Examination of Biological Markers Associated with Neurobehavioral and Neuropsychological Outcomes in Military Veterans with a History of Traumatic Brain Injury

与有脑外伤史的退伍军人的神经行为和神经心理结果相关的生物标志物的检查

• 批准号: 9776149
• 负责人: VICTORIA C. MERRITT
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9776149
• 关键词: Acute; Adopted; Adult; Alleles; Alzheimer' s Disease; Amnesia; Baseline Surveys; Big Data; Biological Factors; Biological Markers; Biometry; Bipolar Disorder; Brain; Brain Injuries; Candidate Disease Gene; Characteristics; Childhood; Chronic; Clinical; Cognition; Cognition Disorders; Cognitive; Cohort Studies; Competence; Complex; Data; Dementia; Demographic Factors; Development; Diagnosis; Dose; Electronic Health Record; Familiarity; Fellowship; Frequencies; Genes; Genetic; Genetic Databases; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic study; Genotype; Goals; Head circumference; Headache; Health Care Costs; Health Personnel; Healthcare Systems; Heritability; Individual; Infant; Informatics; Infrastructure; Injury; Intelligence; K-Series Research Career Programs; Learning; Life Style; Literature; Longevity; Major Depressive Disorder; Medical; Medicine; Memory; Mental disorders; Mentorship; Methods; Military Personnel; Mind; Modeling; Moods; Neurobehavioral Manifestations; Neurobiology; Neurocognitive; Neurodegenerative Disorders; Neuroendocrinology; Neuropsychology; Neurosecretory Systems; Outcome; Outcome Measure; Patients; Pattern; Performance; Persons; Phenotype; Play; Postdoctoral Fellow; Preparation; Process; Psychiatric Diagnosis; Quality of life; Recording of previous events; Recovery; Research; Research Personnel; Risk; Role; Sample Size; Sampling; Single Nucleotide Polymorphism; Sleep disturbances; Surveys; Symptoms; Techniques; Testing; Training; Traumatic Brain Injury; Unconscious State; Veterans; Work; apolipoprotein E-4; base; care outcomes; career; clinical database; clinically relevant; cognitive testing; cohort; combat; comorbidity; comparative; executive function; expectation; experience; genome wide association study; genome-wide; health care service utilization; interest; mild traumatic brain injury; neurobehavioral; neurocognitive disorder; neuropsychiatry; personalized approach; polygenic risk score; precision medicine; programs; psychiatric symptom; psychosocial; response; tool; trait

A major hurdle to studying traumatic brain injury (TBI) has been disentangling the many complicating and compounding factors that influence outcome and recovery. While extensive efforts have been placed on delineating the impact of various environmental contributions (e.g., combat exposure, mechanism of injury, etc.) on TBI outcome, the literature pertaining to the neurobiological underpinnings of poor clinical outcome in the aftermath of TBI is comparatively limited. In particular, our understanding of the influence of genetic factors on outcome and recovery following TBI is incomplete. Notably, among the studies that have examined these relationships, findings are considerably disparate, likely due to inadequate sample sizes and therefore low power to detect meaningful differences in TBI samples. Additionally, existing genetics studies have largely adopted a “candidate gene” approach, focusing on a specific gene of interest, thereby downplaying the possibility that genetic predisposition to complex traits is highly polygenic—that is, the individual contribution of a specific gene may be slight, but the effects of multiple genes could be quite significant. Thus, not only are adequately powered studies needed to better understand the influence of genetic markers on TBI clinical outcome, but a crucial next step is to apply the concept of polygenic risk to TBI and conceptualize post-injury clinical outcome as a complex polygenic phenotype. Moreover, there is accumulating evidence to suggest that the presence of neuroendocrine abnormalities may also contribute to the heterogeneous outcomes observed following TBI, yet these associations are also poorly understood. With this in mind, the present study is an observational cohort study proposing to use data available from the Million Veteran Program to examine the influence of genetic factors and neuroendocrine abnormalities on cognitive and psychiatric outcomes in Veterans with TBI histories in order to increase understanding of the extent to which neurobiological factors influence these important clinical outcomes post-TBI. Strengths of this proposal include (1) the use of large- scale genetic data to expand our understanding of neurobiological factors associated with TBI outcome, (2) the application of polygenic risk to TBI, and (3) a focus on the long-term health care outcomes of Veterans with TBI histories. Findings from this study may have particular relevance to treatments that are currently being developed and optimized within a precision medicine approach to target those most at risk of poor outcome. The applicant is currently a neuropsychology postdoctoral fellow completing the TBI/Polytrauma Fellowship at the VA San Diego Healthcare System. Successful completion of this VA Career Development Award-2 (CDA-2) will allow the candidate to advance toward a long-term career goal of being an independent clinical researcher within the VA, focused on the development of a TBI research program that serves to elucidate the acute and chronic effects of TBI across the lifespan by incorporating the tools and techniques of biological markers such as genetics and neuroendocrinology to study the processes that underlie TBI clinical outcome and recovery. To successfully develop an independent research program, the candidate would benefit from the additional training and experience that this CDA-2 will provide. Specific training goals are to: (1) acquire competencies in the integration of genetic data with clinically-relevant outcome measures (i.e., neurocognitive and psychiatric variables) while gaining familiarity with the methods of genome-wide association studies and the development and modeling of polygenic risk scores; (2) learn fundamental principles and applications of neuroendocrinology within the context of military TBI; (3) develop expertise in advanced biostatistics and big data, and receive training in navigating the VA Informatics & Computing Infrastructure; and (4) obtain mentorship related to scientific and professional development. Working collaboratively with a distinguished mentorship team, the candidate will receive the necessary training and preparation that will allow for advancement toward independence as a clinical researcher within the VA.

