The Acute Phase Serum Zinc Concentration Is a Reliable Biomarker for Predicting the Functional Outcome After Spinal Cord Injury

Abstract

Background: Spinal cord injury (SCI) is a devastating disorder for which the accurate prediction of the functional prognosis is urgently needed. Due to the lack of reliable prediction methods, the acute evaluation of SCI severity and therapeutic intervention efficacy is extremely difficult, presenting major obstacles to the development of acute SCI treatment. We herein report a novel method for accurately predicting the functional prognosis using the acute-phase serum zinc concentration after SCI. Methods: We produced experimental animal SCI models with different prognoses and examined the relationship among the SCI severity, functional outcome, and acute-phase serum zinc concentration. We also examined whether we could predict the functional prognosis by evaluating the serum zinc concentration within 72 h after SCI in a human prospective study. Findings: In a mouse model, the acute serum zinc concentrations decreased in proportion to SCI severity and the serum zinc concentrations at 12 h after SCI accurately predicted the functional prognosis. We clarified the mechanism underlying this serum zinc proportional decrease, showing that activated monocytes took up zinc from blood-serum and then infiltrated the lesion area in a severity-dependent manner. A non-linear regression analysis of 38 SCI patients showed that the serum zinc concentrations in the acute-phase accurately predicted the long-term functional outcome (R2=0·84) more accurately than any other previously reported acute-phase biomarkers. Interpretation: The acute-phase serum zinc concentration could be a useful biomarker for predicting the functional prognosis. This simple method will allow for more objective clinical trials and the development of patient-tailored treatment for SCI. Funding Statement: This study was supported by JSPS KAKENHI Grant Number JP18K16680 (K.K.); a Grant-in-Aid for Scientific Research (B) (16H05450) (S.O.); Challenging Exploratory Research from the Ministry of Education, Science, and Sports (16K15668) (S.O.); and research foundations from the general insurance association of Japan (K.K.). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All animal studies were approved by the Committee of Ethics on Animal Experimentation of our institute and conducted in accordance with the National Institutes of Health guidelines for the care and use of animals. All human study involving the analysis of medical record data was conducted according to the principles expressed in the Declaration of Helsinki and was approved by the Institutional Review Board. Informed consent was obtained from each subject.