Contributions of mild traumatic brain injury to neurodegeneration due to chronic traumatic encephalopathy and alzheimer's disease

轻度创伤性脑损伤对慢性创伤性脑病和阿尔茨海默病引起的神经变性的影响

• 批准号: 10467981
• 负责人: Katherine W Turk
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467981
• 关键词: Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Atrophic; Award; Behavioral; Biological Markers; Brain Injuries; CCL11 gene; Cerebrospinal Fluid; Data; Data Analytics; Dementia; Deposition; Disease; Education; Elderly; Electrophysiology (science); Environmental Risk Factor; Event-Related Potentials; Experimental Designs; Experimental Psychology; Familiarity; Goals; Hippocampus (Brain); Image; Imaging Techniques; Impairment; Knowledge; Late Onset Alzheimer Disease; Life; Light; Magnetic Resonance Imaging; Measurement; Measures; Medial; Memory; Memory Loss; Mentors; Modeling; Nerve Degeneration; Neurofilament-L; Outcome; Outcome Measure; Pathologic; Patients; Populations at Risk; Process; Recording of previous events; Regression Analysis; Reporting; Research; Research Personnel; Risk; Source; Sports; Techniques; Temporal Lobe; Testing; Thick; Time; Training; Traumatic Brain Injury; Veterans; career; career development; cerebral atrophy; chemokine; chronic traumatic encephalopathy; cognitive change; cognitive control; cognitive process; cohort; experience; experimental study; interest; memory recognition; mild cognitive impairment; mild traumatic brain injury; military veteran; neurofilament; quantitative imaging; recruit; research and development; skills; tau Proteins; tau-1; young adult

Understanding the risks mild traumatic brain injury (mTBI) poses for neurodegeneration is critically important for Veterans. Single and repetitive mTBI is common in Veterans, with as many as 17% reporting mTBI during deployment. TBI has been reported as one of the strongest environmental risk factors associated with late-onset Alzheimer’s disease (AD), and repetitive mTBI has been associated with chronic traumatic encephalopathy (CTE). However, there is ongoing debate as to whether mTBI outside of sports, which represents the vast majority of brain injuries, results in neurodegenerative changes. Studies investigating the overlap of AD and CTE, two potentially co-occurring neurodegenerative conditions, are few and more are needed. This proposal examines the contribution of mTBI to neurodegeneration with the intent of detecting behavioral and biomarker evidence of neurodegeneration due AD and CTE in Veterans. Our hypothesis is that, after correcting for age, it is possible to separate the hallmarks of brain trauma related to TBI itself, from deficits related to neurodegeneration. [We will examine recognition memory, separating recollection and familiarity as a model of the cognitive changes underlying potential neurodegeneration in mTBI. As measures of recognition memory, recollection and familiarity are ideal for use in the mTBI population—at risk for neurodegeneration—as they have previously been used to detect neurodegeneration in AD. Our hypothesis is that subjects with more mTBIs and more time since their mTBIs will be more likely to develop neurodegeneration due to AD or CTE, leading to relative decreases in recollection and, eventually, decreases in familiarity as well once the disease reaches the mild dementia stage. In addition to these behavioral techniques, complimentary data regarding the underpinnings of these cognitive processes provided by event-related potentials (ERPs), MRI, and cerebrospinal fluid (CSF) will allow further separation of possible AD and CTE. A total of 220 veterans will be recruited consisting of 65 younger adult veterans with a history of mTBI, 65 older adult veterans with mTBI, 30 older veterans with mild cognitive impairment (MCI) but lacking a history of mTBI to act as cognitive controls, as well as 30 younger healthy control veterans without a history of mTBI and 30 older healthy control veterans without a history of mTBI.] The primary aims will be explored within the mTBI cohort using regression analyses for the relations between [total number of life time mTBIs], time since [first lifetime] mTBI, and outcomes of interest including behavioral, ERP, MRI measures and CSF measures. Multivariate linear mixed-effects models will be used to examine differences between mTBI subjects and non-mTBI controls for all outcomes measures. The models will be adjusted for age, [education, APOE status] and other potential confounding factors. The research and career development activities proposed will prepare Dr. Turk for her long-term goal of a research career in neurodegeneration in veterans following mTBI and will allow her to eventually study this well-characterized population of veterans with mTBI longitudinally. She proposes focused coursework, study and mentoring from a group of well-established investigators who are leaders in their fields, as well as practical research experience completing the project proposed. The proposed training plan focuses on three objectives: (1) training in experimental psychology and experimental design including counterbalancing and data analytic techniques, (2) training in quantitative imaging techniques and data analytic techniques, and (3) training in cerebrospinal fluid biomarker measurements in neurodegeneration. The knowledge, techniques, and experience gained through this proposal will allow Dr. Turk to gain skills needed to compete successfully for a Merit Review Award and become an independent investigator.

