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

项目总结/摘要 创伤性脑损伤（TBI）是常见的，并且与显著的发病率和死亡率相关。后遗症 TBI可能是持久的，多项研究报告了认知能力下降的速度增加， TBI患者患痴呆症的风险。然而，将TBI与痴呆联系起来的机制仍然很差 理解，虽然血管功能障碍，神经炎症和蛋白质聚集已经被 提出了最近，2020年《柳叶刀》痴呆症委员会强调了这一知识差距， 在2019年的NINDS阿尔茨海默氏症中，TBI是痴呆症的12个潜在可改变的风险因素之一， 疾病相关性痴呆（ADRD）峰会，正式建议进一步研究TBI在 包括研究机制和开发TBI-AD/ADRD相关的生物标志物。到 直接解决这个研究需要，这个应用程序建立在我以前的NINDS R25奖，并建议使用 流行病学、临床研究以及血管相关的血液和神经影像学生物标志物， 血管损伤和随后的血管功能障碍作为联系TBI和痴呆的机制。 这项提议的中心假设是，TBI与认知能力下降和痴呆风险部分相关。 通过血管病变介导的途径加速TBI后数年的神经变性。这项建议会 利用来自2项正在进行的前瞻性队列研究（目的1和2）的现有数据和来自 前瞻性招募队列（目标3）。本研究的目的是：1）确定急性血管损伤是否 与创伤中心转型中短期TBI相关认知结果不良相关 TBI研究和临床知识（TRACK-TBI）研究，2）研究慢性血管功能障碍 在社区动脉粥样硬化治疗中， 社区风险（ARIC）研究，以及3）评估TBI后血管功能障碍的轨迹是否 与正在进行的研究中前瞻性招募的队列中的短期认知结果相关 在宾夕法尼亚大学创伤中心本提案的总体目标是使用多模式 血管病变的生物标志物，以研究TBI和神经认知结果之间的联系机制， 未来干预措施可能有效预防TBI相关痴呆的时间段。 除了拟议的研究，这个项目将为我提供关键的差距为基础的培训，包括在 设计、实施和实施临床流行病学研究，并使用生物标志物作为方法 研究TBI与临床流行病学研究结果之间的疾病机制。本次培训将 使我能够建立一个专注于TBI血管健康的独立研究计划，目标是 阐明疾病机制和表征TBI结果使用精心设计的前瞻性临床- TBI患者的流行病学研究。拟议研究的完成将由一个 优先考虑合作并提供示范性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.