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: 10062525
• 负责人: Jennifer Marie Coughlin
• 金额: $ 58.7万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062525
• 关键词: Astrocytes; Binding; Biological Assay; Biological Markers; Biomechanics; Brain; Brain Injuries; Brain imaging; Brain region; Cells; 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 (Brain); Human; Hyperactivity; Image; Immune; Immune response; Immune signaling; Immunologic Markers; Impaired cognition; Individual; Inferior; Inflammatory; Inflammatory Response; Infrastructure; Injury; Interferons; Interleukin-6; Interview; Investigation; Link; Liquid substance; Longitudinal Studies; Manufactured football; Measurement; Measures; Methodology; Methods; Microglia; Mus; Nerve Degeneration; Neuraxis; 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; base; cingulate cortex; cognitive testing; cohort; contact sports; cytokine; design; entorhinal cortex; evidence base; experience; factor A; follow-up; imaging study; immune activation; improved; inflammatory marker; injury and repair; 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.

项目总结