Amyotrophic lateral sclerosis: Correlations between fluid biomarkers of NfL, TDP-43, and tau, and clinical characteristics.

Yuta Kojima,Takamasa Kitaoji,Takashi Kasai,Fukiko Kitani-Morii,Harutsugu Tatebe,David Allsop,Toshiki Mizuno,Yu-Ichi Noto,Makiko Shinomoto,Takahiko Tokuda,Yukiko Tsuji,Takuma Ohmichi,Satoshi Teramukai,Weidong Le

doi:10.1371/journal.pone.0260323

Abstract

We previously reported the diagnostic and prognostic performance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma as amyotrophic lateral sclerosis (ALS) biomarkers. The present study aimed to elucidate associations between clinical characteristics and the markers as well as mutual associations of the markers in ALS patients using the same dataset. NfL, TDP-43, and t-tau levels in CSF and plasma in 75 ALS patients were analyzed. The associations between those markers and clinical details were investigated by uni- and multivariate analyses. Correlations between the markers were analyzed univariately. In multivariate analysis of CSF proteins, the disease progression rate (DPR) was positively correlated with NfL (β: 0.51, p = 0.007) and t-tau (β: 0.37, p = 0.03). Plasma NfL was correlated with age (β: 0.53, p = 0.005) and diagnostic grade (β: -0.42, p = 0.02) in multivariate analysis. Plasma TDP-43 was correlated negatively with split hand index (β: -0.48, p = 0.04) and positively with % vital capacity (β: 0.64, p = 0.03) in multivariate analysis. Regarding mutual biomarker analysis, a negative correlation between CSF-NfL and TDP-43 was identified (r: -0.36, p = 0.002). Elevated NfL and t-tau levels in CSF may be biomarkers to predict rapid DPR from onset to sample collection. The negative relationship between CSF NfL and TDP-43 suggests that elevation of CSF TDP-43 in ALS is not a simple consequence of its release into CSF during neurodegeneration. The negative correlation between plasma TDP-43 and split hand index may support the pathophysiological association between plasma TDP-43 and ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, characterized by progressive muscle weakness and atrophy, resulting in respiratory failure and death
Plasma neurofilament light chain (NfL) was correlated with age (β: 0.53, p = 0.005) and diagnostic grade (β: -0.42, p = 0.02) in multivariate analysis
The level of TAR DNA-binding protein 43 (TDP-43) was reported to be high in the cerebrospinal fluid (CSF) and plasma of ALS patients compared with controls [7,8], but the inconsistency of the TDP-43 immunoassay used to measure the level of this protein has been problematic

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons, characterized by progressive muscle weakness and atrophy, resulting in respiratory failure and death. It is untreatable at present, but an effective therapy is strongly desired [1]. In order to develop novel treatments, objective and responsive biomarkers are essential for successfully carrying out clinical trials. CSF total-tau (t-tau) is expected to serve as a responsive biomarker for ALS diagnosis and progression, despite a lack of consistent results [9,10]. The diagnostic and prognostic value of such biomarkers has been well-investigated at individual levels; associations between biomarkers and clinical characteristics, as well as the mutual associations of those biomarkers, are not fully understood

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