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

了解轻度创伤性脑损伤(MTBI)对神经变性的风险至关重要 对退伍军人来说很重要。单一和重复的mTBI在退伍军人中很常见，高达17% 在部署期间报告mTBI。TBI已被报告为最强的环境风险之一 与迟发性阿尔茨海默病(AD)相关的因素和重复的mTBI已被关联 患有慢性创伤性脑病(CTE)。然而，关于mTBI是否存在争议仍在继续 在运动之外，大脑损伤占绝大多数，导致神经退行性变 改变。调查AD和CTE重叠的研究，这两个潜在的共同发生 神经退行性疾病很少，需要更多。这份提案审查了贡献 MTBI对神经变性的影响，目的是检测行为和生物标志物证据 退伍军人AD和CTE所致神经退行性变。我们的假设是，在对年龄进行修正后， 有可能将与脑外伤本身相关的脑损伤的特征与与脑损伤相关的缺陷区分开来 神经退行性变。[我们将研究识别记忆，将回忆和熟悉分开作为 大脑中脑损伤潜在神经变性潜在的认知改变模型。作为衡量 再认记忆、回忆和熟悉度是mTBI人群的理想选择--有可能 神经退行性变--因为它们以前被用来检测AD的神经退行性变。我们的 假设是，有更多的MTBI和更多的时间从他们的MTBI的受试者更有可能 由于AD或CTE导致神经变性，导致记忆力相对下降， 最终，一旦疾病达到轻度痴呆症阶段，熟悉程度也会降低。在……里面 除了这些行为技术外，关于这些技术基础的补充数据 事件相关电位(ERPs)、磁共振成像(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，包括 在65名有mTBI病史的年轻成年退伍军人中，65名患有mTBI的老年退伍军人，30名老年退伍军人 患有轻度认知障碍(MCI)但缺乏作为认知控制的mTBI病史的退伍军人， 以及30名无脑外伤病史的年轻健康对照组退伍军人和30名老年健康对照组 没有mTBI病史的退伍军人。]主要目标将在mTBI队列中使用 [总寿命MTBIs]与[第一次生命]时间关系的回归分析 MTBI和感兴趣的结果，包括行为、事件相关电位、磁共振测量和脑脊液测量。 多变量线性混合效应模型将被用来检验mTBI受试者之间的差异 以及所有结果测量的非mTBI对照。这些模式将根据年龄进行调整，[教育， APOE状态]和其他潜在的混杂因素。研究和职业发展活动 Proposed将为Turk博士的长期目标做好准备，即在 跟踪mTBI的退伍军人，并将使她最终能够研究这一具有良好特征的人群 患有纵向脑外伤的退伍军人。她建议有重点的课程作业、学习和辅导 一群在各自领域处于领先地位的知名调查人员以及实际研究人员 有完成建议项目的经验。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培训，以及 (3)神经退行性变的脑脊液生物标记物测定训练。这些知识， 通过这项提议获得的技术和经验将使特克博士获得所需的技能 成功角逐功绩评审奖，成为一名独立的调查员。

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.