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

遗忘性 MCI 与轻度创伤性脑损伤史的关联途径 (PATH)

• 批准号: 10525173
• 负责人: Christian Barrett LoBue
• 金额: $ 13.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525173
• 关键词: Acute; Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Biological; Biological Factors; Biological Markers; Biological Process; Blinded; Blood; Blood - brain barrier anatomy; Cells; Clinical; Cognitive; Crossover Design; Data; Dementia; Development; Early Onset Alzheimer Disease; Elderly; Enrollment; Episodic memory; Goals; Growth; Individual; Inflammation; Injury; Interleukin-6; Intervention; Knowledge; Lead; Leadership; Left; Light; Link; Liquid substance; Measures; Memory; Memory impairment; Mentors; Mentorship; Methods; Modeling; Neurofilament-L; Neuronal Injury; Neurons; Pathologic; Pathway interactions; Positioning Attribute; Protein Isoforms; Publications; Publishing; Recording of previous events; Research; Research Design; Risk; Risk Factors; Syndrome; Testing; Theoretical model; Therapeutic Intervention; Training; Translational Research; Traumatic Brain Injury; amnestic mild cognitive impairment; base; career; career development; design; experience; extracellular vesicles; insight; mild cognitive impairment; mild traumatic brain injury; neural circuit; neurobehavioral; neurofilament; neuron loss; noninvasive brain stimulation; public health relevance; research and development; response; skills; tau-1; therapy development; tool

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.

项目摘要： 该NIA K23提案的目的是支持我持续的科学发展，以成为一个 独立的翻译，介入神经心理学家。阿尔茨海默氏症临床综合征（ACS）涉及 敏感的轻度认知障碍（AMCI）是痴呆症之前的阶段，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，仍然了解不足。较早的发作 ACS已与TBI历史相关，我的小组发表了第一个理论机械模型之一 阿尔茨海默氏病和相关痴呆症（ADRD）涉及的后代生物学变化可能是 从TBI增加。虽然中度和重度TBI与AC有一个完善的链接，但尚不清楚是否中间 TBI（MTBI）是最常见的TBI类型，具有相似的关系。需要更多信息来确定是否 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 生物标志物探测。高清经颅直接电流刺激（HD-TDC）的最新进展和 血液来源的生物标志物工具为探测生物标志物提供了精致的新方法，特别是中性的 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， 我们制定了一项全面的培训计划，以开发新技能来探究神经电路的生物标志物 完整性和神经元损伤/炎症，以告知与MTBI史有关的ACS的生物学变化。 通过K23，我将获得有关ADRD和TBI的生物学变化的新知识，基于不同的流体 生物标志物方法，多种无创脑刺激方法，翻译研究，领导力/ 治理和科学网络。培训将包括精通训练，教学课程，动手 经验和科学研究。心理团队是一个具有专业知识的跨学科领导者 在ADRD中，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。科学研究的总体假设是与AMCI相关的风险 MTBI将表现为减少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西南阿尔茨海默氏病中心 入学成年人AMCI。 AIM 1将确定神经回路的完整性是否参与言语情节记忆 通过使用受试者内部设计应用三个HD-TDCS，根据MTBI的历史来减少AMCI 状况。 AIM 2将确定AMCI中神经元损伤/炎症的关键血液标记是否是 根据拥有MTBI历史而提升。 K23提案将提供必要的数据并首先进行 为我的第一个NIA R01准备的出版物，使我能够独立设计临床/翻译研究 结合生物标志物，并将我定位为实现我的整体职业目标，以告知生物学 将AC的发作以及潜在的ADRD连接到TBI史的机制。一旦这些目标 实现的是，我将利用新的见解来探讨我职业生涯后期潜在的治疗干预措施。