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

Kojima, Y. and Kasai, T. and Noto, Y.-I. and Ohmichi, T. and Tatebe, H. and Kitaoji, T. and Tsuji, Y. and Kitani-Morii, F. and Shinomoto, M. and Allsop, D. and Teramukai, S. and Mizuno, T. and Tokuda, T. (2021) Amyotrophic lateral sclerosis : Correlations between fluid biomarkers of NfL, TDP-43, and tau, and clinical characteristics. PLoS ONE, 16 (11): e0260323. ISSN 1932-6203

Abstract

Objectives 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. Methods 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. Results 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). Conclusions 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.