The Prodromal Synucleinopathy Rating Scale

Background and ObjectivesClinical trials in REM sleep behavior disorder (RBD) to delay or prevent the development of Parkinson disease (PD), dementia with Lewy bodies (DLBs), and multiple system atrophy (MSA) will soon begin. The Prodromal Synucleinopathy Rating Scale (PSRS) was developed to capture the breadth and severity of clinical burden of prodromal disease. We analyzed the clinicometric properties and reliability of the PSRS in the North American Prodromal Synucleinopathy (NAPS) cohort. MethodsPSRS ratings were examined for visits conducted from August 2022–June 2025 on participants who did not have overt PD, DLB, or MSA (n = 348). Clinician raters used clinical judgement to evaluate signs and symptoms within each domain. Scores range from 0 (none) to a maximum of 2–4 points per domain, with a total maximum score of 25. The domains include cognitive (COG), behavioral/psychiatric (PSY), motor-axial (MAX), motor-appendicular (MAP), autonomic (AUT), sleep (SLP), and sensory (SEN). Spearman correlations were generated between ratings for each domain, the total sum score (SUM), and with independent measures of similar constructs. Test-retest reliability for 20 case examples protocols among 20 different raters was quantified using Bayesian generalized linear mixed-effects model. ResultsParticipants were 79% male with a mean age of 65.4 ± 10.4 years. The following correlations were statistically significant at p < 0.0001: COG with Montreal Cognitive Assessment (r = −0.42) and Clinical Dementia Rating-Sum of Boxes (r = 0.77); PSY with Neuropsychiatric Inventory-Questionnaire (r = 0.38); MAX and MAP with the Movement Disorders Society—Unified Parkinson Disease Rating Scale Motor (r = 0.65 and 0.75, respectively); AUT with Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (r = 0.39); SLP with Epworth Sleepiness Scale (r = 0.23); and SEN with Brief Smell Identification Test (r = −0.66). The PSRS SUM was correlated with the Functional Assessment Scale (r = 0.47), Schwab and England Activities of Daily Living (r = −0.58), and Clinician Global Impression of Severity (r = 0.29, p < 0.0001 for each). The inter-rater and intrarater reliability means ranged from 0.76 to 0.98. DiscussionIn this large multicenter RBD cohort, moderate to strong correlations were observed between PSRS domains and multiple independent measures of clinical burden. Reliability data were good to excellent. These findings demonstrate preliminary validity for the PSRS for measuring synucleinopathy clinical burden in those with RBD.