NCT06803784

Discovery and Validation of Protein Structural Complexes in Circulating Biofluids As Novel Biomarkers for Early Diagnosis, Prognosis and Therapeutic Management of Patients Affected by Neurodegenerative Disorders

• Status: Recruiting
• Phase: —
• Study type: Observational
• Enrollment: 110 (estimated)
• Sponsor: Neuromed IRCCS · Academic / Other
• Sex: All
• Age: 20 Years
• Healthy volunteers: Accepted

Summary

Neurodegenerative disorders (NDDs), such as Parkinson¿s disease (PD), Alzheimer¿s disease (AD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are characterized by aggregation and intracellular accumulation of misfolded proteins, which are believed to play a key role in synaptic dysfunction and neuronal death. Protein structural complexes in biofluids have been proposed to mirror pathological conditions suggesting their use as biomarkers for NDDs characterized by protein aggregation. In this framework, we plan to: i) collect a large cohort of NDD and prodromal patients and healthy subjects using standardized clinical and genetics procedures; ii) apply a novel method based on genomics, proteomics and bioinformatic analysis to map protein complexes in biofluids; iii) identify novel circulating biomarkers and correlate them to genetic profiling and disease endophenotypes, and; iv) validate the biological properties in human brain tissue and dopaminergic cultures.

Detailed description

The project is a multicrentric observational study. Institutions involved are: OU1 - IRCCS INM Neuromed OU2 -University of Piemonte Orientale The project takes advantage from the availability of a large collection of PD samples from familiar and sporadic cases, recruited at IRCCS Neuromed, for which we already collected and stored clinical information, genetic data as well as DNA, serum, plasma and peripheral blood mononuclear cells (PBMCs) for the entire study cohort. induced pluripotent stem cells (iPSC) are available for 6 PD patients and 5 healthy subjects. The activities of the Operating Unit (OU1) are: 1. Stratification of NDD patients based on genetics and clinical records; 2. Recruitment of CSF sample of NDD patients; 3. Recruitment, WES and bioinformatic analysis of a selected cohort of NDD relatives (200 samples); 4. Bioinformatic analysis to identify protein structural alterations, candidate genes, genetic profiles and deregulatedpathways (OU1/ OU2); 5. Correlation of circulating complex with PD endophenotypes to identify disease biomarkers (OU1/ OU2); 6. Validation in RBD patients and PD relatives to identify early biomarkers for PD (OU1/ OU2); 7. Validation of the protein complexes in human brain slices and analysis of the biological activity of the most relevant CSF and plasmatic complexes in iPSC-derived mdDA neurons (OU1/ OU2). The activities of the Operating Unit (OU2) are: 1. CSF and plasma sample collection and storage for patients with NDDs; 2. Stratification of patients based on genetics and clinical records (in collaboration with OU1); 3. Detect alterations in protein complexes in CSF samples (100 samples); 4. Identification and validation of CSF biomarkers for PD (100 samples) (in collaboration with OU1); 5. Validate complex biomarkers using immunochemical or targeted analysis on plasma samples (450 samples); 6. Identify potential drug targetable complexes (in collaboration with OU1); 7. Assess whether proteins with structural changes in the CSF/plasma have those changes in the brain as well; 8. Correlate protein structural information with genetics and clinical data (in collaboration with OU1).

Conditions

• Parkinson Disease
• Amyotrophic Lateral Sclerosis (ALS)
• Frontotemporal Dementia (FTD)
• Alzheimer's Disease (AD)

Interventions

Type	Name	Description
GENETIC	Genetic: whole genome sequencing	Genetic: whole genome sequencing PD Partecipants will be assessed for disease progression: Stadio di Hoehn and Yahr, MDS-UPDRS part III, MOCA test, no motor symptoms, therapy and LID occurrence, Sleep disorders. Partecipants will be subjected to peripheral blood sampling for the purification of DNA, plasma, serum, PBMC and generation of hiPSC. DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate PD genes
GENETIC	whole exome sequencing	Genetic: whole genome sequencing AD Partecipants will be assessed for disease progression: * assessment of cognitive disorders (MMSE, MOCA test, clock test); * assessment of language disorders; * current drug therapy (and possible start date of treatment); * date of onset of cognitive disorders; * acquisition and assessment of imaging data where present (MRI, CT, PET). DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate AD genes
GENETIC	whole exome sequencing	Genetic: whole genome sequencing ALS/FTD Partecipants will be assessed for disease progression: * clinical classification according to El Escorial - revised; * assessment of cognitive disorders (and classification according to Strong criteria, 2017); * assessment of language disorders; * ongoing pharmacological therapy (and possible start date of treatment); * date of onset of motor and cognitive disorders; * acquisition and assessment of imaging data where present (MRI, CT, PET). DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate ALS/FTD genes

Timeline

• Start date: 2025-02-04
• Primary completion: 2026-08-31
• Completion: 2026-12-01
• First posted: 2025-01-31
• Last updated: 2025-03-18

Locations

1 site across 1 country: Italy