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.

项目摘要 该项目的目的是了解持续性免疫信号对脑损伤和 通过成像和循环细胞因子的研究在前国家橄榄球联盟（NFL）球员中维修。 我们担心这样的人以比一般性更高的认知障碍发展 人口，可能可以推广到参加其他运动或其他形式重复的人 创伤性脑损伤（TBI）。我们专注于测量小胶质细胞的活性，小胶质细胞的活性 中枢神经系统，因为它们在应对脑损伤方面的重要性。根据已发表的证据和我们的 初步数据，我们假设以前的NFL参与者具有功能过多激活的小胶质细胞 在大脑区域，碰撞运动受伤。这种伤害标志着增加的表达 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 重复轴突损伤区域中长时的小胶质细胞激活会引起神经元能和功能 与神经退行性关系机械上的缺陷。我们最近表明[11C] DPA-713（DPA） 正电子发射断层扫描（PET）可用于测量TSPO的表达增加，TSPO的标志 人类神经退行性疾病中的脑损伤和修复。在NFL球员的TSPO的首次研究中，我们 与老年对照组相比，老年玩家大脑中的DPA结合更高。我们的新出版 研究结果还显示，在一群年轻，活跃或最近退休的NFL球员中，DPA绑定更高 在同一皮质和介体颞叶中的一组非碰撞运动运动员的对照组 在已发表的老年玩家飞行员中测试的结构。两名年轻球员最近返回了两年 后续成像揭示了所有测试的大脑区域中稳定的TSPO分布，其中之一也 在第二次访问中，显示了基于宠物的大脑区域的tau负担增加的证据。他是 在15名年轻NFL球员中，有八名在基线DPA中具有高外围促炎标记的概况 成像，支持促炎信号传导与异常tau的脆弱性之间的假设联系 重复TBI后沉积。现在，我们建议使用DPA PET测量TSPO的分布 与35个健康，非碰撞运动员组成的对照组相比，最近有35名前NFL球员的大脑与前NFL球员相比 （AIM 1）与同一人群中炎症标志物的生物流体（CSF，等离子体）并行（目标） 2）。这些免疫标记物的（两年）将在AIM 3中进行测试。我们的设计使用DPA， 比其他第二代放射性示例具有成像TSPO的优势。我们的研究基础设施 精心挑选的年轻，前NFL球员和控件是独一无二的，但与其他方法相符 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，前NFL球员，我们将提供理解随之而来的症状学的基础，并告知 预后，并提出可能将其推广到其他TBI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。

• DOI: 10.1176/appi.neuropsych.18110274
• 发表时间: 2020
• 期刊: The Journal of neuropsychiatry and clinical neurosciences
• 作者: Peters,MatthewE;Rahman,Saudur;Coughlin,JenniferM;Pomper,MartinG;Sair,HarisI
• 通讯作者: Sair,HarisI

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

• DOI: 10.1016/j.biopsych.2020.05.028
• 发表时间: 2021-02-01
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Plavén-Sigray P;Matheson GJ;Coughlin JM;Hafizi S;Laurikainen H;Ottoy J;De Picker L;Rusjan P;Hietala J;Howes OD;Mizrahi R;Morrens M;Pomper MG;Cervenka S
• 通讯作者: Cervenka S