Neurobiological Drivers of Mobility Resilience: The Dopaminergic System

Phase 1

Completed

Conditions: Parkinsonian Signs in Older Persons

Interventions: Drug: carbidopa

Registration Number: NCT04325503

Lead Sponsor: University of Michigan

Brief Summary: Walking with age becomes both slower and less 'automated', requiring more attention and brain resources. As a result, older adults have a greater risk of negative outcomes and falls. There is an urgent need to identify factors that can help compensate for these harmful factors and reduce walking impairments, as there are currently no effective treatments available. Investigators have recently discovered that \~20% of older adults maintain fast walking speed even in the presence of small blood vessel brain changes and leg problems, thus appearing to be protected against these harmful factors. The investigators work suggests that the brain dopamine (DA) system may be a source of this protective capacity. Investigators have also shown that lower levels of dopamine are associated with slow walking. Investigators will be investigating the role of dopamine on slow walking and other parkinsonian signs using detailed clinical assessment, assessment of dopamine activity, and clinical interventions.

Detailed Description: Walking with age becomes both slower and less 'automated', requiring more attention and prefrontal resources. As a result older adults have a greater risk of adverse mobility outcomes and falls. Walking disturbances in the elderly have been linked to changes in both cerebral, in particular small vessel disease (cSVD), and peripheral systems. There is an urgent need to identify factors that can help compensate for these harmful factors and reduce walking impairments, as there are currently no effective treatments available. Although effective mobility is the end result of the functional capacity of both central and peripheral systems, the brain's unique modulatory and adaptive capacity may provide clues for novel interventions. For example, investigators have recently discovered that \~20% of older adults maintain fast walking speed even in the presence of age related cSVD and peripheral system impairments, thus appearing resilient to these harmful factors. The investigators work suggests that the nigrostriatal dopamine (DA) system may be a source of this resilience. As investigators recent findings suggest, DA neurotransmission positively predicts walking speed; it also attenuates the negative effects of age related cSVD and peripheral system impairments on walking speed. These findings are consistent with post-mortem evidence that a combination of loss of nigral DA neurons and cSVD best predict age-related walking impairment. The nigrostriatal DA system plays a critical role in motor control; nigrostriatal. DA neurotransmission regulates the automated execution of overlearned motor tasks via its connections with sensorimotor cortical and subcortical areas.

The investigators hypothesize that higher nigrostriatal DA neurotransmission drives resilience to cSVD and peripheral system impairments, via higher connectivity of sensorimotor networks, thus increasing automaticity of walking and reducing prefrontal engagement while walking. Unlike cSVD and brain structural impairments, DA neurotransmission is potentially modifiable, thereby offering novel approaches to treat non-resilient elderly in a targeted fashion. This translational pilot study will use a biomechanistic target engagement study in older adults with slow walking and/or other parkinsonian signs.

The study will include elderly men and women age 60 or older with evidence of mild parkinsonian signs (MPS, or slow gait (\< 1m/s)) and/or additional cSVD on brain MRI.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Age 60 or older (M/F)
Evidence of mild parkinsonian signs (incl. slow gait (< 1m/s))

Exclusion Criteria

Presence of clinically significant degenerative joint disease and/or neuropathy interfering with proper assessment of the motor UPDRS exam.
Presence of significant dementia.
Evidence of a large vessel stroke in a clinically relevant area (cerebral cortex, basal ganglia, thalamus) or mass lesion on structural brain imaging (MRI).
Participants in whom magnetic resonance imaging (MRI) is contraindicated including, but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant.
Severe claustrophobia precluding neuroimaging procedures.
Hypersensitivity to the carbidopa, levodopa, and tablet components.
Any other medical history determined by investigators to preclude safe participation.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment	carbidopa	carbidopa and carbidopa-levodopa treatment for parkinsonian signs in older persons using standard dosing, frequency for a duration for 1-2 weeks

Primary Outcome Measures

Name	Time	Method
Mini Balance Evaluation Systems Test (Mini-BESTest)	7-13 days after beginning treatment	The mini-BESTest is a 14-item evaluation of dynamic balance and postural control. It is scored from 0-28, with higher scores indicating better performance.
Average Gait Speed	7-13 days after beginning treatment.	Average gait speed as measured using wearable sensors worn during walking tasks. Gait speed is measured in meters per second.
Montreal Cognitive Assessment (MoCA)	7-13 days after beginning treatment	Cognitive assessment used to evaluate individuals for mild cognitive impairment. Scores range from 0-30. Higher scores indicate better performance.
Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III Total	7-13 days after beginning treatment	MDS-UPDRS part III is the motor examination portion of the UPDRS evaluation. Scores range from 0-132, with higher scores indicating greater severity of motor symptoms.
Cognitive Z-score	7-13 days after beginning treatment	Composite variable calculated based on the Stroop Color Word Interference test I-IV (assessment of attention) and Delis-Kaplan Executive Function System Trail Making test I-V (assessment of executive function and working memory), adjusted based on normative data for older adults. A z-score of 0 represents the control population mean. Scores above the mean indicate better performance, while scores below the mean indicate poorer performance.
Wechsler Adult Intelligence System Digit Symbol Substitution Test	7-13 days after beginning treatment	Evaluation of cognitive functioning in which a participant is given a key of numbers 1-9, each paired with a unique symbol. Below the key, is a series of random numbers which they participant must fill in the corresponding symbol for. They have 120 seconds to complete the task. Participants receive one point for each correct symbol written. Score range from 0-133.

Secondary Outcome Measures

Name	Time	Method
Short Activities-specific Balance Confidence Scale Score	7-13 days after beginning treatment	Participants rate their level of confidence in doing specific activities without losing their balance as a percentage, with 0% indicating they are certain they would lose their balance and 100% indicating that they are certain they can complete the task without losing their balance. Scores on these 6 questions are averaged to determine total sABC score. Scores range from 0-100, with higher scores indicating greater balance confidence.