Early Biomarkers of Neurodegeneration in Parkinsonian Syndromes

Study Overview
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Brief Summary
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Parkinson's disease (PD) is the most common degenerative Parkinson's syndrome and is linked, among other things, to the excessive accumulation of an abnormally aggregating protein, alpha-synuclein. Progressive Supranuclear Palsy (PSP) is another Parkinson's syndrome, linked, among other things, to the abnormal accumulation of the protein Tau, and expressed clinically by falls, early cognitive impairment and oculomotor disorders, not present in PD. The onset of these disorders is so gradual that differential diagnosis between the two diseases is only possible at a late stage, on average 3 to 5 years after the onset of symptoms. To date, there is a lack of validated imaging biomarkers for diagnosing and monitoring PD and PSP. There is therefore an urgent need for the development of robust biomarkers capable of detecting neurodegeneration at an early stage, in order to aid differential diagnosis as soon as symptoms appear, and to potentially enable these patients to be included in specific therapeutic trials (as these diseases are pathophysiologically different) with potential neuroprotective effects. The development of cutting-edge technologies such as 7T MRI, combined with optimized image processing methods, now enable non-invasive in vivo exploration and analysis of these small structures in terms of ion homeostasis (sodium), microstructure (volumetry, amount of iron and neuromelanin) and connectivity.

Official Title
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Early Biomarkers of Neurodegeneration in Parkinsonian Syndromes: Analysis in Very High Field (7T) Brain MRI.

Conditions
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Parkinson Disease, Progressive Supranuclear Palsy

Intervention / Treatment
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* Procedure: 7 Tesla MRI


Participation Criteria
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Eligibility Criteria
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For Parkinson Disease: Inclusion Criteria: Patients aged between 40 and 80 Fulfilling the diagnostic criteria for MPI (Postuma et al., 2015) First motor symptom (rigidity, akinesia, tremor) less than 36 months ago Patient entitled to or affiliated with a social security scheme Patients who understood, completed and signed the consent form for study participation. Exclusion Criteria: Patient with a neurological disease of the central nervous system other than those studied (including history of stroke, repeated head trauma, documented encephalitis). In case of doubt, this criterion will be left to the discretion of the principal investigator, who is a neurologist. Contraindications to 7T MRI: presence of an ocular metallic foreign body (accidental shrapnel or other), pacemaker (cardiac simulator) or neurostimulator (pain treatment), cochlear implants or any implanted electronic medical equipment in general, metallic heart valve, vascular clips implanted on a cranial aneurysm. Claustrophobia or any other condition preventing full MRI. Montreal Cognitive Assessment (MOCA) test < 25/30 Pregnant or breast-feeding woman or protected person (under guardianship, curatorship, deprived of liberty). For Progressive Supra-nuclear Palsy: Inclusion criteria: Patients aged 40 to 80 Fulfilling the diagnostic criteria for soPSP (Höglinger et al., 2017) : First motor symptom (rigidity, akinesia, tremor) or falls or cognitive impairment (frontal syndrome or language disorder or cortico-basal syndrome) occurring less than 36 months ago Patients benefiting from or affiliated to a social security scheme Patients who have understood, completed and signed the study participation consent form Exclusion criteria: Patient with a neurological disease of the central nervous system other than those studied (including history of stroke, repeated head trauma, documented encephalitis). In case of doubt, this criterion will be left to the discretion of the principal investigator, who is a neurologist. Contraindications to 7T MRI: presence of an ocular metallic foreign body (accidental shrapnel or other), pacemaker (cardiac simulator) or neurostimulator (pain treatment), cochlear implants or any implanted electronic medical equipment in general, metallic heart valve, vascular clips implanted on a cranial aneurysm. Claustrophobia or any other condition preventing MRI. Pregnant or breast-feeding woman or protected person (under guardianship, curatorship, deprived of liberty). For Control group: Inclusion criteria: Subjects aged between 40 and 80 Subjects benefiting from or affiliated with a social security plan Subjects who have understood, completed and signed the study participation consent form Exclusion criteria: Subjects with a known history of neurological disease of the central nervous system (e.g. Parkinson's disease, Alzheimer's, stroke, brain tumor, multiple sclerosis, amyotrophic lateral sclerosis, repeated head trauma, documented encephalitis, etc.). In case of doubt, this criterion will be left to the discretion of the principal investigator, who is a neurologist. Contraindications to 7T MRI: presence of an ocular metallic foreign body (accidental shrapnel or other), pacemaker (cardiac simulator) or neurostimulator (pain treatment), cochlear implants or any implanted electronic medical equipment in general, metallic heart valve, vascular clips implanted on a cranial aneurysm. Claustrophobia or any other condition preventing MRI. Pregnant or breast-feeding women or protected persons (under guardianship, curatorship, deprived of liberty).

