Alzheimer's disease (AD) involves a progressive global deterioration of intellectual function, manifested by disturbances in cognition, memory, language, visuospatial skills, judgement and personality. Such mental abilities require integration of information across many specialized regions of the cerebral cortex. Preliminary evidence suggests that AD may involve the severe loss of the structural and functional integrity of the corticocortical projection systems. This hypothesis is supported by the close correlation between the regional and laminar distribution of neurofibrillary tangles and the patterns of origin and termination of the major corticocortical systems. Neurofilament protein has been implicated in the formation of neurofibrillary tangles (NFT) in Alzheimer's disease. A monoclonal antibody to non-phosphorylated neurofilament protein (N-PNFP, SMI 32 of Sternberger-Meyer) labels a distinct subset of pyramidal cells in the normal human cortex. The distribution of labeled cells in normal brain is very similar to that of neurofibrillary tangles in brains from patients with Alzheimer's disease. In addition, in brains of AD patients, those regions and layers that normally contain a high density of SMI 32- immunoreactive (ir) cells now show large numbers of NFT and few SMI 32-ir cells. These SMI 32-ir cells have laminar locations identical with those neurons that are most likely to furnish the corticocortical and hippocampal association paths essential for the integrated, cohesive function of human cortex. The experiments outlined in this proposal are directed at determining the following: 1) distribution of SMI 32-labeled cells in normal human and monkey cortex, and the degree to which the cellular, laminar and regional patterns are similar in the two species, 2) the degree to which the labeled cells in monkey furnish long corticocortical projections 3) the regional, laminar, and cellular pathology of the SMI 32-labeled cells in AD and their relationship to other indices of AD pathology, particularly NFT and 4) the neurotransmitters utilized by neurons furnishing long corticortical projections in monkey, particularly in reference to somatostatin. These data will shed light on the neurological consequences of the proposed role of neurofilament protein in AD pathology, and may reveal the degree to which the degeneration of corticocortical projection systems is a key element of dementia.
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