Neurobiological Drivers of Mobility Resilience: The Dopaminergic System - Placebo-Controlled Arm (RES)

Neurobiological Drivers of Mobility Resilience: The Dopaminergic System

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 in this double-blinded, placebo-controlled study using detailed clinical assessment, assessment of dopamine activity, and clinical interventions.

Study Overview

• Status: Recruiting
• Conditions: Parkinsonian Signs in Older Persons
• Intervention / Treatment: Drug: Carbidopa 25 mg; Drug: Carbidopa-Levodopa 25/100 mg; Drug: Placebo 1; Drug: Placebo 2

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 study is an arm of a previously completed translational pilot biomechanistic target engagement study in older adults with slow walking and/or parkinsonian signs (NCT04325503). This sub-study will further investigate this biomechanistic target engagement using a double-blind, placebo-controlled study design.

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

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jaimie Barr, BSc; Phone Number: 734-998-6894; Email: jaimieba@med.umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Recruiting
      • Domino's Farms
      • Contact: Robert Vangel, BSc; Phone Number: 734-936-1168; Email: rvangel@med.umich.edu
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University Hospital
      • Contact: Robert Vangel, BSc; Phone Number: 734-936-1168; Email: rvangel@med.umich.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

• Evidence of prior established diagnosis and/or treatment for PD.
• Presence of clinically significant degenerative joint disease and/or neuropathy interfering with proper assessment of the motor exam.
• Presence of significant dementia.
• History of stroke with residual clinical deficit interfering with walking.
• For optional MR imaging only: 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.
• For optional brain imaging only: Severe claustrophobia precluding neuroimaging procedures.
• Participants that have been on monoamine oxidase inhibitors (MAOIs) within 2 weeks prior to starting study.
• Inability to stand or walk without an assistive device
• Hypersensitivity to the carbidopa, levodopa, and tablet components.
• History of myocardial infarction (MI) with residual arterial, nodal or ventricular arrhythmia
• History of peptic ulcer
• Chronic wide angle glaucoma
• Narrow angle glaucoma
• Major psychotic disorder
• Severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease
• Subjects on dopamine D2 receptor antagonists, dopamine depleting agents, and metoclopramide.
• Any other medical history determined by investigators to preclude safe participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carbidopa Monotherapy and Carbidopa-Levodopa; Participants will begin by taking 25mg of Carbidopa monotherapy three times per day (TID) for 3 days. On day four, participants will begin taking 1 tablet of Carbidopa-Levodopa (25/100mg) TID in addition to the Carbidopa monotherapy. On day seven, participants will increase to 1.5 tablets of Carbidopa-Levodopa (25/100mg) TID while maintaining 25mg Carbidopa monotherapy TID. The intervention will end after ten days of supplementation.	Drug: Carbidopa 25 mg; Participants will take one 25mg Carbidopa tablet 3 times a day for 10 days.; Drug: Carbidopa-Levodopa 25/100 mg; Participants will take one 25/100mg carbidopa-levodopa tablet 3 times a day on days 4-6, then increase to 1.5 tablets 3 times a day on days 7-10.; Other Names: Sinemet
Placebo Comparator: Placebo; Participants will begin by taking a 25mg placebo tablet three times per day (TID) for 3 days. On day four, participants will begin taking a separate placebo tablet TID in addition to the original placebo. On day seven, participants will increase to 1.5 tablets of the second placebo TID while maintaining 25mg original placebo TID. The intervention will end after ten days of supplementation.	Drug: Placebo 1; Participants will take one 25mg placebo tablet 3 times a day for 10 days.; Drug: Placebo 2; Participants will take one 100mg placebo tablet 3 times a day on days 4-6, then increase to 1.5 tablets 3 times a day on days 7-10.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Gait Speed	Average gait speed as measured using wearable sensors and while walking on a sensor mat. Measured in meters per second.	7-13 days after beginning supplement.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parkinson's Disease (PD)-Cognitive Rating Scale score	Cognitive scale designed to capture impairments in cognitive function in Parkinson's disease. (Scoring: 0-134, with higher scores indicating better performance).	7-13 days after beginning supplement.
Mean of Number of Incorrect Responses on the Stroop Color Word Stepping Test	During this test, subjects make steps based on congruent (stimulus prompts the stepping response) and incongruent (stimulus prompts inhibition of the stepping response) arrows and sounds. This will be used to compare the number of incorrect responses (stepping) from pre and post intervention visits to determine if inhibitory control improves (indicated by decrease in number of incorrect responses).	7-13 days after beginning supplement.

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Chatkaew Pongmala, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2024
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: January 12, 2024
• First Submitted That Met QC Criteria: January 12, 2024
• First Posted (Actual): January 23, 2024

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: slow gait; Parkinsonian signs
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunologic Factors; Dopamine Agonists; Dopamine Agents; Adjuvants, Immunologic; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Levodopa; Carbidopa; Carbidopa, levodopa drug combination
• Other Study ID Numbers: HUM00156490-A; 5U01AG061393-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No