Genotypic Influences on Network Progression in Parkinson's Disease

Study Overview
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Brief Summary
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In this longitudinal study, the investigators will follow Parkinson's disease (PD) patients with and without glucocerebrosidase (GBA) mutations. The investigators hypothesize that the rate of increase in brain network activity over time (network progression rate) is faster in patients with GBA gene mutations.

Detailed Description
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Parkinson's disease (PD) patients with mutations in the glucocerebrosidase gene (GBA) tend to have a more aggressive disease course. GBA may therefore provide a target for disease modifying therapies in mutation carriers. Using positron emission tomography (PET) and magnetic resonance imaging (MRI) brain imaging to measure network progression rates in mutation carriers will allow for the assessment of the potential disease modifying effects of new anti-GBA therapies. The investigators will also determine whether magnetic resonance imaging (MRI) network methods, which are less invasive and more broadly available than positron emission tomography (PET), produce comparable network progression measurements in individual patients. These determinations will be critical for the design of clinical trials of new disease-modifying drugs.

Official Title
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Genotypic Influences on Network Progression in Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Genetic: DNA/GeneticTesting
* Radiation: FDG PET scan
* Other: MRI scan
* Other: Clinical and neuropsychological assessments


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PD made according to United Kingdom (UK) Parkinson's Disease Society Brain Bank Criteria Ability to provide written informed consent Age 40-75 Stable dose of antiparkinsonian medication for >1 month prior to study entry Exclusion Criteria: Subjects with pathogenic mutations in LRRK2 History of known causative factors such as encephalitis or neuroleptic treatment Patients with dementia (defined as Mini-Mental Status Exam score <24 or a Telephone Interview for Cognitive Status score <26) Atypical parkinsonian features including oculomotor abnormalities,incontinence, ataxia, sensory loss, or pyramidal signs Known structural brain lesions Patients with history of stroke, head injury, high intracranial pressure or severe headaches Psychiatric disorder, including a history of major depression in the past 36 months Pregnant or breastfeeding women (female subjects of child-bearing potential will be screened for pregnancy before imaging).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Parkinson's disease (PD) glucocerebrosidase (GBA) carriers<br>Parkinson's disease subjects with GBA mutation | Genetic: DNA/GeneticTesting<br>* Subjects will be tested for GBA and LRRK2 mutation status at baseline.<br>Radiation: FDG PET scan<br>* 18F-Fluoro-2-deoxy-glucose (FDG) PET scan is a nuclear medicine test that measures glucose metabolism (energy) in your brain at baseline and 18 months later.<br>Other: MRI scan<br>* Magnetic Resonance Imaging (MRI) is a noninvasive scan which produces detailed pictures of the brain using a magnetic field. In addition, a special type of MRI, called resting state functional MRI (rs-fMRI), will measure and map brain activity. Conducted at baseline and 18 months later.<br>Other: Clinical and neuropsychological assessments<br>* Investigator will evaluate subjects according to the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the standard clinical tool used to measure the severity and progression of PD. Neuropsychological evaluation will assess how one's brain functions (via pencil and paper testing), which indirectly yields information about the structural and functional integrity of the brain. Conducted at baseline and 18 months later.<br>|
| Parkinson's disease (PD) non glucocerebrosidase (GBA) carriers<br>Parkinson's disease subjects without GBA mutation | Genetic: DNA/GeneticTesting<br>* Subjects will be tested for GBA and LRRK2 mutation status at baseline.<br>Radiation: FDG PET scan<br>* 18F-Fluoro-2-deoxy-glucose (FDG) PET scan is a nuclear medicine test that measures glucose metabolism (energy) in your brain at baseline and 18 months later.<br>Other: MRI scan<br>* Magnetic Resonance Imaging (MRI) is a noninvasive scan which produces detailed pictures of the brain using a magnetic field. In addition, a special type of MRI, called resting state functional MRI (rs-fMRI), will measure and map brain activity. Conducted at baseline and 18 months later.<br>Other: Clinical and neuropsychological assessments<br>* Investigator will evaluate subjects according to the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the standard clinical tool used to measure the severity and progression of PD. Neuropsychological evaluation will assess how one's brain functions (via pencil and paper testing), which indirectly yields information about the structural and functional integrity of the brain. Conducted at baseline and 18 months later.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in PD related metabolic pattern expression | Changes in PD related and PD cognition related pattern expression in 18F-2-fluoro-2-deoxy-D-glucose (FDG) PET scans | Baseline and 18 months later | 
| Increase in PD related functional pattern expression | Changes in PD related and PD cognition related pattern expression in resting state functional magnetic resonance imaging (rs-fMRI) | Baseline and 18 months later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in motor function | Change in motor function assessed with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III (The sum score ranges between 0-132 points. Higher scores indicate more severe impairment) | Baseline and 18 months later | 
| Change in cognitive function | Change in cognitive function assessed with neuropsychological testing | Baseline and 18 months later | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GBA, genetic, progression, PD, glucocerebrosidase