Building translationally relevant relationships between neuropathology and abnormal neuroimaging in Veterans and mechanisms of blast-induced neurotrauma in mice

爆炸暴露是伊拉克自由行动/持久自由行动/ 新黎明行动（OIF/OEF/OND）退伍军人。越来越多的人担心，反复的爆炸暴露可能会 是神经系统疾病的危险因素，包括慢性创伤性脑病（CTE）。致病 将早期发生的，通常是短暂的脑损伤与随后的慢性行为和 认知障碍还没有得到很好的理解。这些损伤背后的病理学 明白 目前，一些重要的知识空白阻碍了阐明病理学的进展， 重复性胚细胞相关mTBI的生理学，包括对 冲击波诱导的TBI动物模型中产生的病理学与退伍军人中的神经影像学发现有关 与爆炸有关的创伤性脑损伤此外，来自这些退伍军人的非常有限的神经病理学信息 严重限制了我们对爆炸相关mTBI的理解。 增加了这个问题的复杂性，许多研究小组报告了多种形式的爆炸- 在许多动物原始细胞TBI模型中诱导的病理学包括：异常tau表达，反应性TBI， 星形细胞增多、小胶质细胞增多、轴突损伤、髓鞘损伤和血脑屏障（BBB）破坏。多 由于tau与运动相关CTE的密切关联，因此其受到关注。是否重复 胚细胞相关mTBI遵循与CTE相同的致病途径，CTE主要由特异性tau蛋白定义 存款，仍然是一个悬而未决的问题。 然而，最近的研究结果引起了人们对患有爆炸相关mTBI的退伍军人中突出的神经胶质病理学的关注， 提出了这种形式的神经创伤可能代表一个独特的类别的可能性;或者可能是一个独特的类别。 导致慢性mTBI的致病过程（其也可能涉及tau病理学）。 在重复冲击波暴露的小鼠中，我们发现小胶质细胞和星形胶质细胞病理学，特别是在 大脑皮层下区域，与最近报道的白色物质相关的神经胶质病理学非常相似 与爆炸有关的mTBI的退伍军人。我们也有证据表明，早期发生的血脑屏障的离散微区 不完整性与包括髓鞘吞噬作用的异常小胶质细胞反应密切相关， 星形胶质细胞增生和神经元缺失。这些数据促使我们检验四个密切相关的假设： 具体目标1：将检验这一假设，即在爆炸暴露的小鼠中，特定的大脑区域易受 早期发生的血脑屏障（BBB）破坏;这些破坏可能引发后来的持续性 与髓磷脂破坏以及轴突和神经元损伤相关的病理学。 具体目标2：将检验以下假设：在小鼠中，涉及神经胶质介导的髓鞘的白色病理学 吞噬作用和轴突损伤将与各向异性分数的降低密切相关。 具体目标3：将检验以下假设：具有髓鞘、轴突损伤和BBB的特定脑区域破坏- 在小鼠中的DT 1神经成像结果将对应于在具有爆炸的退伍军人中的类似脑区域中的DT 1神经成像结果。 mTBI相关 具体目标4：将检验以下假设，即爆炸相关退伍军人大脑中的神经病理学发现 mTBI将在与通过神经成像在活着的退伍军人中识别的相同的解剖区域中发现， 将与暴露于爆炸的小鼠的病理学相对应。 成功完成这些目标将：（i）促进对致病性 级联导致慢性行为和认知障碍的退伍军人与爆炸相关的mTBI;和（ii） 完善动物原始细胞TBI模型的翻译相关性，以提高其作为工具的有用性， 加速寻找治疗和预防慢性爆炸相关神经变性的策略。

Blast exposure is a common experience of Operation Iraqi Freedom/Operation Enduring Freedom/ Operation New Dawn (OIF/OEF/OND) Veterans. There is growing concern that repetitive blast exposure may be a risk factor for neurological disorders, including chronic traumatic encephalopathy (CTE). The pathogenic processes that link early-occurring, often transient brain injuries, to subsequent chronic behavioral and cognitive impairments are not well understood. The pathology underlying these impairments is poorly understood. A number of important knowledge gaps currently impede progress toward elucidating the patho- physiology of repetitive blast-related mTBI that include, limited insight into the translational significance of the pathology produced in blast-induced animal TBI models with reference to neuroimaging findings in Veterans with blast-related mTBI. Moreover, the very limited neuropathological information from such Veterans significantly limits our understanding of blast-related mTBI. Adding to the complexity of this issue numerous research groups have reported multiple forms of blast- induced pathology in a number of animal blast TBI models including: aberrant tau expression, reactive astrocytosis, microgliosis, axonal injury, myelin damage, and blood-brain barrier (BBB) disruption. Much attention has been placed on tau because of its close association with sports-related CTE. Whether repetitive blast-related mTBI follows that same pathogenic pathway to CTE, which is defined chiefly by specific tau deposits, remains an open question. However, recent findings call attention to prominent glial pathology in Veterans with blast-related mTBI, raising the possibility that this form of neurotrauma may represent a distinct class; or possibly a distinct pathogenic process leading to chronic mTBI (which also may involve tau pathology). In repetitive blast exposed mice we have found microglial and astroglial pathology that, especially in subcortical regions of the brain, is quite similar to the white matter-associated glial pathology recently reported in Veterans with blast-related mTBI. We also have evidence that discrete microdomains of early-occurring BBB disintegrity are closely associated with aberrant microglial responses that include myelin phagocytosis, astrogliosis, and neuron loss. These data have prompted us test four closely related hypotheses: Specific Aim 1: will test the hypothesis that in blast exposed mice, specific brain regions are vulnerable to early-occurring blood-brain barrier (BBB) disruption; and that these disruptions may trigger later persistent pathology associated with myelin disruption, as well as axonal and neuronal injury. Specific Aim 2: will test the hypothesis that in mice, white matter pathology involving glial-mediated myelin phagocytosis and axonal injury will be closely associated with reduced fractional anisotropy. Specific Aim 3: will test the hypothesis that specific brain regions with myelin, axonal injury, and BBB disrupt- tion in mice will correspond to DTl neuroimaging findings in similar brain regions in Veterans with blast- related mTBI. Specific Aim 4: will test the hypothesis that neuropathology findings in brains from Veterans with blast-related mTBI will be found in the same anatomical regions as those identified by neuroimaging in living Veterans and will correspond with the pathology in blast-exposed mice. Successful completion of these aims will: (i) facilitate progress toward understanding the pathogenic cascades leading to chronic behavioral and cognitive impairments in Veterans with blast-related mTBI; and (ii) refine the translational relevance of animal blast TBI models needed to improve their usefulness as tools to speed the search for strategies to treat and prevent chronic blast-related neurodegeneration.