Clinicopathologic correlates of cognitive impairment in amyotrophic lateral sclerosis and frontotemporal dementia spectrum disorders (ALS-FTD)

项目总结 肌萎缩侧索硬化症和额颞叶痴呆(ALS-FTD)是一种神经退行性疾病， 临床表现从进行性瘫痪到认知障碍。FTD是第二大 65岁以下人群中痴呆的常见原因，占#年痴呆病例的25% 65岁以上的人。大约15%的ALS-FTD患者最初出现运动症状 也被诊断为痴呆症，但大多数ALS-FTD患者表现出一定程度的认知能力 病程中的损害。确定有助于发展的分子途径 到目前为止，ALS-FTD的认知缺陷受到临床信息和尸检质量的限制 组织保存以及可用的技术。我们在爱丁堡大学的合作者 收集了一组具有详细认知特征和高质量的非痴呆ALS-FTD患者 用于分子研究的死后组织保存。新的高度多路复用的蛋白质成像和空间 可分辨的转录学方法使量化细胞类型组成和基因表达成为可能 在死后组织切片上原位观察。这些实验进展有可能阐明分子 与ALS-FTD认知功能障碍相关的机制。 这项建议试图了解TDP-43的病理和组织中的局部变化 微环境在ALS-FTD患者认知功能障碍中的作用。通过集成多路传输 成像和空间转录学数据，我将量化细胞类型比例(目标1)和基因的扰动 ALS-FTD患者死后组织中TDP-43近端病理的表达(目标2) 有详细的临床和神经病理特征。通过比较两种疾病患者的这些特征 在没有认知功能障碍的情况下，我将确定可能有助于或保护免受认知障碍的分子途径 肌萎缩侧索硬化症患者的认知损害。这种多模式方法可以应用于临床病理研究。 与其他蛋白质病的相关性。 我的奖学金提案还概述了一项严格的培训计划，重点是发展智力和 作为一名成功的内科科学家职业生涯所需的专业技能：1)设计严谨、良好的 2)通过口头陈述进行有效的科学交流； 手稿撰写和拨款撰写，3)前沿实验和计算基因组学方法，4) 指导学员并与其他学科的科学家合作，以及5)将研究放在 临床背景。作为一名博士前实习生，我将受益于海马利·帕特纳尼博士和汤姆博士的指导 Maniatis，我们的神经病理学、工程学和计算合作者的专业知识，以及 纽约基因组中心和哥伦比亚大学的协作和支持性培训环境 大学欧文医学中心。

PROJECT SUMMARY Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is a neurodegenerative disorder with clinical presentations ranging from progressive paralysis to cognitive impairment. FTD is the second most common cause of dementia in people under the age of 65 and accounts for 25% of cases of dementia in people over 65 years of age. Approximately 15% of ALS-FTD patients initially presenting with motor symptoms also receive a diagnosis of dementia, but a majority of ALS-FTD patients demonstrate some level of cognitive impairment over the course of disease. Identifying molecular pathways that contribute to the development of cognitive deficits in ALS-FTD has thus far been limited by the quality of clinical information and postmortem tissue preservation as well as available technologies. Our collaborators at the University of Edinburgh have assembled a cohort of non-demented ALS-FTD patients with detailed cognitive profiling and high quality postmortem tissue preservation for molecular studies. Novel highly multiplexed protein imaging and spatially resolved transcriptomics methods have made it possible to quantify cell type composition and gene expression in situ in postmortem tissue sections. These experimental advances have the potential to elucidate molecular mechanisms that are associated with cognitive dysfunction in ALS-FTD. This proposal seeks to understand how TDP-43 pathology and local changes in the tissue microenvironment contribute to cognitive impairment in patients with ALS-FTD. By integrating multiplexed imaging and spatial transcriptomics data, I will quantify cell type proportions (Aim 1) and perturbations in gene expression (Aim 2) proximal to TDP-43 pathology in postmortem tissues from this cohort of ALS-FTD patients with detailed clinical and neuropathological characterization. By comparing these features in patients with and without cognitive dysfunction, I will identify molecular pathways that may contribute to or protect against cognitive impairment in ALS-FTD. This multimodal approach can be applied to study clinicopathologic correlates of other proteinopathies. My fellowship proposal also outlines a rigorous training plan focused on developing the intellectual and professional skills required for a successful career as a physician scientist: 1) designing rigorous, well- controlled and well-powered studies, 2) effective science communication through oral presentations, manuscript writing and grant writing, 3) cutting-edge experimental and computational genomics methods, 4) mentorship of trainees and collaboration with scientists from other disciplines, and 5) placing research in a clinical context. As a predoctoral trainee, I will benefit from the mentorship of Dr. Hemali Phatnani and Dr. Tom Maniatis, the expertise of our neuropathology, engineering, and computational collaborators, and the collaborative and supportive training environments at the New York Genome Center and the Columbia University Irving Medical Center.