title: Comparative Magnetic Resonance Imaging and Histopathological Correlates in Two SOD1 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal disease due to motoneuron degeneration. Magnetic resonance imaging (MRI) is becoming a promising non-invasive approach to monitor the disease course but a direct correlation with neuropathology is not feasible in human. Therefore in this study we aimed to examine MRI changes in relation to histopathology in two mouse models of ALS (C57BL6/J and 129S2/SvHsd SOD1G93A mice) with different disease onset and progression. A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei. An increased T2 value was associated with a significant tissue vacuolization that occurred prior to motoneuron loss in the cranial nuclei of C57 SOD1G93A mice. Conversely, in 129Sv SOD1G93A mice, which exhibit a more severe phenotype, MRI detected a milder increase of T2 value, associated with a milder vacuolization. This suggests that alteration within brainstem nuclei is not predictive of a more severe phenotype in the SOD1G93A mouse model. Using an ex vivo paradigm, Diffusion Tensor Imaging was also applied to study white matter spinal cord degeneration. In contrast to degeneration of cranial nuclei, alterations in white matter and axons loss reflected the different disease phenotype of SOD1G93A mice. The correspondence between MRI and histology further highlights the potential of MRI to monitor progressive motoneuron and axonal degeneration non-invasively in vivo. The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific. Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies.
authors.affiliation: Laboratory of Molecular Neurobiology, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Caron
authors.affiliation: Laboratory of Biology of neurodegenerative disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.affiliation: Laboratory of Biology of neurodegenerative disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Paladini
authors.affiliation: Laboratory of Molecular Neurobiology, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merlino
authors.affiliation: Laboratory of Molecular Neurobiology, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Plebani
authors.affiliation: Laboratory of Biology of neurodegenerative disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: McGowan Institute for Regenerative Medicine & Centre for the Neural Basis of Cognition, Departments of Radiology & Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Michel
authors.initials: M
authors.lastname: Modo
authors.affiliation: Laboratory of Molecular Neurobiology, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000473:pathology; D001933:Brain Stem / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D018450:Disease Progression; D018737:Hand Strength; D006801:Humans; D008161:Lumbosacral Region; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D020125:Mutation, Missense; D017354:Point Mutation; D011897:Random Allocation; D011994:Recombinant Proteins / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014617:Vacuoles / Q000648:ultrastructure; D066127:White Matter / Q000473:pathology
chemical_list: D011994:Recombinant Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1