Objective: Methylmalonic acidemia (MMA) is the most common organic acidemia in children. Many patients with MMA suffered from cognitive impairments. The aim of this study was to identify the significance of cytokines and oxidative stress biomarkers in MMA-induced cognitive impairment. Methods: We enrolled 64 children with combined MMA and homocystinuria and 64 age- and sex-matched healthy volunteers. Participants were subsequently classified as with or without cognitive impairments using a uniform neuropsychological assessment test. Serum samples were collected. The serum levels of cytokines and oxidative stress biomarkers were measured using the ELISA or chemical methods. Results: Compared to control group, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), and nitric oxide (NO) in the MMA patients increased markedly (p #x3c; 0.05); glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (p #x3c; 0.01). The levels of IL-6, TNF-α, NO, and MDA in the serum were negatively associated with DQ or IQ scores. The levels of GSH and SOD in the serum were positively correlated with DQ or IQ scores. After receiver operating characteristic curve analysis, NO was the most useful individual marker for distinguishing the cognitive dysfunction, corresponding to the area under ROC curve (AUC) of 0.82 (95% CI, 0.74–0.91), sensitivity of 76.60%, and specificity of 80.25%. GSH and MDA were also useful for diagnosis of MMA-induced cognitive dysfunction, corresponding to the AUC of 0.80 (95% CI, 0.70–0.89), and 0.73 (95% CI, 0.63–0.82), respectively. The sensitivity and specificity of GSH were 72.34 and 80.25%, respectively. The sensitivity and specificity of MDA were 85.11 and 51.85%, respectively. Conclusions: The high-concentration methylmalonic acid in the blood induced immune cells to release pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines and high-concentration methylmalonic acid stimulated the immune cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). The serum methylmalonic acid, cytokines, ROS, and RNS were across the blood-brain barrier and induced cognitive impairment. The small molecule substances such as serum NO, MDA, and GSH participated in the process of neuroinflammation and oxidative stress injury induced by MMA and could be useful for distinguishing the cognitive impairment.
Neuroimmunomodulation

中文翻译：

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甲基丙二酸血症所致认知障碍中细胞因子和氧化应激生物标志物的测定

目的：甲基丙二酸血症（MMA）是儿童最常见的有机酸血症。许多 MMA 患者患有认知障碍。本研究的目的是确定细胞因子和氧化应激生物标志物在 MMA 诱导的认知障碍中的重要性。方法：我们招募了 64 名合并 MMA 和高胱氨酸尿症的儿童和 64 名年龄和性别匹配的健康志愿者。随后使用统一的神经心理学评估测试将参与者分类为有或没有认知障碍。收集血清样品。使用ELISA或化学方法测量细胞因子和氧化应激生物标志物的血清水平。结果：与对照组相比，MMA患者血清肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、丙二醛（MDA）和一氧化氮（NO）水平显着升高（p #x3c；0.05）；谷胱甘肽（GSH）和超氧化物歧化酶（SOD）明显下降（p#x3c; 0.01）。血清中 IL-6、TNF-α、NO 和 MDA 的水平与 DQ 或 IQ 评分呈负相关。血清中GSH和SOD水平与DQ或IQ评分呈正相关。接受者操作特征曲线分析后，NO是区分认知功能障碍最有用的个体标志物，对应的ROC曲线下面积（AUC）为0.82（95% CI，0.74-0.91），敏感性为76.60%，特异性为80.25%。GSH 和 MDA 也可用于诊断 MMA 引起的认知功能障碍，对应的 AUC 分别为 0.80（95% CI，0.70-0.89）和 0.73（95% CI，0.63-0.82）。GSH的敏感性和特异性分别为72.34%和80.25%。MDA 的敏感性和特异性分别为 85.11 和 51.85%。结论：血液中的高浓度甲基丙二酸诱导免疫细胞释放促炎细胞因子，如 TNF-α 和 IL-6。这些细胞因子和高浓度甲基丙二酸刺激免疫细胞产生活性氧 (ROS) 和活性氮 (RNS)。血清甲基丙二酸、细胞因子、ROS 和 RNS 穿过血脑屏障并诱导认知障碍。血清NO、MDA、GSH等小分子物质参与了MMA诱导的神经炎症和氧化应激损伤过程，可用于鉴别认知障碍。
神经免疫调节