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The importance of neuritic plaques and tangles to the development and evolution of AD

From the Dipartimento di Scienze Neurologiche (Dr. Tiraboschi), Ospedale Niguarda Ca’ Granda, Milan, Italy; Department of Neurosciences (Drs. Hansen, Thal, and Corey-Bloom), University of California, San Diego, La Jolla, CA; and Neurology Service (Drs. Thal and Corey-Bloom), VA San Diego Healthcare System, San Diego, CA.

Address correspondence and reprint requests to Dr. Jody Corey-Bloom, Neurology Service (9127), San Diego VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161-3064; e-mail: jcoreybl{at}vapop.ucsd.edu

Objective: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD).

Methods: An autopsy series of 102 patients with dementia and pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations.

Results: Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone.

Conclusions: Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.

Received December 4, 2003. Accepted in final form February 10, 2004.

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