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

Official title

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

Overview

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

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.

Interventions

• Diagnostic test Clinical assessment
  The clinical assessment consists on behavioural and motor evaluations to determine the characteristics of the population
• Diagnostic test Pain characteristics assessment
  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
• Diagnostic test MRI
  The MRI examination allows anatomical imaging, diffusion imaging and functional imaging to measure specific markers
• Diagnostic test Thermotest
  The thermotest is performed to assess the pain perception threshold
• Diagnostic test UPDRS-III Scale
  The UPDRS-III scale allows to asses motor functionality of PD patients
• Diagnostic test [18F]-MPPF PET scan
  The PET scan after injection of \[18F\]-MPPF at a dose of 200 Megabecquerel/kg +/-10% allows in vivo imaging of 5HT1A receptors

Primary outcome measures

• Distribution volume ratio of [18F]-MPPF [Time frame: during the procedure]

Secondary outcome measures (8)

• Pain intensity and [18F]-MPPF uptake [Time frame: during the procedure]
• Functional impairment and [18F]-MPPF uptake [Time frame: during the procedure]
• Pain perception thresholds and [18F]-MPPF uptake [Time frame: during the procedure]
• Macrostructural markers [Time frame: during the procedure]
• Central pain characteristics measured by Visual Analog Score for pain (VAS) and brain macrostructural markers [Time frame: during the procedure]
• 5HT1A-receptors specific radioligand binding and functional networks connectivity [Time frame: during the procedure]
• Behavioral population characteristics obtained with the Hospital Anxiety and Depression scale (HAD) [Time frame: during the procedure]
• Motor population characteristics obtained with the Movement Disorders Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) [Time frame: during the procedure]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 1 center

• Centre Hospitalier Universitaire de Toulouse — Toulouse

Publications

• Aznavour N, Zimmer L. [18F]MPPF as a tool for the in vivo imaging of 5-HT1A receptors in animal and human brain. Neuropharmacology. 2007 Mar;52(3):695-707. doi: 10.1016/j.neuropharm.2006.09.023. Epub 2006 Nov 13. PMID 17101155
• Boussac M, Arbus C, Dupouy J, Harroch E, Rousseau V, Ory-Magne F, Rascol O, Moreau C, Maltete D, Rouaud T, Meyer M, Houvenaghel JF, Marse C, Tranchant C, Hainque E, Jarraya B, Ansquer S, Bonnet M, Belamri L, Tir M, Marques AR, Danaila T, Eusebio A, Devos D, Brefel-Courbon C; PREDI-STIM study group*. Personality Dimensions Are Associated with Quality of Life in Fluctuating Parkinson's Disease Patie PMID 32444557
• Boussac M, Arbus C, Dupouy J, Harroch E, Rousseau V, Croiset A, Ory-Magne F, Rascol O, Moreau C, Rolland AS, Maltete D, Rouaud T, Meyer M, Drapier S, Giordana B, Anheim M, Hainque E, Jarraya B, Benatru I, Auzou N, Belamri L, Tir M, Marques AR, Thobois S, Eusebio A, Corvol JC, Devos D, Brefel-Courbon C; PREDI-STIM study group. Personality dimensions of patients can change during the course of parki PMID 33411732
• Boussac M, Arbus C, Klinger H, Eusebio A, Hainque E, Corvol JC, Rascol O, Rousseau V, Harroch E, d'Apollonia CS, Croiset A, Ory-Magne F, De Barros A, Fabbri M, Moreau C, Rolland AS, Benatru I, Anheim M, Marques AR, Maltete D, Drapier S, Jarraya B, Hubsch C, Guehl D, Meyer M, Rouaud T, Giordana B, Tir M, Devos D, Brefel-Courbon C; PREDISTIM study group. Personality Related to Quality-of-Life Improv PMID 34897100
• Brefel-Courbon C, Grolleau S, Thalamas C, Bourrel R, Allaria-Lapierre V, Loi R, Micallef-Roll J, Lapeyre-Mestre M. Comparison of chronic analgesic drugs prevalence in Parkinson's disease, other chronic diseases and the general population. Pain. 2009 Jan;141(1-2):14-8. doi: 10.1016/j.pain.2008.04.026. Epub 2008 Dec 4. PMID 19062167
• Brefel-Courbon C, Ory-Magne F, Thalamas C, Payoux P, Rascol O. Nociceptive brain activation in patients with neuropathic pain related to Parkinson's disease. Parkinsonism Relat Disord. 2013 May;19(5):548-52. doi: 10.1016/j.parkreldis.2013.02.003. Epub 2013 Feb 23. PMID 23462484
• Brefel-Courbon C, Payoux P, Thalamas C, Ory F, Quelven I, Chollet F, Montastruc JL, Rascol O. Effect of levodopa on pain threshold in Parkinson's disease: a clinical and positron emission tomography study. Mov Disord. 2005 Dec;20(12):1557-63. doi: 10.1002/mds.20629. PMID 16078219
• Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009 May;8(5):464-74. doi: 10.1016/S1474-4422(09)70068-7. PMID 19375664

Identifiers

NCT: NCT06008704 · RC31/21/0566 · 2022-501123-24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