Abstract
Patients with Parkinson's disease (PD) show a broad heterogeneity in clinical presentation, and subtypes may already arise in prodromal disease stages. Isolated REM sleep behaviour disorder (iRBD) is the most specific marker of prodromal PD, but data on clinical subtyping of patients with iRBD remain scarce. Therefore, this study aimed to identify iRBD subtypes. We conducted comprehensive clinical assessments in 66 patients with polysomnography-proven iRBD, including motor and non-motor evaluations, and applied a two-step cluster analysis. Besides, we compared iRBD clusters to matched healthy controls and related the resulting cluster solution to cortical and subcortical grey matter volumes by voxel-based morphometry analysis. We identified two distinct subtypes of patients based on olfactory function, dominant electroencephalography frequency, amount of REM sleep without atonia, depressive symptoms, disease duration, and motor functions. One iRBD cluster (Cluster I, late onset-aggressive) was characterised by higher non-motor symptom burden despite shorter disease duration than the more benign subtype (Cluster II, early onset-benign). Motor functions were comparable between the clusters. Patients from Cluster I were significantly older at iRBD onset and exhibited a widespread reduction of cortical grey matter volume compared to patients from Cluster II. In conclusion, our findings suggest the existence of clinical subtypes already in the prodromal stage of PD. Future longitudinal studies are warranted that replicate these findings and investigate the risk of the more aggressive phenotype for earlier phenoconversion and dementia development.