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 肌萎缩性侧索硬化和额颞痴呆（ALS-FTD）是一种神经退行性疾病，具有 从进行性瘫痪到认知障碍的临床表现。 FTD是第二个 65岁以下的人的痴呆症常见原因，占痴呆病例的25％ 超过65岁的人。最初出现运动症状的ALS-FTD患者中约有15％ 也接受痴呆症的诊断，但大多数ALS-FTD患者表现出一定程度的认知 疾病过程中的损害。确定有助于发展的分子途径 到目前为止 组织保存以及可用的技术。我们在爱丁堡大学的合作者 组装了一组非痴呆的ALS-FTD患者，具有详细的认知分析和高质量 验尸组织保存用于分子研究。新型高度多重蛋白质成像和空间 解决的转录组学方法使量化细胞类型组成和基因表达成为可能 原位在验尸后切片中。这些实验进步有可能阐明分子 与ALS-FTD中认知功能障碍相关的机制。 该提案试图了解组织中TDP-43病理和局部变化 微环境有助于ALS-FTD患者的认知障碍。通过整合多路复用 成像和空间转录组学数据，我将量化基因中的细胞类型比例（AIM 1）和扰动 表达（AIM 2）来自该ALS-FTD患者队列的验尸组织中TDP-43病理 具有详细的临床和神经病理学特征。通过比较患者和 没有认知功能障碍，我将确定可能有助于或预防的分子途径 ALS-FTD中的认知障碍。这种多模式方法可以应用于研究临床病理学 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，旨在发展知识分子和 作为医师科学家成功职业所需的专业技能：1）设计严格，良好 受控且能力充分的研究，2）通过口头演示的有效科学沟通， 手稿写作和赠款写作，3）尖端实验和计算基因组学方法，4） 学员的指导和与其他学科的科学家合作，以及5）将研究放在 临床环境。作为一名著名的学员，我将从Hemali Phatnani博士和汤姆博士的指导中受益 Maniatis，我们的神经病理学，工程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的协作和支持培训环境 大学欧文医学中心。