The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.

中文翻译：

---

年轻运动员头部撞击受伤后的脑震荡、微血管损伤和早期 tau 病以及撞击脑震荡小鼠模型

人们对脑震荡、创伤性脑损伤和慢性创伤性脑病的机制以及这些疾病之间的关系知之甚少。我们检查了青少年运动员在轻度闭合性头部撞击损伤后的急性亚急性期的死后大脑，发现星形细胞增多、有髓鞘轴突病、微血管损伤、血管周围神经炎症和磷酸化 tau 蛋白病理。为了研究因果机制，我们开发了一种侧向闭合性头部撞击损伤的小鼠模型，该模型利用动量传递来诱导创伤性头部加速。遭受单侧撞击的未麻醉小鼠表现出脑震荡样综合征的突然发作、短暂过程和快速消退，其特征是觉醒改变、对侧偏瘫、躯干共济失调、运动和平衡障碍以及神经行为缺陷。实验性撞击损伤与轴突病变、血脑屏障破坏、星形细胞增多、小胶质细胞增生（与髓样细胞上表达的触发受体 TREM2 激活）、单核细胞浸润以及撞击同侧和撞击下方大脑皮层的磷酸化 tau 蛋白病变有关。损伤后 24 小时在同侧轴突中检测到磷酸化 tau 蛋白病，在损伤后 2 周时在双侧轴突和体细胞中检测到磷酸化 tau 蛋白病，在损伤后 5.5 个月时在双侧远端皮层中检测到磷酸化 tau 蛋白病。冲击病理学与大脑中血清白蛋白外渗共存，通过动态对比增强 MRI 在活体小鼠中可诊断性检测到。这些病理还伴有海马轴突传导速度的早期、持续和双侧损伤，以及内侧前额叶皮层（远离急性脑损伤的大脑区域）突触神经传递长期增强的缺陷。令人惊讶的是，受伤时的急性神经行为缺陷与血脑屏障破坏、小胶质细胞增生、神经炎症、磷酸化tau蛋白病或电生理功能障碍无关。此外，在撞击损伤后观察到了类似脑震荡的缺陷，但在与头部运动学相匹配的实验条件下爆炸暴露后却没有观察到。计算模型表明，与爆炸暴露相比，冲击损伤会在头部产生焦点负载，并且大脑中的峰值剪切应力高出七倍。此外，脑内剪切应力在头部总体运动开始之前达到峰值。相比之下，爆炸会在头部引起分布式力负载，并在大脑中产生分散的、较低幅度的剪切应力。我们得出的结论是，受伤时的力加载机制塑造了神经外伤引发的急性神经行为反应、结构性脑损伤和神经病理学后遗症。这些结果表明，与脑震荡症状无关的闭合性头部撞击损伤可以诱发创伤性脑损伤以及与慢性创伤性脑病相关的早期病理和功能性后遗症。