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

Takashi Kasai,Yu‐Ichi Noto,David Allsop,Takuma Ohmichi,Yuta Kojima,Toshiki Mizuno,Fukiko Kitani‐Morii,Harutsugu Tatebe,Makiko Shinomoto,Yukiko Tsuji,Takahiko Tokuda

doi:10.1002/acn3.50943

Abstract

ObjectiveTo 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.MethodsThis 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.ResultsThe 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.InterpretationCSF 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.

Highlights

There is an urgent need for molecular biomarkers in biofluids for the diagnosis of amyotrophic lateral sclerosis (ALS) 1
The following findings were reproducibly observed among the discovery and validation cohorts: increased levels of cerebrospinal fluid (CSF) neurofilament light chain (NfL), plasma NfL, and CSF TAR DNA-binding protein 43 (TDP-43) in ALS compared with control groups; shorter survival associated with higher levels of CSF and plasma
We previously reported that lower CSF TDP-43 levels were correlated with shorter survival 12

Summary

Introduction

There is an urgent need for molecular biomarkers in biofluids for the diagnosis of amyotrophic lateral sclerosis (ALS) 1. Elevated levels of NfL in CSF and blood plasma/serum have been reported in patients with ALS compared with controls; they were associated with poor outcomes 2-3. (TDP-43) positive inclusions are found in approximately 97% of patients with ALS. This has led to the investigation of TDP-43 as a potential molecular biomarker for ALS. Overall, these studies have identified increased levels of TDP-43 in CSF from ALS patients compared with controls 4. An elevated level of TDP-43 has been reported in plasma from ALS patients in one case-control study 5. The absolute concentrations of TDP-43 in CSF and plasma have varied across studies, suggesting that

Methods

Discussion

Conclusion