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

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.

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)).

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.