Al-Hakeim Hussein Kadhem, Al-Naqeeb Tabarek Hadi, Almulla Abbas F, Maes Michael
Department of Chemistry, Faculty of Science, University of Kufa, Iraq.
College of Pharmacy, The Islamic University, Najaf, Iraq.
J Affect Disord. 2023 Jun 15;331:300-312. doi: 10.1016/j.jad.2023.03.072. Epub 2023 Mar 28.
Major depressive disorder (MDD) is characterized by elevated activity of peripheral neuro-immune and neuro-oxidative pathways, which may cause neuro-affective toxicity by disrupting neuronal circuits in the brain. No study has explored peripheral indicators of neuroaxis damage in MDD in relation to serum inflammatory and insulin resistance (IR) biomarkers, calcium, and the physio-affective phenome consisting of depressive, anxious, chronic fatigue, and physiosomatic symptoms.
Serum levels of phosphorylated tau protein 217 (P-tau217), platelet-derived growth factor receptor beta (PDGFR), neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), C-reactive protein (CRP), calcium and the HOMA2-insulin resistance (IR) index were measured in 94 MDD patients and 47 controls.
61.1 % of the variance in the physio-affective phenome (conceptualized as a factor extracted from depression, anxiety, fatigue and physiosomatic symptoms) is explained by the regression on GFAP, NF-L, P-tau2017, PDGFRβ and HOMA2-IR (all positively associated), and decreased calcium. In addition, CRP and HOMA2-IR predicted 28.9 % of the variance in the neuroaxis index. We observed significant indirect effects of CRP and calcium on the physio-affective phenome which were partly mediated by the four neuroaxis biomarkers. Annotation and enrichment analysis revealed that the enlarged GFAP, P-tau217, PDGFR, and NF-L network was enriched in glial cell and neuronal projections, the cytoskeleton and axonal transport, including a mitochondrion.
Peripheral inflammation and IR may damage the astroglial and neuronal projections thereby interfering with mitochondrial transport. This neurotoxicity, combined with inflammation, IR and lowered calcium, may, at least in part, induce the phenome of MDD.
重度抑郁症（MDD）的特征是外周神经免疫和神经氧化途径的活性升高，这可能通过破坏大脑中的神经元回路而导致神经情感毒性。尚无研究探讨MDD中神经轴损伤的外周指标与血清炎症和胰岛素抵抗（IR）生物标志物、钙以及由抑郁、焦虑、慢性疲劳和心身症状组成的生理情感表型之间的关系。
测量了94例MDD患者和47例对照者血清中磷酸化tau蛋白217（P-tau217）、血小板衍生生长因子受体β（PDGFR）、神经丝轻链（NF-L）、胶质纤维酸性蛋白（GFAP）、C反应蛋白（CRP）、钙和HOMA2-胰岛素抵抗（IR）指数水平。
生理情感表型（概念化为从抑郁、焦虑、疲劳和心身症状中提取的一个因子）中61.1%的变异可由GFAP、NF-L、P-tau2017、PDGFRβ和HOMA2-IR（均呈正相关）以及钙降低的回归分析来解释。此外，CRP和HOMA2-IR预测了神经轴指数中28.9%的变异。我们观察到CRP和钙对生理情感表型有显著的间接影响，部分由四种神经轴生物标志物介导。注释和富集分析显示，扩大的GFAP、P-tau217、PDGFR和NF-L网络在神经胶质细胞和神经元投射、细胞骨架和轴突运输（包括线粒体）中富集。
外周炎症和IR可能损害星形胶质细胞和神经元投射，从而干扰线粒体运输。这种神经毒性，与炎症、IR和钙降低相结合，可能至少部分地诱发MDD的表型。
