Mild TBI and Biomarkers of Neurodegeneration

描述（由申请人提供）： 由爆炸装置的爆炸效应引起的轻度创伤性脑损伤（mTBI）是当前伊拉克和阿富汗冲突中士兵，海军陆战队和其他服务人员的“标志性损伤”。部署到伊拉克自由行动/持久自由行动（OIF/OEF）的部队的重复性mTBI特征可能会对个人，职业和家庭造成毁灭性的后果。记忆力和注意力受损，焦虑、易怒和情绪不稳定增加，以及睡眠障碍，影响工作和家庭关系，造成严重残疾。除了mTBI的这些直接后果之外，对脑组织的爆炸创伤损伤和/或随后的脑修复效应可能引发导致神经变性和痴呆的过程。 该提案将应用先进的功能和结构神经影像学和脑脊液（CSF）生物标志物来解决以下问题：1）是否存在客观的神经影像学和CSF生物标志物：a）表征爆炸诱导的mTBI的行为表型;和B）区分mTBI与战斗创伤创伤后应激障碍（PTSD）？2)重复性冲击波mTBI是否存在长期认知功能障碍，如果存在，认知功能障碍是否与神经退行性痴呆的CSF生物标志物和遗传风险因素相关？术语“mTBI”在此用于表示持续性脑震荡后症状（[PCS]认知、行为和躯体）的综合征，其在产生mTBI的冲击波脑震荡事件后数月和数年继续表现。我们的初步神经影像学结果表明，先前未被识别的结构和功能异常独立于OIF/OEF退伍军人与mTBI和持续PCS的共病PTSD。 具体目标1：描述OIF/OEF退伍军人PCS中爆炸创伤重复性轻度创伤性脑损伤（mTBI）的临床（神经认知、神经功能、行为）和结构/功能神经影像学特征。 具体目标2：确定OIF/OEF退伍军人反复mTBI伴持续性PCS是否表达与神经退行性痴呆症发作和进展相关的CSF生物标志物变化。 具体目标3：确定神经退行性变的遗传风险因素（载脂蛋白E [APOE]多态性和微管相关蛋白tau [MAPT]亚单倍型）对OIF/OEF退伍军人反复mTBI和持续性PCS的临床特征、神经影像学和CSF生物标志物的影响。 该提案涉及RR&D的优先领域，即诊断成像技术的验证和改进以及TBI晚期或长期后果的创新方法。VHA面临着向这一弱势群体提供初级医疗、康复、心理健康和长期护理的巨大负担。鉴定mTBI的客观神经影像学和CSF生物标志物以及阐明mTBI中神经退行性痴呆的长期风险将：1）改善mTBI的诊断，2）提供改善退伍军人医疗保健的目标;以及3）允许适当分配有限的医疗保健、补偿和养老金以及社会资源。成功完成拟议的研究很有可能产生短期和长期的临床影响。在24个月内，该项目将产生用于mTBI的客观生物标志物诊断的工具。在4年内，拟议项目的结果将形成合理设计临床试验的证据基础，以治疗mTBI的当前症状并防止进展为神经退行性痴呆症。 公共卫生相关性： 由爆炸装置的爆炸效应引起的重复性轻度创伤性脑损伤（mTBI）是当前伊拉克和阿富汗冲突中士兵，海军陆战队和其他服务人员的“标志性损伤”，并可能具有破坏性的个人，专业和家庭后果。拟议的项目将使用复杂的脑成像技术和测量脊髓液（大脑周围的液体）中的化学物质，以确定mTBI的客观标志物。这些标志物将有助于改善伊拉克和阿富汗战争退伍军人中mTBI的诊断，改善退伍军人的医疗保健，并允许适当分配有限的医疗保健，补偿和养老金以及社会资源。长期目标是确定重复性爆炸创伤mTBI进展为阿尔茨海默病或职业拳击手和足球运动员中发现的中年痴呆症等致命性痴呆症的风险。

DESCRIPTION (provided by applicant): Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the "signature injury" of soldiers, Marines, and other service members in the current Iraq and Afghanistan conflicts. Repetitive mTBI characteristic of troops deployed to Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF), may have devastating personal, professional and domestic consequences. Impairment of memory and concentration, increased anxiety, irritability and mood instability, and sleep disturbance interfere with job and family relationships, producing substantial disability. In addition to these immediate consequences of mTBI, blast trauma damage to brain tissue and/or subsequent brain reparative effects may initiate processes leading to neurodegeneration and dementia. This proposal will apply advanced functional and structural neuroimaging and cerebrospinal fluid (CSF) biomarkers to address the following questions: 1) Are there objective neuroimaging and CSF biomarkers that: a) characterize the behavioral phenotype of blast-induced mTBI; and b) distinguish mTBI from combat trauma posttraumatic stress disorder (PTSD)? 2) Is there long-term cognitive impairment in repetitive blast mTBI and, if so, is cognitive impairment associated with CSF biomarkers of and genetic risk factors for neurodegenerative dementia? The term "mTBI" here is used to denote a syndrome of persistent postconcussive symptoms ([PCS] cognitive, behavioral, and somatic) that continue to be expressed months and years after blast concussion events that produce mTBI. Our preliminary neuroimaging results demonstrate previously unrecognized structural and functional abnormalities independent of comorbid PTSD in OIF/OEF Veterans with mTBI and persistent PCS. Specific Objective 1: To characterize the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of blast trauma repetitive mild traumatic brain injury (mTBI) in OIF/OEF Veterans with PCS. Specific Objective 2: To determine if OIF/OEF Veterans with repetitive mTBI with persistent PCS express CSF biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Objective 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on both clinical characteristics, and neuroimaging and CSF biomarkers in OIF/OEF Veterans with repetitive mTBI and persistent PCS. This proposal addresses the RR&D priority areas of Validation and Refinement of Diagnostic Imaging Technology and Innovative Approaches to Late or Long-Term Consequences of TBI. VHA faces a huge burden of providing primary medical, rehabilitative, mental health and long term care to this vulnerable population. Identification of objective neuroimaging and CSF biomarkers of mTBI and clarification of the long- term risks of neurodegenerative dementias in mTBI will: 1) improve diagnosis of mTBI, 2) provide targets for improving Veterans' health care; and 3) allow appropriate allocation of limited health care, compensation and pension, and social resources. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. Within 24 months, the project will yield tools for objective biomarker diagnosis of mTBI. Within 4 years, results from the proposed project will form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders. PUBLIC HEALTH RELEVANCE: Repetitive mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the "signature injury" of soldiers, Marines, and other service members in the current Iraq and Afghanistan conflicts and may have devastating personal, professional and domestic consequences. The proposed project will use sophisticated brain imaging techniques and measurement of chemicals in spinal fluid (the fluid surrounding the brain) to identify objective markers of mTBI. These markers will help to improve the diagnosis of mTBI in Veterans of the Iraq and Afghanistan wars, improve Veterans' health care, and allow appropriate allocation of limited health care, compensation and pension, and social resources. A long-term goal is to determine the risks of repetitive blast trauma mTBI for progressing to such fatal dementing disorders as Alzheimer's disease or the mid-life dementia that has been found in professional boxers and football players.