Vigor and the LDR in Parkinson Disease

• ClinicalTrials.gov Identifier: NCT04821830
• Recruitment Status: Recruiting
• First Posted: March 30, 2021
• Last Update Posted: December 21, 2021
• Sponsor: University of Michigan
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Roger L. Albin, University of Michigan

Study Description

Brief Summary:

Parkinson disease (PD) is a common disorder in which reduced speed of movement results from inadequate brain production of the chemical dopamine. The most effective treatment for PD is the drug levo-dopa, which partially replaces brain dopamine. Despite decades of successful use, how levo-dopa improves speed of movement in PD is not understood. This observational study recruits participants who have been prescribed levo-dopa by their treating physicians. Before their first dose, immediately after their first dose and later, when their dose has been stabilized, they will engage with the research team to participate in a few simple experiments to measure speed, grip strength, tremor, and stability (on and off of treatment). The purpose of these experiments is to understand how levo-dopa treatment in Parkinson disease enhances movement speed. An important but not understood component of levo-dopa action, the Long Duration Response (LDR), lasts for days to weeks. A basic function of dopamine signaling in the brain is modulation of motivation - the coupling between effort and action values. These experiments will determine if the LDR is associated with relative normalization of motivation function in the brain. The motivation behavior of recently diagnosed PD participants will be examined before and after treatment with levo-dopa to determine if the magnitude of the LDR is correlated with improvements in motivation behavior.

Condition or disease	Intervention/treatment
Parkinson Disease	Drug: carbidopa/levodopa, as prescribed by treating physician

Detailed Description:

Dopamine replacement therapy (DRT) is the standard symptomatic treatment for early to moderate Parkinson disease (PD). In early to moderate PD, the most important DRT component is the Long Duration Response (LDR), a pharmacodynamic effect that builds up over the course of days-weeks and can be induced by dopamine agonists. Despite its effectiveness, DRT actions are poorly understood and the basis of the LDR is unknown. As the LDR wanes in advancing disease, PD patients develop troublesome motor fluctuations and increasing disability. Improved understanding of the LDR has the potential to prolong the duration of its effects and could have a significant positive effect on clinical practice.

The kinetics of the LDR suggest long-term plastic changes in striatal function. Recent studies of striatal dopamine actions in PD subjects and experimental animals indicate that striatal dopaminergic neurotransmission regulates "vigor," the force, velocity, or amplitude of actions. Vigor is closely allied to the concept that striatal dopaminergic neurotransmission mediates motivation, which involves the assessment of act utility and the appropriate scaling of actions to perceived rewards. Recent theoretical and experimental results suggest that tonic striatal dopamine signaling, mimicked by dopamine agonist administration, is a key determinant of movement vigor. Convergent clinical pharmacologic and experimental data lead to a strong hypothesis that the LDR results from chronic DRT partially restoring motivational coupling of effort to perceived reward and movement vigor. Prior experiments examining vigor in PD subjects did not take the LDR into account, resulting in incomplete examinations of the role of vigor deficits in PD.

Recent non-human primate work on the control and vigor of saccadic eye movements indicates the existence of basal ganglia circuit changes that stably encode motor action values for prolonged periods. Striatal dopaminergic neurotransmission is critical for establishing this remarkably stable form of value-action coupling. This phenomenon is a plausible circuit level mechanism underlying the LDR.

Our long-term goal is to understand the clinically relevant actions of DRT. The primary objective of our proposal is to test the hypothesis that the LDR results from partial restoration of normal action vigor by reinstating the link between motivation and effort. Our secondary objective is to explore potential mechanisms underlying the LDR. The rationale for these experiments is that better understanding of the LDR, a clinically crucial component of DRT action, will lead to improved symptomatic therapy.

We will study recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, cognitive, and motivational features. Subjects will perform incentive motivation tasks assessing movement vigor in response to monetary incentives. Two complementary tasks, one based on modulation of movement velocity and one based on modulation of grip strength, will be employed. To assess whether the recently described stable action-value coupling for saccades is relevant to the LDR, subjects will perform a task that measures saccadic eye movement vigor in response to stable value signals learned prior to LDR induction. Subjects will perform all tasks before and after LDR induction in both the "practical off" and post-acute treatment states.

Specific Aim 1: To use incentive motivation tasks to evaluate the coupling between motivation and movement vigor in recently treated PD subjects before and after LDR induction.

Hypothesis 1A: LDR induction will result in partial restoration of movement vigor in response to monetary incentives in PD subjects in the "practical off" state.

