先兆子痫导致认知功能障碍机制的多模影像学研究

Preeclampsia (PE) is a common severe complication in the middle and late stage of pregnancy. The increased risk of cardiovascular disease in pregnancy with PE is potentially associated with the cognitive dysfunction and the absence or progression of cerebral white matter lesions (WML) on series MRI studies. However, the pathogenic mechanism of cognitive impairment and WML associated with PE remains unclear. Cerebrovascular dysfunction is the core of PE and pregancy related central nervous system emergencies. The blood-brain barrier (BBB) would be destroyed when cerebrovascular reserves decrease. The enhanced remodelling of microvascular and macrovascular after onset of PE would destroy the integrity of cerebral blood flow (CBF), with the consequence of the change of cerebral structure and function, and even directly result in vascular cognitive impairment or indirectly destroy the pathway of white matter. The damage of BBB caused by transient injury of vascular endothelial cells probably is the common pathway resulting in the development of brain edema in PRES caused by PE. We assume PE induced cognitive impairment is potentially related to the decline of CBF directly and BBB is likely to be the pivotal point in this process. Establishing a reliable PE animal model, we aim to explore the changes of CBF, BBB, brain structure and function using multimodal MRI techniques, which would be helpful to further discover the pathogenic mechanism of cognitive dysfunction caused by endothelial dysfunction and increased permeability of BBB. A new therapeutic way based on this pathogenesis through drug intervention experiments is also investigated.

先兆子痫（preeclampsia，PE）是妊娠中晚期的常见严重并发症。PE女性心血管疾病危险性的增加与脑功能认知改变及MRI上脑白质病变（WML）增加可能有关，但与PE相关的认知障碍和WML的发生机制仍不清楚。脑血管功能失调是PE妊娠相关神经系统急症的核心，当脑血管储备下降时血脑屏障（BBB）破坏，而微血管和大血管的改变会破坏血液流动的完整性，导致大脑结构和功能的改变，直接导致血管性认知障碍或者间接破坏白质通路。血管内皮细胞一过性损伤所致的BBB破坏可能是PE导致PRES脑水肿形成的共同通路。我们假定PE引起的认知功能障碍与脑血流量（CBF）下降有关，BBB很可能是参与这一过程的关键环节。建立一个可靠的PE动物模型，利用MRI多模影像学探讨其CBF、BBB、脑结构及功能改变，进一步揭示内皮功能障碍、BBB通透性增加导致认知功能障碍的通路，并通过药物干预实验探索基于发病机制的新型治疗途径。

先兆子痫（PE）是妊娠中晚期的常见严重并发症，是全世界孕产妇围产期死亡和产后认知功能障碍的重要原因，目前发病机制不清。PE女性心血管疾病危险性的增加与脑功能认知改变及MRI上脑微结构及功能的改变可能有关，但相关发病机制仍不清楚。脑血管功能失调是PE妊娠相关神经系统急症的核心，当脑血管储备下降时血脑屏障（BBB）破坏，而微血管和大血管的改变会破坏血液流动的完整性，导致大脑结构和功能的改变，直接导致血管性认知障碍或者间接破坏白质通路。我们假定PE引起的认知功能障碍与脑血流量（CBF）下降有关，BBB很可能是参与这一过程的关键环节。本研究以内皮细胞活化和/或功能障碍学说作为研究理论依据，使用NO合成酶抑制剂N-硝基-L-精氨酸甲基（L-NAME）建立PE大鼠模型，分别选用二甲双胍和普伐他汀治疗，测量对照组、PE组和治疗组孕鼠产前生理、生化指标情况和产后不同时间点生理、生化、病理、行为学、MRI指标和微观蛋白表达情况，并将MRI指标与认知行为指标进行相关性分析，探索神经元的异常、星形胶质细胞和小胶质细胞的激活和血脑屏障（BBB）通透性的破坏是否介导了PE产后的认知功能障碍，尤其是随时间进展是否会进一步加重认知功能损坏及其相关机制，探讨二甲双胍和普伐他汀能否改善PE产后认知功能障碍。重点通过多模MRI评估PE大鼠治疗前后CBF、BBB、脑微结构及功能的改变，进一步揭示内皮功能障碍、BBB通透性增加导致认知功能障碍的可能机制，并通过药物干预实验探索基于发病机制的新型治疗途径。