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Clinical Core

临床核心

基本信息

批准号：
10625539
负责人：
David John Irwin
金额：
$ 22.34万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625539
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyotrophic Lateral Sclerosis Autopsy Biological Markers Biometry Biostatistics Core Blood Blood specimen C9ORF72 Cells Cerebrospinal Fluid Clinical Clinical Markers Clinical Trials Collaborations Complex DNA Data Databases Dementia Development Disease Encephalopathies Family Family member Frontotemporal Lobar Degenerations Functional disorder Genetic Genetic study Goals Heterogeneity Histopathology Image Impairment International Investigation Knowledge Language Life Linguistics Magnetic Resonance Imaging Measures Mediating Natural History Nerve Degeneration Neurodegenerative Disorders Neuropsychology Pathologic Pathology Patient Recruitments Patient imaging Patients Persons Phenotype Primary Progressive Aphasia Prognosis Program Research Project Grants RNA-Binding Proteins Reproducibility Research Personnel Risk Semantics Site Social Functioning Standardization Syndrome Variant Work age related behavioral variant frontotemporal dementia biomarker identification clinical phenotype cost design diagnosis standard diagnostic accuracy executive function frontotemporal degeneration human old age (65+)improved in vivo motor disorder multimodality mutation carrier neural network neuroimaging neuropathology protein TDP-43 rare condition recruit screening social social deficits tau Proteins treatment response treatment trial

项目摘要

Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition even though it is the most common cause of dementia after Alzheimer’s disease (AD) in people <65 years old. The most common frontotemporal lobar degeneration (FTLD) pathology associated with FTD is TDP-43 proteinopathy known as FTLD-TDP. Although rare mutation carriers can be identified who have FTLD-TDP pathology during life, there are no known biomarkers for the vast majority of FTD patients with sporadic disease that can reliably distinguish patients with FTLD-TDP histopathology from those with FTLD-Tau pathology, nor from patients who present with clinical FTD but are atypical variants of pathological AD. This has resulted in major gaps in knowledge that severely limit our understanding of TDP-43-associated pathophysiology, significantly constrain the development of disease-modifying treatment trials, and severely impede designing clinical end-points to follow for prognosis and for treatment trials. It is thus necessary to collect data that help define the specific pathologic form of FTLD during life more accurately, and relate these data to imaging, biofluid biomarker, genetic and autopsy data studied in this PPG. Moreover, disease-modifying treatment trials require well- characterized natural histories of phenotypes related to FTLD-TDP in order to identify clinical markers indicating a beneficial treatment response. The Clinical Core will work with other cores and projects to improve our understanding of the TDP-related degeneration of multilevel neural networks examined in this Program Project Grant (PPG). To these ends, we will recruit patients with sporadic clinical FTD who have a high likelihood of having FTLD-TDP pathology such as semantic variant Primary Progressive Aphasia (svPPA), behavioral variant FTD (bvFTD) co-occurring with svPPA, PPA and bvFTD with co-occurring amyotrophic lateral sclerosis (ALS). We will also recruit symptomatic carriers of mutations associated with FTLD such as PGRN and C9orf72. We will assess these cases annually with a brief but comprehensive neuropsychological battery, recruit cases for imaging and biofluid studies, and recruit cases for autopsy. We propose four Specific Aims to achieve these goals.

额颞叶变性 (FTD) 是一种尚未得到充分研究的临床神经退行性疾病，尽管它是对于 65 岁以下人群来说，这是继阿尔茨海默病 (AD) 后导致痴呆症的最常见原因。最与 FTD 相关的常见额颞叶变性 (FTLD) 病理是 TDP-43 蛋白病称为 FTLD-TDP。尽管罕见的突变携带者可以在 FTLD-TDP 病理学期间被识别出来。在生活中，对于绝大多数患有散发性疾病的 FTD 患者，没有已知的生物标志物可以可靠地区分具有 FTLD-TDP 组织病理学的患者与具有 FTLD-Tau 病理学的患者，也不同于具有 FTLD-Tau 病理学的患者存在临床 FTD，但属于病理性 AD 的非典型变异。这导致了重大差距这些知识严重限制了我们对 TDP-43 相关病理生理学的理解，极大地限制了疾病修饰治疗试验的发展，并严重阻碍临床终点的设计遵循预后和治疗试验。因此，有必要收集有助于定义特定目标的数据。更准确地了解生命期间 FTLD 的病理形式，并将这些数据与成像、生物流体生物标志物、本 PPG 中研究了遗传和尸检数据。此外，疾病修饰治疗试验需要良好的表征与 FTLD-TDP 相关的表型的自然历史，以确定临床标志物表明有益的治疗反应。临床核心将与其他核心和项目合作以改进我们对本计划中检查的多级神经网络 TDP 相关退化的理解项目补助金（PPG）。为此，我们将招募患有散发性临床 FTD 的患者，这些患者具有较高的患有 FTLD-TDP 病理学的可能性，例如语义变异原发性进行性失语症 (svPPA)，行为变异 FTD (bvFTD) 与 svPPA、PPA 和 bvFTD 共同发生，并伴有肌萎缩症侧索硬化症（ALS）。我们还将招募 FTLD 相关突变的症状携带者，例如 PGRN 和 C9orf72。我们每年都会通过简短但全面的神经心理学来评估这些案例电池，招募病例进行成像和生物流体研究，并招募病例进行尸检。我们提出四项具体旨在实现这些目标。