Objective: Determine whether levodopa replacement or cholinergic augmentation improve automaticity of walking in people with Parkinson’s disease (PD).

Background: Degradation of dopaminergic striatal mechanisms of motor control in PD may be initially supplemented by increased cognitive control mediated by cortical cholinergic mechanisms. This shift in motor control from healthy automaticity to compensatory executive control of walking can be quantified by measuring the activity of the pre-frontal cortex (PFC) while walking. Levodopa improves certain aspects of gait and worsens others, and the effects of cholinergic augmentation on gait are mixed. The effects of either Levodopa or cholinergic augmentation on PFC activity while walking is unknown.

Method: A single-site, randomized, double-blind, cross-over trial examined the effect of Levodopa and Donepezil in 20 people with idiopathic PD. Participants were tested at baseline Off Levodopa and randomized to start with either Donepezil (5mg) or Placebo. Each treatment period was 2 weeks with a 2-week washout period between treatments, and after each treatment period participants were tested on Levodopa. The primary outcome was change in PFC activity while walking, as measure of automaticity of walking, and secondary outcomes were change in behavioral measures of gait and dual-task (reaction time and accuracy of the AX-Continuous Performance Test).

Results: Significant change occurred in PFC activity when walking with Donepezil and Levodopa compared to Levodopa alone, with Levodopa alone decreasing PFC activity compared to Off medication (effect size: -0.51). Behavioral measures of gait, such as gait speed and stride length, under both single and dual-task, improved best with the combination of Donepezil and Levodopa compared to Off (effect size: 1 for gait speed and 0.75 for stride length). Lastly, while dual-task reaction time while walking was quicker with Levodopa alone compared to Off medication, accuracy significantly improved only with combined Donepezil and Levodopa.

Conclusion: Cholinergic augmentation in addition to Levodopa, specifically Donepezil 5mg/day for two-weeks, can alter PFC activity when walking, and improve behavioural measures of gait more than Levodopa alone in PD. Further studies will investigate whether higher PFC activity while walking, which is considered potentially a maker of poorer gait automaticity, is associated with improved gait.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/improving-automaticity-of-walking-in-parkinsons-disease-levodopa-or-donepezil/