Serum neurofilament indicates accelerated neurodegeneration and predicts mortality in late-stage Parkinson's disease.

Different stages of Parkinson's disease (PD) are defined by clinical criteria, while late-stage PD is marked by the onset of morbidity milestones and rapid clinical deterioration. Based on neuropathological evidence, degeneration in the dopaminergic system occurs primarily in the early stage of PD, raising the question of what drives disease progression in late-stage PD. This study aimed to investigate whether late-stage PD is associated with increased neurodegeneration dynamics rather than functional decompensation using the blood-based biomarker serum neurofilament light chain (sNfL) as a proxy for the rate of neurodegeneration. The study included 118 patients with PD in the transition and late-stage (minimum disease duration 5 years, mean (SD) disease duration 15 (±7) years). The presence of clinical milestones (hallucinations, dementia, recurrent falls, and admission to a nursing home) and mortality were determined based on chart review. We found that sNfL was higher in patients who presented with at least one clinical milestone and increased with a higher number of milestones (Spearman's ρ = 0.66, p < 0.001). Above a cutoff value of 26.9 pg/ml, death was 13.6 times more likely during the follow-up period (95% CI: 3.53-52.3, p < 0.001), corresponding to a sensitivity of 85.0% and a specificity of 85.7% (AUC 0.91, 95% CI: 0.85-0.97). Similar values were obtained when using an age-adjusted cutoff percentile of 90% for sNfL. Our findings suggest that the rate of ongoing neurodegeneration is higher in advanced PD (as defined by the presence of morbidity milestones) than in earlier disease stages. A better understanding of the biological basis of stage-dependent neurodegeneration may facilitate the development of neuroprotective means.