Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep

Postmortem studies of patients with progressive supranuclear palsy (PSP) have demonstrated loss of cholinergic neurons in the striatum, nucleus basalis of Meynert, and the pedunculopontine nucleus. These findings suggest that cholinergic drugs might be an effective treatment for this disease. We studied the efficacy of RS-86, a direct cholinergic agonist, upon motor abilities, eye movements, and psychometric performance in 10 patients with PSP during a 9-week placebo-controlled, double-blinded, crossover trial. Glycopyrrolate, a peripheral anticholinergic drug, was given throughout the trial to minimize cholinergic side effects. We used changes in rapid eye movement (REM) sleep to assess the degree of cholinergic activation achieved by treatment. Despite the enhancement of cholinergic activity in the CNS as indicated by increases in REM sleep latency and REM sleep time, RS-86 did not improve motor signs, eye movements, or cognition. Pharmacologic replacement of the cholinergic deficits in PSP does not result in significant clinical benefit.