The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease

Objective: To determine the spatiotemperal mapping of neurofibrillary: dege neration (NFD) in normal aging and the different stages of AD. Background: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their intel relation ship and their link with cognitive impairment, Methods: The study included 130 patients of various ages and different cognitive statuses, from nondeme nted control subjects (n = 60, prospective study) to patients with severe d efinite,AD. Paired helical filaments (PHF)-tau and A beta were used as bioc hemical and histologic markers of NFD and amyloid plaques, respectively. Re sults: NFD with PHF-tau was systematically? present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages accord ing to the brain regions affected: transentorhinal cortex (SI), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal co rtex (S5), medium temporal cortex (S6), polymodal association areas (prefro ntal, parietal inferior? temporal superior) (S7), unimodal areas (S8), prim ary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10 ). Up to stage 6? the disease could be asymptomatic. In all cases studied h ere, stage 7 individuals with two polymodal association areas affected by t au pathologic states were cognitively impaired. Conclusions: The relationsh ip between NFD and Alzheimer-type dementia, and the criteria for a biochemi cal diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.