In Vivo Molecular Imaging Laboratory (IMIV), French National Institute of Health and Medical Research (INSERM), French Alternative Energies and Atomic Energy Commission (CEA), French National Center for Scientific Research (CNRS), Paris Saclay University, Frédéric Joliot Hospital service, Orsay, France.
Neurophysiology and Epilepsy Unit, Bicêtre Hospital, Public Hospitals of Paris (AP-HP), France.
Epilepsia. 2018 Jun;59(6):1234-1244. doi: 10.1111/epi.14083. Epub 2018 Apr 19.
Mesiotemporal lobe epilepsy is the most common type of drug-resistant partial epilepsy, with a specific history that often begins with status epilepticus due to various neurological insults followed by a silent period. During this period, before the first seizure occurs, a specific lesion develops, described as unilateral hippocampal sclerosis (HS). It is still challenging to determine which drugs, administered at which time point, will be most effective during the formation of this epileptic process. Neuroinflammation plays an important role in pathophysiological mechanisms in epilepsy, and therefore brain inflammation biomarkers such as translocator protein 18 kDa (TSPO) can be potent epilepsy biomarkers. TSPO is associated with reactive astrocytes and microglia. A unilateral intrahippocampal kainate injection mouse model can reproduce the defining features of human temporal lobe epilepsy with unilateral HS and the pattern of chronic pharmacoresistant temporal seizures. We hypothesized that longitudinal imaging using TSPO positron emission tomography (PET) with F-DPA-714 could identify optimal treatment windows in a mouse model during the formation of HS.
The model was induced into the right dorsal hippocampus of male C57/Bl6 mice. Micro-PET/computed tomographic scanning was performed before model induction and along the development of the HS at 7 days, 14 days, 1 month, and 6 months. In vitro autoradiography and immunohistofluorescence were performed on additional mice at each time point.
TSPO PET uptake reached peak at 7 days and mostly related to microglial activation, whereas after 14 days, reactive astrocytes were shown to be the main cells expressing TSPO, reflected by a continuing increased PET uptake.
TSPO-targeted PET is a highly potent longitudinal biomarker of epilepsy and could be of interest to determine the therapeutic windows in epilepsy and to monitor response to treatment.
颞叶内侧癫痫是最常见的耐药性部分性癫痫类型，具有特定的病史，通常由各种神经损伤引起的癫痫持续状态开始，随后是沉默期。在此期间，在首次发作之前，会出现特定的病变，描述为单侧海马硬化（HS）。仍然难以确定在这种癫痫过程形成期间，何时、何种药物治疗最有效。神经炎症在癫痫的病理生理机制中起着重要作用，因此脑炎症生物标志物，如转位蛋白 18 kDa（TSPO），可以作为有效的癫痫生物标志物。TSPO 与反应性星形胶质细胞和小胶质细胞有关。单侧海马内海人酸注射小鼠模型可以重现具有单侧 HS 和慢性药物难治性颞叶发作模式的人类颞叶癫痫的特征。我们假设使用 F-DPA-714 的 TSPO 正电子发射断层扫描（PET）进行纵向成像可以在 HS 形成过程中确定小鼠模型的最佳治疗窗口。
该模型被诱导到雄性 C57/Bl6 小鼠的右背侧海马中。在模型诱导前以及在 HS 形成的 7 天、14 天、1 个月和 6 个月时进行微 PET/计算机断层扫描扫描。在每个时间点，还对额外的小鼠进行体外放射自显影和免疫荧光。
TSPO PET 摄取在 7 天达到峰值，主要与小胶质细胞激活有关，而在 14 天之后，反应性星形胶质细胞被证明是表达 TSPO 的主要细胞，反映出持续增加的 PET 摄取。
TSPO 靶向 PET 是一种非常有效的癫痫纵向生物标志物，可能有助于确定癫痫的治疗窗口，并监测对治疗的反应。
