Serum Neurofilament Light Chain Correlates With Clinical Severity and Predicts Mortality in Anti-IgLON5 Disease.

BACKGROUND AND OBJECTIVES: Anti-IgLON5 disease manifests by various neurologic symptoms, the severity of which can be evaluated using the anti-IgLON5 composite score (ICS). This study assessed the correlation of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) with the ICS and investigated these biomarkers as predictors of long-term clinical severity and mortality in anti-IgLON5 disease. METHODS: Patients diagnosed with anti-IgLON5 disease at a national reference center (2016-2024) with available serum and CSF samples were included. NfL and GFAP concentrations were measured in these samples using Simoa assay Neurology 2-Plex B Kit. The severity of symptoms was classified according to the ICS, which was retrospectively evaluated at diagnosis, at last clinical evaluation, and at any other timepoint when samples were collected. RESULTS: Thirty patients (60% male, median age 72 years) were included. Serum NfL concentration was significantly correlated with the total ICS (rho = 0.38, p = 0.025) and its partial bulbar score (rho = 0.39, p = 0.020); serum GFAP concentration was significantly correlated only with the bulbar ICS (rho = 0.34, p = 0.044). CSF NfL and GFAP concentrations were not significantly correlated with the total ICS nor any of its partial scores. Anti-IgLON5 antibody CSF titers, but not serum titers, showed a significant inverse correlation with the total ICS (rho = -0.44, p = 0.04). In 26 patients sampled <4 months after diagnosis, neither NfL nor GFAP predicted the total or partial ICS at last clinical evaluation (median 18 months after diagnosis), but serum NfL increased the risk of 1-year mortality independently of age (hazard ratio for each 10 pg/mL increase: 2.05, 95% CI [1.21-3.45], p = 0.007). In patients with bulbar involvement (n = 22), serum NfL concentration was lower than in 10 controls with bulbar amyotrophic lateral sclerosis (median interquartile range [IQR] 26 pg/mL [21-51] vs 158 pg/mL [100-340], p < 0.001) and higher than in 10 controls with bulbar myasthenia gravis (median [IQR] 15 pg/mL [8-26], p = 0.040). DISCUSSION: In anti-IgLON5 disease, serum NfL and GFAP are elevated and correlate with the clinical severity, especially of bulbar symptoms. In clinical practice, serum NfL could be useful for disease monitoring and to predict the risk of death.