Decoding Prodromal Lewy Body Disease: Clinical Differences Between Isolated REM Sleep Behavior Disorder and Hyposmia With Dopamine Transporter Deficit

Background: Lewy body diseases (LBDs) are heterogeneous, and this variability is already evident in the prodromal phase. Several frameworks propose that prodromal heterogeneity reflects distinct phenotypic and biological subtypes, supported by differences in clinical profiles, imaging, and α-synuclein biomarkers. We provide a detailed clinical characterization of two enriched prodromal cohorts: isolated REM Sleep Behavior Disorder (iRBD) and Hyposmia with Dopamine Transporter Deficit. Methods: This cross-sectional study included 360 participants with iRBD, 1101 with hyposmia and abnormal dopamine transporter imaging and 283 healthy controls from the Parkinson's Progression Markers Initiative. Using the earliest assessments available, we compared the Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction (SCOPA-AUT) and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III. Group differences were assessed using age and sex-adjusted permutation testing. Secondary descriptive analysis identified the individual items contributing most to between-group differences. Results: Both prodromal cohorts had significantly worse scores than healthy controls in all assessments. Compared with hyposmia, iRBD was associated with higher SCOPA-AUT and MDS-UPDRS Part I scores, driven mainly by constipation and urinary symptoms. Conclusion: In prodromal Lewy body disease, iRBD is associated with a statistically significant excess of autonomic symptom burden compared with hyposmia with dopamine transporter deficit, with the largest item-level differences in urinary and constipation measures.