Molecular imaging of brain injury and repair in NFL players

项目摘要 该项目的目标是了解持续免疫信号对脑损伤的贡献， 通过成像和循环细胞因子的研究，在前国家橄榄球联盟（NFL）球员的修复。 我们担心这些人比一般人更容易出现认知障碍。 人口，这可能是概括为那些参加其他运动或与其他形式的重复 创伤性脑损伤（TBI）。我们专注于测量小胶质细胞的活性，小胶质细胞是大脑中的常驻免疫细胞。 CNS，因为它们在对脑损伤的反应中的重要性。根据已发表的证据和我们的 初步数据，我们假设前NFL球员有功能性超激活的小胶质细胞位于 大脑中易受碰撞运动伤害的区域。这种损伤的标志是 转运蛋白18 KDa（TSPO）通过小胶质细胞和反应性星形胶质细胞。我们进一步假设， 在反复轴突损伤的区域中延长的小胶质细胞活化引起神经元能量和功能性损伤。 与神经退行性疾病有关的缺陷。我们最近发现[11 C]DPA-713（DPA） 正电子发射断层扫描（PET）可用于测量TSPO表达的增加，TSPO是肿瘤的标志物， 脑损伤和修复，在人类神经退行性疾病。在NFL球员的TSPO的第一项研究中，我们 发现老年运动员的大脑比老年对照组有更高的DPA结合。我们最新发布的 研究结果还显示，与年轻、活跃或最近退役的NFL球员相比， 对照组的非碰撞运动员在几个相同的皮质和内侧颞叶 结构测试中公布的试点老球员。两名年轻球员最近回来了两年 随访成像显示TSPO在所有测试的大脑区域中分布稳定，其中一个区域还 在第二次访视时，显示了基于PET的证据，表明在几个脑区域中tau负荷增加。他是 在15名年轻的NFL球员中，有8名在基线DPA时具有高外周促炎标记物 成像，支持促炎信号传导和异常tau蛋白易感性之间的假设联系 反复TBI后沉积。我们现在提出使用DPA PET测量TSPO的分布， 将35名最近退役的NFL球员的大脑与35名健康、无碰撞运动员的对照组进行比较 (Aim 1）与生物流体（CSF，血浆）测定平行，用于相同群体中的炎症标志物（目的 2）。这些免疫标志物的（两年）持久性将在目标3中进行测试。我们的设计使用DPA， 与其他第二代放射性示踪剂相比，具有用于TSPO成像的优势。我们的研究基础设施 精心挑选的年轻，前NFL球员和控制是独特的，但与其他方法保持一致。 研究老年NFL球员的组织。通过描述大脑中持续的炎症反应， 年轻的前NFL球员，我们将为了解随后的症状提供基础，并告知 预后，并提出新的治疗方法，可能推广到其他人群与TBI。

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.