ABSTRACT
The integrity of cholinergic pathways was investigated in a set of five neuropsychologically characterized elderly subjects at the stages of MCI or early AD and their seven cognitively normal controls. The subjects were rigorously characterized and had multiple longitudinal assessments that allowed a determination of the approximate time of conversion from ‘normal’ to MCI and from MCI to early AD.81 Each subject had at least two neuropsychological assessments, the last of which happened 18 months or less before death. Thioflavin-S histofluorescence was used to identify fully formed NFTs in the Ch4-nucleus basalis complex, whereas the Alz-50 and AT8 antibodies were used to identify stages of tauopathy preceding NFT formation.82-84
The principal findings were that Ch4-nucleus basalis cytopathology starts during cognitively normal aging, that it becomes more severe at the MCI and early AD stages, and that its magnitude is correlated with memory function throughout this continuum. In all cases, the nucleus basalis contained fully formed NFTs as well as Alz-50 and AT8-positive intracellular accumulations reflecting pretangle stages of tauopathy (Figure 4.2). In many specimens, the nucleus basalis was the only forebrain structure outside of medial temporal areas consistently displaying NFTs and tauopathy, illustrating its selective vulnerability to age-related and tau-based neurofibrillary pathology.81,85
The vast majority of AT8 or Alz-50 accumulations were located within neurons that still had an active biosynthetic machinery, as shown by the persistence of ChAT immunoreactivity. This observation is consistent with studies where the number of cholinergic nucleus basalis neurons in MCI and early AD were not found to be reduced when compared with agematched controls.79 Nevertheless, neurons at these putatively pretangle stages of cytopathology are unlikely to function normally since early stages of
The initial reports of cortical cholinergic denervation and of cell loss in the nucleus basalis were based on patients who had advanced disease.68,75 Nonetheless, the implicit assumption during the ‘cholinergic era’ was that these transmitter-specific events occurred early in the course of the disease, perhaps as initiating events. Two sets of observations seemed to corroborate this impression. In one of these, Perry and colleagues reported that the cholinergic denervation of the temporal lobe was present even in patients at the early stages of AD neuropathology.7 In another landmark study, Bowen and colleagues obtained biopsy specimens from patients with presenile dementia and found a significant loss of ChAT activity even within 1 year of symptom onset in patients with a diagnosis of AD.76
