D-AMINO ACID OXIDASE CORRELATION WITH NEUROFILAMENT LIGHT CHAIN IN COVID-INFECTED PATIENTS
Authors: Liu *Yu-Li , Liu Tung-Hsia , Wang Chih-Hui , Kuo Hsiang-Wei , Huang Shiu-Feng , Tsou Hsiao-Hui , Chen Wei J 
Published: February 2025

Abstract

Background
COVID-19, which stands for Coronavirus Disease 2019, is caused by SARS-CoV-2 coronavirus and primarily manifests as a respiratory disease. However, the literature has reported its influence upon brain structure [1] and this observation finds additional support in the brain injury indicator, neurofilament light chain (NFL) [2]. Our NFL analysis in COVID-infected patients has indicated a correlation with the disease’ s severity. Nevertheless, the exact pathological pathway leading to brain neuronal injury remains elusive.

Aims & Objectives
In our prior analyses, we presented the findings on the NFL levels and their association with the syndrome observed in COVID-19-infected patients. In this study, we extended our investigation to include the examination of the oxidative stress indicator, D-amino acid oxidase (DAO) [3], in order to assess its correlation with NFL and its potential significance in COVID-infected patients.

Method
Plasma samples from 400 COVID-19 patients, drawn from 24 hospitals across Taiwan and sourced from the National Health Research Institutes (NHRI) Biobank, were utilized for the analysis of DAO via immunoassay. The NFL data was incorporated from our previous investigation. Statistical analyses encompassed the Mann-Whitney U test for comparing two groups, Spearman's correlation analysis for assessing bivariate correlations. To address the distribution in plasma DAO and NFL levels, we applied log-transformation before subjecting them to the general linear model, with age and gender adjustment.

Results
Among the 391 COVID-infected patients analyzed, the average plasma DAO level was 136 ng/ml. Notably, the 10 patients exhibiting the most severe brain injury (NFL levels above 200 pg/ml) had a significantly higher average plasma DAO level of 568.2 ng/ml, in contrast to the group with less severe brain injury (NFL levels less than 200 pg.ml) composed of 381 patients, who had an average DAO level of 124.7 ng/ml (P=0.002). The DAO level displayed a significant correlation with the NFL level (Spearman’ s r=0.31, P&lt;0.0001). Both the average NFL and DAO levels were significantly higher in patients over 50 years of age (P&lt;0.0001, respectively), indicating a significant age-related trend. Male patients showed higher NFL and DAO levels than females (P=0.0002, and P&lt;0.0001, respectively). The elevation in plasma NFL and DAO levels was most pronounced within the first 1-7 days after the COVID-19 diagnosis was confirmed, subsequently declining over the course of a month. Additionally, the correlation between DAO and NFL levels became more pronounced in patients age 50 and above (Spearman’ s r=0.37, P=0.0001) compared to those under 50 years of age (Spearman’ s r=0.237, P&lt;0.0001). Furthermore, the DAO level exhibited strong correlations with renal function indicators, specifically creatinine (Spearman’ s r=0.30, P=0.0002), and blood urea nitrogen (BUN) (Spearman’ s r=0.23, P=0.008).

Discussion & Conclusion
COVID-19 infection may lead to brain neuronal injury, particularly among male patients aged 50 and above. This neuronal injury exhibited a significant correlation with oxidative stress, as indicated by DAO. Furthermore, higher plasma DAO levels were associated with impaired kidney function, as indicated by elevated creatinine and BUN levels in clinical assessments. These results imply the involvement of oxidative stress in the pathological processes underlying brain neuronal injury.

References
1.Douaud, G., et al., SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature, 2022. 604(7907): p. 697-707.
2.Khalil, M., et al., Neurofilaments as biomarkers in neurological disorders. Nature Reviews Neurology, 2018. 14(10): p. 577-589.
3.Nagano, T., et al., d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species. Life Sci Alliance, 2019. 2(1): e201800045.