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 alpha4beta2* nicotinic acetylcholine receptor (nAChR) stimulation improves attention and gait-balance function, we assessed target engagement 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: 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 alpha4beta2* 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.

中文翻译：

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alpha4beta2 *帕金森病中的烟碱胆碱能受体靶标参与。

目的：继发于脑胆碱能系统退化的注意功能缺陷是帕金森病（PD）步态平衡缺陷的重要原因。作为评估alpha4beta2 *烟碱乙酰胆碱受体（nAChR）刺激是否能改善注意力和步态平衡功能的第一步，我们评估了alpha4beta2 * nAChR部分激动剂伐尼克兰的靶标参与度。方法：采用[18F]氟乙氧基苯甲酰胺正电子发射断层显像（PET）鉴定胆碱能缺乏的非痴呆PD参与者。用[18F]氟丁汀PET测量亚急性口服缬草碱治疗后α4beta2* nAChR的占有率。通过从受体占用实验中选择的剂量，在双重掩盖的安慰剂对照交叉研究中评估了伐尼克兰对步态，平衡和认知的影响。主要终点是正常的步态步态速度和姿势稳定性的量度。结果：所有伐尼克兰剂量（每天0.25 mg，0.25 mg bid，0.5 mg bid和1.0 mg bid）产生60％-70％的受体占有率。我们为交叉研究选择了0.5 mg po bid。33名参与者（三十四名）以出色的耐受性完成了交叉研究。瓦伦尼克林对姿势稳定性的测量没有明显影响，并导致正常步态步态速度减慢。Varenicline缩小了双重任务和无双重任务步态条件之间正常步速步态速度的差异，降低了双重任务成本，并提高了持续注意力测试的性能。我们在28名参与者中获得了相同的结论，这些参与者通过血浆缬尼克酸的测定证实治疗依从性。解释：Varenicline占据了很大一部分的alpha4beta2 *烟碱乙酰胆碱受体，耐受性良好，注意力功能增强，步态改变。这些结果与相关的目标参与一致。对于缓解PD的步态和平衡障碍，可能需要进一步评估瓦伦尼克碱或类似药物。