A grading system of Alzheimer disease lesions in neocortical areas

Progression of neuritic and Aβ pathology in the cerebral cortex during aging and Alzheimer disease is well known, but the chronology of the various types of lesions (Aβ deposition, amyloid formation, inflammation, ubiquitination, tangle formation) within a given area has not been fully elucidated. We examined these lesions in the primary visual cortex (Brodmann area 17), correlating them with the severity of the disease (as evaluated by the cognitive status and the number of cortical samples that contained neurofibrillary tangles). Four ‘grades’ were identified. At grade 1, only deposits of Aβ peptide were noticed. At grade 2, Congo red positive deposits, and processes containing ubiquitin and cathepsin D immunoreactivity around plaque cores could also be found. At grade 3, neuritic plaques and neuropil threads were present, and at grade 4, neurofibrillary tangles. The density of all the lesions dramatically increased at grade 4. The sequence of isocortical lesions from grade 1 to grade 4 is compatible with a cascade of events beginning with deposition of Aβ peptide and ending with neurofibrillary tangle.