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

项目摘要/摘要 创伤性脑损伤(TBI)是一种常见的疾病，与严重的发病率和死亡率有关。后遗症 脑外伤可能会持续很长时间，多项研究报告称，认知功能减退率增加，甚至更高 脑外伤患者患痴呆症的风险。然而，将脑外伤与痴呆症联系起来的机制仍然很差。 理解，尽管血管功能障碍、神经炎症和蛋白质聚集 建议。这一知识差距最近在2020年的《柳叶刀》痴呆症委员会上得到了强调，该委员会 将脑损伤添加为痴呆症的12个潜在可修改风险因素之一，并在2019年NINDS阿尔茨海默氏症 疾病相关痴呆症(ADRD)峰会，正式建议进一步研究创伤性脑损伤在 痴呆，包括强调研究机制和开发与TBI-AD/ADRD相关的生物标记物。至 直接满足此研究需求，此应用程序构建在我之前的NINDS R25奖的基础上，并建议使用 流行病学、临床研究和血管相关的血液和神经影像生物标记物的研究 血管损伤和随后的血管功能障碍是脑外伤和痴呆之间的联系机制。 这项提议的中心假设是，脑外伤与认知能力下降和痴呆症风险部分相关。 通过血管病变介导的通路加速脑损伤后数年的神经退化。这项提议将 利用来自2个正在进行的前瞻性队列研究(目标1和2)的现有数据和来自 预期招募的队列(目标3)。这项研究的目的是：1)确定急性血管损伤是否 以创伤中心为基础的转化中与较差的短期脑外伤相关认知结果相关 颅脑损伤(Track-TBI)研究中的研究和临床知识，2)调查慢性血管功能障碍 以社区为基础的动脉粥样硬化患者脑外伤与不良长期认知结果之间的关系 社区风险(ARIC)研究，以及3)评估脑外伤后血管功能障碍的轨迹是否 与正在进行的研究中嵌套的前瞻性招募队列中的短期认知结果相关 在宾夕法尼亚大学创伤中心。这项提议的总体目标是使用多式联运 血管病变的生物标记物，以研究脑外伤与神经认知结果的联系机制并确定 未来干预在预防脑外伤相关痴呆方面可能有效的时间段。 除了拟议的研究外，该项目还将为我提供关键的基于差距的培训，包括 设计、进行和实施临床流行病学研究，并使用生物标志物作为一种方法 研究脑损伤与临床流行病学研究结果之间的联系的疾病机制。这次培训将 使我能够建立一个独立的研究计划，专注于TBI的血管健康，目标是 使用精心设计的前瞻性临床试验阐明疾病机制和表征脑外伤的预后 脑损伤患者的流行病学研究。完成拟议的研究将由一项 重视协作并提供模范研究和职业支持的机构环境。

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.