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alpha4beta2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease

Objective: Attentional function deficits secondary to degeneration of brain cholinergic systems are significant contributors to gait-balance deficits in Parkinson disease (PD). To assess whether alpha4beta2* nicotinic acetylcholine receptor (nAChR) stimulation improves attention and gait-balance function, we performed a target engagement study of the alpha4beta2* nAChR partial agonist varenicline. Methods: Non-demented PD participants with cholinergic deficits were identified with [18F]fluoroethoxybenzamicol positron emission tomography (PET). alpha4beta2* nAChR occupancy after subacute oral varenicline treatment was measured with [18F]flubatine PET. With a dose selected from the receptor occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability. Results: Varenicline, 0.25 mg per day, 0.25 mg b.i.d., 0.5 mg b.i.d., and 1.0 mg b.i.d., produced 60% - 70% receptor occupancy, with 0.5 mg po b.i.d chosen for the crossover study. Thirty-three (of thirty-four) participants, completed the crossover study with excellent tolerability. Varenicline had no impact on the postural stability measure and resulted in slower normal pace gait speed. Varenicline reduced distraction effects under dual task gait conditions and improved performance on a sustained attention test. In 28 participants in whom treatment compliance was confirmed by plasma varenicline measurements, we obtained identical conclusions. Interpretation: Varenicline occupied a significant fraction of alpha4beta2* nicotinic acetylcholine receptors, was tolerated well, enhanced attentional function, and improved dual task gait performance. alpha4beta2* nicotinic agonists may be useful in mitigating gait and balance disorders in PD.