研究创伤性脑损伤 (TBI) 的一个主要障碍是解开许多复杂的因素 以及影响结果和恢复的复合因素，同时我们也付出了广泛的努力。 描述各种环境因素的影响（例如，战斗暴露、伤害机制、 等）关于TBI结果，有关不良临床结果的神经生物学基础的文献 TBI 的后果尤其是我们对遗传因素影响的了解相对有限。 值得注意的是，在检验这些的研究中，关于 TBI 后的结果和恢复的研究并不完整。 关系，结果相差很大，可能是由于样本量不足，因此较低 此外，现有的遗传学研究在很大程度上还没有能力检测 TBI 样本中有意义的差异。 采用“候选基因”方法，专注于感兴趣的特定基因，从而淡化了 复杂性状的遗传易感性可能是高度多基因的，即个体的贡献 一个特定基因的影响可能很小，但多个基因的影响可能相当显着。 需要足够有力的研究来更好地了解遗传标记对 TBI 临床的影响 结果，但下一步关键是将多基因风险的概念应用于 TBI 并概念化损伤后 此外，越来越多的证据表明，临床结果是一种复杂的多基因表型。 神经内分泌异常的存在也可能导致观察到的异质性结果 TBI 后，但人们对这些关联还知之甚少，考虑到这一点，本研究是一项。 观察性队列研究建议使用百万退伍军人计划提供的数据来检查 遗传因素和神经内分泌异常对精神疾病结局的影响 有 TBI 病史的退伍军人，以增加对神经生物学因素影响程度的了解 影响 TBI 后这些重要的临床结果 该提案的优点包括 (1) 使用大的 扩展遗传数据以扩大我们对与 TBI 结果相关的神经生物学因素的理解，(2) 多基因风险在 TBI 中的应用，以及 (3) 关注患有 TBI 的退伍军人的长期医疗保健结果 这项研究的结果可能与目前正在进行的治疗有特别的相关性。 通过精准医学方法进行开发和优化，以针对那些最有可能出现不良结果的人。 申请人目前是一名神经心理学博士后研究员，正在完成 TBI/多发伤 退伍军人管理局圣地亚哥医疗系统的奖学金成功完成退伍军人管理局职业发展。 Award-2 (CDA-2) 将使候选人能够朝着成为独立人士的长期职业目标前进 VA 内的临床研究员，专注于 TBI 研究计划的开发，该计划旨在 通过结合以下工具和技术，阐明 TBI 在整个生命周期中的急性和慢性影响 生物学标记，如遗传学和神经内分泌学，用于研究 TBI 临床基础的过程 为了成功制定独立研究计划，候选人将 受益于 CDA-2 将提供的额外培训和经验 具体培训目标是： (1) 获得将遗传数据与临床相关结果测量相整合的能力（即， 神经认知和精神变量），同时熟悉全基因组方法 (2)学习基础 (3) 发展专业知识 先进的生物统计学和大数据，并接受 VA 信息学和计算方面的培训 基础设施；(4) 获得与科学和专业发展相关的指导。 与杰出的导师团队合作，候选人将接受必要的培训和 为作为 VA 内的临床研究人员走向独立而做的准备。