DEEPEN-iRBD — Prodromal DEtErminants for PhENoconversion of idiopathic RBD to alpha-synucleinopathies (PD, DLB and MSA)

Problem: Increasing evidence shows that individuals affected by idiopathic REM sleep behavior disorder (iRBD) have a high risk of conversion to Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA), conditions that have a common cellular pathological hallmark, the aggregation of alpha-synuclein (aSYN). Despite phenotypic similarities in the early stages, clinical phenotypes differ significantly in later stages with substantial therapeutic and prognostic consequences. Goal and methodology: DEEPEN-iRBD aims to develop a proof of concept for phenoconversion based on pre-clinical/clinical research and data analysis to implement correct diagnosis and accurate prognosis and facilitate personalized interventions. To achieve this goal, we will integrate existing and new data, including both advanced clinical assessments and molecular markers to deepen iRBD and reveal PD, MSA and DLB specific profiling. Clinical electrophysiological signals from polysomnographic recordings, continuous electrocardiographic and arterial blood will determine autonomic functions. A comprehensive genetic screening will be applied to identify genetic modifiers. Patient samples as body fluids, skin biopsy, and iPSC-derived brain cells will be employed to determine structure and properties of aSYN aggregates and disease-specific cellular pathways. Pathogenicity model, a system for prediction and description of diseases, will be implemented and applied for diagnosis and patient stratification. On this basis, a personalized symptomatologic therapeutical approach combined with early rehabilitative intervention will be offered to iRBD patients. Finally, ethical and social aspects related to communication and screening issues will be analyzed. Benefit: DEEPEN-iRBD consortium of multidisciplinary experts will address secondary and tertiary prevention, mainly through individual risk assessment and strategies to develop tailored interventions and care in iRBD.