Improving Walking Automaticity in Parkinson's Disease: Levodopa or Donepezil
| Status: | Recruiting |
|---|---|
| Conditions: | Parkinsons Disease |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 50 - 90 |
| Updated: | 3/15/2019 |
| Start Date: | July 30, 2018 |
| End Date: | July 30, 2019 |
| Contact: | Makena Strand |
| Email: | strandm@ohsu.edu |
| Phone: | 5034182602 |
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).
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).
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.
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.
Inclusion Criteria:
- Subjects must be able to stand unassisted for a minute and to walk continuously for 2
minutes without assistance or assistive devices.
- Diagnosis of idiopathic Parkinson's disease with sensitivity to levodopa and
off-medication Hoehn & Yahr scores of III-IV.
- Subjects must be currently taking levodopa, and not already taking donepezil
- The subjects must be able to appreciate the purpose of the research, give informed
consent to participate, be able to cooperate with the testing and be compliant with
taking the experimental medications.
Exclusion Criteria:
- Other factors affecting gait (hip replacement, musculoskeletal disorder, uncorrected
vision or vestibular problem), or an inability to stand or walk for 2 minutes at a
time. Major depression, hallucinations or other psychiatric disturbances will be
exclusions.
- Medical problems that might be worsened by donepezil are exclusion criteria and
include tachycardia, bradycardia, arrhythmias, and peptic ulcer disease.
- Use of anticholinergics for parkinsonism, cholinesterase inhibitors for cognitive
problems, bladder antispasmodics for urinary urgency or tricyclic antidepressants for
depression are contraindications.
We found this trial at
1
site
3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
Portland, Oregon 97239
503 494-8311
Principal Investigator: Martina Mancini, PhD
Phone: 503-418-2602
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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