Tau Quantitation in AD with High Resolution MRI and PET

使用高分辨率 MRI 和 PET 对 AD 中的 Tau 蛋白进行定量

• 批准号: 8949099
• 负责人: Joyita Dutta
• 金额: $ 12.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949099
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid deposition; Amyloidosis; Appearance; Area; Autopsy; Award; Binding; Brain; Cells; Characteristics; Clinical; Cognitive deficits; Computational Technique; Data; Data Sources; Detection; Development; Development Plans; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Disease Progression; Early Diagnosis; Elderly; Engineering; Faculty; General Hospitals; Goals; Graph; Hippocampus (Brain); Histology; Human; Image; Image Analysis; Imaging Techniques; Impaired cognition; Individual; Instruction; International; Joints; K-Series Research Career Programs; Kinetics; Legal patent; Ligands; Link; Magnetic Resonance Imaging; Massachusetts; Measures; Medical Imaging; Mentored Research Scientist Development Award; Mentors; Methods; Modeling; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Neuropsychological Tests; Neurosciences; One-Step dentin bonding system; Participant; Pathology; Pathway Analysis; Pattern; Positron-Emission Tomography; Property; Recovery; Research; Research Infrastructure; Resolution; Scanning; Structure; Supervision; Synapses; Techniques; Technology; Testing; Time; Tracer; Training; age related; base; career; career development; cognitive performance; cohort; data modeling; entorhinal cortex; image reconstruction; imaging modality; improved; in vivo; indexing; innovation; medical schools; meetings; member; mild cognitive impairment; molecular imaging; neuroimaging; novel; public health relevance; radiotracer; reconstruction; research and development; signal processing; spatiotemporal; symposium; tau Proteins; tau aggregation; tau mutation

 DESCRIPTION (provided by applicant): The overarching research goal of this Mentored Research Scientist Development Award is to enable improved estimation and quantitative analysis of tau neurofibrillary tangle (NFT) distributions in vivo using [18F]T807 PET. The candidate is a junior faculty member at Harvard Medical School and Massachusetts General Hospital with expertise in signal processing, image analysis, and quantitative molecular imaging who intends to specialize in the imaging of neurodegenerative and aging-related disorders. The training goal of this award is to provide the candidate with instruction in neuroimaging, neuroscience, and neurology, which will enable her to extend her existing skillset to Alzheimer's disease (AD) imaging and pursue independent research in this area. The candidate proposes to perform kinetic modeling and network analysis on dynamic PET data obtained using a novel PET tracer known as [18F]T807 that binds to NFTs, which are a hallmark of AD. The importance of in vivo tau quantitation in AD is supported by autopsy data which indicate that the NFT burden is strongly correlated with neurodegeneration and cognitive deficits. Despite the availability of novel compounds for imaging NFTs, quantitation still remains challenging due to the resolution limits of PET, which are typically much higher than the dimensions of the subcortical structures where NFTs initially appear. This project will address the major challenges in tau quantitation. Accurate tau quantitation would enable early diagnosis of AD, allow accurate monitoring of disease progression, and be a vehicle for the development of disease-modifying therapies (e.g. anti-amyloid and anti-tau treatments). Specifically this application seeks to: (1) perform MR-guided resolution recovery of PET images of tau, (2) perform MR-guided denoising of high-resolution dynamic [18F]T807 images and compute Logan distribution volume ratio images in order to generate tau connectivity networks, (3) study the spatiotemporal characteristics of tau networks and the relationship between tau networks and structural networks obtained from MR tractography. The third and final goal will enable us to test our hypothesis that cell- to-cell propagation of tau has strong links to the structural networ in the brain. The aforementioned steps will be applied to a cohort of subjects comprised of both elderly cognitively normal and impaired individuals. To achieve her research and career goals, the candidate will pursue a rigorous career development plan which will include formal coursework in neuroimaging, neuroscience, and neurology, attendance of seminars covering state-of-the-art topics in neuroimaging and AD, and participation in domestic and international conferences on medical imaging and AD. Throughout the award period, she will receive advice and guidance from a mentoring team comprised of renowned experts in the fields of quantitative molecular imaging, neuroscience, and neurology. Both individual meetings with the mentors and collective meetings with the full mentoring team will be held periodically to monitor the research and career development progress of the candidate.

 描述（由申请人提供）：该指导研究科学家发展奖的总体研究目标是使用[18 F]T807 PET改进体内tau神经元缠结（NFT）分布的估计和定量分析。该候选人是哈佛医学院和马萨诸塞州总医院的初级教员，具有信号处理、图像分析和定量分子成像方面的专业知识，打算专门从事神经退行性疾病和衰老相关疾病的成像。该奖项的培训目标是为候选人提供神经影像学，神经科学和神经学方面的指导，这将使她能够将现有的技能扩展到阿尔茨海默病（AD）成像，并在该领域进行独立研究。候选人建议对使用称为[18 F]T807的新型PET示踪剂获得的动态PET数据进行动力学建模和网络分析，该示踪剂与NFT结合，这是AD的标志。AD中体内tau定量的重要性得到尸检数据的支持，尸检数据表明NFT负荷与神经变性和认知缺陷密切相关。尽管有新的化合物可用于NFT成像，但由于PET的分辨率限制，定量仍然具有挑战性，PET的分辨率限制通常远高于NFT最初出现的皮质下结构的尺寸。该项目将解决tau定量的主要挑战。准确的tau定量将能够早期诊断AD，允许准确监测疾病进展，并成为开发疾病修饰疗法（例如抗淀粉样蛋白和抗tau治疗）的载体。具体地，本申请寻求：（1）执行tau的PET图像的MR引导的分辨率恢复，（2）执行高分辨率动态[18 F]T807图像的MR引导的去噪，并计算Logan分布体积比图像，以便生成tau连接网络，（三）研究了tau网络的时空特征以及tau网络与MR结构网络之间的关系纤维束成像第三个也是最后一个目标将使我们能够测试我们的假设，即tau的细胞间传播与大脑中的结构性神经元有很强的联系。上述步骤将应用于由老年认知正常和受损个体组成的受试者队列。为了实现她的研究和职业目标，候选人将追求严格的职业发展计划，其中包括神经影像学，神经科学和神经病学的正式课程，参加研讨会，涵盖神经影像学和AD的最新主题，并参加国内和国际医学成像和AD会议。在整个获奖期间，她将获得由定量分子成像，神经科学和神经病学领域的知名专家组成的指导团队的建议和指导。与导师的单独会议和与整个辅导团队的集体会议将定期举行，以监测候选人的研究和职业发展进展。