Previous studies with cholinesterase inhibitors in patients with Alzheimer's Disease (AD), and the ongoing multi-center study of THA, suggests that a subgroup of patients with (AD) are responsive to this pharmacological intervention. However, a substantial proportion of patients are virtually unaffected by the administration of cholinesterase inhibitors. Data generated in animals with combined lesions of the nucleus basalis and locus coeruleus indicate that the addition of a locus coeruleus lesion to animals with nucleus basalis lesion completely eliminated responsivity to cholinomimetic agents. However the administration of the alpha II agonist clonidine, combined with a cholinomimetic, restores the ability of the cholinomimetic compound to reverse the poor performance associated with a nucleus basalis lesion. These data suggest that it is essential to the efficacy of a cholinergic compound that there be an intact central noradrenergic system. In addition these data constitute the foundation of a hypothesis proposing that some of the nonresponsivity to cholinomimetic agents, and the variable therapeutic effects observed following the administration of these compounds, may be a manifestation of variable noradrenergic degeneration in the AD brain. Specifically, those Alzheimer;s patients with a profound noradrenergic deficit would be anticipated to have no alleviation of symptoms following the administration of a cholinesterase inhibitor. In order to test this hypothesis a series of antemortem noradrenergic markers will be investigated for the possibility that they will be predictive of responsivity to the cholinesterase inhibitor THA alone combined with either clonidine, deprenyl, or desipramine. In a second parallel investigation the validity of these antemortem noradrenergic markers will be tested in a separate cohort of new stage Alzheimer;s patients whose antemortem parameters will be composed with the changes on post mortem examination in noradrenergic parameters when these same Alzheimer;s patients are autopsied.
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