Abstract
BackgroundImpaired mobility and falls are clinically important complications of Parkinson’s disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait.DesignThe study is a single-site, proof of concept, randomized, double-blind, cross-over trial in patients with PD. Each treatment period will be 6 weeks with a 6-week washout between treatments for a total of 18 weeks for each subject. Donepezil in 2.5 mg capsules or identical appearing placebo capsules will be increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks, if tolerated. Subjects will have idiopathic Parkinson’s disease, Hoehn and Yahr stages 2 to 4. We anticipate recruiting up to 100 subjects for screening to have 54 enrolled and 44 subjects complete both phases of treatment. Dropouts will be replaced. As this is a crossover trial, all subjects will be exposed to both donepezil and to placebo. The primary outcome measures will be the root mean square of the mediolateral sway when standing and the variability of the stride duration when walking for two minutes. Secondary outcomes will be the computerized Attention Network Test to examine three domains of attention and the Short-latency Afferent Inhibition (SAI), a physiological marker obtained with transcranial magnetic stimulation as a putative marker of cholinergic activity.DiscussionThe results of this study will be the most direct test of the hypothesized role of cholinergic neurotransmission in gait and balance. The study is exploratory because we do not know whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. We hypothesize that change in cholinergic activity, as measured with SAI, will predict the relative effectiveness of donepezil on gait and balance. Our immediate goal is to determine the potential utility of cholinergic manipulation as a strategy for preventing or treating balance and gait dysfunction in PD. The findings of this trial are intended to lead to more sharply focused questions about the role of cholinergic neurotransmission in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility. Trial registrationThis trial is registered at clinical trials.gov (NCT02206620).
Highlights
Impaired mobility and falls are clinically important complications of Parkinson’s disease (PD) and a major detractor from quality of life for which there are limited therapies
The study is exploratory because we do not know whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation
We hypothesize that change in cholinergic activity, as measured with Short-latency Afferent Inhibition (SAI), will predict the relative effectiveness of donepezil on gait and balance
Summary
We are interested in determining whether gait and balance are directly influenced by cholinergic manipulation or whether changes in attention capacity are primarily responsible for changes in balance and gait. For example, we find that ability to balance and walk when dual tasking is altered out of proportion to changes during standing and walking without dual tasking, it would suggest that cholinergic systems mainly contribute to attentional capacity required for balance and gait. Competing interests OHSU and Dr Horak have a significant financial interest in APDM, a company that may have a commercial interest in the results of this research and technology. This potential institutional and individual conflict has been reviewed and managed by OHSU.
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