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

• 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
• 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' 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

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 通过参与接触性运动暴露于重复性头部撞击（RHI）可导致症状性 脑震荡和无症状的亚脑震荡，并可能增加神经退行性疾病的风险 慢性创伤性脑病（CTE）。CTE的特异性病变是磷酸化tau蛋白（p-tau） 沉积在神经元和小血管周围的其他细胞过程中，在皮层沟的深处。 CTE只能在尸检中诊断，严重限制了对风险和弹性因素，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） 成像是用于检测阿尔茨海默病（AD）中的p-tau聚集体的有前途的工具。初始人体成像 在CTE高危个体中使用tau PET配体18F-flortaucipir（18F-FTP）的研究显示， 死前成像和死后tau之间的结合和适度相关性。18F-MK-6240是第二个- 具有改善的体内成像性质和减少的“脱靶”（非tau 与18F-FTP相比，我们的目标是测试tau-PET配体MK-6240可以 检测CTE高危人群中的p-tau病理。我们将比较MK-6240标准摄取值 比率（SUVR）在30名男性前国家橄榄球联盟（NFL）球员与认知症状，年龄45-74， 和10名匹配的无TBI病史的男性认知正常个体（即，“控制”）。我们将利用 由美国国家情报局资助的加州大学旧金山弗朗西斯科广告研究中心（UCSF ADRC）和 美国国立卫生研究院资助的波士顿大学AD研究中心（BU ADRC）以及这些中心在 评估有症状的前NFL球员和PET成像。前NFL球员和控制将 根据其地理位置，在UCSF或BU ADRC注册，并完成统一考试， 包括神经学、神经心理学和自我报告的情绪/行为测量; MRI检查;以及脑 捐赠同意书本提案的资源将补充tau-PET（MK-6240）的中心访视 和淀粉样蛋白（18F-florbetapir）成像。我们将测试的假设相比，控制，前NFL 有CTE风险的球员将在与CTE一致的分布中显示MK-6240保留增加 神经病理学分期和示踪剂保留将与更差的认知和神经精神功能相关 和更多的暴露于RHI。这将是第一项研究，以检查tau-PET MK-6240的有用性， 检测CTE p-tau。如果成功，它将为更大的研究MK-6240的提案提供初步数据。 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，并将其与 其他神经系统疾病。准确检测和诊断生活中CTE的能力是关键的下一步 在临床研究的危险因素，机制，和治疗这种脑部疾病。