Investigation of the Serotoninergic System in Multiple System Atrophy: a Positron Emission Tomography (PET) Study

Study Overview
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Brief Summary
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Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of the adult associated to a poor prognosis. MSA is clinically characterized by the association of extra-pyramidal, dysautonomic, cerebellar and pyramidal symptoms. Histological and biological studies have raised the hypothesis that, beside the well known dopamine deficiency, some of the symptoms could be related to a dysfunction in serotoninergic neurotransmission. Serotonin is involved in the modulation of several functions impaired in MSA, such as mood, motricity or sleep. The recent description of an association between loss of brainstem serotonin neurons and sudden death in patients with MSA reinforced the hypothesis of a critical role played by this neurotransmitter in the pathophysiology of this disease. Autoreceptors called 5-HT1a are strongly involved in the regulation of serotonin neurotransmission. During the last years several radio-ligands allowing in vivo PET quantification of 5-HT1a receptors, such as 18F-MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2''-piridinyl)-p-fluorobenzamide]methylpiperazine), were developed. Moreover, the investigators recently demonstrated the ability of this brain functional imaging method to investigate, in healthy volunteers, the functional properties of 5-HT1a autoreceptors through an evaluation of their desensitization after a single oral dose of fluoxetine.

Official Title
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Morphological and Functional Investigation of the Serotoninergic System in Multiple System Atrophy: a 18F-MPPF PET Study

Conditions
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Multiple System Atrophy

Intervention / Treatment
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* Radiation: PET (Positron Emission Tomography) Study
* Other: Brain MRI (magnetic resonance imaging)
* Drug: Fluoxétine / Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Multiple system atrophy (MSA) MSA possible or probable Male and female Age : 30 to 80 No cognitive impairment Unmodified treatment for 2 months Able to give informed consent Affiliated to social insurance Patients with idiopathic Parkinson's disease (IPD): Positive clinical criteria for IPD Male and female Age : 30 to 80 No cognitive impairment Unmodified treatment for 2 months Able to give informed consent Affiliated to social insurance Healthy controls: Absence of neuropsychiatric disorder Male and female Age : 30 to 80 Able to give informed consent Affiliated to social insurance Exclusion Criteria: Patients with Multiple system atrophy (MSA) Other Parkinsonian syndrome Dementia Recent intake (< 4 weeks or 8 weeks for fluoxetine) of medication acting on 5-HT1a receptors History of major depression Contraindication to brain MRI Contraindication to PET Patients with idiopathic Parkinson's disease Other Parkinsonian syndrome Dementia Recent intake (< 4 weeks or 8 weeks for fluoxetine) of medication acting on 5-HT1a receptors History of major depression Contraindication to brain MRI Contraindication to PET Healthy controls: Patient having a neuropsychiatric disease Recent intake (< 4 weeks or 8 weeks for fluoxetine) of medication acting on 5-HT1a receptors History of major depression Contraindication to brain MRI Contraindication to PET

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 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 |
| --- | --- |
| Multiple system atrophy<br> | Radiation: PET (Positron Emission Tomography) Study<br>* 5-HT1a auto-receptors will be visualized in vivo using 18F-MPPF PET study. Two PET studies will be performed, one after the intake of a single oral dose of fluoxetine and the other after placebo. The order of fluoxetine and placebo intake will be randomly assigned.<br>Other: Brain MRI (magnetic resonance imaging)<br>* A brain MRI (magnetic resonance imaging)will be performed the day of the first PET study.<br>Drug: Fluoxétine / Placebo<br>* The two PET studies will be performed, one after the intake of a single oral dose of fluoxetine and the other after placebo. The order of fluoxetine and placebo intake will be randomly assigned.<br>|
| Idiopathic Parkinson Disease<br> | Radiation: PET (Positron Emission Tomography) Study<br>* 5-HT1a auto-receptors will be visualized in vivo using 18F-MPPF PET study. Two PET studies will be performed, one after the intake of a single oral dose of fluoxetine and the other after placebo. The order of fluoxetine and placebo intake will be randomly assigned.<br>Other: Brain MRI (magnetic resonance imaging)<br>* A brain MRI (magnetic resonance imaging)will be performed the day of the first PET study.<br>Drug: Fluoxétine / Placebo<br>* The two PET studies will be performed, one after the intake of a single oral dose of fluoxetine and the other after placebo. The order of fluoxetine and placebo intake will be randomly assigned.<br>|
| Volunteers without neuropsychiatric disorder (Control)<br> | Radiation: PET (Positron Emission Tomography) Study<br>* 5-HT1a auto-receptors will be visualized in vivo using 18F-MPPF PET study. Two PET studies will be performed, one after the intake of a single oral dose of fluoxetine and the other after placebo. The order of fluoxetine and placebo intake will be randomly assigned.<br>Other: Brain MRI (magnetic resonance imaging)<br>* A brain MRI (magnetic resonance imaging)will be performed the day of the first PET study.<br>Drug: Fluoxétine / Placebo<br>* The two PET studies will be performed, one after the intake of a single oral dose of fluoxetine and the other after placebo. The order of fluoxetine and placebo intake will be randomly assigned.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 18F-MPPF binding potential - Biding potential (BP) under placebo in the raphe nucleus | Amount of 5-HT1a autoreceptors (evaluated by measurement of 18F-MPPF binding potential) after intake of placebo in the raphe nucleus. | Second visit (day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 18F-MPPF binding potential - Biding potential (BP) in other brain areas | Amount of 5-HT1a autoreceptors (evaluated by measurement of 18F-MPPF binding potential) in other brain areas (brainstem, hippocampus, etc.) | Second visit (day 1) | 
| Clinical parameters (motor handicap, orthostatic hypotension, quality of life, sleep, pain, tiredness) |  | Second visit (day 1) | 
| 18F-MPPF binding potential - Biding potential (BP) under placebo in other brain areas | Amount of 5-HT1a autoreceptors (evaluated by measurement of 18F-MPPF binding potential) after intake of placebo in other brain areas (brainstem, hippocampus, etc.). | Third visit (day 30) | 
| 18F-MPPF binding potential - BP under fluoxetine in all brain areas | Amount of 5-HT1a autoreceptors (evaluated by measurement of 18F-MPPF binding potential - BP) after intake of fluoxetine in all brain areas. | Third visit (day 30) | 
| Clinical parameters (motor handicap, orthostatic hypotension, quality of life, sleep, pain, tiredness) |  | Third visit (day 30) |