Mild TBI and Biomarkers of Neurodegeneration

爆炸装置爆炸效应所致的轻度颅脑损伤(MTBI)是“标志性损伤” 部署在伊拉克和阿富汗作战的军人人数。合成的持久性 脑震荡后症状(PCS)，如记忆力和注意力障碍、易怒、情绪 不稳定、睡眠障碍和偏头痛经常会导致个人、职业和 国内后果。除了这些直接后果外，重复的mTBI可能会启动过程 导致神经退化和痴呆症。 此竞争性续订申请计划纵向延续目前资助的VA RR&D 优点评论：B77421，“轻度脑外伤和神经退行性变的生物标志物”。在当前的资助期内，我们 在1)确定客观的结构和功能神经成像生物标记物方面取得了实质性进展 2)识别客观损害和 应用我们改进的神经心理学评估方法研究mTBI退伍军人认知功能的纵向下降 3)在脑脊液(CSF)和血浆中鉴定mTBI特异性相互关系 神经炎性化学吸引物、血管紊乱和神经变性生物标记物。我们有 将神经成像、认知和生物标记物的发现整合到一个一致的局部小脑模型中 反复冲击性脑损伤患者丘脑-额顶顶叶皮质和脑干功能障碍。本次续展的目标 建议是确定认知能力是否与神经成像和/或脑脊液和 血浆脑损伤生物标志物和/或神经退行性痴呆的遗传危险因素，并确定 无论神经影像和脑脊液及血浆生物标记物异常是暂时性的、静止性的还是进行性的。我们 还提出了1)一个新的血浆生物标志物目标：中枢神经系统(CNS)来源的血浆胞外体货物 蛋白质，2)睡眠的新临床评估：战区内睡眠病史和睡眠/活动监测 3)附加的高级神经成像分析：扩散张量成像自动化-光纤- 肌束量化。 具体目标1：继续纵向描述临床(神经认知、神经、行为) 小脑-丘脑-额顶叶皮质受损的结构/功能神经影像特征 OIF/OEF/OND反复冲击伤患者的脑干功能。 特定目标2：确定患有重复mTBI的OEF/OIF/OND退伍军人是否表现出脑脊液和血浆 神经血管、神经炎性和神经变性生物标记物的变化与发病和 神经退行性痴呆的进展。 具体目标3：确定神经退行性变(载脂蛋白E)的遗传危险因素的影响 [APOE]基因多态性和微管相关蛋白tau[MAPT]亚型)临床意义 反复mTBI的OEF/OIF/OND退伍军人的特征和神经影像和生物流体生物标记物。 这项建议是对RFA RX-18-014的回应：关于神经创伤和 重点关注重复性mTBI的长期后果。通过识别目标神经成像和脑脊液和 对于急性脑损伤和神经退行性痴呆的血浆生物标记物，拟议的研究具有以下潜力： 1)提高BLAST诊断的准确性；2)确定临床特征和生物标志物。 提供潜在治疗建议并提供跟踪潜在治疗反应的能力的BLAST mTBI； 以及3)确定mTBI退伍军人特有的医疗保健需求。圆满完成拟议中的 研究很有可能产生短期和长期的临床影响。这个项目将会取得成果 MTBI的客观生物标志物诊断工具，为临床试验的合理设计提供证据基础 治疗目前的mTBI症状，防止进展为神经退行性痴呆障碍。

Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the “signature injury” of Servicemembers deployed to combat operations in Iraq and Afghanistan. Resultant persistent postconcussive symptoms (PCS), such as impairment of memory and concentration, irritability, mood instability, sleep disturbances, and migraine headaches 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 competitive renewal application proposes to continue longitudinally 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, 2) identifying objective impairment and longitudinal decline in cognitive function in mTBI Veterans using our refined neuropsychological assessment battery, and 3) identifying in cerebrospinal fluid (CSF) and plasma a group mTBI-specific inter-related neuroinflammatory chemoattractant, vascular disturbance, and neurodegeneration biomarkers. We have integrated neuroimaging, cognitive, and biomarker findings into a consistent model of regional cerebellar- thalamic-frontoparietal cortical and brainstem dysfunction in repetitive blast mTBI. Goals of this continuation proposal are to determine whether cognitive performance is associated with neuroimaging and/or CSF and plasma biomarkers of mTBI and/or genetic risk factors for neurodegenerative dementia, and to determine whether neuroimaging and CSF and plasma biomarker abnormalities are transient, static, or progressive. We also propose 1) a new plasma biomarker goal: central nervous system (CNS)-derived plasma exosomal cargo proteins, 2) new clinical assessments of sleep: in-theater sleep history and sleep/activity monitoring via Actigraphy, and 3) an additional advanced neuroimaging analyses: diffusion tensor imaging Automating-Fiber- Tract Quantification. Specific Aim 1: To continue characterizing longitudinally the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of disrupted cerebellar-thalamic-frontoparietal cortical and brainstem function in OIF/OEF/OND Veterans with repetitive blast trauma mTBI. Specific Aim 2: To determine if OEF/OIF/OND Veterans with repetitive mTBI exhibit CSF and plasma neurovascular, neuroinflammatory, and neurodegeneration biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Aim 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on clinical characteristics and neuroimaging and biofluid biomarkers in OEF/OIF/OND Veterans with repetitive mTBI. This proposal is in response to RFA RX-18-014: Studies on the Chronic Effects of Neurotrauma and focuses on the long-term consequences of repetitive mTBI. By identifying objective neuroimaging and CSF and plasma biomarkers of blast mTBI and neurodegenerative dementias, the proposed research has potential for: 1) improving the accuracy of blast mTBI diagnoses; 2) identifying clinical characteristics and biomarkers of blast mTBI that suggest potential treatments and provide the ability to track response to potential treatments; and 3) identifying health care needs unique to blast mTBI Veterans. 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.