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/持久自由行动的共同经历/ 新黎明行动(OIF/OEF/OND)退伍军人。人们越来越担心重复的爆炸暴露可能会 是神经疾病的危险因素，包括慢性创伤性脑病(CTE)。致病的 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基础很差。 明白了。 目前，许多重要的知识空白阻碍了阐明这一致病机制的进展。 重复冲击波相关mTBI的生理学，包括对翻译意义的有限洞察 爆炸性脑损伤动物模型的病理改变与退伍军人的神经影像表现 与爆炸相关的mTBI。此外，这些退伍军人提供的神经病理信息非常有限 极大地限制了我们对爆炸相关mTBI的理解。 让这个问题变得更加复杂的是，许多研究小组报告了多种形式的爆炸- 在许多动物原始创伤性脑损伤模型中诱导的病理包括：tau的异常表达，反应性 星形胶质细胞增多症、小胶质细胞增多症、轴索损伤、髓鞘损伤和血脑屏障(BBB)破坏。大有可为 Tau因其与运动相关的CTE密切相关而备受关注。是否重复 BLAST相关mTBI遵循与CTE相同的致病途径，主要由特定的tau定义 存款，仍然是一个悬而未决的问题。 然而，最近的发现提醒人们注意患有爆炸相关mTBI的退伍军人的突出神经胶质病理， 增加了这种形式的神经创伤可能代表一个不同的类别；或者可能是一个不同的 导致慢性mTBI的致病过程(也可能涉及tau病理)。 在反复冲击波暴露的小鼠中，我们发现了小胶质细胞和星形胶质细胞的病理，特别是在 大脑皮质下区域，与最近报道的白质相关神经胶质病理非常相似。 在患有爆炸相关mTBI的退伍军人中。我们也有证据表明早发性血脑屏障的离散微区 不诚信与异常的小胶质细胞反应密切相关，包括髓鞘吞噬， 星形胶质细胞增多症和神经元丢失。这些数据促使我们检验了四个密切相关的假设： 具体目标1：将检验在冲击波暴露的小鼠中，特定大脑区域容易受到 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 与髓鞘断裂相关的病理学，以及轴突和神经元损伤。 具体目标2：将检验这样一个假设，即在小鼠中，涉及神经胶质介导的髓鞘的白质病理 吞噬和轴突损伤与分数各向异性降低密切相关。 具体目标3：将检验有髓鞘、轴突损伤和血脑屏障的特定脑区破坏- 小鼠的Ttion将与退伍军人BLAST-T相似脑区的DTL神经成像结果相对应。 相关mTBI。 具体目标4：将检验这样一种假设，即退伍军人大脑中的神经病理结果与爆炸性疾病有关 MTBI将在与神经成像确定的相同解剖区域被发现，在活的退伍军人和 将与冲击波暴露的小鼠的病理相一致。 成功地完成这些目标将：(I)促进在理解致病原方面的进展 导致爆炸相关mTBI退伍军人慢性行为和认知障碍的级联反应；和(Ii) 完善动物BLAST脑损伤模型的翻译相关性，以提高其作为工具的有效性 加快寻找治疗和预防慢性冲击波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.