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In Vivo Detection of Chronic Traumatic Encephalopathy with 18F-MK-6240 Tau PET

使用 18F-MK-6240 Tau PET 体内检测慢性创伤性脑病

基本信息

批准号：
10323058
负责人：
Michael Alosco
金额：
$ 20.27万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323058
关键词：
Age Alzheimer disease prevention Alzheimer&apos s Disease American Amyloid Autopsy Autoradiography Behavior Behavioral Binding Biological Markers Blood Vessels Boston Brain Brain Concussion Brain Diseases California Cell physiology Clinical Clinical Research Cognitive Consent Data Dementia Deposition Detection Diagnosis Enrollment Epidemiology Evaluation Exposure to Funding Future Generations Geographic Locations Goals Image Individual Infrastructure Lesion Life Ligands Magnetic Resonance Imaging Manufactured football Measures Medial Moods Neurobehavioral Manifestations Neurodegenerative Disorders Neurologic Neurons Neuropsychology Pathology Patient Self-Report Persons Play Population Positron-Emission Tomography Prevention Recording of previous events Registries Reporting Research Resources Risk Risk Factors Sampling San Francisco Senile Plaques Signal Transduction Source Staging Temporal Lobe Testing Tracer Traumatic Brain Injury Universities Visit Wisconsin affective disturbance chronic traumatic encephalopathy clinical diagnosis cognitive function contact sports experience formycin triphosphate head impact high risk human imaging imaging properties imaging study improved in vivo in vivo imaging indexing interest male military service nervous system disorder neuropathology neuropsychiatry ranpirnase resilience subconcussion tau Proteins tau aggregation tau-1 tool uptake

项目摘要

PROJECT ABSTRACT Exposure to repetitive head impacts (RHI) through participation in contact sports can result in symptomatic concussions and asymptomatic sub-concussions and may increase risk for the neurodegenerative disease chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE is phosphorylated tau (p-tau) deposition in neurons and other cell processes around small blood vessels, at the depths of the cortical sulci. CTE can only be diagnosed at autopsy, severely limiting research on risk and resilience factors, mechanisms, epidemiology and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE and differentiate it from other neurological disorders in living people. Tau positron emission tomography (PET) imaging is a promising tool for detecting p-tau aggregates in Alzheimer’s disease (AD). Initial human imaging studies using the tau PET ligand 18F-flortaucipir (18F-FTP) in individuals at high risk for CTE show low intensity binding and modest correlations between antemortem imaging and post-mortem tau. 18F-MK-6240 is a second- generation tau PET ligand that has improved in vivo imaging properties and reduced “off-target” (non-tau related) binding compared to 18F-FTP. Our goal is to test the premise that the tau-PET ligand MK-6240 can detect p-tau pathology in living people at high risk for CTE. We will compare MK-6240 standard uptake value ratios (SUVR) in 30 male former National Football League (NFL) players with cognitive symptoms, ages 45-74, and 10 matched male cognitively normal individuals without a TBI history (i.e., “controls”). We will leverage the infrastructure of the NIA-funded Univ. of California, San Francisco AD Research Center (UCSF ADRC) and the NIA-funded Boston University AD Research Center (BU ADRC) and the experience these centers have in the evaluation of symptomatic former NFL players and with PET imaging. Former NFL players and controls will enroll in the UCSF or BU ADRC, depending on their geographical location, and complete harmonized exams, including neurological, neuropsychological, and self-report mood/behavior measures; MRI exams; and brain donation consent. The resources from this proposal will supplement the Center visits with tau-PET (MK-6240) and amyloid (18F-florbetapir) imaging. We will test the hypothesis that that compared to controls, former NFL players at-risk for CTE will show increased MK-6240 retention in a distribution consistent with CTE neuropathological staging, and tracer retention will correlate with worse cognitive and neuropsychiatric function and greater exposure to RHI. This will be the first study to examine the usefulness of tau-PET MK-6240 in the detection of CTE p-tau. If successful, it will provide preliminary data for larger proposals to examine MK-6240 as an accurate and reliable biomarker to support a clinical diagnosis of probable CTE and differentiate it from other neurological disorders. The ability to accurately detect and diagnose CTE during life is a critical next step in clinical research on the risk factors, mechanisms, and treatment of this brain disease.

项目摘要通过参加接触性运动而遭受重复性头部撞击 (RHI) 可能会导致出现症状脑震荡和无症状的亚脑震荡，可能会增加患神经退行性疾病的风险慢性创伤性脑病（CTE）。 CTE 的特征性病变是磷酸化 tau (p-tau) 沉积在皮层沟深处小血管周围的神经元和其他细胞突起中。 CTE 只能通过尸检来诊断，严重限制了对风险和恢复因素、机制、流行病学和治疗。迫切需要能够准确检测CTE的体内生物标志物并将其与活人的其他神经系统疾病区分开来。 Tau 正电子发射断层扫描 (PET) 成像是检测阿尔茨海默病 (AD) 中 p-tau 聚集体的一种有前途的工具。最初的人体成像使用 tau PET 配体 18F-flortaucipir (18F-FTP) 对 CTE 高风险个体进行的研究显示低强度生前成像和死后 tau 蛋白之间存在一定的结合和适度相关性。 18F-MK-6240 是第二个一代 tau PET 配体，改善了体内成像特性并减少了“脱靶”（非 tau 相关）结合与 18F-FTP 相比。我们的目标是测试 tau-PET 配体 MK-6240 能够检测 CTE 高风险人群中的 p-tau 病理学。我们将比较MK-6240标准摄取值 30 名年龄 45-74 岁、有认知症状的前美国国家橄榄球联盟 (NFL) 男性球员的比率 (SUVR) 以及 10 名匹配的、认知正常、没有 TBI 病史的男性个体（即“对照”）。我们将利用 NIA 资助的大学的基础设施。加利福尼亚州旧金山 AD 研究中心 (UCSF ADRC) 和 NIA 资助的波士顿大学 AD 研究中心 (BU ADRC) 以及这些中心在对有症状的前 NFL 球员进行评估并使用 PET 成像。前 NFL 球员和控制人员将根据地理位置注册 UCSF 或 BU ADRC，并完成统一考试，包括神经学、神经心理学和自我报告情绪/行为测量；核磁共振检查；和大脑捐赠同意书。该提案的资源将补充 tau-PET (MK-6240) 中心访问和淀粉样蛋白（18F-florbetapir）成像。我们将检验以下假设：与对照组相比，前 NFL 球员有 CTE 风险的玩家将表现出与 CTE 一致的分布中 MK-6240 保留率的增加神经病理学分期和示踪剂保留将与较差的认知和神经精神功能相关以及更多地接触 RHI。这将是第一项研究 tau-PET MK-6240 在 CTE p-tau 的检测。如果成功，它将为检查 MK-6240 的更大提案提供初步数据作为准确可靠的生物标志物，支持可能的 CTE 的临床诊断并将其与其他神经系统疾病。下一步关键是能够准确检测和诊断生命期间的 CTE 从事这种脑部疾病的危险因素、机制和治疗的临床研究。