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 prodromal body-first LBD, but the duration of the prodromal phase remains unknown. We aimed to determine the progression rate of cardiac sympathetic denervation using [123I]meta-iodobenzylguanidine (MIBG) scintigraphy and employ the resulting curves to estimate the prodromal period of body-first LBD. We analysed longitudinal MIBG and dopaminergic imaging data from three cohorts: early Parkinsons disease (PD) patients from KPD, Korea (KPD-PD; n=195); de novo PD (n=74) and iRBD (n=54) patients from the PACE cohort, Aarhus, Denmark; and DaT SPECT data from PPMI PD (n=426) and iRBD (n=37). Heart-to-mediastinum ratios (MIBG) and putamen-to-occipital ratios (DaT SPECT) were converted to percent of normal value (healthy control mean). Patients were binned into quartiles according to baseline imaging data and progression curves were constructed by using median decline rates within each quartile. Onset of cardiac sympathetic (peripheral) and nigrostriatal dopaminergic (central) neurodegeneration were determined for iRBD patients by back-extrapolation from baseline imaging values. Longitudinal MIBG trajectories were highly consistent across the KPD and PACE cohorts, showing a rapid early decline ([~]10%-points/year) followed by gradual slowing, reaching 50% of normal value after [~]5 years and 25% after [~]10 years. PACE-iRBD patients displayed severe baseline cardiac sympathetic loss (median 21.3% of normal), corresponding to an estimated onset of peripheral neurodegeneration 11.3 years prior to study enrolment. Dopaminergic decline was slightly slower, reaching 50% of normal value after [~]8 years and 25% after [~]15 years. PACE-iRBD patients exhibited mild baseline dopaminergic deficit (median 81.6% of normal), indicating onset of nigrostriatal degeneration 2.7 years prior to enrolment. Thus, cardiac sympathetic degeneration preceded nigrostriatal involvement by 8.6 years. Based on baseline dopaminergic degeneration in PACE-PD patients, predicted time to phenoconversion for PACE-iRBD patients was 8.4 years. The combined model estimated the total prodromal period in body-first LBD to exceed 19 years. In conclusion, our study suggests that cardiac sympathetic degeneration begins more than a decade before study enrolment in iRBD subjects and nearly two decades before LBD diagnosis. Therefore, MIBG scintigraphy is a robust biomarker for detecting the earliest measurable neurodegeneration of body-first LBD and may be integrated in biological staging of -synucleinopathies. Furthermore, our findings have implications for drug trial design in SAA-positive individuals, and for identifying patients at the optimal window for disease-modifying therapies.