Pain in Parkinson's Disease: Exploration of the Serotonin System in Positron Emission Tomography (PET [18F]-MPPF)

Study Overview
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Brief Summary
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This project will explore the involvement of the serotonin system in the pathophysiology of PD-related central pain. Thus, the serotonin system will be evaluated in PD patients with and without central pain who will benefit from brain positron emission tomography (PET) allowing in vivo imaging of 5HT1A receptors and multimodal brain MRI including morphometric imaging and functional connectivity (resting state acquisition).

Detailed Description
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The prevalence of chronic pain in PD can be estimated at 60-80% from several epidemiological studies. Both semiological and pathophysiological classification proposes specific and non-specific pain in PD. While non-specific pain is not directly related to PD but may be aggravated by the disease, specific pain is a direct result of the disease with dystonic pain characterized by painful cramps in relation to motor symptoms and non-systematic central pain such as burning, paresthesia, compression (central parkinsonian pain). A case-control study reported that cramp-like pain and central pain were three times more frequent in parkinsonian patients than in the general population. Pathophysiologically, several studies suggest an abnormal nociceptive integration process in PD patients. Previous studies have indicated that the nociceptive signal is amplified along the pain transmission pathways. This could be related to increased facilitation through central sensitization of pain pathways or decreased inhibition (reduced activity of descending inhibitory control systems). Several recent studies suggest that the noradrenergic and/or serotonergic systems may be involved in the pathophysiology of PD-related pain. Therefore, this project will explore the involvement of the serotonergic system in the pathophysiology of pain using brain neuroimaging in PD patients with central pain. The present study hypothesize that the binding of the radiotracer [18F]-MPPF, allowing in vivo imaging of 5HT1A receptors, will be reduced in PD patients with central pain compared to non-painful PD patients at the level of the median raphe, but also at the level of several brain structures involved in the pain matrix such as the insula, the anterior and posterior cingulate cortex, the orbitofrontal cortex, etc. A correlation between the clinical parameters of pain and the brain structures in which MRP binding is decreased should make it possible to confirm the link between these serotonin binding anomalies and pain. Finally, the morphological and functional MRI study should make it possible to identify structural and functional abnormalities within the pain networks in painful Parkinson's patients.

Official Title
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Pathophysiology of Pain in Parkinson's Disease: Exploration of the Serotonin System in Positron Emission Tomography (PET [18F]-MPPF)

Conditions
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Parkinson Disease

Intervention / Treatment
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* Diagnostic Test: Clinical assessment
* Diagnostic Test: Pain characteristics assessment
* Diagnostic Test: MRI
* Diagnostic Test: Thermotest
* Diagnostic Test: UPDRS-III Scale
* Diagnostic Test: [18F]-MPPF PET scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with PD defined according to United Kingdom Parkinson's Disease Brain Bank (UKPDSBB) criteria Patients with stable anti-parkinsonian treatment for at least 4 weeks prior to inclusion Patients with a Montreal Cognitive Assessment (MoCA) score > 25 Patients with a Hospital Anxiety and Depression Scale (HADS)-D score ≥ 11 Person affiliated or benefiting from a social security scheme. Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research). • For patients with pain Patients with PD-related central pain defined according to the criteria of Marques et al, 2019 Patients with chronic central pain (i.e. present for at least 3 months) Patients who have average pain over the previous month according to a VAS ≥ 4. • For patients without pain Patients who do not have pain defined as VAS ≤ 4, meaning that it does not interfere with daily activity. Exclusion Criteria: Patients treated with second line therapy Patients with a history of significant psychiatric pathology according to the investigator Patients treated with drugs interacting with 5HT1A receptors in the previous 4 weeks Patients with contraindication to MRI Patients refusing to be informed of an abnormality discovered during brain imaging Patients with dyskinesias judged by the investigator to be disabling for imaging. Patients under guardianship or other legal protection, deprived of their liberty by judicial or administrative decision Pregnant woman, breastfeeding woman

