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）是部署到伊拉克和阿富汗作战行动的服务人员的“标志性损伤”。持续性脑震荡后症状（PCS），如记忆力和注意力障碍，易怒，情绪不稳定，睡眠障碍，经常有残疾的个人，专业和家庭的后果。除了这些直接后果外，重复性mTBI可能引发导致神经变性和痴呆的过程。 本申请是一个提案的重新提交，继续目前资助的VA RR & D优点审查：B77421，“轻度TBI和神经变性的生物标志物”。在当前的资助期内，我们在以下方面取得了实质性进展：1）确定客观的结构和功能神经影像学生物标志物，这些生物标志物表征了爆炸诱导的mTBI的临床表型，并将mTBI与战斗创伤后创伤应激障碍（PTSD）区分开来，2）使用我们改进的神经心理学评估组合确定mTBI退伍军人中认知功能的客观损害，3）鉴定潜在的mTBI特异性脑脊液（CSF）生物标志物，和4）鉴定与mTBI的存在或不存在无关的部署的非预期CSF神经变性和神经炎症生物标志物。我们将神经影像学、认知和生物标志物研究结果整合到重复性冲击波mTBI中区域脑功能障碍的一致模型中。本延续提案的目的是确定认知能力是否与神经退行性痴呆的CSF生物标志物和/或遗传风险因素相关，并确定神经影像学和CSF生物标志物异常是否为一过性、静态或进行性。我们还提出了三个新的临床评估：在剧院的睡眠史，睡眠/活动监测通过Activography，和平衡/前庭功能测试;和两个额外的神经影像学分析：白色物质纤维束成像和磁敏感加权成像（SWI）检测微血管。 具体目标1：继续纵向表征OIF/OEF/OND重复性爆炸创伤mTBI退伍军人小脑-丘脑-额顶叶皮质功能受损的临床（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OEF/OIF/OND重复性mTBI退伍军人是否表现出与神经退行性痴呆疾病（如慢性创伤性脑病（CTE）和阿尔茨海默病（AD））发作和进展相关的CSF生物标志物变化。 具体目标3：确定神经变性遗传风险因素（载脂蛋白E [APOE]多态性和微管相关蛋白tau [MAPT]亚单倍型）对OEF/OIF/OND重复性mTBI退伍军人临床特征和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生物标志物并阐明mTBI中神经退行性痴呆的长期风险将：改善mTBI的诊断和监测对潜在治疗的反应的能力;为改善退伍军人的医疗保健提供目标;并允许适当分配有限的VHA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。该项目将产生用于mTBI的客观生物标志物诊断的工具，并为临床试验的合理设计形成证据基础，以治疗mTBI的当前症状并防止进展为神经退行性痴呆症。

 DESCRIPTION (provided by applicant): Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the "signature injury" of service members deployed to combat operations in Iraq and Afghanistan. Resultant persistent postconcussive symptoms (PCS), such as impairment of memory and concentration, irritability, mood instability, and sleep disturbances, frequently have disabling personal, professional and domestic consequences. In addition to these immediate consequences, repetitive mTBI may initiate processes leading to neurodegeneration and dementia. This application is a resubmission of a proposal to continue a currently funded VA RR&D Merit Review: B77421, "Mild TBI and Biomarkers of Neurodegeneration". In the current funding period, we have made substantial progress in 1) identifying objective structural and functional neuroimaging biomarkers that characterize the clinical phenotype of blast-induced mTBI and distinguish mTBI from combat trauma posttraumatic stress disorder (PTSD), 2) identifying objective impairment of cognitive function in mTBI Veterans using our refined neuropsychological assessment battery, 3) identifying a potential mTBI-specific cerebrospinal fluid (CSF) biomarker, and 4) identifying unanticipated CSF neurodegenerative and neuroinflammatory biomarkers of deployment independent of presence or absence of mTBI. We have integrated neuroimaging, cognitive, and biomarker findings into a consistent model of regional brain dysfunction in repetitive blast mTBI. Goals of this continuation proposal are to determine whether cognitive performance is associated with CSF biomarkers of and/or genetic risk factors for neurodegenerative dementia, and to determine whether neuroimaging and CSF biomarker abnormalities are transient, static, or progressive. We also propose three new clinical assessments: in-theater sleep history, sleep/activity monitoring via Actigraphy, and balance/vestibular function testing; and two additional neuroimaging analyses: white matter tractography and susceptibility weighted imaging (SWI) for detection of microhemorrhages. Specific Objective 1: To continue characterizing longitudinally the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of disrupted cerebellar-thalamic- frontoparietal cortical function in OIF/OEF/OND Veterans with repetitive blast trauma mTBI. Specific Objective 2: To determine if OEF/OIF/OND Veterans with repetitive mTBI exhibit CSF biomarker changes associated with the onset and progression of neurodegenerative dementing disorders, such as chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). 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 CSF biomarkers in OEF/OIF/OND Veterans with repetitive mTBI. 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: improve diagnosis of mTBI and ability to monitor response to potential treatments; provide targets for improving Veterans' health care; and allow appropriate allocation of limited VHA resources. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. The project will yield tools for objective biomarker diagnosis of mTBI and form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.