Improving Walking Automaticity in Parkinson's Disease: Levodopa or Donepezil
Condition: Parkinson Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Safe and independent mobility at home and in the community requires control of walking while
      accomplishing other functional tasks. A hallmark of healthy control of walking is
      automaticity, defined as the ability of the nervous system to successfully coordinate
      movement with minimal use of attention-demanding executive resources [1]. Recent evidence
      indicates that walking disorders are often characterized by a shift in the locomotor control
      strategy from healthy automaticity to compensatory executive control. This shift is
      potentially detrimental to walking performance as an executive control strategy is not
      optimized for locomotor control and it places excessive demands on a limited pool of
      cognitive reserve.

      Here, the investigators hypothesize that walking automaticity, as measured by the prefrontal
      cortex activity while walking, will be improved by donepezil (a cholinesterase inhibitor).
    

Detailed description: 
      A challenge to studying automaticity is that central nervous system circuitry for locomotion
      cannot be directly assessed in humans so shifts between automaticity and executive control
      have been inferred with a dual-task paradigm. If gait slows or deteriorates during a
      concurrent cognitive task, gait is deemed less automatic and using more cortical control.
      Recently, a more direct measure of automaticity has been studied with functional near
      infrared spectroscopy (fNIRS). fNIRS is used to measure changes in cortical oxygenated
      hemoglobin (HbO2) levels using light-tissue interaction properties of light within the near
      infrared range, similar to the way the HbO2 is detected with magnetic resonance imaging.
      Increased oxygenated hemoglobin are related to increased blood flow, which, in turn, reflects
      increased cortical activity.

      A recent study shows higher than normal activation of the prefrontal cortex during usual
      walking in patients with PD, an indicator of increased cortical control and reduced
      automaticity. An enhanced understanding of the neurochemistry underlying gait automaticity in
      PD will have implications for pharmacologic management of gait impairment in PD. If reduced
      gait automaticity is due to depressed central dopamine, then more aggressive dopaminergic
      strategies may be in order. On the other hand, if reduced gait automaticity is due to
      depressed central cholinergic tone (as the investigators hypothesize), then cholinergic
      strategies will be more effective for optimizing gait in PD. Few studies have explored the
      positive effects of cholinergic augmentation on gait and falls but none have examined its
      direct effects on gait automaticity.

      Aim I. Examine the effect of donepezil or levodopa on walking automaticity, as measured by
      prefrontal cortex activity while walking. This study will employ a double-blind, two-way
      crossover design in which 20 participants with idiopathic PD will be tested either after 14
      days of placebo and their regular dose of levodopa or after 14 days of donepezil (5 mg/day
      oral) and their regular dose of levodopa. Levodopa doses are not determined or controlled by
      the investigators, as the recruited participants are already on levodopa specific to their
      own needs. The investigators will measure automaticity by measuring the activity of the
      prefrontal cortex while walking in single- and dual-task conditions with a wireless fNIRS
      system. The investigators predict that donepezil plus levodopa will decrease the prefrontal
      cortex activity, indicating more automaticity, during walking compared to placebo and
      levodopa.

      Aim II. Relate walking automaticity with spatio-temporal measures of walking. In addition to
      walking automaticity measured with fNIRS while walking, subjects will be equipped with 3
      inertial sensors to measure spatio-temporal features of gait, such as stride time, stride
      length and their variability. The investigators hypothesize that variability of gait will be
      related to level of prefrontal cortex activity. The investigators predict that variability of
      gait will not change with levodopa, reflecting prefrontal control of walking. In contrast,
      the investigators predict that donepezil will improve variability of gait, both with and
      without a concurrent, cognitive task.
    

Intervention name(s): Donepezil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Donepezil 5 mg per day for week 1-2 or 5-6; Placebo 5 mg per day for week 1-2 or 5-6
Other intervention name(s): Aricept
Intervention MeSH terms: Donepezil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science