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

肌萎缩侧索硬化症和额颞叶痴呆谱系障碍 (ALS-FTD) 认知障碍的临床病理相关性

• 批准号: 10389064
• 负责人: Joana Petrescu
• 金额: $ 4.73万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389064
• 关键词: Age; Age-Years; Autopsy; Behavioral; Brain; Cell physiology; Cells; Clinical; Cognitive; Cognitive deficits; Collaborations; Communication; Data; Dementia; Diagnosis; Discipline; Disease; Engineering; Environment; Exhibits; Fellowship; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Genomics; Genotype; Grant; Image; Impaired cognition; In Situ; MFGE8 gene; Manuscripts; Measures; Medical center; Mentorship; Methods; Modality; Molecular; Morphology; Motor; Motor Manifestations; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; New York; Oral; Paralysed; Pathologic; Pathology; Pathway interactions; Patients; Persons; Phenotype; Physicians; Prefrontal Cortex; Proteins; Research; Sampling; Scheme; Science; Scientist; Spinal Cord; Staging; Stains; Sudden Death; Syndrome; Technology; Tissue Preservation; Tissues; Training; Universities; Writing; automated segmentation; base; career; cell type; cognitive development; cohort; density; design; diagnostic criteria; differential expression; frontotemporal lobar dementia-amyotrophic lateral sclerosis; insight; motor symptom; multimodality; multiplexed imaging; neuropathology; non-demented; novel; patient subsets; pre-doctoral; protein TDP-43; sex; skills; transcriptomics

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.

项目摘要 肌萎缩侧索硬化和额颞叶痴呆（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 是65岁以下人群痴呆症的常见原因，占25%的痴呆症病例， 65岁以上的人。约15%的ALS-FTD患者最初出现运动症状 也接受痴呆的诊断，但大多数ALS-FTD患者表现出一定程度的认知障碍， 在疾病过程中的损害。确定有助于发展的分子途径 迄今为止，ALS-FTD的认知缺陷受到临床信息质量和尸检结果的限制。 组织保存以及可用技术。我们在爱丁堡大学的合作者 收集了一个具有详细认知特征和高质量的非痴呆ALS-FTD患者队列 死后组织保存用于分子研究新型高度多重蛋白质成像和空间 解析转录组学方法使得量化细胞类型组成和基因表达成为可能 在死后组织切片中的原位。这些实验进展有可能阐明 与ALS-FTD中认知功能障碍相关的机制。 该提案旨在了解TDP-43病理学和组织中的局部变化 微环境导致ALS-FTD患者的认知损害。通过集成多路复用 成像和空间转录组学数据，我将量化细胞类型比例（目标1）和基因干扰 该ALS-FTD患者队列尸检组织中TDP-43病理学近端的表达（Aim 2） 详细的临床和神经病理学特征。通过比较这些特征， 如果没有认知功能障碍，我将确定可能有助于或防止 ALS-FTD中的认知障碍。这种多模式方法可用于研究临床病理学 与其他蛋白质病相关。 我的奖学金申请还概述了一个严格的培训计划，重点是发展知识和技能， 作为一名医生科学家，成功的职业生涯所需的专业技能：1）设计严谨，良好， 控制和有力的研究，2）通过口头报告进行有效的科学交流， 手稿写作和赠款写作，3）尖端的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）将研究置于 临床背景。作为一名博士前实习生，我将受益于Hemali Phatnani博士和Tom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， 纽约基因组中心和哥伦比亚基因组中心的协作和支持性培训环境 欧文大学医学中心。