Frequency and Longitudinal Course of Autonomic Reflex Testing Abnormalities in Isolated REM Sleep Behavior Disorder

Abstract Study Objectives Autonomic dysfunction is common across the α-synucleinopathies including isolated RBD (iRBD), however the presence, severity and distribution of autonomic dysfunction as a risk factor for phenoconversion in iRBD remains unclear. We aimed to characterize autonomic reflex testing (ART) abnormalities in a cohort of participants with iRBD and assess them as phenoconversion biomarkers. Methods We performed ART on 45 individuals with iRBD and evaluated the ability of ART components (sympathetic cholinergic, cardiovagal, sympathetic adrenergic) to predict phenoconversion using univariate and multivariate models combined with measures of olfaction, cognition, motor function, and skin biopsy assessment of dermal synuclein. Results Forty-one individuals with iRBD were enrolled (age 66.7 ± 7.4 yrs, 27% female), and followed annually for an average of 2.9 ± 2.4 yrs, with four participants lost to follow-up. Eight participants with iRBD phenoconverted during their follow-up period (3 Parkinson’s disease, 4 dementia with Lewy bodies and 1 multiple system atrophy), yielding a phenoconversion rate of 6.6% per year. Eighty-seven percent of iRBD participants had an abnormal baseline ART, and 100% had an abnormal follow-up ART. A combination of MDS-UPDRS III score and cardiovagal dysfunction (abnormal HRVdb) best predicted phenoconversion (AUC = 0.77), especially when combined with iRBD disease duration (AUC = 0.89). Conclusions ANS dysfunction was common and spanned all domains of autonomic function. Cardiovagal function was the most common domain affected and most predictive of phenoconversion, especially if combined with motor examination and disease duration. Longitudinal studies with larger sample sizes are needed to confirm these findings.