Maes Michael, Barbosa Décio Sabbatini, Almulla Abbas F, Kanchanatawan Buranee
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Psychiatry, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria.
Antioxidants (Basel). 2022 Apr 20;11(5):803. doi: 10.3390/antiox11050803.
No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV, which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter, we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion, (a) PP symptoms belong to the TLE phenome, and the signal increased severity; and (b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.
迄今为止，尚未建立颞叶癫痫（TLE）及相关精神共病的精准医学模型。这项观察性研究旨在开发一种基于数据驱动的精准通用共病TLE模型，该模型具有内表型类别和通路表型，可能具有预后和治疗意义。我们招募了40名健康对照者和108名TLE患者进行本研究，并评估了TLE和精神病理学（PP）特征以及氧化应激（OSTOX，如丙二醛或MDA、脂质氢过氧化物和晚期氧化蛋白产物）和抗氧化剂（对氧磷酶1或PON1状态、-SH基团和总自由基捕获能力或TRAP）生物标志物。从上述TLE和PP特征中提取的潜在向量（LV）中，很大一部分（57.2%）的方差可由这些OSTOX和抗氧化剂生物标志物解释。PON1 Q192R基因变异对该LV有间接影响，这些影响完全由PON1活性和MDA介导。因子分析表明，可以从TLE、PP、OSTOX和抗氧化剂评分中提取一个共同核心，这表明这些特征是一个共同潜在结构的表现，即TLE的一种新的通路表型。基于此，我们构建了一个新的表型类别，其特征是TLE、PP和OSTOX特征的严重程度增加，抗氧化防御能力降低。发作频率的很大一部分方差可由MDA增加、抗氧化剂降低和一氧化氮代谢物水平降低来解释。总之，（a）PP症状属于TLE表型组且信号严重程度增加；（b）醛形成和抗氧化剂降低的累积效应决定癫痫发作的点燃。
