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: 10578649
• 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/10578649
• 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; Classification; Clinical; Cognition; Cognition Disorders; Cognitive; Competence; Complex; Data; Dementia; Demographic Factors; Development; Diagnosis; Disparate; Dose; Education; 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 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; 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; care outcomes; career; clinical database; clinically relevant; cognitive testing; cohort; combat; comparative; cost; 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; observational cohort study; personalized approach; polygenic risk score; precision medicine; programs; psychiatric comorbidity; 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 以及影响结果和恢复的复合因素。虽然已作出广泛努力， 描述各种环境贡献的影响（例如，战斗暴露，受伤机制， 等等）。关于TBI结果，与TBI患者临床结果不良的神经生物学基础相关的文献， 创伤性脑损伤的后果相对有限。特别是我们对遗传因素影响的理解 TBI后的结果和恢复是不完整的。值得注意的是，在这些研究中， 关系，调查结果差异很大，可能是由于样本量不足， 检测TBI样本中有意义差异的能力。此外，现有的遗传学研究主要 采用了“候选基因”的方法，专注于特定的感兴趣的基因，从而淡化了 复杂性状的遗传倾向是高度多基因的可能性，也就是说， 一个特定的基因可能是轻微的，但多个基因的影响可能是相当显著的。不仅如此， 需要进行足够有力的研究，以更好地了解遗传标记对TBI临床的影响。 结果，但关键的下一步是将多基因风险的概念应用于TBI和概念化损伤后 临床结果作为一个复杂的多基因表型。此外，越来越多的证据表明， 神经内分泌异常的存在也可能导致观察到的异质性结局 TBI后，但这些协会也知之甚少。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老年痴呆症患者认知和精神预后的影响 有TBI病史的退伍军人，以增加对神经生物学因素 影响TBI后这些重要的临床结果。该提案的优点包括：（1）使用大型- 规模遗传数据，以扩大我们对与TBI结果相关的神经生物学因素的理解，（2） 应用多基因风险TBI，（3）关注TBI退伍军人的长期医疗保健结果 历史这项研究的结果可能与目前正在进行的治疗特别相关。 在精准医学方法中开发和优化，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，完成了TBI/多发性创伤 在VA圣地亚哥医疗保健系统的奖学金。成功完成此VA职业发展 Award-2（CDA-2）将允许候选人朝着独立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， 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，以研究TBI临床基础的过程。 结果和恢复。为了成功地开发一个独立的研究项目，候选人将 从CDA-2提供的额外培训和经验中受益。具体的培训目标是： (1)获得将遗传数据与临床相关结果指标整合的能力（即， 神经认知和精神病学变量），同时熟悉全基因组方法 关联研究和多基因风险评分的开发和建模;（2）学习基本的 军事TBI背景下神经内分泌学的原理和应用;（3）发展以下方面的专业知识 先进的生物统计学和大数据，并接受导航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指导。工作 与杰出的导师团队合作，候选人将接受必要的培训， 准备，这将允许向独立的VA内的临床研究人员的进步。