The distribution of pathological changes seen in Alzheimer's disease suggests that the disease process begins in the archicortex of the medial temporal lobe and spreads through the brain via normal pathways of synaptic connectivity. Unfortunately, it is not possible to trace Alzheimer's disease back to its source, both because of the difficulty in obtaining brains from patients early in the course of the illness,and because of the lack of agreement concerning the classification of brains with minimal neurofibrillary pathology. To investigate the hypothesis of transsynaptic spread of Alzheimer's disease, we will need to establish a reliable marker for the disease process that precedes neurofibrillary degeneration. A panel of antibodies, that recognize antigens that are abundant in Alzheimer, but not normal brains, will be investigated to determine if one or more of these markers may provide such a marker. We will systematically determine the distribution of immunocytochemical staining in sections from each level of the brain, in normals and in pathological states, using two monoclonal antibodies (ALZ50 and PHF1) against the Alzheimer specific A68 protein, and a polyclonal antiserum against the beta-amyloid protein (BAP). First, we will map the ALZ50, PHF1 and BAP immunoreactivity in a series of normal human brains, and in a series of patients with Alzheimer's disease. Relative staining densities will be compared between different areas within individual cases, and this information will be used to construct statistical measures for abnormal staining ratios in pathological brains. Then we will perform similar mapping and quantitative studies in a variety of non-Alzheimer dementing illnesses, to examine the specificity of the immunocytochemical staining patterns for Alzheimer's disease. Next, we will evaluate ALZ50, PHF1 and BAP staining in a series of patients with early dementia who so not meet the criteria for diagnosis of Alzheimer's disease, to determine whether there is a population of """"""""pre-Alzheimer"""""""" patients who have immunocytochemical staining in the same pattern seen in Alzheimer's disease. Finally, we will examine ALZ50, PHF1 and BAP staining in a series of cortical biopsies, compare these with neurofibrillary degeneration in the same biopsies, compare these with neurofibrillary degeneration in the same biopsy sample, then re-examine the dame brains at autopsy, to determine the temporal relationships of the pathological markers.
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