
1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; 2Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan

The underlying mechanisms of neurodegenerative disease are still unclear. However, the cerebral microcirculation may play an important role. This study aimed to explore the microvasculature in a transgenic mouse model of Huntington¡¦s disease using newly developed microscopy MRA.

16:12 463.  

Longitudinal Changes in the Neurochemical Profile of Hungtington R6/2 Mice
Ivan Tkac1, Lori A. Zacharoff2, Silvia Mangia1, Patrick J. Bolan1, Janet M. Dubinsky2
Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States; 2Dept. of Neuroscience, University of Minnesota, Minneapolis, MN, United States

In vivo 1H NMR spectroscopy at 9.4T was used to measure neurochemical changes in striatum and cerebral cortex of R6/2 transgenic mice during their lifespan, starting from a presymptomatic age of 4 weeks. Significant differences were observed for multiple brain metabolites between R6/2 and WT controls. Concentration changes in cortex were parallel to those observed in striatum. Changes in the neurochemical profiles correlated with reduced volumes of these brain regions. Behavioral differences were observed at all time points, although different tests distinguished R6/2 mice from WT controls at early and older ages.

16:24 464

Cingulate and Sensorimotor Cortical Changes in the R6/2 Huntington's Disease Mouse: A Study of 116 Brains
Stephen J. Sawiak1,2, Nigel I. Wood3, Guy B. Williams1, A J. Morton3, T A. Carpenter1
Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, Cambs, United Kingdom; 2Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, United Kingdom; 3Department of Pharmacology, University of Cambridge, United Kingdom

We present an improved method of cortical thickness measurement in the mouse brain and apply it to 116 brains in the R6/2 mouse model of Huntington's disease. Significant changes are seen in the sensorimotor cortices (S1, S2, M1) which would be expected in a HD model. Cingulate cortex (Cg1, Cg2) differences are also shown which have not been previously reported in these mice.

16:36 465.  

Detection of Early Neurochemical Changes Related to Neurodegeneration in a Spinocerebellar Ataxia Type 1 (SCA1) Mouse Model by 1H MRS at 9.4 Tesla
Uzay Emrah Emir1, H Brent Clark1, Manda Vollmers1, Dee M. Koski1, Lynn E. Eberly1, Harry T. Orr1, Huda Y. Zoghbi2, Gulin Oz1
University of Minnesota, Minneapolis, MN, United States; 2Baylor College of Medicine, Houston, TX, United States

In order to identify MRS biomarkers of very early neurochemical changes related to neurodegeneration, we utilized a knockin (KI) mouse model of SCA1. We measured cerebellar neurochemical profiles of KI mice and wild-type (WT) littermates longitudinally at 9.4T using short-echo LASER. Total choline, taurine and glutamine were the most robust biomarkers in this model. The KI mice displayed very mild cerebellar pathology even at 9 months, however they were distinguished from WTs by MRS starting at 6 weeks.  Therefore, this study demonstrated that the MRS biomarkers are sensitive to very early changes related to neurodegeneration prior to overt pathology.

16:48 466.

Hyperoximic Therapy of Hypoxic Neonatals Increases Cerebral Injury. DTI Study in Rats
Kurt Hermann Bockhorst1, Harriet Charmaine Rea2, Rui Liu3, Jarek Wosik3, Jose Regino Perez-Polo2, Ponnada A. Narayana1
Diagnostic and Interventional Imaging, University of Texas, Houston, TX, United States; 2Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States; 3Electronics and Computer Science, University of Houston, Houston, TX, United States

International guidelines recommend the treatment of perinatal hypoxia with 100% oxygen. This treatment is controversial. We therefore initiated a study of a neonatal rat model, which is widely accepted for perinatal hypoxia in infants. Our findings confirm the concerns, that hyperoximia actually exacerbates the injuries caused by perinatal hypoxia

17:00 467

Region Specific-Alteration of Blood-Brain Barrier Development Caused by Prenatal Exposure to Inflammation
Sylvie Girard1, Luc Tremblay2, Guillaume Sebire1, Martin Lepage2
Pediatric, Universite de Sherbrooke, Sherbrooke, Qc, Canada; 2Radiobiology, Universite de Sherbrooke, Sherbrooke, Qc, Canada

Perinatal inflammation affects brain development and could modify the permeability of the developing blood-brain barrier (BBB). This can have an impact on the accessibility of both inflammatory mediators and therapeutics drugs, to the brain. This study aimed at evaluating the postnatal variations of permeability of the developing BBB. Using a contrast agent, we observed a decreased permeability of the BBB during normal development. However, prenatal exposure to a pro-inflammatory agent led to a region-specific increased permeability during the first 30 days after birth. This provides new insights into the mechanisms explaining the vulnerability to aggressions in newborns causing brain damage.

