Pathological and cognitive correlations of real time quaking induced conversion in LBD and AD

项目摘要/摘要 路易体病的准确临床诊断(LBD：帕金森氏病(PD)、路易氏痴呆 躯体(DLB)，阿尔茨海默病(AD)受到重叠临床特征的挑战。新型生物流体 包括实时颤动诱导转换(RT-QuIC)在内的生物标志物提供了诊断患者的能力 通过识别病理性α-突触核蛋白(a-syn)或tau种子，提高了生命中的准确性。然而，在LBD中， 大约50%的病例会有明显的AD病理改变，在AD中高达50%的病例会有边缘a-syn 可能会使对生物标志物签名的解释复杂化。因此，全面的病理验证研究 对于了解这些新的检测方法的实用性以及它们与组织病理学负担和 临床相关性。如果RT-QuIC度量与病理负担或认知结果相关，则可以使用它们 作为LBD的客观生物标记物，这是一个持续的关键需求。这项建议的目的是测试a-syn 在LBD和AD中，tau RT-QuIC与1)组织病理学特征和2)认知结局相关。这个 假设a-syn和tau RT-QuIC将能够预测LBD和AD的原发和共病 更高程度的RT-QuIC活性将与更大的神经病理负担和更糟糕的 认知结果。拟议的实验将利用先前存在的死前脑脊液尸检队列。 和认知测试收集在加州大学圣地亚哥分校(UCSD)和加州大学伯克利分校 宾夕法尼亚州拥有NIH/NIAID落基山实验室的RT-QuIC专业知识。 K23候选人是加州大学圣迭戈分校的神经科学助理教授，之前完成了 运动障碍联谊会和NIH TL1支持的翻译研究硕士。他有一段历史 在神经科学方面进行了翻译和临床研究，最近专注于 帕金森病、DLB和AD的神经病理学。应聘者致力于翻译研究和职业生涯 提出了一个全面的五年计划，包括指导、正式培训、自我指导学习和研究。 这项K23职业发展奖将支持考夫林博士的短期目标，包括1)开发 详细了解RT-QuIC及其与组织病理学和认知结果的关系，2) 利用免疫组织化学和Western blotting获得多模式组织表征的技能 技术，3)学习痴呆症的神经心理学，重点是LBD和AD，以及4)学习 统计方法，开展这些和未来的研究。考夫林博士将在 指导团队的指导，包括生物流体生物标记物专家Douglas Galasko博士，Robert博士 里斯曼博士，神经退行性疾病分子病理学专家，大卫·萨蒙博士 在LBD和AD方面有长期研究记录的专家神经心理学家。这个奖项将支持考夫林博士的 成为具有生物标记物病理学专长的独立临床医生和科学家的发展方向 在翻译神经病理学方面的验证研究和独特的研究计划。

Project Summary/Abstract The accurate clinical diagnosis of Lewy body diseases (LBD: Parkinson’s disease (PD), dementia with Lewy bodies (DLB)), and Alzheimer’s disease (AD) is challenged by overlapping clinical features. Novel biofluid biomarkers including real time quaking induced conversion (RT-QuIC) offer the ability to diagnose patients with greater accuracy during life by identifying pathologic α-synuclein (a-syn) or tau seeds. However, in LBD, approximately 50% of cases will harbor significant AD pathology, and in AD up to 50% harbor limbic a-syn which can complicate interpretation of biomarker signatures. Therefore, comprehensive pathological validation studies are essential to understand the utility of these new assays and their association with histopathologic burden and clinical correlations. If RT-QuIC metrics relate to pathological burden or cognitive outcomes, they could be used as an objective biomarker in LBD, an ongoing critical need. The aims of this proposal are to test whether a-syn and tau RT-QuIC is associated with 1) histopathological features and 2) cognitive outcomes in LBD and AD. The hypotheses are that a-syn and tau RT-QuIC will be able to predict primary and co-pathologies in LBD and AD and that higher degrees of RT-QuIC activity will associate with greater neuropathological burden and worse cognitive outcomes. The proposed experiments will leverage pre-existing autopsy cohorts with antemortem CSF and cognitive testing collected at the University of California San Diego (UCSD) and the University of Pennsylvania with the RT-QuIC expertise of the NIH/NIAID Rocky Mountain Laboratories. The K23 candidate is an Assistant Professor of Neurosciences at the UCSD, having previously completed movement disorders fellowship and a NIH TL1-supported Masters of Translational Research. He has a history of productivity, having conducted translational and clinical research in neuroscience, recently focusing on the neuropathology of PD, DLB, and AD. The candidate is committed to a career in translational research and proposes a comprehensive five year plan of mentorship, formal training, self-directed learning, and research. This K23 career development award will support Dr. Coughlin’s short-term goals, including 1) developing a detailed understanding of RT-QuIC and its association with histopathological and cognitive outcomes, 2) acquisition of skills for multimodal tissue characterization using immunohistochemistry and Western blotting techniques, 3) learning the neuropsychology of dementia with a focus on LBD and AD, and 4) learning the statistical methods to carry out these and future studies. Dr. Coughlin will meet these objectives under the guidance of a mentorship team, including Dr. Douglas Galasko, an expert in biofluid biomarkers, Dr. Robert Rissman PhD, an expert in the molecular pathology of neurodegenerative disease and Dr. David Salmon PhD expert neuropsychologist with a long research track record in LBD and AD. This award will support Dr. Coughlin’s development towards becoming an independent clinician-scientist with expertise in biomarker-pathological validation studies and a unique research program in translational neuropathology.