title: Progressive volume loss and white matter degeneration in cstb-deficient mice: a diffusion tensor and longitudinal volumetry MRI study.
abstract: Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized by onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused by mutations in the gene encoding cystatin B. Previously, widespread white matter changes and atrophy has been detected both in adult EPM1 patients and in 6-month-old cystatin B-deficient mice, a mouse model for the EPM1 disease. In order to elucidate the spatiotemporal dynamics of the brain atrophy and white matter changes in EPM1, we conducted longitudinal in vivo magnetic resonance imaging and ex vivo diffusion tensor imaging accompanied with tract-based spatial statistics analysis to compare volumetric changes and fractional anisotropy in the brains of 1 to 6 months of age cystatin B-deficient and control mice. The results reveal progressive but non-uniform volume loss of the cystatin B-deficient mouse brains, indicating that different neuronal populations possess distinct sensitivity to the damage caused by cystatin B deficiency. The diffusion tensor imaging data reveal early and progressive white matter alterations in cystatin B-deficient mice affecting all major tracts. The results also indicate that the white matter damage in the cystatin B-deficient brain is most likely secondary to glial activation and neurodegenerative events rather than a primary result of CSTB deficiency. The data also show that diffusion tensor imaging combined with TBSS analysis provides a feasible approach not only to follow white matter damage in neurodegenerative mouse models but also to detect fractional anisotropy changes related to normal white matter maturation and reorganisation.
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Medical Genetics and Research Program's Unit Haartman Institute, University of Helsinki, Helsinki, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Manninen
authors.affiliation: Department of Neurobiology A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Laitinen
authors.affiliation: Department of Neurobiology A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kimmo K
authors.initials: KK
authors.lastname: Lehtimäki
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Medical Genetics and Research Program's Unit Haartman Institute, University of Helsinki, Helsinki, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Tegelberg
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Medical Genetics and Research Program's Unit Haartman Institute, University of Helsinki, Helsinki, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Department of Neurobiology A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Gröhn
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Medical Genetics and Research Program's Unit Haartman Institute, University of Helsinki, Helsinki, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology*; D055313:Cystatin B / Q000172:deficiency*; D056324:Diffusion Tensor Imaging; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D018345:Mice, Knockout; D009929:Organ Size; D013788:Thalamus / Q000473:pathology*; D020194:Unverricht-Lundborg Syndrome / Q000473:pathology*
chemical_list: C524992:Cstb protein, mouse; D055313:Cystatin B