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

项目摘要： 这个NIA K23提案的目的是支持我继续科学发展，成为一个 独立翻译的介入神经心理学家阿尔茨海默氏症临床综合征（ACS）涉及 遗忘型轻度认知功能障碍（aMCI）是痴呆之前的一个阶段，具有多种风险因素。 创伤性脑损伤（TBI）是一个重要的危险因素，仍然知之甚少。发生时间早 ACS与TBI的历史有关，我的团队发表了第一个理论机制模型之一 阿尔茨海默氏病和相关痴呆症（ADRD）的生物学变化可能是 从TBI上升。虽然中度和重度TBI与ACS有明确的联系，但尚不清楚轻度TBI是否与ACS有关。 TBI（mTBI）是最常见的TBI类型，具有类似的关系。需要更多的信息来确定是否 ACS和可能的ADRD的生物学变化可能与mTBI有关。这些信息可以从 生物标记探测。最近出现的高清晰度经颅直流电刺激（HD-tDCS）和 血液来源的生物标志物工具提供了复杂的新方法来探测生物标志物，特别是神经 回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，以开发新的技能，以探测神经回路的生物标志物， 完整性和神经元损伤/炎症，以告知ACS中的生物学变化是否与mTBI病史相关。 通过K23，我将获得有关ADRD和TBI的生物学变化的新知识，不同的液体基础 生物标志物方法，多种非侵入性脑刺激方法，转化研究，领导力/ 管理和科学网络。培训将包括指导，教学课程，动手 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，TBI，无创脑刺激，生物标志物，神经行为研究设计和学术 职业发展。这项科学研究的首要假设是，与以下因素相关的aMCI风险 mTBI将表现为降低的HD-tDCS测量的神经回路完整性和升高的血液生物标志物， 神经元损伤/炎症。该提案将利用UT西南阿尔茨海默病中心， 招募患有aMCI的成年人。目的1将确定是否神经回路的完整性参与言语情景记忆， 基于mTBI病史，通过使用受试者内设计应用三种HD-tDCS降低aMCI 条件目的2将确定aMCI中神经元损伤/炎症的关键血液来源标志物是否是 根据mTBI病史升高。K23提案将提供基本数据和第一作者 出版物准备我的第一个NIA R 01，使我能够独立设计临床/转化研究， 结合生物标志物，并使我能够实现我的总体职业目标，即告知生物标志物， 将ACS和潜在ADRD的发作与TBI病史联系起来的机制。一旦实现这些目标， 我将利用这些新的见解，在我的职业生涯后期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.