α4β2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders

Objective Attentional function deficits secondary to degeneration of brain cholinergic systems are significant contributors to gait-balance deficits in Parkinson disease (PD). As an initial step towards assessing if α4β2 * nicotinic acetylcholine receptor (nAChR) stimulation improves attention and gait-balance function, we assessed target engagement of the α4β2 * nAChR partial agonist varenicline. Methods Non-demented PD participants with cholinergic deficits were identified with [ 18 F]fluoroethoxybenzamicol positron emission tomography (PET). α4β2 * nAChR occupancy after subacute oral varenicline treatment was measured with [ 18 F]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 All varenicline doses (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. We selected 0.5 mg po b.i.d for the crossover study. Thirty-three (of thirty-four) participants, completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved performance on a sustained attention test. We obtained identical conclusions in 28 participants in whom treatment compliance was confirmed by plasma varenicline measurements. Interpretation Varenicline occupied a significant fraction of α4β2 * nicotinic acetylcholine receptors, was tolerated well, enhanced attentional function, and altered gait performance. These results are consistent with relevant target engagement. Varenicline or similar agents may be worth further evaluation for mitigation of gait and balance disorders in PD.