Neuroimaging and Molecular Markers of AD and Neurodegenerative Disease after Concussion

AD 和脑震荡后神经退行性疾病的神经影像学和分子标记

• 批准号: 10092055
• 负责人: Jasmeet Pannu Hayes
• 金额: $ 49.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092055
• 关键词: Afghanistan; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Biological Markers; Biomedical Research; Blood; Brain; Brain Concussion; Brain region; Center for Translational Science Activities; Clinical; Craniocerebral Trauma; DNA Methylation; Data; Databases; Dementia; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Disease model; Early treatment; Environmental Risk Factor; Epigenetic Process; Exposure to; Functional Magnetic Resonance Imaging; Genetic; Genetic Risk; Goals; Individual; Injury; Iraq; Judgment; Knowledge; Lead; Light; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Mediation; Memory; Military Personnel; Mission; Nature; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neuronal Injury; Onset of illness; Parkinson Disease; Performance; Plasma; Positioning Attribute; Prevalence; Prevention; Preventive care; Process; Proteins; Public Health; Publishing; Research; Rest; Risk; Risk Factors; Site; TBI treatment; Testing; Thick; Thinness; Time; Traumatic Brain Injury; Treatment Protocols; United States National Institutes of Health; Veterans; War; Work; base; cerebral atrophy; chronic traumatic encephalopathy; dementia risk; epigenetic marker; high risk; innovation; insight; methylation biomarker; mild traumatic brain injury; molecular marker; multimodal data; neurofilament; neuroimaging marker; pre-clinical; prevent; protein biomarkers; screening; stress disorder; tau Proteins; tau-1; treatment strategy

Project Summary Neurodegenerative disease processes leading to Alzheimer’s disease (AD) start decades before they are clinically observed and are difficult to treat at the stage of a formal diagnosis. It is therefore imperative to determine risk factors early in the course of the disease. Accumulating evidence suggests that concussion, or mild TBI, is associated with dementia when combined with additional risk factors such as genetic risk for AD, repetitive injury, and age at injury. As mild TBI has widespread prevalence and represents the majority of all head injuries, the potential link to neurodegenerative disease presents a major public health problem. However, there is a fundamental gap in understanding the mechanisms by which mild TBI confers risk for AD and other neurodegenerative diseases. The long-term goal of this project is to identify preclinical biomarkers for neurodegenerative disease following mild TBI that provide insight into the mechanisms linking mild TBI to neurodegenerative disease. The overall objective of the current application is to identify genetic, epigenetic, and blood-based protein biomarkers of neurodegeneration that are associated with MRI brain metrics of AD pathology longitudinally following mild TBI. The central hypothesis of the proposed project is that mild TBI confers risk for AD and other neurodegenerative diseases when combined with genetic, epigenetic, and other risk factors. We will test our hypothesis by pursuing three specific aims: Aim 1. Determine the longitudinal effects of genetic risk for AD and mild TBI on MRI-based measures of early AD pathology. Aim 2. Identify epigenetic markers of AD and mild TBI that are associated with MRI-based measures of early AD pathology. Aim 3. Identify fluid biomarkers of neurodegenerative disease in mild TBI that are associated with MRI-based measures of early AD pathology. The proposed research is significant because it is expected to advance understanding of who may be at increased risk for AD in the preclinical course of the disease and, in the long term, facilitate the development of a temporal model of disease progression that outlines when each biomarker becomes predictive of AD. The approach is innovative because it leverages longitudinal and multimodal data (genetics, epigenetics, blood-based proteins, MRI, neurocognitive data) from an unparalleled database of close to 600 recent war veterans. Ultimately, such knowledge has the potential to inform clinical judgments regarding who may need to start a treatment regimen to prevent the onset of dementia.

项目摘要 导致阿尔茨海默病（AD）的神经退行性疾病过程在他们被发现之前几十年就开始了。 临床上观察到的，并且在正式诊断阶段难以治疗。因此，必须 在疾病的早期确定危险因素。越来越多的证据表明，脑震荡，或 轻度TBI，当与其他风险因素如AD的遗传风险结合时，与痴呆相关， 重复性损伤和损伤时的年龄。由于轻度TBI具有广泛的患病率， 头部受伤，与神经退行性疾病的潜在联系提出了一个重大的公共卫生问题。 然而，在理解轻度TBI赋予AD风险的机制方面存在根本性的差距 和其他神经退行性疾病。该项目的长期目标是确定临床前生物标志物 对于轻度TBI后的神经退行性疾病， 神经退行性疾病本申请的总体目标是鉴定遗传的、表观遗传的、 以及与AD的MRI脑指标相关的神经变性的基于血液的蛋白质生物标志物 病理纵向后轻度TBI。该项目的核心假设是轻度TBI 当与遗传、表观遗传和其他遗传因素结合时， 危险因素我们将通过追求三个具体目标来测试我们的假设：目标1。确定纵 AD和轻度TBI的遗传风险对基于MRI的早期AD病理学指标的影响。目标二。识别 AD和轻度TBI的表观遗传标记，与早期AD病理学的MRI测量相关。 目标3.识别与基于MRI的轻度TBI中神经退行性疾病相关的液体生物标志物 早期AD病理学指标。这项拟议中的研究意义重大，因为它有望推动 了解谁可能在疾病的临床前过程中增加AD的风险， 术语，促进疾病进展的时间模型的开发，该模型概述了当每个生物标志物 成为AD的预测指标。该方法是创新的，因为它利用了纵向和多模态数据 （遗传学，表观遗传学，血液蛋白质，MRI，神经认知数据）从一个无与伦比的数据库， 到600名刚参加过战争的老兵最终，这些知识有可能为临床判断提供信息， 他们可能需要开始治疗方案来预防痴呆症的发生。