了解轻度创伤性脑损伤（mTBI）对神经退行性变的风险至关重要 对退伍军人很重要。单次和重复性mTBI在退伍军人中很常见，高达17% 在部署期间报告mTBI。TBI已被报道为最强的环境风险之一 与迟发性阿尔茨海默病（AD）相关的因素，以及重复性mTBI已与 慢性创伤性脑病（CTE）然而，关于mTBI是否 在运动之外，这代表了绝大多数的脑损伤，导致神经退行性疾病， 变化研究AD和CTE（两种可能同时发生的疾病）重叠的研究 神经退行性疾病，很少，需要更多。本提案审查了 目的是检测mTBI的行为和生物标志物证据， 退伍军人中的AD和CTE引起的神经变性。我们的假设是，在校正年龄后， 有可能将与TBI本身相关的脑创伤的标志与与TBI相关的缺陷分开， 神经变性[We将研究识别记忆，将回忆和熟悉分开， mTBI中潜在神经变性的认知变化模型。作为衡量 识别记忆，回忆和熟悉是理想的mTBI人群中使用的风险 神经退行性变-因为它们以前被用于检测AD中的神经退行性变。我们 假设mTBI越多且自mTBI以来时间越长的受试者更有可能 由于AD或CTE而发生神经变性，导致回忆相对减少， 最终，一旦疾病达到轻度痴呆阶段，熟悉度也会下降。在 除了这些行为技术，关于这些基础的补充数据 事件相关电位（ERP）、MRI和脑脊液（CSF）提供的认知过程 将允许进一步分离可能的AD和CTE。总共将招募220名退伍军人， 65名有mTBI病史的年轻成年退伍军人，65名有mTBI病史的老年退伍军人，30名有mTBI病史的老年退伍军人， 具有轻度认知障碍（MCI）但缺乏mTBI史的退伍军人作为认知对照， 以及30名没有mTBI病史的年轻健康对照退伍军人和30名老年健康对照 没有mTBI病史的退伍军人。将使用以下方法在mTBI队列中探索主要目标 [寿命mTBI总数]、自[首次寿命]以来的时间之间关系的回归分析 mTBI和关注的结果，包括行为、ERP、MRI测量和CSF测量。 多变量线性混合效应模型将用于检查mTBI受试者之间的差异 和非mTBI对照的所有结果指标。这些模型将根据年龄，[教育， APOE状态]和其他潜在混杂因素。研究和职业发展活动 提出将准备博士特克为她的长期目标的研究生涯中的神经变性， mTBI后的退伍军人，并将允许她最终研究这一特征良好的人群， mTBI的退伍军人纵向。她提出了重点课程，研究和指导，从一个 一群在各自领域以及实际研究中处于领先地位的知名调查人员 完成所提出的项目。拟议的培训计划侧重于三个目标： (1)实验心理学和实验设计培训，包括平衡和数据 分析技术，（2）定量成像技术和数据分析技术的培训，以及 (3)在神经退行性疾病中进行脑脊液生物标志物测量的培训。知识， 技术，并通过这项建议获得的经验将使特克博士获得所需的技能， 成功竞争优异评审奖并成为独立调查员。