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: physio-pathological prospective open study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: PD patients with central chronic pain<br>Patients from both groups will receive the same interventions, the difference between groups is the eligibility criteria. In this arm only patients presenting central chronic pain will be included | Diagnostic Test: Clinical assessment<br>* The clinical assessment consists on behavioural and motor evaluations to determine the characteristics of the population<br>Diagnostic Test: Pain characteristics assessment<br>* The pain characteristics assessment will be made with a variety of scales and questionnaires which allow to identify the extent of central pain and functional impairment<br>Diagnostic Test: MRI<br>* The MRI examination allows anatomical imaging, diffusion imaging and functional imaging to measure specific markers<br>Diagnostic Test: Thermotest<br>* The thermotest is performed to assess the pain perception threshold<br>Diagnostic Test: UPDRS-III Scale<br>* The UPDRS-III scale allows to asses motor functionality of PD patients<br>Diagnostic Test: [18F]-MPPF PET scan<br>* The PET scan after injection of [18F]-MPPF at a dose of 200 Megabecquerel/kg +/-10% allows in vivo imaging of 5HT1A receptors<br>|
| Other: PD patients without pain<br>Patients from both groups will receive the same interventions, the difference between groups is the eligibility criteria. In this arm only patients without central chronic pain will be included | Diagnostic Test: Clinical assessment<br>* The clinical assessment consists on behavioural and motor evaluations to determine the characteristics of the population<br>Diagnostic Test: Pain characteristics assessment<br>* The pain characteristics assessment will be made with a variety of scales and questionnaires which allow to identify the extent of central pain and functional impairment<br>Diagnostic Test: MRI<br>* The MRI examination allows anatomical imaging, diffusion imaging and functional imaging to measure specific markers<br>Diagnostic Test: Thermotest<br>* The thermotest is performed to assess the pain perception threshold<br>Diagnostic Test: UPDRS-III Scale<br>* The UPDRS-III scale allows to asses motor functionality of PD patients<br>Diagnostic Test: [18F]-MPPF PET scan<br>* The PET scan after injection of [18F]-MPPF at a dose of 200 Megabecquerel/kg +/-10% allows in vivo imaging of 5HT1A receptors<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution volume ratio of [18F]-MPPF | The MRP [18F]-MPPF marking the 5 HT1A receptors allows the in vivo visualization of serotonergic neurons and it's sensitive to extracellular variations of serotonin | during the procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity and [18F]-MPPF uptake | Correlation between [18F]-MPPF uptake and central pain intensity measured with the Visual Analog Score for pain (Scale from 0 to 10, 10 being the most fote intensity of pain) | during the procedure | 
| Functional impairment and [18F]-MPPF uptake | Correlation between [18F]-MPPF uptake and functional impairment, measured with the Primary Parkinsonian Pain Diagnostic Questionnaire . It is a 39-item self-questionnaire evaluating the motor and psychological quality of life of Parkinson's patients over the past month. Each question is rated from 0 (no disturbance) to 4 (maximum disturbance), and items are divided into 8 dimensions (mobility, activities of daily life, emotional well-being, psychological discomfort, social support, cognitive disorders, communication, physical discomfort). A score is calculte in percentage. The higher the score, the lower the quality of life in this dimension. It is a simple and fast scale of transfer, reliable and validated, sensitive to change. | during the procedure | 
| Pain perception thresholds and [18F]-MPPF uptake | Correlation between [18F]-MPPF uptake and pain perception thresholds, measured with the thermotest | during the procedure | 
| Macrostructural markers | Measurement of macrostructural markers obtained by MRI Macrostructural markers measured by T1 and T2 sequences: density of gray matter | during the procedure | 
| Central pain characteristics measured by Visual Analog Score for pain (VAS) and brain macrostructural markers | Correlation between brain macrostructural markers and central pain characteristics measured with the Visual Analog Score for pain (VAS) which consists of a 10cm line, with two end points representing 0 ('no pain') and 10 ('pain as bad as it could possibly be') | during the procedure | 
| 5HT1A-receptors specific radioligand binding and functional networks connectivity | Correlation between 5HT1A receptors specific radioligand binding and functional networks connectivity, obtained by IRM | during the procedure | 
| Behavioral population characteristics obtained with the Hospital Anxiety and Depression scale (HAD) | Mean of patient's behavioral characteristics score obtained with the Hospital Anxiety and Depression scale (HAD) which is scored between 0 meaning no impairment and 3 being severe impairment | during the procedure | 
| Motor population characteristics obtained with the Movement Disorders Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) | Mean of patient's motor characteristics score obtained with the Movement Disorders Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS), which score ranges from 0 to 260, with 0 indicating no disability and 260 indicating total disability | during the procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-related central pain, PET [18F] MPPF, serotoninergic system, multimodal imaging, pain threshold