Molecular imaging of brain injury and repair in NFL players

项目总结 该项目的目标是了解持续免疫信号在脑损伤和 通过成像和循环细胞因子的研究对前国家橄榄球联盟(NFL)球员进行修复。 我们担心这些人发展认知障碍的比率比一般人高。 人口，这可以推广到那些参加其他运动或有其他形式的重复的人 创伤性脑损伤(TBI)。我们专注于测量小胶质细胞的活性，小胶质细胞是 中枢神经系统，因为它们在应对脑损伤方面的重要性。基于已公布的证据和我们的 初步数据，我们假设前NFL球员有功能性过度激活的小胶质细胞 在容易受到碰撞运动伤害的大脑区域。这种损伤的特点是表达增加的 小胶质细胞和反应性星形胶质细胞的转运蛋白18 KDa(TSPO)。我们进一步假设 反复轴索损伤区域小胶质细胞的长时间激活导致神经元能量和功能 与神经退化有机械联系的缺陷。我们最近发现[11C]DPA-713(DPA) 正电子发射断层扫描(PET)可以用来测量TSPO的表达增加，TSPO是一种 人类神经退行性疾病中的脑损伤和修复。在NFL球员TSPO的第一次研究中，我们 与老年对照组相比，老年球员的大脑中发现了更高的DPA结合。我们最新出版的 研究结果还显示，在一组年轻的、活跃的或最近退役的NFL球员中，DPA的结合量比 给几个相同皮质和内侧颞叶的无碰撞运动运动员的对照组 在公布的较老玩家的试点中测试的结构。两名年轻球员最近复出，为期两年 后续成像显示TSPO在所有测试的脑区都有稳定的分布，其中一个区域还 在第二次检查中，显示了基于PET的证据表明几个大脑区域的tau负荷增加。他是 在15名年轻的NFL球员中，有8名在基线DPA时外周血促炎症标志物水平较高 成像，支持促炎信号与异常tau易感性之间的假设联系 反复颅脑损伤后的沉积。我们现在建议使用DPA PET来测量TSPO在 35名新近退役的NFL球员的大脑与35名健康、无碰撞的运动运动员的对照组进行比较 (目标1)与生物体液(脑脊液、血浆)同时检测同一人群中的炎症标志物(目标1) 2)。这些免疫标记的(两年)持久性将在目标3中进行测试。我们的设计使用DPA，它 与其他第二代放射性示踪剂相比，具有成像TSPO的优势。我们用于研究的基础设施 精心挑选的年轻、前NFL球员和控制组是独特的，但又与其他 研究年长NFL球员的小组。通过对脑部持续性炎症反应的研究 年轻的，前NFL球员，我们将提供一个基础，了解随后的症状，告知 预后，并建议新的治疗方法，可以推广到其他患有脑外伤的人群。

PROJECT SUMMARY The goal of this project is to understand the contribution of persistent immune signaling to brain injury and repair in former National Football League (NFL) players through imaging and the study of circulating cytokines. We are concerned that such individuals develop cognitive impairment at a higher rate than the general population, which may be generalizable to those participating in other sports or with other forms of repeated traumatic brain injury (TBI). We focus on measuring the activity of microglia, the resident immune cells of the CNS, because of their importance in responding to brain injury. Based on published evidence and our preliminary data, we hypothesize that former NFL players have functionally hyper-activated microglia located in brain regions vulnerable to injury from collision sports. Such injury is marked by increased expression of translocator protein 18 KDa (TSPO) by microglial cells and reactive astrocytes. We further hypothesize that prolonged microglial activation in regions of repeated axonal injury causes neuronal energy and functional deficits that are mechanistically linked to neurodegeneration. We recently showed that [11C]DPA-713 (DPA) positron emission tomography (PET) can be used to measure increased expression of TSPO, a marker of brain injury and repair, in human neurodegenerative disease. In the first study of TSPO in NFL players, we found higher DPA binding in the brains of elderly players compared to elderly controls. Our newer published findings also reveal higher DPA binding in a cohort of young, active or recently retired NFL players compared to a control group of non-collision sport athletes in several of the same cortical and mesial temporal lobe structures tested in the published pilot of older players. Two young players recently returned for two-year follow-up imaging that revealed stable TSPO distribution in all brain regions tested, and one of them also showed PET-based evidence of increased tau burden in several brain regions at this second visit. He was among eight of 15 young NFL players with high peripheral pro-inflammatory marker profile at his baseline DPA imaging, supporting the hypothesized link between pro-inflammatory signaling and vulnerability to aberrant tau deposition after repeated TBI. We now propose to measure the distribution of TSPO using DPA PET in the brains of 35 recently former NFL players compared to a control group of 35 healthy, non-collision sport athletes (Aim 1) in parallel with biofluid (CSF, plasma) assays for markers of inflammation in the same population (Aim 2). The (two-year) persistence of these immune markers will be tested in Aim 3. Our design uses DPA, which has advantages over other 2nd-generation radiotracers for imaging TSPO. Our infrastructure for research of carefully selected young, former NFL players and controls is unique and yet aligns with methodology of other groups studying elderly NFL players. By characterizing the persistent inflammatory response in the brains of young, former NFL players, we will provide a basis for understanding ensuing symptomatology, informing prognosis, and suggesting new therapies that may generalize to other populations with TBI.