Plasma CAF22 Predicts Incident Freezing of Gait in Parkinson's Disease: A Prospective Cohort Study

Freezing of gait (FOG) is a disabling complication of Parkinson's disease (PD), but peripheral associations remain poorly defined. C-terminal agrin fragment-22 (CAF22) is a circulating biomarker of neuromuscular junction degradation. We investigated whether baseline plasma CAF22 predicts the development of FOG in PD patients. In this prospective cohort study, 233 patients with idiopathic PD and no baseline FOG were followed for 24 months with assessments at 6-month intervals. Incident FOG was identified using the New Freezing of Gait Questionnaire. Cox proportional hazards models assessed associations between CAF22 and time to first FOG, adjusting for age, sex, disease duration, motor severity, gait speed, muscle strength, cognitive performance, and levodopa-equivalent daily dose. During follow-up, 55 participants (23.6%) developed incident FOG. Higher baseline plasma CAF22 was associated with an increased risk of FOG per standard deviation increase (HR 1.4, 95% CI 1.09-1.81). This association remained significant after multivariate adjustment (adjusted HR 1.37, 95% CI 1.03-1.82). Baseline CAF22 concentrations were higher in participants with greater motor severity and slower gait speed, but showed weaker associations with global cognitive performance. Faster gait speed was independently protective against FOG (HR 0.64, 95% CI 0.52-0.78). Kaplan-Meier analyses demonstrated progressively lower FOG-free survival across increasing CAF22 tertiles (log-rank p = 0.046). Elevated baseline plasma CAF22 independently predicts incident FOG in PD. CAF22 may reflect peripheral neuromuscular dysfunction and could serve as a biomarker of FOG risk.