Abstract：
OBJECTIVE: Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the putative association between in vivo synaptic loss and cognitive outcomes in TLE patients by PET imaging of synaptic vesicle glycoprotein 2A (SV2A).
METHODS: We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [18F]SynVesT-1 and cognitive assessment. Lithium chloride-pilocarpine-induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [18F]SynVesT-1 micro-PET/CT. The novel object recognition and Morris water maze tests evaluated TLE-related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry.
RESULTS: Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment.
CONCLUSIONS: This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [18F]SynVesT-1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients.
METHODS: We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [18F]SynVesT-1 and cognitive assessment. Lithium chloride-pilocarpine-induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [18F]SynVesT-1 micro-PET/CT. The novel object recognition and Morris water maze tests evaluated TLE-related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry.
RESULTS: Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment.
CONCLUSIONS: This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [18F]SynVesT-1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients.
摘要：
目的：认知损害是颞叶癫痫（TLE）患者的常见合并症，然而潜在的机制仍然未知。这项研究通过突触小泡糖蛋白2A（SV2A）的PET成像探索了TLE患者体内突触损失与认知结果之间的推定关联。
方法：我们招募了16名TLE患者和10名认知正常对照。所有参与者使用[18F]SynVesT-1进行SV2APET成像和认知评估。氯化锂-毛果芸香碱诱导的癫痫持续状态大鼠（n=20）和对照组（n=6）接受左乙拉西坦（LEV，与SV2A特异性结合)，丙戊酸(VPA),或生理盐水14天。然后，突触密度通过[18F]SynVesT-1micro-PET/CT定量。新颖的物体识别和Morris水迷宫测试评估了与TLE相关的认知功能。通过免疫组织化学检查并确认SV2A表达。
结果：颞叶癫痫患者海马突触密度显著降低，这与认知表现有关。在TLE大鼠模型中,SV2A的表达和突触密度在更广泛的脑区持续下降，包括内嗅皮层，脑岛,海马体,杏仁核,丘脑,和皮质。我们用LEV或VPA治疗TLE动物模型，以探索突触损失是否会导致认知缺陷。发现LEV对脑突触缺陷和认知障碍具有明显的保护作用。
结论：这是第一个将突触损失与TLE的认知缺陷联系起来的研究，提示[18F]SynVesT-1PET可能是监测突触丢失和认知功能障碍的有前途的生物标志物。LEV可能有助于逆转TLE患者的突触缺陷并改善学习和记忆障碍。
方法：我们招募了16名TLE患者和10名认知正常对照。所有参与者使用[18F]SynVesT-1进行SV2APET成像和认知评估。氯化锂-毛果芸香碱诱导的癫痫持续状态大鼠（n=20）和对照组（n=6）接受左乙拉西坦（LEV，与SV2A特异性结合)，丙戊酸(VPA),或生理盐水14天。然后，突触密度通过[18F]SynVesT-1micro-PET/CT定量。新颖的物体识别和Morris水迷宫测试评估了与TLE相关的认知功能。通过免疫组织化学检查并确认SV2A表达。
结果：颞叶癫痫患者海马突触密度显著降低，这与认知表现有关。在TLE大鼠模型中,SV2A的表达和突触密度在更广泛的脑区持续下降，包括内嗅皮层，脑岛,海马体,杏仁核,丘脑,和皮质。我们用LEV或VPA治疗TLE动物模型，以探索突触损失是否会导致认知缺陷。发现LEV对脑突触缺陷和认知障碍具有明显的保护作用。
结论：这是第一个将突触损失与TLE的认知缺陷联系起来的研究，提示[18F]SynVesT-1PET可能是监测突触丢失和认知功能障碍的有前途的生物标志物。LEV可能有助于逆转TLE患者的突触缺陷并改善学习和记忆障碍。
