Evaluating the neurofilament light chain-derived gap between biological and chronological age in multiple sclerosis and controls.

OBJECTIVE: To compare chronological age and neurofilament light chain (NfL)-derived age in people with multiple sclerosis (pwMS) and controls, and to explore clinical correlates of the NfL age gap. METHODS: We conducted a real-world, retrospective analysis including 792 pwMS (without evidence of clinical or MRI activity in the previous year and during follow-up) and 302 controls. NfL-derived age was computed using established age-adjusted reference. We used logistic regression models to compare pwMS and controls in chronological and NfL-derived age groups, and linear regression models to evaluate the associations of chronological age and NfL-derived age with clinical variables (Expanded Disability Status Scale (EDSS), disease duration, disease course, disease modifying treatment (DMT) class, number of previous DMTs) and the associations between the NfL age gap (difference between biological and chronological age) and clinical variables. RESULTS: PwMS showed a higher likelihood than controls of having a NfL-derived age above their chronological age (OR = 1.44;95%CI 1.10-1.87; p = 0.007). EDSS, disease duration, and progressive disease course were associated with both chronological and NfL-derived age (all p < 0.001). The NfL age gap showed independent associations with EDSS (Coeff = 0.147; 95%CI 0.097-0.197; p < 0.001), progressive disease course (Coeff = 0.34; 95%CI 0.16-0.53; p < 0.001), and number of previous DMTs (Coeff = 0.06; 95% CI 0.01-0.11; p = 0.028), but not with disease duration or DMT class. Similar results were observed in a sub-analysis excluding pwMS with EDSS progression. CONCLUSIONS: MS is associated with a shift in age-associated NfL trajectory, with an older biological profile especially in pwMS with greater disability and progressive course.