Despite remarkable progress in the understanding of the molecular pathogenesis of neurodegenerative diseases (NDD), no causative or disease-modifying treatment is currently available. Aggregation of misfolded proteins are thought to play a crucial role in the pathogenesis, but attempts to exploit this knowledge for novel treatments have not been successful. Also, pathogenetically relevant biomarkers of protein aggregation are lacking.In order to overcome this critical road-block, we have assembled an interdisciplinary consortium, consisting of world-leading experts in structural biology and ligand development, multimodal neuroimaging, animal models and clinical trials to develop a novel imaging system for combined simultaneous molecular and functional imaging (PET-MRI/fMRI) for two rare diseases caused by excessive accumulation of misfolded alpha-synuclein (αSYN), multiple systems atrophy (MSA) and parkinsonism caused by mutations in the alpha-synuclein gene (SNCA), which will serve as proof-of-principle models for the more common and heterogeneous NDD. With this technology we will pioneer the monitoring of protein aggregation as a biomarker for therapeutic effects in the framework of individualized causative treatment. The central aspects of the work-flow including ligand design, software development and drug trials will be driven by three highly specialized SMEs, while translation to animal models and clinical use will be implemented by top academic centers. The groundbreaking progress will include:1. Establish a multimodal imaging algorithm based on a new PET tracer and embracing structural and functional MRI methods to yield an αSYN specific tool2. Test this multimodal, molecular neuroimaging algorithm in animal models with regard to its potential for diagnosis, mirroring the natural disease course and response to therapy3. Translate the algorithm including the therapeutic modality (i.e. immunotherapy with PD01, NCT01568099) to the clinical setting.