Goetzl Laura, Merabova Nana, Darbinian Nune, Martirosyan Diana, Poletto Erica, Fugarolas Keri, Menkiti Ogechukwu
Departments of Obstetrics & Gynecology Lewis Katz School of Medicine at Temple University Philadelphia Pennsylvania.
Shriner's Hospital Pediatric Research Center for Neural Repair and Rehabilitation Philadelphia Pennsylvania.
Ann Clin Transl Neurol. 2017 Nov 24;5(1):4-10. doi: 10.1002/acn3.499. eCollection 2018 Jan.
Neuronal exosomes purified from peripheral blood samples have been proposed as diagnostic tool in the setting of acute brain injury but never tested clinically. We hypothesized that exosome protein biomarkers would change over time following acute hypoxic brain injury and would predict response to therapy.
Synaptopodin (SYNPO), an actin-associated protein present in postsynaptic spines, was evaluated as a potential biomarker as well as: synaptophysin, neuron-specific enolase, and mitochondrial cytochrome c oxidase. A secondary analysis was performed on neonatal samples collected at 8, 10, and 14 h after the initiation of therapeutic-controlled hypothermia for acute hypoxic-ischemic encephalopathy ( = 14). Neuronal exosomes were purified from serum and protein levels were quantified using standard ELISA methods. The primary study outcomes were length of stay (LOS), discharge on seizure medication (DCMED), and composite neuroimaging score (NIS).
The slope of change in neuronal exosome SYNPO between 8 and 14 h appeared to be the most promising biomarker for all three clinical study outcomes. SYNPO was highly correlated with LOS (-0.91, < 0.001). SYNPO increased in 6/8 without DCMED and was worse or neutral in 5/5 with DCMED ( = 0.02). All four neonates with an abnormal NIS had neutral or decreasing SYNPO ( = 0.055). Other candidate biomarkers were not associated with outcomes.
This report provides the first clinical evidence that neural exosomes turn over rapidly enough in the peripheral circulation to be used as a "troponin-like" test following acute brain injury. Optimal sampling and biomarkers likely vary with type of brain injury.
从外周血样本中纯化的神经元外泌体已被提议作为急性脑损伤诊断工具，但尚未进行临床测试。我们假设外泌体蛋白生物标志物在急性缺氧性脑损伤后会随时间变化，并可预测治疗反应。
评估突触后棘中存在的一种肌动蛋白相关蛋白——突触足蛋白（SYNPO）作为潜在生物标志物，同时评估突触素、神经元特异性烯醇化酶和线粒体细胞色素c氧化酶。对因急性缺氧缺血性脑病接受治疗性低温治疗开始后8、10和14小时收集的新生儿样本进行二次分析（n = 14）。从血清中纯化神经元外泌体，并使用标准ELISA方法对蛋白质水平进行定量。主要研究结局为住院时间（LOS）、出院时服用抗癫痫药物情况（DCMED）和综合神经影像评分（NIS）。
8至14小时期间神经元外泌体SYNPO的变化斜率似乎是所有三个临床研究结局最有前景的生物标志物。SYNPO与LOS高度相关（-0.91，P < 0.001）。6/8未服用DCMED的患儿SYNPO升高，而5/5服用DCMED的患儿SYNPO降低或无变化（P = 0.02）。所有四名NIS异常的新生儿SYNPO均无变化或降低（P = 0.055）。其他候选生物标志物与结局无关。
本报告提供了首个临床证据，表明神经外泌体在外周循环中周转速度足够快，可在急性脑损伤后用作“肌钙蛋白样”检测。最佳采样和生物标志物可能因脑损伤类型而异。