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patients with Parkinson Disease<br> | Procedure: 7 Tesla MRI<br>* Patients will have a 7T MRI and questionnaires<br>* Other names: Questionnaires;|
| Other: Patients with Progressive Supranuclear Palsy<br> | Procedure: 7 Tesla MRI<br>* Patients will have a 7T MRI and questionnaires<br>* Other names: Questionnaires;|
| Other: Healthy volunteers<br> | Procedure: 7 Tesla MRI<br>* Patients will have a 7T MRI and questionnaires<br>* Other names: Questionnaires;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sodium accumulation between Parkinson disease patients and Progressive Supranuclear Palsy | Comparison of intracerebral sodium accumulation measured by very high-field (7T) cerebral MRI between subjects with Idiopathic Parkinson's Disease and subjects with early-stage Progressive Supra-Nuclear Palsy | Between month 0 and month 3 after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sodium accumulation between Parkinson disease patients (MPI) and control subjects | Comparison of intracerebral sodium accumulation between subjects with early-stage Parkinson's Disease (PD) and control subjects. | Between month 0 and month 3 after inclusion | 
| Sodium accumulation between Progressive Supra-nuclear patients (soPSP) and control subjects | Comparison of intracerebral sodium accumulation between subjects with soPSP and control subjects. | Between month 0 and month 3 after inclusion | 
| Brain atrophy between MPI and soPSP patients | 3D mapping of brain atrophy differences measured in Voxel Based Morphometry (VBM), value in cm3 | Between month 0 and month 3 after inclusion | 
| Brain atrophy between MPI and control group | 3D mapping of brain atrophy differences measured in Voxel Based Morphometry (VBM), value in cm3 | Between month 0 and month 3 after inclusion | 
| Brain atrophy between soPSP and control group | 3D mapping of brain atrophy differences measured in Voxel Based Morphometry (VBM), value in cm3 | Between month 0 and month 3 after inclusion | 
| Iron accumulation between soPSP and control group | 3D mapping of iron accumulation differences measured by Quantitative Susceptibility Mapping (QSM), values in ppm | Between month 0 and month 3 after inclusion | 
| Iron accumulation between MPI and soPSP patients | 3D mapping of iron accumulation differences measured by Quantitative Susceptibility Mapping (QSM), values in ppm | Between month 0 and month 3 after inclusion | 
| Iron accumulation between soPSP patients and control group | 3D mapping of iron accumulation differences measured by Quantitative Susceptibility Mapping (QSM), values in ppm | Between month 0 and month 3 after inclusion | 
| Accumulation of neuromelanin between MPI and soPSP patients | 3D mapping of neuromelanin differences (signal/MT ratio) | Between month 0 and month 3 after inclusion | 
| Accumulation of neuromelanin between MPI patients and control group | 3D mapping of neuromelanin differences (signal/MT ratio) | Between month 0 and month 3 after inclusion | 
| Accumulation of neuromelanin between soPSP patients and control group | 3D mapping of neuromelanin differences (signal/MT ratio) | Between month 0 and month 3 after inclusion | 
| Movement of water molecules between MPI and soPSP patients | 3D mapping of differences in mean diffusivity (DM), values in mm2/s | Between month 0 and month 3 after inclusion | 
| Movement of water molecules between MPI patients and control group | 3D mapping of differences in mean diffusivity (DM), values in mm2/s | Between month 0 and month 3 after inclusion | 
| Movement of water molecules between soPSP patients and control group | 3D mapping of differences in mean diffusivity (DM), values in mm2/s | Between month 0 and month 3 after inclusion | 
| Structural connectivity between MPI and soPSP patients | 3D mapping of anisotropy fraction (AF) differences, values between 0 and 1 | Between month 0 and month 3 after inclusion | 
| Structural connectivity between soPSP patients and control group | 3D mapping of anisotropy fraction (AF) differences, values between 0 and 1 | Between month 0 and month 3 after inclusion | 
| Structural connectivity between MPI patients and control group | 3D mapping of anisotropy fraction (AF) differences, values between 0 and 1 | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and age | Correlation between sodium concentration (mmol/L) and age | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and sex | Correlation between sodium concentration (mmol/L) and sex | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and laterality | Correlation between sodium concentration (mmol/L) and laterality | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and sex | Measure by Voxel Based Morphometry (VBM) in cm3 and sex | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and age | Measure by Voxel Based Morphometry (VBM) in cm3 and age | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and laterality | Measure by Voxel Based Morphometry (VBM) in cm3 and laterality | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and age | Measure by Quantitative Susceptibility Mapping (QSM) in ppm and age | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and sex | Measure by Quantitative Susceptibility Mapping (QSM) in ppm and sex | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and laterality | Measure by Quantitative Susceptibility Mapping (QSM) in ppm and laterality | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and age | Correlation between ratio of signal/MT and age | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and sex | Correlation between ratio of signal/MT and sex | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and laterality | Correlation between ratio of signal/MT and laterality | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and age | Correlation between anisotropy fraction (AF) and age | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and sex | Correlation between anisotropy fraction (AF) and sex | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and laterality | Correlation between anisotropy fraction (AF) and laterality | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and duration of disease progression | Correlation between anisotropy fraction (AF) and duration of the disease | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and duration of disease progression | Correlation between ratio of signal/MT and duration of the disease | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and duration of disease progression | Measure by Quantitative Susceptibility Mapping (QSM) in ppm and duration of the disease | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and duration of disease progression | Measure by Voxel Based Morphometry (VBM) in cm3 and duration of disease progression | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and duration of disease progression | Correlation between sodium concentration (mmol/L) and duration of disease | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and sense of smell | Correlation between sodium concentration (mmol/L) and sense of smell (questionnaire) | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and sense of smell | Measure by Voxel Based Morphometry (VBM) in cm3 and sense of smell (questionnaire) | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and sense of smell | Measure by Quantitative Susceptibility Mapping (QSM) in ppm and sense of smell (questionnaire) | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and sense of smell | Correlation between ratio of signal/MT and sense of smell (questionnaire) | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and sense of smell | Correlation between anisotropy fraction (AF) and sense of smell (questionnaire) | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and severity of disease | Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and quality of life | Schwab & England score, 0 to 100%, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and quality of life | Schwab & England score, 0 to 100%, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and quality of life | Schwab & England score, 0 to 100%, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and quality of life | Schwab & England score, 0 to 100%, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and quality of life | Correlation between Schwab & England score (Schwab & England score, 0 to 100%, 0 means better outcome) and sodium concentration (mmol/L) | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and severity of disease | Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and severity of disease | Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and severity of disease | Unified Parkinson's Disease Rating Scale (UPDRS), 0 to 199, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and Hospital Anxiety and Depression | HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and Hospital Anxiety and Depression | HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and Hospital Anxiety and Depression | HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and Hospital Anxiety and Depression | HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and Hospital Anxiety and Depression | HAD Echelle (Hospital Anxiety and Depression), 0 to 3, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and Sleep Behavior Disorder | REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and Sleep Behavior Disorder | REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and Sleep Behavior Disorder | REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and Sleep Behavior Disorder | REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and Sleep Behavior Disorder | REM Sleep Behavior Disorder Screening Questionnaire, 0 to 13, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and motivation scale | Starkstein motivation scale, 0 to 42, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and motivation scale | Starkstein motivation scale, 0 to 42, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and motivation scale | Starkstein motivation scale, 0 to 42, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and motivation scale | Starkstein motivation scale, 0 to 42, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and motivation scale | Starkstein motivation scale, 0 to 42, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and non-motor fluctuations | Number of non-motor fluctuations | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and non-motor fluctuations | Number of non-motor fluctuations | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and non-motor fluctuations | Number of non-motor fluctuations | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and non-motor fluctuations | Number of non-motor fluctuations | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and non-motor fluctuations | Number of non-motor fluctuations | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and cognitives functions | Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and cognitives functions | Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and cognitives functions | Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and cognitives functions | Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and cognitives functions | Score Montreal Cognitive Assessment (MoCA), 0 to 30, 0 means worse outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and quality of life | Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and quality of life | Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and quality of life | Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and quality of life | Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and quality of life | Parkinson's Disease Questionnaire (PDQ 39), 0 to 156, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and hypotension | Blood pressure test for orthostatic hypotension | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and hypotension | Blood pressure test for orthostatic hypotension | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and hypotension | Blood pressure test for orthostatic hypotension | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and hypotension | Blood pressure test for orthostatic hypotension | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and hypotension | Blood pressure test for orthostatic hypotension | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between structural connectivity and hallucinations | Miami Questionnaire, 0 to 70, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between accumulation of neuromelanin and hallucinations | Miami Questionnaire, 0 to 70, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between iron accumulation and hallucinations | Miami Questionnaire, 0 to 70, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between brain atrophy and hallucinations | Miami Questionnaire, 0 to 70, 0 means better outcome | Between month 0 and month 3 after inclusion | 
| Measurement of the dependency between sodium accumulation and hallucinations | Miami Questionnaire, 0 to 70, 0 means better outcome | Between month 0 and month 3 after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, Parkinson disease, progressive supranuclear palsy, biomarkers