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: 10041708
• 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/10041708
• 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; Multiple Trauma; 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; military veteran; 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）的主要障碍已经使许多复杂的障碍 以及影响结果和恢复的复合因素。虽然已经进行了广泛的努力 描述各种环境贡献的影响（例如，战斗暴露，伤害机制， 等）关于TBI结果，与临床不良结果的神经生物学基础有关的文献 TBI的后果相对有限。特别是我们对遗传因素影响的理解 关于TBI后的结果和恢复是不完整的。值得注意的是，在研究了这些的研究中 人际关系，发现是仔细的，可能是由于样本量不足，因此很低 检测TBI样品中有意义差异的功率。此外，现有的遗传学研究在很大程度上已经 采用了一种“候选基因”方法，重点关注特定感兴趣的基因，从而淡化了 对复杂性状的遗传倾向是高度多基因的可能性，即 特定基因可能略有，但是多个基因的影响可能非常重要。那不仅是 充分了解遗传标记对TBI临床的影响所需的充分动力研究 结果，但下一步至关重要的是将多基因风险的概念应用于TBI并概念化伤害后 临床结果作为复杂的多基因表型。此外，有积累的证据表明 神经内分泌异常的存在也可能有助于观察到的异质结果 遵循TBI，但是这些关联也很熟悉。考虑到这一点，本研究是 观察队列研究建议使用百万退伍军人计划可用的数据来检查 遗传因素和神经内分泌异常对认知和精神病结果的影响 具有TBI历史的退伍军人，以增加对神经生物学因素的程度的理解 在TBI后影响这些重要的临床结果。该提案的优势包括（1）使用大型 扩展遗传数据以扩展我们对与TBI结果相关的神经生物学因素的理解，（2） 将多基因风险应用于TBI，（3）重点是TBI退伍军人的长期医疗保健结果 历史。这项研究的发现可能与目前正在正在的治疗 在精确的医学方法中开发和优化，以针对那些最有可能不良预后风险的人。 申请人目前是完成TBI/Polytrauma的神经心理学博士学位研究员 VA圣地亚哥医疗保健系统的奖学金。成功完成了VA职业发展 Award-2（CDA-2）将允许候选人朝着成为独立的长期职业目标迈向长期的职业目标 VA中的临床研究人员，重点是制定TBI研究计划 通过合并工具和技术，阐明了整个生命周期中TBI的急性和慢性影响 生物标记物（例如遗传学和神经内分泌学）研究了TBI临床基础的过程 结果和恢复。为了成功制定独立研究计划，候选人将 从该CDA-2提供的额外培训和经验中受益。具体的培训目标是： （1）获得与遗传数据相结合的能力与临床相关的结果指标（即 神经认知和精神病变量）在熟悉全基因组方法的同时 关联研究以及多基因风险评分的发展和建模； （2）学习基本 在军事TBI的背景下，神经内分泌学的原则和应用； （3）发展专业知识 高级生物统计学和大数据，并接受浏览VA信息学和计算的培训 基础设施; （4）获得与科学和专业发展有关的概括。在职的 与杰出的Mentalship团队合作，候选人将接受必要的培训，并 作为VA内的临床研究人员，可以使独立发展的准备工作。