Limbic Vulnerability Characterises REM Sleep Behaviour Disorder Across Prodromal and Established Lewy Body Disease

Isolated rapid eye movement sleep behaviour disorder (iRBD) strongly predicts future Lewy body disease and identifies a more aggressive, non-motor phenotype in Parkinson’s disease (PD). Limbic degeneration may contribute to this phenotype with abnormalities reported separately in iRBD and PD with RBD (PD-RBD). However, whether limbic vulnerability reflects RBD status independent of disease stage remains unknown. We investigated multimodal limbic vulnerability across prodromal and established disease using structural and functional MRI from 175 polysomnography-confirmed isolated RBD (iRBD), 79 Parkinson’s disease with RBD (PD-RBD), 250 Parkinson’s disease without RBD (PD-nRBD) and 54 healthy controls from the Parkinson’s Progression Markers Initiative. Hippocampal, amygdala and anterior cingulate measures were integrated into structural, functional and multimodal Limbic Vulnerability Indices. iRBD showed greater structural and multimodal limbic vulnerability than healthy controls and PD-nRBD, while PD-RBD showed greater structural and multimodal vulnerability than PD-nRBD. Greater limbic vulnerability was associated with RBD symptom burden, reduced dopamine transporter binding and cognitive impairment. In iRBD, greater structural and multimodal limbic vulnerability predicted future incident hallucinations. These findings identify limbic vulnerability as a feature associated with the RBD phenotype across disease stages and suggest a role in neuropsychiatric progression.