Objective We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS).
Methods We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment.
Results Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (r=−0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis.
Conclusions Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.
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Contributors SY: designed and conceptualised study; acquired clinical data; performed statistical analysis; analysed the data; interpreted the data and drafted the manuscript. AHa: designed and conceptualised study; acquired clinical data; performed statistical analysis; analysed the data; interpreted the data and revised the manuscript for intellectual content. YH, DI, YK, MI and HK: acquired clinical data. AHi: performed statistical analysis. MK: designed and conceptualised study; analysed the data; interpreted the data and revised the manuscript for intellectual content.
Funding This work was funded by JSPS KAKENHI (Grant Numbers JP17H04195 and JP20H00527); grants from the Japan Agency for Medical Research and Development (Nos. 19ek0109221 and 19ek0109359); a grant from the Naito Foundation and a grant from the Hori Sciences and Arts Foundation. SY is supported by JSPS KAKENHI (Grant Number JP19K17060). AH is supported by KAKENHI (Grant Number JP18K07523). YH is supported by JSPS KAKENHI (Grant Number JP18K07497). MI is supported by JSPS KAKENHI (Grant Number JP18K15361). HK is supported by JSPS KAKENHI (Grant Number JP17K09777). He received honoraria from Takeda Pharmaceutical Co. Ltd., Pfizer Japan Co. Ltd., Alnylam Japan, Japan Blood Products Organization, CSL Behring Co. Ltd., Daiichi Sankyo Co. Ltd. and Teijin Parma Co. Ltd. MK is supported by JSPS KAKENHI (Grant Numbers JP17H04195 and JP20H00527), grants from the Japan Agency for Medical Research and Development (Nos. 19ek0109221, 19ek0109359, 19dk0207027, 19lk0201101 and 19dm0107155) and a grant from the Hori Sciences and Arts Foundation. He received honoraria from Takeda Pharmaceutical Co. Ltd., Alnylam Japan, Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Novartis Pharma Co. Ltd., Biogen Japan and UCB Japan as well as grants from Zenyaku Kogyo Co. Ltd., Japan Blood Products Organization, Mitsubishi-Tanabe Pharma, CSL Behring Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd. and Daiichi Sankyo Co. Ltd.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Ethics Review Committee of Nagoya University Graduate School of Medicine (Approval number: 2015–0041).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Anonymised data of this study will be shared by request from any qualified investigator.
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