Clinical and imaging biomarker evolution of early progressive supranuclear palsy

摘要 这是一份K23奖的申请，申请人是理查德·蔡博士，他是哈佛大学神经病学助理兼职教授， 加州大学旧金山弗朗西斯科（UCSF）记忆与衰老中心（MAC）。蔡博士建议 对早期进行性核上性麻痹（ePSP）的临床和影像学演变进行临床研究 将帮助他实现成为神经退行性疾病独立研究者和专家的目标。 疾病成像和临床试验方法学。这个K23将为蔡博士提供资源和支持 必须实现以下目标：（1）成为以患者为导向的临床研究专家， 原发性tau蛋白病，如PSP;（2）提高他的临床试验方法学和生物统计学知识; (3)为了实现结构（体积MRI、扩散张量成像）和分子（τ正电子发射 断层扫描[PET]）成像技术在原发性tau蛋白病的临床研究和试验;（4）开发一种 独立从事临床研究。为了实现这些目标，蔡博士组建了一个指导团队， 两位主要导师：亚当·博克瑟博士，阿尔茨海默病和额颞叶痴呆症主任 临床试验计划和PSP的世界专家之一，Gil Rabinovici博士，MAC PET主任 他也是世界上痴呆症分子成像领域的专家之一。指导团队还 包括两名合作者：霍华德罗森博士，一位在认知神经成像方面具有专长的神经学家。 Iryna Lobach博士是一位统计学家，是研究设计和生物统计分析方面的专家。 神经退行性疾病迫切需要有效的治疗，目前的经验表明， 潜在的疾病改善疗法应该在疾病的早期阶段开始。拟议的研究项目 将应用先进的结构MR成像和分子成像技术，使用新型tau PET配体， 评估ePSP的临床演变。Tsai博士将描述临床演变ePSP，一种新的诊断 类别（目标1），并使用体积MRI、扩散张量成像 和tau PET成像（Aim 2），有一天可能被用作治疗临床试验的结果。此外，本发明还 博士Tsai将确定这些成像测量的基线特征（目标3），这些特征可预测ePSP疾病 进展这项研究将是一系列研究的关键一步，将发展纵向成像 PSP和其他神经退行性疾病早期阶段的生物标志物，并为该领域铺平道路 建立可用于未来临床试验的疾病监测生物标志物。

ABSTRACT This is an application for a K23 award for Dr. Richard Tsai, an Assistant Adjunct Professor of Neurology at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). Dr. Tsai's proposal to conduct clinical research on the clinical and imaging evolution of early progressive supranuclear palsy (ePSP) will help him achieve his goal of becoming an independent investigator and expert in neurodegenerative disease imaging and clinical trials methodology. This K23 will provide Dr. Tsai with the resources and support essential to accomplish the following goals: (1) to become an expert at patient-oriented clinical research in primary tauopathies such as PSP; (2) to advance his knowledge of clinical trials methodology and biostatistics; (3) to implement structural (volumetric MRI, diffusion tensor imaging) and molecular (tau positron emission tomography [PET]) imaging techniques in clinical studies and trials of primary tauopathies; (4) to develop an independent career in clinical research. To achieve these goals, Dr. Tsai has assembled a mentoring team of two primary mentors: Dr. Adam Boxer, director of the Alzheimer's Disease and Frontotemporal Dementia Clinical Trials Program and one of the world's experts in PSP, Dr. Gil Rabinovici, director of the MAC PET imaging program and one of the world's expert on molecular imaging in dementia. The mentoring team also includes two collaborators: Dr. Howard Rosen, a neurologist with expertise in neuroimaging in cognitive disorders and Dr. Iryna Lobach, a statistician who is an expert in study design and biostatistical analysis. There is an urgent need for effective therapy in neurodegenerative disease, and current experience indicates potential disease modifying therapies should begin in early stages of disease. The proposed research project will apply advanced structural MR imaging and molecular imaging techniques using novel tau PET ligands to evaluate the clinical evolution of ePSP. Dr. Tsai will characterize the clinical evolution ePSP, a new diagnostic category (Aim 1) and develop innovative imaging biomarkers using volumetric MRI, diffusion tensor imaging and tau PET imaging (Aim 2) that may one day be used as outcomes in therapeutic clinical trials. Additionally, Dr. Tsai will identify baseline signatures (Aim 3) of these imaging measures that may predict ePSP disease progression. This research will be a key step in a series of investigation that will develop longitudinal imaging biomarkers for PSP and other neurodegenerative disease in their early stages, and pave the way for the field to establish disease monitoring biomarkers useful for future clinical trials.