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

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

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

IRCCS National Neurological Institute "C. Mondino" Foundation, Istituto Neurologico Mediterraneo Neuromed S. R. L, Azienda Ospedaliera Universitaria Policlinico "G. Martino"

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.

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)

patients will be evaluated by means of validated clinical scales Non-Motor Symptoms scale (min 0- 360 max , better clinical conditions has lower scores)

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).

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.

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

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

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

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