Leveraging Biomarkers of Traumatic Brain Injury in Adults to Assess Cerebral Injury in Children with Sickle Cell Disease

摘要： 脑损伤是镰状细胞病（SCD）的一个主要和衰弱的并发症。这些伤害开始 在患有SCD的儿童的早期发展中，并且通常在其一生中进展。脑损伤的类型 包括中风、无症状脑梗塞（SCI）、短暂性脑缺血发作和亚临床损伤。检测这些 活动可能困难重重，费用高昂，预防措施有限。迫切需要临床 用于早期检测SCD患者发育中大脑损伤以监测进展的实验室检查 和治疗效果。我们的团队先前进行的一项研究使用了单一分析物免疫测定， 研究表明，与健康儿童相比，儿童SCD患者的胶质细胞酸性蛋白（GFAP）升高， 儿童，检测急性梗死，并与智商呈负相关。Meso Scale Diagnostics（MSD） 创建了一个多重免疫测定面板，用于检测成人创伤性脑损伤（TBI）的生物标志物。 这种全面、高灵敏度的面板测量非常低水平（fg-pg/mL）的已知TBI生物标志物（tau， GFAP、S100β、UCH-L1、BDNF、NSE、MMP-9、CKBB、NRGN、NPTX 1、PRDX6、NF-L、MCP-1和VILIP-1）在 血浆和血清。我们这项提案的主要目标是确定血液中一种或多种 已建立的TBI生物标志物与通过磁共振成像（MRI）证实的脑损伤相关，或 神经认知功能评估为了在确诊的儿童中测试TBI生物标志物面板， 脑损伤后，将对来自无症状输血（SIT）试验的血浆样品进行分析。SIT试验测试了 定期输血是否可以减少SCI的复发或进展以及显性损伤的发生率， 通过MRI证实的中风，以及在这些损伤中观察到的神经认知的下降（如确定的 通过Wechsler和BRIEF评估）。在该提案中，SIT筛选来自 在试验入组时通过MRI判定为SCI阳性（SCI+）或阴性（SCI-）的SCD儿童， 分析与成人TBI相关的脑损伤生物标志物，以确定它们是否可以区分 SCI+组与SCI-组和健康对照组比较。时间点0、6、12、24和36个月的血浆 将对SCI-和SCI+受试者（随机分配至输注组或观察组）进行分析，以研究时间 脑损伤生物标志物在3年内的模式。我们还将评估治疗效果 分配（输血与观察），并寻找与新的神经损伤和事件的相关性， 研究期间发生的事件，包括退出MRI。使用线性回归模型，水平之间的相关性 的生物标志物和神经认知评估将进行探索，以确定神经认知的生物标志物 SCD患儿的发病率下降。这项研究将利用重要的现有资源来寻找生物标志物， 测量脑损伤和认知的微妙变化，这可以减少或消除昂贵测试的需要 如MRI，为SCD脑损伤的病因学提供了重要线索，并作为临床急需的 为患有SCD和其他脑损伤疾病的儿童和成人提供实验室工具。

Abstract: Cerebral injury is a major and debilitating complication of sickle cell disease (SCD). These injuries begin early in the development of children with SCD and often progress throughout their lives. Types of cerebral injury include stroke, silent cerebral infarct (SCI), transient ischemic attacks and subclinical injury. Detection of these events can be difficult and expensive, and preventive measures are limited. There is a critical need for clinical laboratory tests for early detection of injury in the developing brains of patients with SCD to monitor progression and treatment effect. A previous study conducted by our team using a single analyte immunoassay that we developed showed that glial fibrillary acidic protein (GFAP) is elevated in pediatric SCD patients vs. healthy children, detects acute infarcts and correlates negatively with IQ. Meso Scale Diagnostics (MSD) has recently created a multiplexed immunoassay panel for detection of biomarkers of traumatic brain injury (TBI) in adults. This comprehensive, highly sensitive panel measures very low levels (fg-pg/mL) of known TBI biomarkers (tau, GFAP, S100β, UCH-L1, BDNF, NSE, MMP-9, CKBB, NRGN, NPTX1, PRDX6, NF-L, MCP-1 and VILIP-1) in plasma and sera. Our primary goal for this proposal is to determine if the blood levels of one or more of these established TBI biomarkers correlate with brain injury confirmed by magnetic resonance imaging (MRI) or neurocognitive assessment in children with SCD. To test the TBI biomarker panel in children with confirmed brain injury, plasma samples from the Silent Infarct Transfusion (SIT) trial will be assayed. The SIT trial tested whether regular blood transfusions could reduce the recurrence or progression of SCI and incidence of overt stroke confirmed by MRI, as well as the decline in neurocognition that is seen with these injuries (as determined by Wechsler and BRIEF assessments), in children with SCD. In this proposal, SIT screening plasma from children with SCD that are either SCI positive (SCI+) or negative (SCI-), as adjudicated by MRI at trial entry, will be assayed for the brain injury biomarkers that correlate with TBI in adults, to determine if they can differentiate the SCI+ group from the SCI- group and healthy controls. Plasma from time points 0, 6, 12, 24 and 36 months from SCI- and SCI+ participants (randomized to transfusion or observation) will be assayed to study temporal patterns of the brain injury biomarkers over a 3-year period. We will also assess the effect of treatment assignment (transfusion vs. observation) and look for correlations with new neurologic injuries and events that occurred during the study, including exit MRI. Using linear regression modeling, correlations between the levels of the biomarkers and neurocognitive assessments will be explored to identify biomarkers of neurocognitive decline in children with SCD. This study will leverage important existing resources to find biomarkers that measure brain injury and subtle changes in cognition, which could reduce or obviate the need for expensive tests such as MRI, provide important clues to the etiology of brain injury in SCD, and serve as much needed clinical laboratory tools for children and adults with SCD and other brain injury disorders.