Role of the Striatal Cholinergic System in the Pathophysiology of Dystonia

Study Overview
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Brief Summary
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Dystonia is defined as a syndrome of sustained muscle contractions resulting in repetitive movements and abnormal postures. DYT1 is the most common form of genetic dystonia, but the link between genomic mutations and phenotypic expression remains largely unknown. Furthermore, secondary forms of dystonia have highlighted the role of the basal ganglia, particularly the putamen in the pathophysiology of the disease. Experimental results in a genetic model of dystonia in rodents suggest that cholinergic inter-neurons (ACh-I) of the putamen play a critical role in the pathological process of plasticity in the cortico-striatal synapse. However, these results have not been demonstrated in humans.

Detailed Description
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The purpose of this study is to demonstrate that the phenotype of dystonia is associated with the degree of striatal ACh-I alterations. In this molecular imaging study, the investigators will directly test this hypothesis using a PET radiotracer of the vesicular acetylcholine transporter (VAT). Their goal is to explore the relationships between cholinergic dysfunction and clinical disease expression and the associated morphological and functional alterations. The experimental protocol will also include multimodal MRI, MRI diffusion tensor (to study the microscopic structure of white matter) and functional MRI of the resting state (to study the functional organization of cerebral cholinergic networks at rest).

Conditions
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Dystonia

Intervention / Treatment
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* Radiation: PET (Positron Emission Tomography) imaging
* Other: MRI : Magnetic Resonance Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Man or woman 18 to 75 years, with health insurance European health insurance card (for resident patients in EU), insurance by bilateral social security agreement signed between his country and France (for resident patients outside the EU) Diagnosis of dystonia DYT1 confirmed by molecular biology (TORSINE- A gene mutation) Patient who stopped his anticholinergic treatment 48 hours before imaging Exclusion Criteria: Patients who underwent surgery for deep brain stimulation or under cholinergic treatment. Presence of a counter-indication for MRI Presence of a counter-indication for TEP Scan with [18F]-FEOBV Woman premenopausal without effective ongoing contraception (intrauterine device or combined hormonal) Patient who underwent a PET examination in the previous month Presence of any health problem preventing travel to the imaging service of the University Hospital Being under the legal guardianship of another person or being unable to provide consent to participate Pregnant or breastfeeding woman

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Health Services Research
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cholinergic striatal imaging<br>Cholinergic striatal imaging (IRM and TEP) to compare the intensity of the binding of cholinergic tracer | Radiation: PET (Positron Emission Tomography) imaging<br>* Molecular imaging using a PET radiotracer of the vesicular acetylcholine transporter.<br>Other: MRI : Magnetic Resonance Imaging<br>* Multimodal MRI, MRI diffusion tensor (to study the microscopic structure of white matter) and functional MRI of the resting state (to study the functional organization of cerebral cholinergic networks at rest).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Binding potential | Image (PET) of the intensity of fixation of Cholinergic tracer (Binding potential) | Inclusion (V0) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dystonia, Binding potential, FEOBV