Hypothesis 1B: The magnitude of partially restored movement vigor in response to monetary incentives will correlate with reduced bradykinesia in PD subjects in the "practical off" state.

Hypothesis 1C: Identical effects will be found with an incentive motivation task based on movement amplitude and one based on grip strength.

Specific Aim 2: To use a saccadic eye movement task to assess saccadic eye movement vigor in response to stable value signals in recently treated PD subjects before and after LDR induction.

Hypothesis 2: LDR induction will result in partial restoration of saccadic eye movement vigor in response to previously learned stable value signals in PD subjects in the "practical off" state.

Validation of our hypotheses would have considerable impact by identifying a specific functional process underlying the LDR and a potential mechanism of the LDR. This will facilitate research into LDR mechanisms, provide a rational basis for developing valid animal models of the LDR, and open a new path towards improved symptomatic management of PD.

Study Design

• Study Type: Observational
• Estimated Enrollment: 40 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Vigor and the LDR in Parkinson Disease
• Actual Study Start Date: February 12, 2020
• Estimated Primary Completion Date: February 12, 2023
• Estimated Study Completion Date: February 12, 2023

Groups and Cohorts

Group/Cohort

Intervention/treatment

Parkinson's disease patients who take levo-dopa as standard of care; Participants will undergo evaluation of the relationship between the LDR and movement vigor. All participants will undergo standard evaluation with standard clinical rating scales and three outcome measures: Tapping Speed Task - Measurement of Bradykinesia; Grip Strength Task - Measurement of Incentive-Outcome Coupling - Movement Vigor; Joystick Movement Task - Measurement of Incentive-Outcome Coupling - Movement Vigor. Some participants may opt in to an additional training and evaluation: Value Driven Attentional Oculomotor Capture.

Drug: carbidopa/levodopa, as prescribed by treating physician; There will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR).; Other Name: Parcopa, Sinemet

Outcome Measures

Primary Outcome Measures :

1. Tapping Speed Task [ Time Frame: 15 Minutes ]
   Measurement of Bradykinesia
2. Grip Force Task [ Time Frame: 20 Minutes ]
   Measurement of Incentive-Outcome Coupling - Movement Vigor
3. Joystick Movement Task [ Time Frame: 20 Minutes ]
   Measurement of Incentive-Outcome Coupling - Movement Vigor
4. Value Driven Attentional Oculomotor Capture Task [ Time Frame: 1 Hours ]
   Measurement of Value Signal Stability

Eligibility Criteria

• Ages Eligible for Study: 45 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

The study population is newly diagnosed Parkinson disease in the early stages of PD (Hoehn & Yahr Stages I & II).

Criteria

Inclusion Criteria:

• Diagnosis of Parkinson Disease
• Previously Untreated or treated for <4 weeks
• Mild to Moderate Parkinson disease (Hoehn & Yahr Stages I-II)
• About to start treatment with a L-Dopa preparation (Sinemet)

Exclusion Criteria:

• The presence of other neurologic disease or findings on examination
• Depression: Geriatric Depression Scale score >11
• Use of dopamine agonists or stimulants
• Evidence of a stroke or mass lesion on prior structural brain imaging (MRI or CT)
• Evidence of any confounding medical or psychiatric problem that would preclude task participation.
• Participants with cognitive impairment that might impair their capacity to provide informed consent.

Contacts and Locations

Contacts

Contact: Teresa Scerbak; 734-763-2211; tescerba@med.umich.edu

Contact: Roger L Albin, MD; 734-764-1347

Locations

United States, Michigan

University of Michigan; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Teresa Scerbak, BS 734-763-2211 tescerba@med.umich.edu

Sponsors and Collaborators

University of Michigan

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Roger Albin; University of Michigan

More Information

• Responsible Party: Roger L. Albin, Professor of Neurology, University of Michigan
• ClinicalTrials.gov Identifier: NCT04821830
• Other Study ID Numbers: HUM00166765; R21NS114749 ( U.S. NIH Grant/Contract )
• First Posted: March 30, 2021
• Last Update Posted: December 21, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Roger L. Albin, University of Michigan:

Parkinson's Disease

Additional relevant MeSH terms:

Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Levodopa; Carbidopa; Carbidopa, levodopa drug combination; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Aromatic Amino Acid Decarboxylase Inhibitors; Enzyme Inhibitors; Adjuvants, Immunologic; Immunologic Factors; Dopamine Agonists