Objective To evaluate the diagnostic performance of serum neurofilament light chain (sNfL) and cardiac troponin T (cTnT) as biomarkers for amyotrophic lateral sclerosis (ALS) and to determine whether their combination improves diagnostic accuracy.

Methods We retrospectively analyzed 293 ALS patients, 47 neurodegenerative disease controls and 24 healthy controls. An independent validation cohort of 501 ALS patients was additionally 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 8.35 ng/L was determined using the Youden index and applied in subgroup analyses, in which biomarker-negative ALS patients (normal sNfL and cTnT) were compared to biomarker-positive patients regarding disease duration and progression rate.

Results sNfL alone showed excellent performance in discriminating ALS patients from healthy controls (AUC = 0.951), but only moderate performance in discriminating neurodegenerative disease controls (AUC = 0.789). Combining sNfL and cTnT improved diagnostic accuracy for ALS over neurodegenerative disease controls, with a combined AUC of 0.866. Similar AUCs were observed in the validation cohort. 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 While sNfL alone performs well in distinguishing ALS from healthy controls, cTnT provides additional value in distinguishing ALS from disease controls. The combination of sNfL and cTnT improves diagnostic accuracy and may help identify clinically distinct ALS subgroups.

The authors have declared no competing interest.

The research was supported through unrestricted donations from our patients (to TG and PW), especially Bruno Schmidt (1965 2022) and the Initiative Alle Lieben Schmidt e. V. to PW. TG and PW are also grateful for support from the Boris Canessa Foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

As both laboratory measurements and clinical assessments were part of routine diagnostic procedures and analyzed retrospectively, no formal ethical approval was required according to our institutional ethics committee (decision no. 324/20 Institutional Ethics Review Board University Hospital Bonn).

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All data produced in the present study are available upon reasonable request to the authors.