Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.
Biomedical Engineering, College of Engineering, Texas A&M University, College Station, Texas.
Ann N Y Acad Sci. 2020 Nov;1480(1):116-135. doi: 10.1111/nyas.14431. Epub 2020 Jul 15.
Nerve agents (NAs) produce acute and long-term brain injury and dysfunction, as evident from the Japan and Syria incidents. Magnetic resonance imaging (MRI) is a versatile technique to examine such chronic anatomical, functional, and neuronal damage in the brain. The objective of this study was to investigate long-term structural and neuronal lesion abnormalities in rats exposed to acute soman intoxication. T2-weighted MRI images of 10 control and 17 soman-exposed rats were acquired using a Siemens MRI system at 90 days after soman exposure. Quantification of brain tissue volumes and T2 signal intensity was conducted using the Inveon Research Workplace software and the extent of damage was correlated with histopathology and cognitive function. Soman-exposed rats showed drastic hippocampal atrophy with neuronal loss and reduced hippocampal volume (HV), indicating severe damage, but had similar T2 relaxation times to the control group, suggesting limited scarring and fluid density changes despite the volume decrease. Conversely, soman-exposed rats displayed significant increases in lateral ventricle volumes and T2 times, signifying strong cerebrospinal fluid expansion in compensation for tissue atrophy. The total brain volume, thalamic volume, and thalamic T2 time were similar in both groups, however, suggesting that some brain regions remained more intact long-term after soman intoxication. The MRI neuronal lesions were positively correlated with the histological markers of neurodegeneration and neuroinflammation 90 days after soman exposure. The predominant MRI hippocampal atrophy (25%) was highly consistent with massive reduction (35%) of neuronal nuclear antigen-positive (NeuN ) principal neurons and parvalbumin-positive (PV ) inhibitory interneurons within this brain region. The HV was significantly correlated with both inflammatory markers of GFAP astrogliosis and IBA1 microgliosis. The reduced HV was also directly correlated with significant memory deficits in the soman-exposed cohort, confirming a possible neurobiological basis for neurological dysfunction. Together, these findings provide powerful insight on long-term region-specific neurodegenerative patterns after soman exposure and demonstrate the feasibility of in vivo neuroimaging to monitor neuropathology, predict the risk of neurological deficits, and evaluate response to medical countermeasures for NAs.
神经毒剂（NAs）会导致急性和长期的脑损伤和功能障碍，这从日本和叙利亚事件中可见一斑。磁共振成像（MRI）是一种多功能技术，可用于检查大脑中的这种慢性解剖、功能和神经元损伤。本研究的目的是研究急性梭曼中毒后暴露于梭曼的大鼠的长期结构和神经元损伤异常。在梭曼暴露 90 天后，使用西门子 MRI 系统获得了 10 只对照大鼠和 17 只梭曼暴露大鼠的 T2 加权 MRI 图像。使用 Inveon Research Workplace 软件对脑组织体积和 T2 信号强度进行量化，并将损伤程度与组织病理学和认知功能相关联。梭曼暴露的大鼠表现出明显的海马萎缩和神经元丧失，海马体积（HV）减小，表明严重损伤，但与对照组的 T2 弛豫时间相似，表明尽管体积减小，但疤痕形成和液体密度变化有限。相反，梭曼暴露的大鼠表现出侧脑室体积和 T2 时间的显著增加，表明脑脊液强烈扩张以代偿组织萎缩。两组的总脑体积、丘脑体积和丘脑 T2 时间相似，但表明梭曼中毒后，一些大脑区域长期保持更完整。MRI 神经元损伤与梭曼暴露 90 天后神经退行性变和神经炎症的组织学标志物呈正相关。MRI 海马萎缩（25%）与该脑区神经元核抗原阳性（NeuN）主要神经元和钙结合蛋白阳性（PV）抑制性中间神经元数量减少（35%）高度一致。HV 与星形胶质细胞增生的 GFAP 和小胶质细胞增生的 IBA1 这两种炎症标志物均显著相关。HV 的减少与梭曼暴露组的显著记忆缺陷直接相关，证实了神经功能障碍的可能神经生物学基础。总之，这些发现为梭曼暴露后长期特定区域的神经退行性模式提供了有力的见解，并证明了体内神经影像学监测神经病理学、预测神经功能缺陷风险以及评估神经毒剂医学对策的可行性。
