Establishing Mechanisms Between Traumatic Brain Injury and Dementia Using Epidemiology, Clinical Studies, Blood-Based Biomarkers, and Neuroimaging Biomarkers

利用流行病学、临床研究、血液生物标志物和神经影像生物标志物建立创伤性脑损伤和痴呆之间的机制

• 批准号: 10449172
• 负责人: Andrea Lauren Christman Schneider
• 金额: $ 19.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449172
• 关键词: Acute; Address; Alzheimer' s disease related dementia; Atherosclerosis Risk in Communities; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Cerebrovascular Circulation; Cerebrovascular Trauma; Chronic; Clinical; Clinical Research; Cognitive; Cohort Studies; Collaborations; Communities; Data; Data Collection; Dementia; Disease; Endothelium; Environment; Epidemiology; Freezing; Functional disorder; Funding; Future; Goals; Health; Impaired cognition; Individual; Injury; Intervention; Knowledge; Lead; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Methods; Morbidity - disease rate; Multicenter Studies; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurocognitive; Outcome; Pathway interactions; Patient Recruitments; Pennsylvania; Persons; Population Scientist Supplement (R25); Prevention; Process; Prospective cohort study; Reporting; Research; Research Project Grants; Role; Sampling; Source; Specimen; TBI treatment; Time; Training; Traumatic Brain Injury; Traumatic brain injury related dementia; United States; Universities; Vascular Diseases; Work; acute care; base; blood-based biomarker; blood-brain barrier function; career; cerebrovascular; clinical center; clinical implementation; cohort; dementia risk; design; effective therapy; epidemiology study; follow-up; high risk; improved; modifiable risk; mortality; multimodality; neuroimaging marker; neuroinflammation; novel; prevent; programs; prospective; protein aggregation; recruit; skills; symposium; therapeutic target; trauma centers; validation studies; vascular injury

PROJECT SUMMARY / ABSTRACT Traumatic brain injury (TBI) is common and is associated with significant morbidity and mortality. The sequelae from TBI can be long-lasting, and multiple studies have reported an increased rate of cognitive decline and higher risk of dementia among persons with TBI. However, the mechanisms linking TBI to dementia remain poorly understood, although vascular dysfunction, neuroinflammation, and aggregation of proteins have been proposed. This gap in knowledge was recently highlighted in the 2020 Lancet Commission on Dementia, which added TBI as one of twelve potentially modifiable risk factors for dementia, and in the 2019 NINDS Alzheimer’s Disease-Related Dementias (ADRD) Summit, which formally recommended further study into the role of TBI in dementia, including an emphasis on studying mechanism and developing TBI-AD/ADRD-related biomarkers. To directly address this research need, this application builds on my prior NINDS R25 award and proposes to use epidemiology, clinical studies, and vascular-related blood-based and neuroimaging biomarkers to investigate vascular injury and subsequent vascular dysfunction as mechanisms linking TBI and dementia. The central hypothesis of this proposal is that TBI is associated with cognitive decline and dementia risk in part via vasculopathy-mediated pathways which accelerate neurodegeneration for years post-TBI. This proposal will leverage existing data from 2 ongoing prospective cohort studies (Aims 1 and 2) and new data from a prospectively recruited cohort (Aim 3). The aims of this study are: 1) to determine if acute vascular injury is associated with poor short-term TBI-related cognitive outcomes in the trauma center-based Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Study, 2) to investigate if chronic vascular dysfunction mediates associations of TBI with poor long-term cognitive outcomes in the community-based Atherosclerosis Risk in Communities (ARIC) Study, and 3) to evaluate if the trajectory of post-TBI vascular dysfunction is associated with short-term cognitive outcomes in a prospectively recruited cohort nested within ongoing studies at the University of Pennsylvania Trauma Center. The overall objective of this proposal is to use multi-modal biomarkers of vasculopathy to investigate mechanisms linking TBI and neurocognitive outcomes and to identify time-periods during which future interventions may be effective at preventing TBI-related dementia. In addition to the proposed research, this project will provide me with critical gap-based training, including in the design, conduct, and implementation of clinical-epidemiologic studies and in the use of biomarkers as a method to investigate disease mechanisms linking TBI to outcomes in clinical-epidemiologic studies. This training will enable me to build an independent research program focused on vascular health in TBI with the goal of elucidating disease mechanisms and characterizing TBI outcomes using well-designed prospective clinical- epidemiologic studies of individuals with TBI. Completion of the proposed study will be facilitated by an institutional environment that prioritizes collaboration and provides exemplary research and career support.

项目摘要 /摘要 创伤性脑损伤（TBI）很常见，与显着的发病率和死亡率有关。后遗症 从TBI可以是持久的，并且多项研究报告了认知能力下降的率提高，并且更高 TBI患者痴呆症的风险。但是，将TBI与痴呆症联系起来的机制仍然很差 了解，尽管血管功能障碍，神经炎症和蛋白质聚集已经 建议的。最近在2020年柳叶刀痴呆委员会中强调了这一知识的差距， 将TBI添加为痴呆症的十二个潜在可修改的危险因素之一，在2019年Ninds Alzheimer's中 与疾病相关的痴呆症（ADRD）峰会，该峰会正式建议进一步研究TBI在 痴呆症，包括强调研究机制并开发与TBI-AD/ADRD相关的生物标志物。到 直接满足了这项研究需求，该应用程序建立在我以前的Ninds R25奖和建议的建议基础上 流行病学，临床研究以及与血管相关的血液和神经影像学家研究 血管损伤和随后的血管功能障碍作为将TBI和痴呆联系起来的机制。 该提议的核心假设是TBI与认知能力下降和痴呆症风险有关 通过血管病介导的途径，TBI多年来加速了神经退行性的途径。该提议将 利用2项正在进行的前瞻性队列研究（目标1和2）的现有数据以及来自 前瞻性招募的队列（AIM 3）。这项研究的目的是：1）确定急性血管损伤是否为 与不良的短期TBI相关的认知结果相关，基于创伤中心的转化 TBI（TRACK-TBI）研究中的研究和临床知识，2）研究是否慢性血管功能障碍 介导基于社区的动脉粥样硬化中TBI与长期认知结果不良的关联 社区（ARIC）研究的风险，以及3）评估TBI后血管功能障碍的轨迹是否是 与正在进行的研究中的前瞻性招募队列中的短期认知结果有关 在宾夕法尼亚大学创伤中心。该提案的总体目的是使用多模式 血管病的生物标志物研究将TBI和神经认知结果联系起来的机制并鉴定 在此期，将来的干预措施可能有效预防与TBI相关的痴呆症。 除了拟议的研究外，该项目还将为我提供基于差距的关键培训，包括 设计，进行和实施临床流行病学研究以及使用生物标志物作为一种方法 研究将TBI与临床流行病学研究中的结果联系起来的疾病机制。这个培训将 使我能够建立一个针对TBI血管健康的独立研究计划，目的是 阐明疾病机制和使用精心设计的前瞻性临床 - TBI个体的流行病学研究。拟议研究的完成将由 优先协作并提供典范研究和职业支持的机构环境。