Molecular imaging of brain injury and repair in NFL players

NFL 球员脑损伤和修复的分子成像

• 批准号: 10307103
• 负责人: Jennifer Marie Coughlin
• 金额: $ 51.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307103
• 关键词: Astrocytes; Binding; Biological Assay; Biological Markers; Biomechanics; Brain; Brain Injuries; Brain imaging; Brain region; Cells; Central Nervous System; Cerebrospinal Fluid; Cerebrum; Chronic; Clinical; Cognitive deficits; Control Groups; Corpus Callosum; Data; Deposition; Elderly; Exposure to; General Population; Generations; Genetic Predisposition to Disease; Genotype; Goals; Hippocampus; Human; Hyperactivity; Image; Immune; Immune response; Immune signaling; Immunologic Markers; Impaired cognition; Individual; Inferior; Inflammatory; Inflammatory Response; Infrastructure; Injury; Interferon Type II; Interleukin-6; Interview; Investigation; Link; Liquid substance; Longitudinal Studies; Manufactured football; Measurement; Measures; Methodology; Methods; Microglia; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuroimmune; Neurons; Neuropsychological Tests; Oxygen Consumption; Parietal Lobe; Participant; Peripheral; Plasma; Population; Positron-Emission Tomography; Predictive Factor; Prognosis; Proteins; Publishing; Recovery; Research; Research Infrastructure; Role; Sampling; Secondary to; Signal Transduction; Sports; Structure; Structure of supramarginal gyrus; TNF gene; Tauopathies; Temporal Lobe; Testing; Thalamic structure; Therapeutic; Time; Tissues; Traumatic Brain Injury; Visit; Work; axon injury; brain repair; cingulate cortex; cognitive testing; cohort; comparison control; contact sports; cytokine; design; entorhinal cortex; evidence base; experience; follow-up; glial activation; immune activation; improved; inflammatory marker; innovation; mild traumatic brain injury; molecular imaging; novel therapeutics; radiotracer; symptomatology; tau Proteins; white matter change

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.

项目概要 该项目的目标是了解持续免疫信号对脑损伤和 通过成像和循环细胞因子研究修复前国家橄榄球联盟 (NFL) 球员。 我们担心这些人比一般人更容易出现认知障碍 人口，这可能适用于参加其他运动或其他形式的重复运动的人 创伤性脑损伤（TBI）。我们专注于测量小胶质细胞的活性，小胶质细胞是人体的常驻免疫细胞。 中枢神经系统，因为它们在应对脑损伤方面很重要。根据已发表的证据和我们的 根据初步数据，我们假设前 NFL 球员的小胶质细胞功能高度激活 大脑区域容易因碰撞运动而受伤。这种损伤的特点是表达增加 小胶质细胞和反应性星形胶质细胞的易位蛋白 18 KDa (TSPO)。我们进一步假设 反复轴突损伤区域的小胶质细胞长期激活会导致神经元能量和功能下降 与神经退行性变在机制上相关的缺陷。我们最近证明 [11C]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 人类神经退行性疾病中的脑损伤和修复。在第一项 NFL 球员 TSPO 研究中，我们 研究发现，与老年对照相比，老年玩家大脑中的 DPA 结合更高。我们最新发布的 研究结果还表明，与年轻、现役或最近退役的 NFL 球员相比，DPA 结合率更高 对照组的非碰撞运动运动员的几个相同的皮质和内侧颞叶 在已发布的老玩家试点中测试的结构。两名年轻球员最近回归两年 后续成像显示所有测试的大脑区域都有稳定的 TSPO 分布，其中一个区域还 在第二次就诊时，基于 PET 的证据显示几个大脑区域的 tau 蛋白负荷增加。他是 15 名年轻 NFL 球员中的 8 名在其基线 DPA 上具有高外周促炎标记物特征 成像，支持促炎信号传导与异常 tau 易感性之间的假设联系 反复TBI后沉积。我们现在建议使用 DPA PET 测量 TSPO 的分布 35 名最近退役的 NFL 球员的大脑与 35 名健康、无碰撞运动运动员的对照组进行比较 （目标 1）与同一人群中炎症标志物的生物流体（脑脊液、血浆）检测平行（目标 2）。这些免疫标记物的（两年）持久性将在目标 3 中进行测试。我们的设计使用 DPA，它 与其他第二代放射性示踪剂相比，TSPO 成像具有优势。我们的研究基础设施 精心挑选的年轻前 NFL 球员和控制措施是独一无二的，但与其他方法一致 研究老年 NFL 球员的小组。通过表征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，告知 预后，并提出可能推广到其他 TBI 人群的新疗法。

项目成果

Characterizing the Link Between Glial Activation and Changed Functional Connectivity in National Football League Players Using Multimodal Neuroimaging.

使用多模态神经影像学表征国家橄榄球联盟球员中神经胶质激活和功能连接变化之间的联系。

• 发表时间: 2020
• 作者: Peters, Matthew E;Rahman, Saudur;Coughlin, Jennifer M;Pomper, Martin G;Sair, Haris I
• 通讯作者: Sair, Haris I

Meta-analysis of the Glial Marker TSPO in Psychosis Revisited: Reconciling Inconclusive Findings of Patient-Control Differences.

精神病中神经胶质标记物 TSPO 的荟萃分析重温：调和患者控制差异的不确定结果。

• 发表时间: 2021
• 影响因子: 10.6
• 作者: Plavén;Matheson, Granville J;Coughlin, Jennifer M;Hafizi, Sina;Laurikainen, Heikki;Ottoy, Julie;De Picker, Livia;Rusjan, Pablo;Hietala, Jarmo;Howes, Oliver D;Mizrahi, Romina;Morrens, Manuel;Pomper, Martin G;Cervenka, Simon
• 通讯作者: Cervenka, Simon