Identification of novel components of neurofibrillary tangles in Alzheimer brains

Abstract

Background: Increases in cortical capillary densities have been described in AD compared to control cases. Pathological characterization of such changes and their relationship to the hallmark amyloid plaques (NP) and neurofibrillary tangles (NFT) seen in AD has not been performed. Understanding the pathological basis for such microvascular alterations may provide important clues to the relationship between cerebrovascular disease and AD. Methods: Stereologic quantitation of brain capillary length-density was performed on Alzheimer’s disease (all cases met NIA-Reagan criteria for high-likelihood of AD in the absence of other significant pathological features including cerebrovascular disease, n 1⁄4 10) vs. normal control (all cases met NIA-Reagan criteria for low-likelihood of AD, n 1⁄4 10) neocortical sections including frontal, temporal, parietal, and occipital regions. Capillary length density was correlated with quantitative neuropathological burden of NP and NFT in each discrete neocortical region. Results: Capillary length-density was greater in AD compared to control cases for all areas studied, although these differences reached statistical significance only in frontal neocortex (Brodman’s area 9; p< 0.03, Students t-Test) in the small sample studied. Frontal lobe capillary length-density was strongly associated with NFT burden (p< 0.0005, Student’s t-Test), less so with NP burden (p< 0.05), and not at all with diffuse senile plaque burden. NFT burden was significantly higher in temporal and parietal compared to frontal and occipital regions in the cases sampled. Conclusions: This study represents the first in-depth, quantitative assessment of neocortical microvascular alterations in AD subjects that lacked detectable pathological evidence for cerebrovascular disease. The findings clearly demonstrate microvascular alterations in frontal neocortex that are associated with neurofibrillary degeneration. While atrophy as a result of the degenerative process could be postulated as responsible, a higher NFT burden in temporal and parietal regions argues strongly against this possibility. Further studies investigating the changes that may underlie aberrant microvascular alterations in the frontal neocortex of AD subjects are clearly warranted.