Neocortical Neurofibrillary Tangles Correlate With Dementia Severity in Alzheimer's Disease

OBJECTIVE: To determine the relationships between dementia severity and the extent of histopathologic lesions in a variety of brain regions. Neocortical and hippocampal ratings for neurofibrillary tangles (NFTs) and senile plaques (SPs) were compared in 70 cases of clinically and neuropathologically confirmed Alzheimer's disease. DESIGN: Neuropathologic case series. Dementia severity was assessed by postmortem chart review with use of the extended Clinical Dementia Rating Scale (CDR). Linear association between CDR scores and NFT and SP scores were assessed by partial correlation, controlling for age at death. SETTING: Studies were conducted at the Alzheimer's Disease Research Center of the Mount Sinai Medical Center, New York, NY. MAIN OUTCOME MEASURE: Association between CDR scores and neuropathologic changes assessed with the Consortium to Establish a Registry for Alzheimer's Disease semiquantitative scale. RESULTS: Among these lesion scores, only NFTs showed a significant association with CDR score, and only for neocortical regions. In particular, NFT densities in the superior temporal cortex were most strongly correlated with dementia severity, followed by those in the inferior parietal and midfrontal cortex. No such correlations were apparent for the amygdala, hippocampus, or entorhinal cortex. Medial temporal lobe structures displayed high NFT scores, even in cases of mild dementia. Senile plaques did not correlate significantly with CDR score in any region. CONCLUSIONS: These data support the notion that neocortical neuronal degeneration, as indicated by NFT formation, is a critical determinant of the clinical progression of Alzheimer's disease and suggest that medial temporal lobe structures may represent the initial site of NFT formation. While SP density correlates with age at death, there is no correlation between SP counts and dementia severity. These results further suggest that the clinical presentation of dementia may be closely related to neurodegeneration in neocortical regions within the temporal lobe.