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From the Department of Anatomy (Drs. Thal, Rüb, and Braak), J. W. Goethe University, Frankfurt am Main; Department of Neuropathology (Dr. Thal), University of Bonn Medical Center, Bonn; and Department of Pathology (Dr. Orantes), Municipal Hospital of Offenbach, Offenbach am Main, Germany.
Address correspondence and reprint requests to Dr. D.R. Thal, Institut für Neuropathologie, Universität Bonn, Sigmund Freud Str. 25, D-53105 Bonn, Germany; e-mail: Dietmar.Thal{at}uni-bonn.de
Background: The deposition of the amyloid ß protein (Aß) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Aß-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 Aß-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 ß-amyloidosis in the MTL (AßMTL phases) and four control brains without any AD-related pathology.
Methods: Aß 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 Aß deposits.
Results: In the first of five phases in the evolution of ß-amyloidosis Aß 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 Aß deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Aß-deposition. The 17 clinically proven AD cases exhibit Aß-phases 3, 4, or 5. The nine nondemented cases with AD-related Aß pathology show Aß-phases 1, 2, or 3.
Conclusions: Aß-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Aß-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Aß. There are also indications that clinically proven AD cases with full-blown ß-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Aß pathology.
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