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)是部署在伊拉克和阿富汗作战行动的军人的“标志性损伤”。由此产生的持续性脑震荡后症状(PCS)，如记忆力和注意力受损、易怒、情绪不稳定和睡眠障碍，经常会导致个人、职业和家庭的残疾后果。除了这些直接后果外，重复的mTBI还可能启动导致神经退化和痴呆的过程。这项申请是继续目前资助的VA RR&D功绩审查的提案的重新提交：B77421，“轻度脑损伤和神经退行性变的生物标记物”。在当前的资助期内，我们在以下方面取得了实质性进展：1)确定了表征冲击性脑损伤临床表型的客观结构和功能神经成像生物标记物，并将其与战斗创伤后应激障碍(PTSD)区分开来；2)使用我们改进的神经心理评估单元识别mTBI退伍军人的客观认知功能损害；3)识别潜在的mTBI特异性脑脊液(CSF)生物标记物；以及4)识别非预期的脑脊液神经退行性和神经炎性生物标记物，这些生物标记物的部署独立于mTBI的存在与否。我们已经将神经成像、认知和生物标记物的发现整合到重复冲击性脑损伤中局部脑功能障碍的一致模型中。这个延续方案的目的是确定认知能力是否与神经退行性痴呆的脑脊液生物标记物和/或遗传危险因素有关，并确定神经影像和脑脊液生物标记物异常是一过性的、静态的还是进行性的。我们还提出了三项新的临床评估：战区内睡眠史、通过活动描记监测睡眠/活动以及平衡/前庭功能测试；以及两项额外的神经成像分析：白质纤维束成像和敏感性加权成像(SWI)用于检测微小出血。具体目标1：继续研究反复冲击伤退伍军人小脑-丘脑-额顶叶皮质功能紊乱的临床(神经认知、神经、行为)和结构/功能神经影像特征。具体目标2：确定患有重复mTBI的OEF/OIF/OND退伍军人脑脊液生物标志物的变化是否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))的发生和发展有关。目的3：探讨神经退行性变的遗传危险因素(载脂蛋白E基因多态性和微管相关蛋白tau亚型)对反复脑损伤患者临床特征和脑脊液生物标志物的影响。该提案涉及诊断成像技术的验证和改进的RR&D优先领域，以及针对TBI的后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。确定mTBI的客观神经影像和脑脊液生物标志物，并澄清mTBI中神经退行性痴呆的长期风险，将：提高mTBI的诊断和监测潜在治疗反应的能力；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。拟议研究的成功完成很有可能产生短期和长期的临床影响。该项目将为mTBI的客观生物标记物诊断提供工具，并为合理设计临床试验以治疗当前的mTBI症状和防止进展为神经退行性痴呆疾病奠定证据基础。

 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.