Understanding Alpha-Synuclein Spread in Parkinson's Disease Through Blood Biomarkers and Neuroimaging

ConditionsParkinson's Disease (PD)GBA1 Parkinson Disease REM Sleep Behavior Disorder (iRBD)

Trial statusNot yet recruiting

Trial phaseNot applicable

Trial typeInterventional

Biological sexAll

Age18+

SponsorUniversity of Pavia

About this trial

The project aims to investigate how abnormal accumulation of alpha synuclein and its interaction with tau influence brain function across the Parkinson's disease (PD) spectrum, with particular focus on individuals carrying GBA1 mutations. This interventional, monocentric, cross sectional study includes patients with PD, individuals with idiopathic REM sleep behavior disorder, and participants without PD.

All enrolled subjects will undergo clinical and neuropsychological assessments, blood based biomarker analyses related to neurodegeneration, synaptic and mitochondrial function, and multimodal brain MRI to evaluate brain structure, white matter integrity, and functional connectivity.

The study aims to:

* characterize the relationship between alpha synuclein/tau pathology and synaptic mitochondrial dysfunction; * identify biomarker and connectivity signatures across disease stages and genetic backgrounds; * integrate preclinical, clinical, biological, and imaging data to support the development of mechanistic models of alpha synuclein propagation.

In parallel, preclinical studies in GBA PD mouse models and wild type mice will be used to investigate how changes in PD-related pathology (alpha-synuclein and tau) relates to behavior, brain imaging alterations and mitochondrial, axonal and synaptic damage. Animal model will also aid the validation of a new PET tracer that targets alpha synuclein (i.e., \[¹⁸F\]Syntacasyn).

Together, human and preclinical studies are designed to provide a translational framework integrating molecular changes with brain network alterations and clinical heterogeneity in PD.

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

Diagnosis of PD according to MDS-PD criteria and, for the GBA-PD group, presence of heterozygous GBA mutations (with a balanced distribution of severe, risk, mild, and complex variants);

Disease duration between 3 and 7 years;

Disease stage according to Hoehn & Yahr ≤ 3;

Absence of mutations in other known genes associated with PD susceptibility;

Disqualifiers

Diagnosis of atypical and/or secondary parkinsonism;

Diagnosis of dementia according to DSM-5 criteria;

Presence of other neurological disorders and/or essential tremor;

Presence of systemic inflammatory or infectious diseases, autoimmune diseases, or malignant tumors at the time of enrollment.

Trial design

Design model

Parallel

Treatments tested in this trial

brain imaging
Diagnostic test
Participants will undergo a single brain MRI acquisition, including structural, diffusion-weighted, and resting-state functional MRI.
blood draw
Procedure/Surgery
Collection of a venous blood sample for biochemical analyses
Skin biopsy
Procedure/Surgery
A small punch skin biopsy (about 3-4 mm) will be performed under local anesthesia on a small sample of enrolled participants (n=10)

Treatment groups

160 Participants

are divided into 6 treatment groups

Treatment groups

See each treatment group below.

Group A: GBA-PDExperimental treatment 3 interventions

Group B: nonGBA-PDExperimental treatment 3 interventions

Group C: nonGBA-iRBDExperimental treatment 3 interventions

Group D: GBA-iRBDExperimental treatment 3 interventions

Group E: GBA-nonPDExperimental treatment 2 interventions

Group F: Healthy controlsExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

Concentration of alpha-synuclein levels in plasma

Quantification of levels of Total alpha-synuclein and 129P-alpha-synuclein (pg/ml) in neuronal-derived extracellular vesicles using ultrasensitive immunoassays (NULISA).

Time frame

Baseline visit

Concentration of tau levels in plasma

Quantification of total-tau and p-tau18 (pg/ml) in neuronal-derived extracellular vesicles using ultrasensitive immunoassays (NULISA).

Time frame

Baseline visit

Investigation of glucocerebrosidase activity in Peripheral Blood Mononuclear Cells

Glucocereborsidase activity will be estimated in Peripheral Blood Mononuclear Cells usign a flourimetry assay

Time frame

Baseline visit

Secondary outcomes

Assessment of mitochondrial damage in plasma

Quantification of circulating cell-free mitochondrial DNA (cf-mtDNA) in plasma, including total concentration and deletion fraction.

Time frame

Baseline visit

Plasma synaptic protein concentration

Quantification of SNAP25, STX1A, and VAMP2 in neuronal-derived extracellular vesiclesusing ultrasensitive immunoassay (NULISA)

Time frame

Baseline visit

Brain network connectivity in Parkinson's disease

We will exctract structural and functional connectivity information form MRI, resting-state functional MRI and diffusion weighted MRI. Connectivity metrics will include global and nodal efficiency, participation coefficient and indexes of withe matter tract integrity.

Time frame

Baseline visit

In vitro neuronal responses in hiPSC-derived dopaminergic neurons

In vitro neuronal responses will be assessed in dopaminergic neurons derived from human induced pluripotent stem cells (hiPSC), following exposure to alpha-synuclein and alpha-synuclein+tau.

Time frame

Baseline visit

Other outcomes

Comprehensive clinical and neuropsychological assessement

Time frame

Baseline visit

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

University of Pavia

Lead sponsor

Pavia IRCCS Mondino di Pavia

Collaborator

Source ClinicalTrials.gov

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