Combined use of CSF NfL and CSF TDP-43 improves diagnostic performance in ALS

Ann Clin Transl Neurol. 2019 Dec;6(12):2489-2502. doi: 10.1002/acn3.50943. Epub 2019 Nov 19.


Objective: To determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma of patients with amyotrophic lateral sclerosis (ALS) and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance.

Methods: This was a single-center, prospective, longitudinal study. CSF and plasma samples were collected at the time of enrollment from a discovery cohort of 29 patients with ALS and 29 age-matched controls without neurodegenerative disease. In a validation cohort, there were 46 patients with ALS, and 46 control (not age-matched) patients with motor weakness resulting from neuromuscular diseases. NfL, TDP-43, and t-tau levels in CSF and plasma were measured using ultrasensitive single molecule assay (Simoa) technology.

Results: The following findings were reproducibly observed among the discovery and validation cohorts: increased levels of CSF NfL, plasma NfL, and CSF TDP-43 in ALS compared with control groups; shorter survival associated with higher levels of CSF and plasma NfL. When the CSF NfL and CSF TDP-43 levels were combined, the areas under the ROC curves (AUC) were slightly improved relative to AUCs for each biomarker alone.

Interpretation: CSF and plasma NfL may not only serve as diagnostic biomarkers but also provide a measure of disease progression. CSF TDP-43 is also useful as a diagnostic biomarker of ALS, but has no prognostic value. The combined use of CSF NfL and CSF TDP-43 may be a useful biomarker for the diagnosis of ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / blood
  • Amyotrophic Lateral Sclerosis / cerebrospinal fluid*
  • Amyotrophic Lateral Sclerosis / diagnosis*
  • DNA-Binding Proteins / cerebrospinal fluid*
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Neurofilament Proteins / cerebrospinal fluid*


  • DNA-Binding Proteins
  • Neurofilament Proteins
  • TARDBP protein, human
  • neurofilament protein L