Department of Neurology, Peking University First Hospital, Beijing, China.
Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China.
Eur J Neurol. 2024 Dec;31(12):e16493. doi: 10.1111/ene.16493. Epub 2024 Sep 26.
The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.
The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.
Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 10 mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038).
Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.
炎症在肌萎缩侧索硬化症（ALS）中的重要作用正得到越来越多的研究支持。研究表明，循环无细胞线粒体 DNA（ccf-mtDNA）可以激活免疫系统，并与神经退行性疾病相关。本研究旨在定量检测 ALS 患者血清中的 ccf-mtDNA 水平。
回顾性分析 ALS 患者的病历资料。测量并比较了 62 例 ALS 患者和 46 例年龄匹配的健康对照者的血清 ccf-mtDNA 水平。此外，还使用酶联免疫吸附试验测量了 26 例 ALS 患者的血清白细胞介素 6（IL-6）水平。分析了变量之间的相关性。
ALS 患者的血清 ccf-mtDNA 明显升高。按基因型分层，超氧化物歧化酶 1（SOD1）突变组的 ccf-mtDNA 水平升高最显著。在所有 108 例个体中，ROC 曲线的截断值设定为 1.1×10 mtDNA 拷贝时，可识别出 ALS 患者，其敏感性为 80.7%，特异性为 50.0%；曲线下面积为 0.69（p<0.001）。此外，血清 ccf-mtDNA 水平与 ALS 的进展率（ΔFS；rs=-0.26，p=0.044）呈负相关，但与 ALSFRS-R 评分（rs=0.06，p=0.625）无关。重要的是，在 SOD1 突变组中，ccf-mtDNA 与 ΔFS 之间的相关性更为显著（rs=-0.62，p=0.018）。最后，我们发现 ALS 患者血清 ccf-mtDNA 水平与 IL-6 水平呈显著正相关（r s=0.41，p=0.038）。
本研究发现 ALS 患者血清中 ccf-mtDNA 升高，提示其与炎症过程和疾病机制有关。此外，ccf-mtDNA 可能是 ALS 进展的一个指标，特别是在 SOD1 突变患者中。
