title: Identification of clinical target areas in the brainstem of prion-infected mice.
abstract: OBJECTIVE
  While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas.
  
  
  METHODS
  We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset).
  
  
  RESULTS
  We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre-Bötzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem.
  
  
  CONCLUSIONS
  Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre-Bötzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt-Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases.
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Mirabile
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Parmjit S
authors.initials: PS
authors.lastname: Jat
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011328:Prions / Q000472:pathogenicity*; D016019:Survival Analysis
chemical_list: D011328:Prions
keywords: brainstem; clinical target areas; cre-lox system; locus coeruleus; neurodegeneration; prions