This study will be the first systematic neuropharmacological approach to the monoaminergic system in dementia. The primary goal of this project is to determine the dependence upon monoaminergic systems of specific cognitive abilities and mood in patients with Alzheimer's disease. Accordingly, in separate protocols, we will examine the effects of administering single drugs that increase and decrease noradrenergic turnover; the drugs are yohimbine and clonidine respectively. A related goal of this project is to improve cognitive capacities in patients with Alzheimer's disease by administering drugs that alter monoaminergic neurotransmission. Although the cholinergic hypothesis of memory dysfunction in Alzheimer's disease remains compelling, the finding of multiple neurotransmitter deficits in the Alzheimer's disease brain militates against the success of simple cholinergic replacement therapy. We therefore propose to extend our current studies with cholinergic drugs by combining lecithin (phosphatidylcholine, or PC) with clonidine or yohimbine and, in a separate protocol, PC with tryptophan (TRY), a drug that increases the synthesis and release of serotonin (5-HT). Patients with Alzheimer's disease will be selected according to strict inclusion and exclusion criteria. The protocols call for measurements of neurological signs, psychiatric state, neuropsychological test performance, and neurotransmitter markers in plasma and cerebrospinal fluid (CSF). Special emphasis will be placed upon the development and implementation of new tests that improve the characterization of specific cognitive deficits in Alzheimer's disease, and on the use of these tests as measures of change induced by drugs. Tests of forgetting, attentional focusing, and praxis will be highlighted. The results of this research will provide new information regarding the biochemical substrates of cognition.
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