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Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis

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Abstract

Objective

To assess the changes of muscle-related biomarkers at the early stage of amyotrophic lateral sclerosis, and to confirm these findings in an experimental animal model.

Methods

Thirty-nine subjects with sporadic amyotrophic lateral sclerosis and 20 healthy controls were enrolled and longitudinally evaluated. We evaluated serum creatine kinase and creatinine levels and appendicular lean soft-tissue mass using dual X-ray absorptiometry. The levels of biomarkers at early ALS stages were estimated using linear mixed models with unstructured correlation and random intercepts. We also analyzed the longitudinal changes of serum creatine kinase and creatinine, together with the mRNA levels of acetylcholine receptor subunit γ (Chrng) and muscle-associated receptor tyrosine kinase, markers of denervation, in the gastrocnemius muscle of superoxide dismutase 1 (SOD1)G93A transgenic mice, an animal model of amyotrophic lateral sclerosis.

Results

The estimated levels of creatine kinase were higher in subjects with amyotrophic lateral sclerosis at the early stage than in healthy controls, although the estimated appendicular lean soft-tissue mass and creatinine levels were equivalent between both groups, suggesting that the elevation of creatine kinase precedes both muscular atrophy and subjective motor symptoms in sporadic amyotrophic lateral sclerosis. In SOD1G93A mice, the serum levels of creatine kinase were elevated at 9 weeks of age (peri-onset) when Chrng started to be up-regulated, and were then down-regulated at 15 weeks of age, consistent with the clinical data from patients with sporadic amyotrophic lateral sclerosis.

Interpretation

Creatine kinase elevation precedes muscular atrophy and reflects muscle denervation at the early stage.

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Acknowledgements

This work was funded by a Grant-in-Aid (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 17H04195); grants from the Japan Agency for Medical Research and Development (Nos. 17ek0109221h0001 and 18ek0109221h0002); a Grant from the Naito Foundation; and a Grant from the Hori Sciences and Arts Foundation.

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Authors and Affiliations

  1. Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Daisuke Ito, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Madoka Iida, Yoshiyuki Kishimoto, Hideyuki Moriyoshi & Masahisa Katsuno

  2. Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Akihiro Hirakawa

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  1. Daisuke Ito
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Contributions

DI, AH, and MK conceived and designed the study. DI, AH, YH, SY, YK, and HM contributed to the acquisition of clinical data. DI, MI, and YI performed animal experiments. DI and MK performed analysis and interpretation of the data. AH performed statistical analysis. DI drafted the manuscript, and AH and MK revised it for intellectual content.

Corresponding authors

Correspondence to Atsushi Hashizume or Masahisa Katsuno.

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Conflicts of interest

The authors have no relevant conflicts of interest to report.

Ethical standards

This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments, the Ethics Guidelines for Human Genome/Gene Analysis Research, and the Ethical Guidelines for Medical and Health Research Involving Human Subjects endorsed by the Japanese government. This study was approved by the Ethics Review Committee of Nagoya University Graduate School of Medicine (Nos. 2013–0035 and 2015–0041), and all participants gave written informed consent before participation. All of the animal experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and under the approval of the Nagoya University Animal Experiment Committee (No. 29170).

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Ito, D., Hashizume, A., Hijikata, Y. et al. Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. J Neurol 266, 2952–2961 (2019). https://doi.org/10.1007/s00415-019-09507-6

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  • DOI: https://doi.org/10.1007/s00415-019-09507-6

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