Cardiac sympathetic degeneration informs the duration of the prodromal stage of body-first Lewy body disease

Body-first Lewy body disease (LBD) is hypothesized to begin in the peripheral autonomic nervous system years before nigrostriatal involvement. Isolated REM sleep behaviour disorder (iRBD) is considered an early manifestation of body-first LBD but is preceded by an unknown period of peripheral autonomic degeneration. Consequently, the total duration of the prodromal phase remains unknown. We used longitudinal imaging data to model the progression of cardiac sympathetic and nigrostriatal dopaminergic degeneration and employed the resulting curves to estimate the prodromal period of body-first LBD. Cardiac sympathetic trajectories were highly consistent across two cohorts, showing rapid early decline followed by gradual slowing, reaching 50% of the normal value after ~5 years and 25% after ~10 years. Dopaminergic decline was slightly slower, reaching 50% of the normal value after ~8 years and 25% after ~15 years. iRBD patients displayed severe baseline cardiac sympathetic loss (median 21.3% of normal), but mild baseline dopaminergic deficit (median 81.5% of normal), indicating that cardiac sympathetic degeneration may precede dopaminergic nigrostriatal involvement by 8.6 years. Based on baseline dopaminergic deficits in Parkinson's disease (PD), the combined model estimated that the prodromal phase of body-first LBD, from onset of cardiac sympathetic degeneration to predicted clinical PD diagnosis, exceeds 20 years.