Clinical, Molecular and Electrophysiological Profiling of Parkinson's Disease: the Role of Non-pharmacological Therapies

Study Overview
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Brief Summary
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In Parkinson's disease (PD), direct evidence linking inflammation to the harmful activities of alpha-synuclein (a-syn) aggregates, the disease onset, and its progression is still lacking. This translational project aims to reveal the causal relationship between a-syn and inflammation. The investigators will also investigate the mechanisms underlying the beneficial effects of two non-pharmacological approaches, motor exercise and neuromodulation, with particular focus on neuroinflammation and brain-derived neurotrophic factor (BDNF) production. the investigators will investigate the molecular pathways and synaptic alterations underlying disease progression. This will be paralleled by a clinical study, in which clinical assessment will be associated with cerebrospinal fluid (CSF) and blood neurodegeneration and inflammatory biomarkers measures. Then, the investigators will test the hypothesis that intensive exercise and neuromodulation may reduce neuroinflammation and a-syn spreading via the activation of BDNF-related pathways.

Official Title
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Clinical, Molecular and Electrophysiological Profiling of Parkinson's Disease: the Role of Non-pharmacological Therapies

Conditions
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Parkinson Disease

Intervention / Treatment
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* Other: physical activity
* Other: iTBS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: clinically established diagnosis of PD according to the Movement Disorders Society (MDS) diagnostic criteria Hoehn & Yahr (H&Y) stage between 1 and 3 Exclusion Criteria: Pregnancy Oncological or autoimmune comorbidities

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Biomarkers<br> | |
| Active Comparator: physical activity<br> | Other: physical activity<br>* treadmill running 3 times weekly<br>|
| No Intervention: sedentary<br> | |
| Active Comparator: iTBS active<br> | Other: iTBS<br>* repetitive TMS stimulation 5 days weekly for two weeks<br>|
| Sham Comparator: iTBS sham<br> | Other: iTBS<br>* repetitive TMS stimulation 5 days weekly for two weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CLINICAL PROFILING OF PD PATIENTS (n=400) | patients will be evaluated by means of validated clinical scales Movement disorders society-unified Parkinson's Disease Rating Scale (min 0- max 260, better clinical conditions has lower scores) | at enrolling | 
| CLINICAL PROFILING OF PD PATIENTS (n=400) | patients will be evaluated by means of validated clinical scales Non-Motor Symptoms scale (min 0- 360 max , better clinical conditions has lower scores) | at enrolling | 
| MOLECULAR PROFILING OF PD PATIENTS (n=400) | Biomarkers related to axonal damage (total tau (t-Tau), neurofilament light chain, (NfL), and phosphorylated neurofilament heavy chain, (p-NfH), synaptic dysfunction (a-synuclein (a-syn) and neurogranin, (Ng)), neuroinflammation (soluble triggering receptor expressed on myeloid cells 2, sTREM2, and chitinase-3- like protein 1, YKL-40) will be analysed in cerebrospinal fluid (CSF) and blood samples and extracellular vesicles (EVs) (UO1, UO2) (for all the biomarkers, ng/ml). | at enrolling | 
| ELECTROPHYSIOLOGICAL PROFILING OF PD PATIENTS (n=400) | Motor evoked potentials (MEPs) from the First Digital Interosseus muscle of the most affected hand of each patient, a brief pattern of iTBS will be applied to promote enhancement of cortical excitability. MEPs size will be then assessed again using single-pulse TMS. | at enrolling | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UPDRS CHANGES AFTER NON-PHARMACOLOGICAL INTERVENTIONS (n=240) CLINICAL PROFILING OF PD PATIENTS (n=400) | patients will be evaluated by means of validated clinical scales, Movement disorders society- Unified Parkinson's disease rating scale, (min 0- 260 max , better clinical conditions has lower scores) | at the end of the non-pharmacological intervention (2 weeks for TMS branches, 3 months for physical activity branches) and 3 and 6 months after | 
| NMSS CHANGES AFTER NON-PHARMACOLOGICAL INTERVENTIONS (n=240) CLINICAL PROFILING OF PD PATIENTS (n=400) | patients will be evaluated by means of validated clinical scales Non-Motor Symptoms Scale (min 0- 360 max , better clinical conditions has lower scores) | at the end of the non-pharmacological intervention (2 weeks for TMS branches, 3 months for physical activity branches) and 3 and 6 months after | 
| MOLECULAR CHANGES AFTER NON-PHARMACOLOGICAL INTERVENTIONS (n=240) | Biomarkers related to axonal damage (total tau (t-Tau), neurofilament light chain, (NfL), and phosphorylated neurofilament heavy chain, (p-NfH), synaptic dysfunction (a-synuclein (a-syn) and neurogranin, (Ng)), neuroinflammation (soluble triggering receptor expressed on myeloid cells 2, sTREM2, and chitinase-3- like protein 1, YKL-40) will be analysed in cerebrospinal fluid (CSF) and blood samples and extracellular vesicles (EVs) (UO1, UO2) (for all the biomarkers, ng/ml). | at the end of the non-pharmacological intervention (2 weeks for TMS branches, 3 months for physical activity branches) and 3 and 6 months after | 
| ELECTROPHYSIOLOGICAL CHANGES AFTER NON-PHARMACOLOGICAL INTERVENTIONS (n=240) | Motor evoked potentials (MEPs) from the FDI muscle of the most affected hand of each patient, a brief pattern of iTBS will be applied to promote enhancement of cortical excitability. MEPs size will be then assessed again using single-pulse TMS. | at the end of the non-pharmacological intervention (2 weeks for TMS branches, 3 months for physical activity branches) and 3 and 6 months after |