A new clinical rating scale designed to capture the breadth and severity of early-stage synucleinopathy has shown good to excellent reliability in a large multicenter cohort of patients with REM sleep behavior disorder (RBD), according to a study published in Neurology. The Prodromal Synucleinopathy Rating Scale (PSRS) may become a key tool for upcoming clinical trials aimed at preventing Parkinson disease, dementia with Lewy bodies, and related disorders.
RBD is one of the strongest known predictors of future synucleinopathy: the majority of people with polysomnography-confirmed idiopathic RBD will eventually develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. As disease-modifying therapies advance toward clinical trials, researchers need standardized instruments to measure clinical burden in the prodromal phase before overt neurodegeneration sets in.
What they found
The study, led by Bradley Boeve (Mayo Clinic) and Yo-El Ju (Washington University) through the North American Prodromal Synucleinopathy (NAPS) consortium, analyzed PSRS ratings from 348 participants with RBD who did not yet have a diagnosis of Parkinson disease, dementia with Lewy bodies, or multiple system atrophy (79% male, mean age 65.4). The scale covers seven domains: cognitive, behavioral/psychiatric, motor-axial, motor-appendicular, autonomic, sleep, and sensory. Scores in each domain range from 0 to 2-4 points, with a total maximum of 25.
The PSRS showed moderate to strong correlations with established independent measures of the same constructs:
- Cognitive domain correlated with the Montreal Cognitive Assessment (r = -0.42) and Clinical Dementia Rating-Sum of Boxes (r = 0.77), both p < 0.0001.
- Motor-appendicular domain correlated with the MDS-UPDRS motor score (r = 0.75).
- Sensory domain (olfaction) correlated with the Brief Smell Identification Test (r = -0.66).
- Motor-axial domain correlated with the MDS-UPDRS motor score (r = 0.65).
- Autonomic domain correlated with the SCOPA-AUT scale (r = 0.39).
- Behavioral/psychiatric domain correlated with the Neuropsychiatric Inventory-Questionnaire (r = 0.38).
- Total PSRS score correlated with the Functional Assessment Scale (r = 0.47), the Schwab and England Activities of Daily Living scale (r = -0.58), and the Clinician Global Impression of Severity (r = 0.29).
Reliability was good to excellent: inter-rater and intrarater reliability scores ranged from 0.76 to 0.98 across domains.
Why it matters
Several disease-modifying therapies targeting alpha-synuclein pathology are moving toward clinical trials in the prodromal phase. The PSRS provides a composite measure of clinical burden that captures the multisystem nature of early synucleinopathy — from mild motor signs and autonomic dysfunction to cognitive decline and sleep disturbance. Unlike single-domain instruments (e.g., motor scales or cognitive tests alone), the PSRS is designed to reflect the full clinical picture, which may better detect treatment effects in trials and track disease progression in natural history studies.
The strong correlation between the cognitive domain and the CDR-Sum of Boxes (r = 0.77) suggests that the PSRS captures cognitive changes that are clinically meaningful even at the prodromal stage.
Limits
The PSRS relies on clinician judgment rather than fully objective measurements, and training procedures will need to be standardized for wider use. The cohort is predominantly White and male, reflecting the demographics of research-volunteer RBD cohorts, and the generalizability to more diverse populations needs to be established. Longitudinal follow-up will be required to determine whether baseline PSRS scores predict the rate of phenoconversion to overt synucleinopathy.
Bottom line
The Prodromal Synucleinopathy Rating Scale demonstrates preliminary validity and good reliability in a large multicenter RBD cohort, providing a much-needed instrument for quantifying clinical burden in the prodromal phase of synucleinopathy. As prevention trials approach, the PSRS could serve as both an enrichment and outcome measure.
Source: Boeve BF, Nie Y, Lu R, et al. The Prodromal Synucleinopathy Rating Scale: An Assessment in Patients With REM Sleep Behavior Disorder. Neurology. 2026 Jul 14;107(1):e218176. DOI: 10.1212/WNL.0000000000218176. PMID: 42302227.