Alzheimer's disease (AD) is thought to terminate in a final common neuropathology with loss of large pyramids, neurofibrillary tangles, and senile plaques. Although well-documented clinical heterogeneity could result from random expression of a single mechanism of cell death, there may be subtypes with unique etiologies. For example, patients with early spastic paraparesis and deletion of exon 9 of the presenilin 1 gene have large, diffuse plaques and degeneration of the corticospinal tract. Also, studies of posterior cingulate cortex fail to confirm the common endpoint hypothesis and multivariate analysis of neurons showed that small-medium pyramids in layers IIIab and IV are often impacted, there is no single laminar pattern of neurodegeneration (LPND), and each LPND has a full range of duration's and little association with neurofibrillary tangles. The proposed studies will use design-based stereology to estimate neuron numbers in the entire cingulate gyrus in controls and early-mild AD cases from Mount Sinai ADRC. This information will be used to test the neuropathological subtypes hypothesis with multivariate models and these will be extended to measures of four domains of cognitive function.
The specific aims follow: 1) Estimate neuron numbers in posterior cingulate cortex with systematic and random sampling in 15 control (#1a) and 70 early-mild AD cases (#1b) followed by multivariate analysis. 2) Extend these analyses to anterior cingulate areas and volumetric analysis of areas in temporal, parietal, prefrontal, and occipital cortices. 3) Evaluate the laminar load of amyloid-beta peptides. 4) Evaluate disease progression in LPND with tau immunohistochemistry and disease onset determined with the Clinical Dementia Rating score. 5) Test the subtypes hypothesis by including measures of cognitive and demographic patient characteristics will be tabulated for each neuropathological subtype so that they can be consistently identified and guide studies of the etiology of each.
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