背景:动脉瘤性蛛网膜下腔出血(aSAH)等损伤后的脑恢复机制,缺血性卒中(IS),创伤性脑损伤(TBI)涉及大脑可塑性,突触再生,和神经炎症。我们假设p75神经营养受体(p75NTR)和相关信号蛋白的血清水平,以及差异表达(DE)microRNAs,无论损伤类型如何,都可以预测康复结果。
方法:缺血性卒中的前瞻性患者队列(IS,n=30),动脉瘤性蛛网膜下腔出血(aSAH,n=31),和创伤性脑损伤(TBI,n=13)进行了评估(总共n=74)。在两个伤后间隔(早期:1-3天,迟到:4-8天),三个月后使用改良的Rankin量表(mRS)评估结果,将结果分为有利(mRS0-3)或不利(mRS4-6)。使用ELISA测量六种蛋白质:p75NTR,NGF,sortilin,IL1β,TNFα,和亲环素。使用DESeq2鉴定DEmicroRNA,并预测其靶基因。使用Kolmogorov-Smirnov检验比较具有不同结果的患者之间的血清分子,双尾t检验和多元线性判别分析(LDA)。
结果:有利(n=46)和不利(n=28)结果队列与年龄和性别相平衡(p=0.25和0.63)。研究的蛋白质都与年龄无关。6种蛋白质生物标志物的组合LDA显示良好预后价值(OR2.09;AUC=70.3%,p=0.0058)。在aSAH中鉴定了微小RNA表达随时间的变化,TBI,和IS组(p<0.05,FDR校正)。当比较有利和不利结果时,23个微小RNA在所有脑损伤组中通常是DE(p<0.05)。针对所研究蛋白质的四种microRNA的LDA显示出较高的预后准确性(OR11.7;AUC=94.1%,p=0.016)。
结论:联合预测microRNA和蛋白质生物标志物模型证明了不同损伤类型的准确预后预测,暗示存在共同的恢复机制。发现DEmicroRNA靶向研究的分子,表明在恢复中的潜在机制作用。需要进一步的研究来研究这些分子的预后,以及增强恢复的治疗目标。
BACKGROUND: Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type.
METHODS: A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74). Serum samples were collected at two post-injury intervals (early: 1-3 days, late: 4-8 days), and outcomes were assessed after three months using the modified Rankin Scale (mRS), categorizing outcomes as favorable (mRS 0-3) or unfavorable (mRS 4-6). Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1β, TNFα, and cyclophilin. DE microRNAs were identified using DESeq2, and their target genes were predicted. Serum molecules between patients with differing outcomes were compared using a Kolmogorov-Smirnov test, 2-tailed t-test and multivariate linear discriminant analysis (LDA).
RESULTS: Favorable (n = 46) and unfavorable (n = 28) outcome cohorts were balanced with age and sex (p = 0.25 and 0.63). None of the studied proteins correlated with age. Combinatory LDA of the six protein biomarkers indicated strong prognostic value for favorable outcomes (OR 2.09; AUC = 70.3%, p = 0.0058). MicroRNA expression changes over time were identified in the aSAH, TBI, and IS groups (p < 0.05, FDR corrected). Twenty-three microRNAs were commonly DE across all brain injury groups when comparing favorable and unfavorable outcomes (p < 0.05). LDA of four microRNAs targeting the studied proteins showed high prognostic accuracy (OR 11.7; AUC = 94.1%, p = 0.016).
CONCLUSIONS: The combined prognostic microRNA and protein biomarker models demonstrated accurate outcome prognostication across diverse injury types, implying the presence of a common recovery mechanism. DE microRNAs were found to target the studied molecules, suggesting a potential mechanistic role in recovery. Further investigation is warranted to study these molecules in prognostication, as well as therapeutic targets for enhancing recovery.