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 Animal research

 Structural and biochemical alterations in the transgenic SOD1 mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease characterized by a selective degeneration of motor neurons in the spinal cord, brain stem and motor cortex. Over-expressing the human mutant Gly93®Ala Superoxide dismutase 1 protein (G93A-SOD1) in mice causes a phenotype characterized by degenerating motor neurons.
MR images of G93A-SOD1 mice recorded between days 70 and 130 revealed clear signal intensity enhancements compared to surrounding tissue in specific motor nuclei within the brain stem, which are normally not distinguishable in age-matched normal mice. A detectable enhancement in MRI signal intensities of motor nuclei within the brain stem starts at day 90, parallel to first clinical symptoms of the motor neuron disease. The increase in signal intensity correlates well with morphological changes of motor neurons, such as size and appearance of vacuoles, and consequently with the progression of the disease. A method to visualize such motor neuron degradation in vivo can be used to evaluate therapeutic approaches in order to prevent and/or delay the progression of this disease.
In addition to MRI, we use magnetic resonance spectroscopy (MRS) to evaluate biochemical alterations in the cortex, cerebellum, brain stem and spine of transgenic G93A-SOD1 mice. 

Collaboration: Dr. Jürgen Goldschmidt (IfN), PD Dr. S. Vielhaber (Department of Neurology II, OvGU), Prof. Dr. A. C. Ludolph (Department of Neurology, University of Ulm), Prof. D. Leibfritz (Department of Organic Chemistry, University of Bremen)

Fig. 1. T2-weighted MR-images of mice over-expressing the human mutant G93A-SOD. At age of 130d a clear increase in signal intensity could be observed in the hypoglossal nucleus (Nc. Nv. XII; arrow top row left), the nucleus of the solitary tract (arrow top row middle), and the trigeminal nucleus, the facial nucleus, and the nucleus ambiguus (Nc. Nv. V, VII and motoric part of Nc Nv. IX, X, arrows top row left). These nuclei are not detectable in an identical T2- weighted image in aged-matched litter-mates, that do not express the G93A-SOD (lower row). Section thickness 600 µm, field of view 30x30 mm, matrix 256x256 (calculated in plane resolution 117 µm).

Fig. 2. The signal intensity of motoric nuclei within the brain stem changes over time.  Sequential T2-weighted MR-images of G93A-SOD mice were obtained at day 50, 90, 112, and 130. The left side shows representative sagital sections at various time-points, which are used to measure the signal intensity changes of the hypoglossal nucleus. The signal intensities of the hypoglossal nucleus (Nc. Nv. XII), facial nucleus (Nc. Nv. VII), trigeminal nucleus (Nc. Nv. V) were measured and calculated as ratio to the surrounding brain stem tissue (right side). Whereas at day 50 no motoric nuclei were detectable by T2-weighted MRI, the signal intensities of all measured nuclei increases over time.

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