Plasma Neurofilament Light Chain as a Biomarker for Motor Progression and Disease Milestones in Multiple System Atrophy: An Updated Prospective Cohort Study

BACKGROUND: Plasma neurofilament light chain (NfL) is a promising biomarker in multiple system atrophy (MSA). This study aimed to evaluate the prognostic utility of both baseline and longitudinal plasma NfL for predicting motor progression, disease milestones, and survival. METHODS: This prospective cohort study enrolled 93 patients with clinically established MSA, and participants were monitored annually for 4 years. Baseline plasma NfL concentrations were quantified using ultrasensitive single molecule array (Simoa™) technology. Disease progression and milestones were systematically assessed at each follow-up using the Unified Multiple System Atrophy Rating Scale (UMSARS). Linear mixed-effects models analyzed the association between NfL and UMSARS progression. Cox proportional hazards models and Kaplan-Meier analyses assessed the relationship between NfL levels, disease milestones, and mortality. RESULTS: Higher baseline plasma NfL predicted faster progression of UMSARS-I (β = 2.285), UMSARS-II (β = 1.811), and UMSARS-IV (β = 0.267). Patients in the high-risk group (baseline plasma NfL higher than 46.3 pg/mL) had an increased risk of attaining critical milestones, including severe dysarthria (hazard ratio [HR] = 3.85), global disability (HR = 4.54), and mortality (2.28). However, longitudinal NfL trajectories did not correlate with disease progression and prognosis; instead there was a decline in mid-to-late disease course. CONCLUSIONS: Baseline plasma NfL, rather than NfL dynamics, represents a promising biomarker for monitoring and predicting poor prognosis in early-stage MSA. Plasma NfL is anticipated to be a biomarker for prognostic stratification of early-stage MSA patients in future clinical trials. © 2026 International Parkinson and Movement Disorder Society.