Pathways Relating Amnestic MCI to a Mild Traumatic Brain Injury History (PATH)

项目摘要： 这项NIA K23计划的目标是支持我继续科学成长，成为一名 独立翻译、干预性神经心理学家。阿尔茨海默氏症临床综合征(ACS)涉及 遗忘性轻度认知障碍(AMCI)是痴呆的前驱阶段，具有多种危险因素。 创伤性脑损伤(TBI)是一个重要的危险因素，目前仍知之甚少。较早发病的 急性冠脉综合征与脑损伤的历史联系在一起，我的团队发表了最早的理论机制模型之一 与阿尔茨海默病和相关痴呆(ADRD)有关的生物学变化可能是 从TBI增加。虽然中度和严重的脑外伤与急性冠脉综合征有明确的联系，但尚不清楚是否轻度 颅脑损伤(MTBI)是最常见的脑损伤类型，也有类似的关系。需要更多的信息来确定 急性冠脉综合征的生物学变化，以及可能的ADRD，可能与mTBI有关。这样的信息可以从 生物标志物探测。最近出现的高清晰度经颅直流电刺激(HD-TDC)和 血液衍生生物标记物工具提供了复杂的新方法来探测生物标记物，特别是神经生物标记物 电路完整性和神经元损伤/炎症。为了实现我的职业发展和研究目标， 我们已经制定了一个全面的培训计划，以发展新的技能来探测神经回路的生物标记物 完整性和神经元损伤/炎症，以告知急性冠脉综合征的生物学变化是否与创伤性脑损伤病史有关。 通过K23，我将获得关于ADRD和TBI的生物变化的新知识，不同的液体为基础 生物标志物方法、多种非侵入性脑刺激方法、转化性研究、领导力/ 治理和科学网络。培训将包括指导、授课课程、动手操作 经验和科学研究。指导团队是一个由具有专业知识的领导者组成的跨学科小组 在ADRD、脑损伤、无创脑刺激、生物标记物、神经行为研究设计和学术方面 职业发展。这项科学研究的首要假设是，急性心肌梗死的风险与 MTBI将表现为HD-TDC测量的神经回路完整性降低和血液生物标记物升高。 神经元损伤/炎症。该提案将利用德克萨斯大学西南阿尔茨海默病中心来 为成人注册AMCI。目标1将确定语言情景记忆中是否涉及神经回路的完整性 通过使用受试者内设计来应用三个HD-TDC，基于mTBI的历史减少了aMCI 条件。Aim 2将确定aMCI中神经元损伤/炎症的关键血源性标志物是否 基于有mTBI历史而提升。K23提案将提供基本数据和第一次编写 准备我的第一个NIA R01的出版物，使我能够独立设计临床/翻译研究 整合了生物标记物，并使我能够实现我的总体职业目标--告知生物 将急性冠脉综合征和潜在的急性呼吸窘迫综合征的发病机制与脑外伤病史联系起来。一旦这些目标实现了 在我的职业生涯后期，我将利用这些新的见解来探索潜在的治疗干预措施。

PROJECT ABSTRACT: The objective of this NIA K23 proposal is to support my continued scientific growth towards becoming an independent translational, interventional neuropsychologist. Alzheimer’s clinical syndrome (ACS) involves amnestic mild cognitive impairment (aMCI), a stage preceding dementia, and has multiple risk factors. Traumatic brain injury (TBI) is one significant risk factor that remains poorly understood. An earlier onset of ACS has been linked to a TBI history, and my group published one of the first theoretical mechanistic models that posited biological changes involved in Alzheimer’s disease and related dementias (ADRD) may be increased from TBI. While moderate and severe TBI have a well-established link to ACS, it is unclear if mild TBI (mTBI), the most common TBI type, has a similar relationship. More information is needed to determine if biological changes in ACS, and possibly ADRD, might relate to mTBI. Such information can be generated from biomarker probing. The recent advent of high definition transcranial direct current stimulation (HD-tDCS) and blood-derived biomarker tools provide sophisticated new methods to probe biomarkers, specifically neural circuit integrity and neuronal injury/inflammation. To accomplish my career development and research goals, we have created a comprehensive training plan to develop new skills to probe biomarkers of neural circuit integrity and neuronal injury/inflammation to inform if biological changes in ACS relate to a history of mTBI. Through the K23, I will gain new knowledge about biological changes in ADRD and TBI, different fluid-based biomarker approaches, multiple noninvasive brain stimulation methods, translational research, leadership/ governance, and scientific networking. Training will include mentorship, didactic coursework, hands-on experiences, and the scientific study. The mentoring team is an interdisciplinary group of leaders with expertise in ADRD, TBI, noninvasive brain stimulation, biomarkers, neurobehavioral research design, and academic career development. The scientific study’s overarching hypothesis is that the risk for aMCI associated with mTBI will manifest as reduced HD-tDCS-measured neural circuit integrity and elevated blood biomarkers of neuronal injury/inflammation. The proposal will leverage the UT Southwestern Alzheimer Disease Center to enroll adults with aMCI. Aim 1 will determine if neural circuit integrity involved in verbal episodic memory in aMCI is reduced based on a history of mTBI by using a within-subjects design to apply three HD-tDCS conditions. Aim 2 will determine if key blood-derived markers of neuronal injury/inflammation in aMCI are elevated based on having an mTBI history. The K23 proposal will provide essential data and first-authored publications to prepare my first NIA R01, enable me to independently design clinical/translational research that incorporates biomarkers, and position me to achieve my overall career goal of informing the biological mechanisms linking onset of ACS, and potentially ADRD, to a history of TBI. Once these goals have been achieved, I will utilize the new insights to explore potential therapeutic interventions later in my career.