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

Roger L. Albin, Martijn L.T.M. Müller, Nicolaas I. Bohnen, Cathie Spino, Martin Sarter, Robert A. Koeppe, Ashley Szpara, Kamin Kim, Cindy Lustig, William T. Dauer

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Attentional deficits following degeneration of brain cholinergic systems contribute to gait–balance deficits in Parkinson disease (PD). As a step toward assessing whether α4β2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait–balance function, we assessed target engagement of the α4β2* nAChR partial agonist varenicline. Methods: Nondemented PD participants with cholinergic deficits were identified with [18F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4β2* nAChR occupancy after subacute oral varenicline treatment was measured with [18F]flubatine PET. With a dose selected from the nAChR 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 doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three 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 sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements. Interpretation: Varenicline occupied α4β2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4β2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130–142.

Original languageEnglish (US)
Pages (from-to)130-142
Number of pages13
JournalAnnals of Neurology
Volume90
Issue number1
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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