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 的典型病变是磷酸化 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。成像是检测阿尔茨海默病 (AD) 中 p-tau 聚集体的一种很有前景的工具。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死前成像和死后 tau 之间的结合和适度相关性是第二个。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 可以的前提。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) 我们将利用 10 名没有 TBI 病史且认知正常的男性个体（即“对照”）。 NIA 资助的加州大学旧金山 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 球员以及前 NFL 球员和对照进行 PET 成像评估。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/行为测量和大脑；该提案的资源将补充 tau-PET (MK-6240) 的中心访问。我们将测试与对照组、前 NFL 相比的假设。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神经精神功能相关以及更多地接触 RHI，这将是第一项检验 tau-PET MK-6240 在治疗中的有用性的研究。 CTE p-tau 的检测如果成功，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下一步至关重要的是能够在生命期间准确检测和诊断 CTE。从事这种脑部疾病的危险因素、机制和治疗的临床研究。