Cerebral Contributions to Symptom Progression in PD

Study Overview
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Brief Summary
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Motor symptom progression in early-stage Parkinson's disease varies substantially between individual patients. This progression correlates poorly with striatal dopamine depletion, which is largely complete four years post-diagnosis. Identification of alternative mechanisms, such as cortical compensatory processes, may enable more accurate predictions of individual motor progression.

Detailed Description
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Striatal dopamine depletion leads to dysfunction in the cortico-striatal motor circuit and is an important contributor to motor symptoms in Parkinson's disease (PD). However, dopamine depletion in striatal motor regions is already severe at symptom onset and tends to correlate poorly with progressive worsening. This indicates that the severity of motor symptoms in PD may not be solely dependent on basal ganglia dysfunction. In PD, the deleterious effect of basal ganglia dysfunction on motor control may be partially counteracted by neuroplasticity and the compensatory recruitment of parieto-premotor areas of cortex that drive movement based on sensory cueing and goal-directed cognitive control. The efficacy of cortical compensation could therefore be a core determinant of motor impairment in PD. This study utilizes longitudinal clinical and brain imaging data from early-stage PD patients included in the Personalized Parkinson Project (ClinicalTrials.gov Identifier: NCT03364894) to test whether motor symptom severity and progression can be predicted by action selection-related brain activity in parieto-premotor cortex, basal ganglia, or a combination of both. Additional control analyses will be performed to investigate the effects of disease and medication on action selection-related brain activity. Action selection-related brain activity will be compared between PD patients and a cohort of healthy controls to assess the effect of disease (PD vs Healthy). Effects of medication (on vs. off) on action selection-related brain activity will be investigated through within-subject comparisons in subset of PD patients who underwent functional brain imaging in both on- and off-medicated states.

Official Title
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How Cerebral Plasticity Shapes Symptom Progression in Parkinson's Disease: A Longitudinal Neuroimaging Study

Conditions
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Parkinson Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (patients): Subject is included in the Personalized Parkinson Project and has already participated in all baseline measurements (this means that inclusion and exclusion criteria of the Personalized Parkinson Project have already been fulfilled) Subject has completed the Informed Consent Form, as approved by the Ethics Committee Exclusion Criteria (patients): Subject is not taking dopaminergic medication Inclusion Criteria (healthy controls): Subject is at least 40 years old Subject can read and understand Dutch Subject has completed the Informed Consent Form, as approved by the Ethics Committee Subject is willing, competent, and able to comply with all aspects of the protocol, including follow-up schedule. Exclusion Criteria (healthy controls): Subject has no co-morbidities that would negatively influence the interpretability of results from a comparison with PD patients (e.g. other neurodegenerative diseases or mental health disorders)

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PD-OFF<br>Patients with PD who have previously been included in the Personalized Parkinson Project return for fMRI measurements in an off-medicated state (12h withdrawal). N = 60. The PD-OFF group undergoes a single testing session. | |
| Healthy controls<br>Healthy individuals who are matched on age and sex with respect to the PD-OFF group. N = 60. The healthy group undergoes baseline and two year follow-up testing sessions. | |
| PD-ON<br>Patients with PD who are included in the Personalized Parkinson Project. N = 360. Available data will be used. There will be no further data collection in this group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mid-term disease progression in terms of overall motor symptoms | Change in Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, measured in off state. This scale assesses 18 motor symptoms (33 items) that are specific for Parkinson's disease. Item scores range from 0 to 4 and are summed, resulting in a total score ranging from 0 to 132, with higher scores representing worse outcomes. | Baseline and 2 years | 
| Mid-term disease progression in terms of bradykinesia and rigidity | Change in Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, measured in off state. This scale assesses 18 motor symptoms (33 items) that are specific for Parkinson's disease. Item scores range from 0 to 4. 17 items assessing bradykinesia and rigidity and are summed, resulting in a total score ranging from 0 to 68, with higher scores representing worse outcomes. | Baseline and 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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magnetic resonance imaging, motor assessment, symptom progression, action selection, compensation, basal ganglia