title: Phases of A beta-deposition in the human brain and its relevance for the development of AD.
abstract: BACKGROUND
  The deposition of the amyloid beta protein (Abeta) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Abeta-deposition.
  
  
  OBJECTIVE
  To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Abeta-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of beta-amyloidosis in the MTL (AbetaMTL phases) and four control brains without any AD-related pathology.
  
  
  METHODS
  Abeta deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Abeta deposits.
  
  
  RESULTS
  In the first of five phases in the evolution of beta-amyloidosis Abeta deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Abeta deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Abeta-deposition. The 17 clinically proven AD cases exhibit Abeta-phases 3, 4, or 5. The nine nondemented cases with AD-related Abeta pathology show Abeta-phases 1, 2, or 3.
  
  
  CONCLUSIONS
  Abeta-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Abeta-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Abeta. There are also indications that clinically proven AD cases with full-blown beta-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Abeta pathology.
authors.affiliation: Department of Anatomy, J. W. Goethe University, Frankfurt am Main, Germany. Dietmar.Thal@uni-bonn.de
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
authors.forename: Mario
authors.initials: M
authors.lastname: Orantes
authors.forename: Heiko
authors.initials: H
authors.lastname: Braak
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D018709:Statistics, Nonparametric
chemical_list: D016229:Amyloid beta-Peptides