Association of Cardiovascular Autonomic Failure With Progression and Phenoconversion in Isolated REM Sleep Behavior Disorder

Background and objectives: Isolated REM sleep behavior disorder (iRBD) is a prodromal state of α-synucleinopathies, presenting years before overt neurodegenerative disorders. Autonomic nervous system (ANS) involvement, particularly cardiovascular autonomic failure, may indicate progression. However, its role as a (multidimensional) marker for disease progression and phenoconversion remains unclear. This study aimed to investigate whether cardiovascular autonomic failure and symptoms of autonomic dysfunction serve as multidimensional markers in patients with iRBD. Methods: We conducted a prospective cohort study of patients with iRBD (iRBDs) and controls. Participants underwent cardiovascular reflex tests (CRTs) with beat-to-beat monitoring of blood pressure (BP) and ANS symptom assessments at baseline and annually. Primary outcomes were prevalence and progression of cardiovascular autonomic failure and the risk factors of phenoconversion. Longitudinal changes were evaluated through mixed-effects regression, predictors associated with conversion with Cox regression analysis. Results: Sixty-four iRBDs (mean age 68.89 ± 6.75 years, 75% male) and 67 controls (66.57 ± 7.91 years, 68% male) were recruited. At baseline, iRBDs exhibited a prevalent sympathetic cardiovascular dysfunction, with more frequent neurogenic orthostatic hypotension (nOH in 9 iRBDs) and abnormal BP responses to CRTs (pathologic Valsalva maneuver [VM] overshoot in 27 iRBDs). Longitudinal data demonstrated progressive deterioration of sympathetic baroreflex function, with increased prevalence of nOH (7 iRBDs with incident nOH; yearly odds ratio [OR] = 2.44) and deterioration of parasympathetic cardiovagal function. Thirteen patients (20.3%) phenoconverted to α-synucleinopathies. Neurogenic OH (hazard ratio [HR] = 5.05), altered sympathetic baroreflex function (pathologic VM HR = 3.49), and blunted parasympathetic cardiovagal responses (pathologic deep breathing heart rate ratio HR = 3.27) were significant risk factors for phenoconversion; their early appearance 5 years from iRBD onset increased the conversion risk, up to 4-fold. Symptoms of autonomic failure were more prevalent in iRBD and deteriorated over time but failed to predict conversion. Discussion: Progressive deterioration of cardiovascular autonomic function is a feature of iRBDs and affects the risk of phenoconversion. Limitations include the relatively short follow-up period and small number of converters. This study highlights the importance of objective cardiovascular autonomic testing as a multidimensional marker for risk stratification in iRBD.