Stereological analysis of neuropil threads in the hippocampal formation: Relationships with Alzheimer's disease neuronal pathology and cognition

Although neuropil threads are thought to account for 85-90% of cortical tau pathology in brain ageing, their clinical significance remains controversial. Previous studies have measured densities, rather than absolute numbers, and most did not take into account possible interactions among the pathological hallmarks of Alzheimer's disease (AD). We report here stereological estimates of total neurofibrillary tangle (NFT) and neuron numbers as well as total amyloid volume and neuropil thread (NT) length, in the hippocampus and entorhinal cortex of 19 very old individuals (age range: 83-101 years) with various degrees of cognitive decline. Total NT length in all areas studied increased in mildly demented cases but showed a marked decrease in Clinical Dementia Rating (CDR) scale 3 cases. Both total NFT and neuron numbers were related to NT length in the CA1 field and entorhinal cortex. A strong positive relationship was also present between the total NFT numbers in the entorhinal cortex and NT length in the CA1 field and dentate gyrus. Total NT length in the CA1 field was related to both CDR scores and presence or absence of dementia explaining 7% and 37% of their variability respectively. In multivariate models, this relationship was highly dependent on the severity of NFT formation in this area. Our data reveal that NT formation in hippocampal subdivisions and entorhinal cortex accompanies AD neuronal pathology in early stages of the degenerative process, yet its rate may decrease in severe dementia. In terms of clinicopathological correlations, NT length in the hippocampal formation does not represent an independent marker of dementia severity.