Combination of Serum Neurofilament Light Chain and Serum Cardiac Troponin T as Biomarkers Improves Diagnostic Accuracy in Amyotrophic Lateral Sclerosis

OBJECTIVE: We aimed to evaluate the clinical utility of serum neurofilament light chain (sNfL) and cardiac troponin T (cTnT) in amyotrophic lateral sclerosis (ALS) and assess whether their combination improves diagnostic accuracy. METHODS: We retrospectively analyzed 293 ALS patients, 85 neurodegenerative disease controls, and 29 healthy controls. A validation cohort of 501 ALS patients was analyzed to confirm reproducibility of the results. Receiver operating characteristic (ROC) curve analysis was performed for sNfL, cTnT, and their combination, and the area under the curve (AUC) was compared across groups. An ALS-specific cTnT cut-off of 8.35ng/L was determined using the Youden index and applied in subgroup analyses, in which "biomarker-negative" ALS patients were compared to "biomarker-positive" patients regarding disease duration and progression. RESULTS: sNfL showed excellent performance in discriminating ALS patients from healthy controls (AUC = 0.94), but only moderate performance in discriminating neurodegenerative disease controls (AUC = 0.82). Combining sNfL and cTnT improved diagnostic accuracy for ALS over neurodegenerative controls, with an AUC of 0.90, whereas cTnT alone showed an AUC of 0.77. The validation cohort showed similar AUCs. "Biomarker-negative" ALS patients had a longer disease duration (73.0 vs 18.0 months, p = 0.0003) and a lower progression rate (0.19 vs 0.70 points per months, p < 0.0001) than "biomarker-positive" patients. INTERPRETATION: Although sNfL alone performs well in distinguishing ALS from healthy controls, repurposing cTnT for ALS provides additional value in discriminating ALS from disease controls. The combination of sNfL and cTnT improves diagnostic accuracy and may help identify prognostically distinct ALS subgroups. ANN NEUROL 2026;99:408-417.