Development of Serial PET-Based Spatiotemporal Models of Tau Accumulation in AD as a Feasible and More Accurate Alternative to SUVR

开发基于串行 PET 的 AD 中 Tau 积累时空模型，作为 SUVR 的可行且更准确的替代方案

• 批准号: 9899188
• 负责人: John Alex Becker
• 金额: $ 21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899188
• 关键词: Address; Age-Years; Alzheimer' s Disease; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid; Amyloidosis; Binding; Biological Markers; Characteristics; Clinical Trials; Cross-Sectional Studies; Data; Data Analyses; Data Set; Deposition; Detection; Development; Disease; Ensure; Evolution; Generations; Goals; Human; Injections; Investigation; Kinetics; Label; Ligand Binding; Ligands; Measurement; Measures; Methodology; Methods; Modeling; Modification; Noise; Observational Study; Partner in relationship; Pathology; Pharmaceutical Preparations; Positron-Emission Tomography; Proteins; Proxy; Research; Research Design; Scanning; Staging; Structure; Tauopathies; Technology; Testing; Therapeutic; Therapeutic Studies; Time; Tissues; Tracer; Work; base; biomarker development; cohort; course development; follow-up; formycin triphosphate; improved; in vivo; in vivo imaging; innovation; model development; models and simulation; neuroimaging; normal aging; novel; radioligand; rate of change; simulation; spatiotemporal; tau Proteins; tau aggregation; therapy development; treatment effect

PROJECT SUMMARY Substantial progress in Alzheimer’s Disease (AD) biomarker development over the past decade has resulted in improved understanding of early stages of the disease. One of the earliest ​18​F-labeled PET radioligands for tau, AV1451 or FTP, has been followed recently by newer ligands, including ​18​F-MK6240. These radioligands permit the ​in vivo​ detection of tau pathology and thus open the door for investigation of intra-subject evolution of tauopathy from an isolated phenomenon of normal aging to a full-blown, widespread component of AD. Recently available data suggest that tau PET might allow identification of a set of identifiable stages of regional tau binding, from normal aging through asymptomatic amyloidosis to early and advanced AD dementia. The ​in vivo​ staging of AD tauopathy could represent a breakthrough technology for AD therapy development, but will require the careful analysis of serial tau PET in order to succeed. Traditional methods of PET quantification are limited to the analysis of isolated time points of PET, and are not capable of leveraging the richer structure inherent in a sequence of intra-subject PET scans. Much of the serial tau PET data being acquired in ongoing therapeutic or observational studies is quantified by the SUVR parameter, which suffers from bias when applied in either cross-sectional or serial study designs. The serial PET data that is becoming more prevalent in present day neuroimaging research and in clinical trials requires methods of analysis tailored to its specific structure. We propose to develop new reference-tissue-based models of serial PET that, by encompassing all tissue regions and all serial time-points, will yield estimates of ligand binding and binding rates-of-change that are more accurate and precise than those based on binding quantified by SUVR. Our models will also improve kinetic parameter estimation from fully-dynamic PET data of reduced scan durations (e.g., 60 min or less). We will develop and test our models based on legacy serial tau and amyloid PET data, and also data from a cohort of 20 subjects currently undergoing serial study with the MK6240 tau ligand as part of an independent study. Legacy data will include 18 subjects with 3 or more time points of late-time FTP data, and 111 subjects with 3 or more time points of fully-dynamic PiB. We also propose to acquire a 4th serial time point to supplement the pre-existing, fully-dynamic (120 min) serial MK6240 tau PET data in a cohort of 20 subjects. Fully-dynamic data will be crucial in validating the proposed models for application to radioligands with varying kinetics, and in identifying optimal, ligand-specific reference tissues.

项目摘要 在过去十年中，阿尔茨海默病（AD）生物标志物开发的实质性进展已经导致 提高对疾病早期阶段的认识。最早的18F标记PET放射性配体之一， tau、AV 1451或FTP之后，最近有更新的配体，包括18 F-MK 6240。这些放射性配体 从而打开了研究受试者内进化的大门 从正常衰老的孤立现象到AD的全面、广泛的组成部分。 最近可用的数据表明，tau PET可能允许识别一组可识别的区域性阶段， tau结合，从正常衰老到无症状淀粉样变性到早期和晚期AD痴呆。的in AD tau蛋白病的体内分期可能代表AD治疗开发的突破性技术，但将 需要仔细分析连续的tau PET才能成功。 PET定量的传统方法局限于PET的孤立时间点的分析，并且不 能够利用对象内PET扫描序列中固有的更丰富的结构。大部分的系列 通过SUVR对正在进行的治疗或观察性研究中采集的tau PET数据进行量化 参数，当应用于横截面或系列研究设计时会出现偏倚。串行 PET数据在当今神经成像研究和临床试验中变得越来越普遍，需要 分析方法适合其特定结构。我们建议开发新的基于参考组织的 系列PET模型，通过涵盖所有组织区域和所有系列时间点，将产生 配体结合和结合变化率比基于结合的那些更准确和精确 通过SUVR量化。我们的模型也将改善动力学参数估计从全动态PET数据的 减少的扫描持续时间（例如，60分钟或更少）。 我们将根据传统的连续tau蛋白和淀粉样蛋白PET数据以及来自一个研究中心的数据开发和测试我们的模型。 目前正在接受MK 6240 tau配体系列研究的20名受试者队列，作为独立研究的一部分。 study.遗留数据将包括18例受试者（有3个或更多时间点的晚期FTP数据）和111例受试者（有3个或更多时间点的晚期FTP数据） 3个或更多时间点的全动态PiB。我们还建议采集第4个连续时间点， 补充20例受试者队列中既存的全动态（120 min）系列MK 6240 tau PET数据。 完全动态的数据将是至关重要的，在验证所提出的模型应用于放射性配体与不同的 动力学，以及鉴定最佳的配体特异性参考组织。