title: White matter degeneration with Unverricht-Lundborg progressive myoclonus epilepsy: a translational diffusion-tensor imaging study in patients and cystatin B-deficient mice.
abstract: OBJECTIVE
  To study white matter (WM) changes in patients with Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) caused by mutations in the cystatin B gene and in the cystatin B-deficient (Cstb-/-) mouse model and to validate imaging findings with histopathologic analysis of mice.
  
  
  METHODS
  Informed consent was obtained and the study was approved by an institutional ethics committee. Animal work was approved by the Animal Experiment Board of Finland. Diffusion-tensor imaging and tract-based spatial statistics (TBSS) were used to compare fractional anisotropic (FA) results and axial, radial, and mean diffusion among patients with EPM1 (n = 19) and control subjects (n = 18). Ex vivo diffusion-tensor imaging and TBSS were used to compare Cstb-/- mice (n = 9) with wild controls (n = 4). Areas of FA decrease in mice were characterized by means of immunohistochemical analysis and transmission electron microscopy. Student t test statistics were applied to report significant findings (threshold-free cluster enhancement, P < .05).
  
  
  RESULTS
  Patients with EPM1 showed significantly (P < .05) reduced FA and increased radial and mean diffusion in all major WM tracts compared with those of control subjects, shown as global FA decrease along the TBSS skeleton (0.41 ± 0.03 vs 0.45 ± 0.02, respectively; P < 5 × 10(-6)). Cstb-/- mice exhibited significantly reduced FA (P < .05) and antimyelin basic protein staining. Transmission electron microscopy revealed degenerating axons in Cstb-/- mice vs controls (979 axons counted, 51 degenerating axons; 2.09 ± 0.29 per field vs 1072 axons counted, nine degenerating axons; 0.48 ± 0.19 per field; P = .002).
  
  
  CONCLUSIONS
  EPM1 is characterized by widespread alterations in subcortical WM, the thalamocortical system, and the cerebellum, which result in axonal degeneration and WM loss. These data suggest that motor disturbances and other symptoms in patients with EPM1 involve not only the cortical system but also the thalamocortical system and cerebellum.
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland; Haartman Institute, Department of Medical Genetics and Research Program's Unit, Molecular Medicine, Neuroscience Center, and Haartman Institute, Department of Pathology, University of Helsinki, Helsinki, Finland; Departments of Clinical Radiology, Clinical Neurophysiology, and Neurology, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland; A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, and Institute of Clinical Medicine, School of Medicine, Departments of Neurology and Clinical Radiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Manninen
authors.forename: Päivi
authors.initials: P
authors.lastname: Koskenkorva
authors.forename: Kimmo K
authors.initials: KK
authors.lastname: Lehtimäki
authors.forename: Jelena
authors.initials: J
authors.lastname: Hyppönen
authors.forename: Mervi
authors.initials: M
authors.lastname: Könönen
authors.forename: Teemu
authors.initials: T
authors.lastname: Laitinen
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Reetta
authors.initials: R
authors.lastname: Kälviäinen
authors.forename: Olli
authors.initials: O
authors.lastname: Gröhn
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Ritva
authors.initials: R
authors.lastname: Vanninen
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D055313:Cystatin B / Q000172:deficiency*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D057170:Translational Research, Biomedical; D020194:Unverricht-Lundborg Syndrome / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
chemical_list: C524992:Cstb protein, mouse; D055313:Cystatin B