Effects of Cholinergic Augmentation on Measures of Balance and Gait

Phase 2

Completed

Conditions: Parkinson's Disease

Interventions: Drug: Donepezil

Registration Number: NCT02206620

Lead Sponsor: Oregon Health and Science University

Brief Summary: This study will compare the effects of placebo and donepezil, a drug that helps conserve concentrations of the neurotransmitter, acetylcholine, on measures of balance and gait in subjects with Parkinson's disease (PD). This study is a double-blind, placebo controlled, cross-over randomized clinical trial. Short-latency afferent inhibition (SAI), a physiological index of cholinergic function will be measured to determine if the deficits in balance and gait correlate with abnormalities of the SAI and if SAI is altered by donepezil as a measure of drug efficacy. Cognitive tests like the Attention Network Test (ANT) will be administered to determine if changes in gait and balance are mediated by changes in attention.

The results of this study will be the most direct test of the hypothesized role of cholinergic neurons and the neurotransmitter, acetylcholine in terms of gait and balance. The study is exploratory because it is not known whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. The study's 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 neurons in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 49

Inclusion Criteria

30 years old or older
Diagnosis of idiopathic Parkinson's disease
Stand unassisted (without use of an assistance device) and walk continuously for at least 2 minutes.

Exclusion Criteria

musculoskeletal disorders that affect standing and walking
Uncorrected vision disturbance
Vestibular problems
Major depression
Hallucinations or other psychiatric disturbances
Tachycardia
Bradycardia
Arrhythmias
Peptic ulcer disease
Use of anticholinergics
Use of cholinesterase inhibitors
Use of bladder antispasmodics
Use of tricyclic antidepressants

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Donepezil	Donepezil	Donepezil 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated.
Placebo	Donepezil	Placebo 5 mg per day for week 1-3 or 12-14. 10 mg/day for weeks 4-6 or 14-18, if tolerated.

Primary Outcome Measures

Name	Time	Method
Delta of the Variability of Stride Time While Walking	Six weeks	Variability in stride time time and an increase with dual tasking is another marker for increased fall risk in Parkinson's disease. Stride time variability was measured with inertial sensors attached to both feet. The delta for each phase is reported \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\].
Delta Medio-lateral Postural Sway Range (Foam)	Six weeks	Increased body sway while standing may be markers for increased risk of falling in Parkinson's disease. Sway was measured with an inertial sensor attached to the waist. Participants did this task on a foam pad. We reported the delta in the donepezil and placebo phases \[post-donepezil - pre-donepezil for the donepezil phase, and post-placebo - pre-placebo for the placebo phase\].

Secondary Outcome Measures

Name	Time	Method
Short-latency Afferent Inhibition is a Marker of Cortical Cholinergic Activity	Six weeks	Short-latency afferent inhibition (SAI) by a peripheral stimulation is a transcranial magnetic stimulation method to evaluate cortical cholinergic activity. Short-latency afferent Inhibition will be used to determine if our subjects with Parkinson's disease have evidence of reduced cholinergic tone which correlates with their measures of postural and gait instability. We report the SAI at the end of each phase (post-placebo phase and post-donepezil phase). SAI is reported in motor-evoked potential (MEP).
Attention Network Test	Six weeks	Attention Network Test (ANT) is 15 minute computerized test or reaction times with various cues and targets designed to assess alerting, orienting and executive control of attention. Deficits of attention are related to fall risk and may be affected by donepezil. The delta of the Orienting Network Efficiency is reported for each phase (pre- and post-donepezil phase and pre- and post-placebo phase). Details: In accordance with Fan et al. (2002), the subtraction method was applied to isolate the efficiency of the three attentional networks as follows: for the alerting network efficiency: mean RT NC trials - mean RT DC trials; for the orienting network efficiency: mean RT CC trials - mean RT SC trials; and for the executive network efficiency: mean RT I trials - mean RT C trials. For both the alerting and orienting effects, higher subtraction scores indicate greater efficiency; by contrast, the more efficient the executive network is, the lower the subtraction score.