Shady Rahayel, PhD, Montreal Neurological Institute and Hospital (McGill University), Montreal, Canada, discusses current evidence on the factors that regulate the spread of alpha-synuclein (α-syn) in isolated REM sleep behavior disorder (iRBD). iRBD is considered as a prodromal state of clinical α-synucleinopathies, with longitudinal data showing that over 80% of iRBD patients convert to a definite α-synucleinopathy within 14-16 years. Research suggests that α-syn fibrils have prion-like properties, spreading from one cell to another to drive disease progression. Others argue against the hypothesis of prion-like seeding driving pathology expansion, instead implicating cell vulnerability. Dr Rahayel used computational modelling to look at the role of these factors in the spread of α-syn in iRBD. The model was able to recreate the patterns of atrophy seen in disease via in silico protein propagation. It was demonstrated that both spread based on the selective vulnerability of the region and its structural connectivity were crucial to recreate the atrophy seen in patients, suggesting that both prion-like spread and cell vulnerability are determinants of pathology spread. This interview took place at the AD/PD™ 2023 congress in Gothenburg, Sweden.
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