17:12 468

In-Vivo Mouse Brain Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) Detects Gender and Region Specific Pathology Induced by Cuprizone
Laura-Adela Harsan1, Yi Sun1, Nicoleta Baxan1, Jürgen Hennig1, Dominik von Elverfeldt1
1Department of Diagnostic Radiology, Medical Physics, University Hospital, Freiburg, Germany

Long-term cuprizone treatment in female and male mice, underlined the course of the disease from acute demyelinating to the chronic state. In-vivo DT-MRI, performed using 45 gradient diffusion directions sensitively assessed the myelin and axonal damage in relationship with the modifications of radial and axial diffusivity. When compared with females, the progressing pathology in the male brains had a stronger impact on the values of DT-MRI derived indices (D_radial , D_axial), suggesting a faster and more severe course of the disease. The existence of a sexual dimorphism in demyelination implies a gender-specific response to different strategies developed to induce recovery.

17:24 469

Susceptibility of the Optic Nerve and the Involvement of Retrograde Neuronal Degeneration in a Delayed Radiation Induced Injury Model: Evidence from a Diffusion Tensor Imaging Study
Deqiang Qiu1, Silun Wang1,2, Kwok-Fai So3, Ed Xuekui Wu4, Lucullus Hing-Tong Leung5, Pek-Lan Khong

1Diagnostic Radiology, The University of Hong Kong, Hong Kong, China; 2Radiology, Johns Hopkins University, Baltimore, MD, United States; 3Anatomy, The University of Hong Kong, Hong Kong, China; 4Laboratory of Biomedical Imaging and Signal Processing, The University of Hong Kong; 5Oncology, Princess Margaret Hospital, Hong Kong, China

In the present study, we evaluated changes of multiple white matter tracts following radiation using diffusion tensor imaging. A novel finding of severe changes in FA in the contralateral optic nerve as compared to the ipsilateral optic nerve was observed, and these changes were confirmed by histological evaluation. These findings cannot be explained by difference in radiation dose and suggests, for the first time, an important role of retrograde neuronal degeneration in the underlying mechanism for radiation induced injury to the visual pathway. The results also suggest susceptibility of the optic nerve relative to the cerebral peduncle.

17:36 470.

Biphasic Expression of Aquaporin 4 During the Course of Brain Inflammation
Thomas Tourdias1, Iulius Dragonu2, Nadège Cassagno1, Mathilde Deloire-Grassin1, Claudine Boiziau1, Bruno Brochet1, Chrit Moonen2, Klaus Petry1, Vincent Dousset1
1Laboratoire de Neurobiologie des affections de la myéline, Bordeaux, France; 2UMR-CNRS 5231, laboratoire d’imagerie moléculaire et fonctionnelle, Bordeaux, France

We combined MRI, histology and molecular biology to assess the time course of aquaporin 4 (AQP4) expression during brain inflammation in the rat brain. We reported a moderate AQP4 up-regulation during the active phase of inflammation that was insufficient to remove interstitial water excess as assessed by diffusion MRI. We found a second AQP4 up-regulation that was delayed and with a different pattern, i.e. pan astrocytic and not confined to the blood brain barrier interface. Again, this delayed up-regulation was insufficient to remove vasogenic edema but was probably involved in the glial scar formation.

17:48 471

Axonal Injury and Myelin Loss in Glutaric Acidemia Type I (GA-1) Mouse Model of Diet Induced Encephalopathy
Jelena Lazovic1, William J. Zinnanti2, Russell E. Jacobs1

1Biology, California Institute of Technology, Pasadena, CA, United States; 2Pediatrics, Children's hospital at SUNY Downstate, Brooklyn, NY, United States

In recent years white matter abnormalities, including leukoencephalopathy, are being increasingly recognized in patients suffering from glutaric acidemia type I (GA-1).  The mechanism leading to leukoencephalopathy remains unknown, as well as the extent of myelin degradation.  In this work we use a mouse model of GA-1 and combination of MRI, histology and behavioral testing to establish the basis for abnormal appearance of white matter in this disorder.  Presented data suggest myelin degradation to be secondary to axonal loss in GA-1.  Behavioral data implicate damaged neuronal populations to be involved in sensory-motor integration.



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