Alzheimer's Disease has been associated with a reduction in central cholinergic activity. This deflcit has been hypothesized to account for the decline in memory, cognition and emotional control: The Cholinergic Hypothesis. Recently, our group has found that the administration of chronic oral physostigmine, a central and peripheral acetycholinesterase inhibitor, in optimal doses, improved behavioral and/or memory measures in 9 of 19 (50%) of patients with mild Alzheimer's Disease. Response to therapy appeared to be predicted by the baseline ratio of red cell choline concentration/plasma choline concentration. In the proposed work, we would like to expand the number of treated individuals (50-60 patients) in order to: (1) identify peripheral biologic markers (blood cholinergic activity, cerebral blood flow, and electrophysiological activity) and clinical features (age of onset, severity, subtype) that predict responsiveness; (2) assess the long-term benefits of therapy; and (3) assess the type of memory functions enhanced by physostigmine. The results of this study should (1) provide indepth information on the utility of physostigmine in the treatment of Alzheimer's Disease, (2) permit the clinical and biological markers of responsiveness to be identified, and (3) increase our basic scientific understanding of memory processing in disease states.
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