Disease Course Map progression markers transfer from isolated REM sleep behavior disorder to non-RBD prodromal...

A Disease Course Map (DCM) summarizes each participant's trajectory with three individual markers: how early in life a participant reaches a given disease stage (time-shift, τ), how fast it then progresses (acceleration, α), and whether motor change runs ahead of cognitive change (intermarker spacing, ω). These markers were recently shown to track progression in isolated REM sleep behavior disorder (iRBD), but whether they apply to prodromal populations without RBD is unknown. We studied 1499 non-RBD prodromal participants from the Parkinson's Progression Markers Initiative (1088 hyposmia, 411 genetic carriers; 187 phenoconverters), each with ≥2 longitudinal MoCA and MDS-UPDRS-III assessments. We trained a new DCM in this cohort and separately applied the published iRBD model unchanged. The two models ranked participants almost identically (Spearman ρ = 0.87-0.97), showing the iRBD map is recoverable without recalibration. Earlier onset (lower τ) and faster progression (higher α) were both associated with lower baseline striatal dopamine-transporter binding (n = 1426), replicating the iRBD biology, and progression was faster in α-synuclein seed-amplification (SAA)-positive participants (n = 1375; Benjamini-Hochberg-adjusted P < 0.001). Converters had an earlier model-estimated onset than non-converters, and this difference persisted after censoring all post-diagnosis visits (adjusted P = 0.003), whereas their faster progression did not (adjusted P = 0.08). Motor change tended to run ahead of cognitive change, particularly in genetic carriers, but this was the least robust signal and did not persist when follow-up was restricted. DCM progression markers transfer from iRBD to non-RBD prodromal alpha-synucleinopathy and retain dopaminergic and molecular validity, supporting their use as continuous, individual-level endpoints in non-RBD prodromal phenotypes.