Integration of Serum Neurofilament Light Chain and Cortical Dysfunction Improves Diagnostic Accuracy in ALS

OBJECTIVE: To determine whether integration of serum neurofilament light chain (NfL) and cortical dysfunction improves diagnostic accuracy in amyotrophic lateral sclerosis (ALS) when applied alongside the Gold Coast criteria (GCC). METHODS: In this prospective study, 148 participants with suspected ALS were recruited (101 ALS and 47 with ALS mimicking disorders). Participants taking medications known to influence TMS measures were excluded. Serum NfL levels were quantified using a single-molecule array assay. Cortical function was assessed using threshold tracking transcranial magnetic stimulation, with cortical dysfunction defined by reduced mean short interval intracortical inhibition or motor cortex inexcitability. Diagnostic performance was evaluated using sensitivity, specificity, and diagnostic odds ratios (DOR), with 95% confidence intervals (CI). RESULTS: Serum NfL demonstrated excellent discrimination (area under the curve 0.92, p < 0.001), with cut-off ≥ 33.5 pg/mL providing a sensitivity of 0.85 (95% CI 0.77-0.91) and specificity 0.87 (95% CI 0.75-0.94). Cortical dysfunction demonstrated very good diagnostic performance (sensitivity 0.77 [95% CI 0.68-0.84], specificity 0.77 [95% CI 0.63-0.86]). The GCC achieved a sensitivity of 0.89 (95% CI 0.82-0.94) and specificity 0.89 (95% CI 0.77-0.95). Combining GCC with elevated NfL or cortical dysfunction increased the specificity to 0.98 (95% CI 0.89-1.00) while maintaining high sensitivity at 0.87 (95% CI 0.79-0.92), yielding the highest DOR. INTERPRETATION: Integration of serum NfL and cortical dysfunction with the Gold Coast criteria improves diagnostic accuracy in ALS, particularly by increasing specificity. This multimodal approach provides a practical framework for earlier and more definitive diagnosis that may facilitate more efficient clinical trial recruitment.