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

项目摘要 通过参加接触性运动暴露在重复头部撞击(RHI)中可能会导致症状 脑震荡和无症状亚脑震荡，并可能增加神经退行性疾病的风险 慢性创伤性脑病。CTE的病因学损害是磷酸化tau(p-tau)。 在皮质沟深处的小血管周围的神经元和其他细胞突起中的沉积。 CTE只能在尸检中诊断，这严重限制了对风险和复原力因素、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疾病区分开来。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聚集体的一种很有前途的工具。初始人体成像 在CTE高危人群中使用tau PET配体18F-flortaucipir(18F-ftp)的研究显示强度低 死前成像和死后tau之间的约束性和适度的相关性。18F-MK-6240是第二款- 一代tau PET配体，改善了体内成像性能并减少了“脱靶”(非tau 相关)绑定与18F-FTP相比。我们的目标是测试tau-PET配体MK-6240可以 在活体CTE高危人群中检测p-tau病理。我们将比较MK-6240标准摄取值 30名有认知症状的前国家橄榄球联盟(NFL)男性球员的比率(SUVR)，年龄45-74岁， 另10名匹配的无脑损伤病史的男性认知正常个体(即“对照”)。我们将利用 NIA资助的大学的基础设施。加州大学旧金山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球员和PET成像进行评估。前NFL球员和控球手将 根据地理位置，注册加州大学旧金山分校或北卡罗来纳大学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；以及大脑 捐赠同意书。这项提案的资源将用Tau-PET补充中心访问(MK-6240) 淀粉样蛋白(18F-florbetapir)显像。我们将测试这一假设，与对照组相比，前NFL 面临CTE风险的玩家将在与CTE一致的分布中显示MK-6240保留率增加 神经病理分期和示踪剂滞留与较差的认知和神经精神功能相关 以及更多地暴露在RHI中。这将是第一次研究tau-PET MK-6240在 CTEβ-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 作为一种准确可靠的生物标志物，支持可能的CTE的临床诊断并与 其他神经系统疾病。在生活中准确检测和诊断CTE的能力是关键的下一步 在临床上研究这种脑部疾病的危险因素、发病机制和治疗方法。

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.