性激素调节阿尔茨海默病进程中情绪记忆性别差异的海马-杏仁核-皮层通路的研究

Sex differences in Alzheimer's disease (AD) have attracted more and more attention in recent years. Previous studies have shown that the decline of sex hormone plays an important role in the progress of AD, but its relationship with sex differences in cognition and the underlying neural mechanisms are still unclear. Our previous study have found that there was a sex difference in emotional memory in mild cognitive impairment (aMCI) patients,which was the early stage of AD: female aMCI patients retained the emotional enhancement of memory (EEM) effect of positive high arousal pictures, while male aMCI patients retained the EEM effect of negative high arousal pictures. Since the hippocampus, which plays important roles in memory, is distributed with more estrogen receptors; while the amygdala, which participates in emotion regulation, is distributed with more androgen receptors. We hypothesize that the changes in the hippocampal-amygdala neuromodulation pathway would be associated with abnormally decreasing sex hormones during the process of AD, and it might be the potential neural mechanisms for sex differences in emotional memory. This project intends to establish correlation, regression and mediation models by coupling sex hormones, multi-modal magnetic resonance imaging and cognitive behavior together, to explore the structure, function and perfusion changes of hippocampal-amygdala-cortical pathway between male and female in the progress of AD; and their relationships with sex hormones. This study will help to deepen the understanding of the pattern of memory impairment in AD patients, and to provide a theoretical basis for the sex-specific, individualized intervention and treatments.

阿尔茨海默病(AD)的性别差异近年来开始被关注。研究表明性激素下降在AD进程中发挥着重要的作用，但与认知性别差异之间的关系及其神经机制目前尚不明确。我们前期的研究发现在AD早期的轻度认知障碍(aMCI)阶段，情绪记忆存在性别差异：女性aMCI保留正性高唤醒图片对记忆的增强(EEM)效应，男性aMCI则保留负性高唤醒图片的EEM效应。由于海马分布着较多的雌激素受体，参与记忆功能；杏仁核分布着较多的雄激素受体，参与情绪调节。据此我们提出假设：AD进程中海马-杏仁核-皮层调节通路的改变与异常下降的性激素有关，是情绪记忆性别差异的潜在神经机制。本项目拟通过耦合性激素、多模态磁共振及认知行为学，建立相关、回归及中介模型，探索AD进程中及性别间海马-杏仁核-皮层通路结构、功能、灌注的改变情况，及与性激素之间的关系。这将有助于加深对AD记忆损伤规律的认识，为实现性别针对性、个体化的干预治疗提供理论依据。

本研究联合多模态磁共振、情绪记忆行为学及性激素探索了AD进程中的性别差异及潜在的神经机制。我们发现AD进程中脑灰质萎缩、脑血流灌注、神经血管耦合、静息态脑功能网络拓扑结构等均存在着性别差异，具体表现为：女性认知障碍患者部分脑区的灰质萎缩程度更明显；女性患者脑血流灌注减低的亦更为显著，女性AD患者的神经血管耦合比值增高，提示单位灌注需要消耗的能量更多。但男性AD患者在部分网络间和网络内的功能连接存在减低，这可能与教育程度对脑储备的保护作用有关。以上存在性别差异的脑区在相关分析中进一步发现与分性别的认知能力评分显著相关。AD进程中情绪对记忆的增强效应（EEM）逐步损伤，且存在性别差异，主要体现在aMCI阶段，女性患者保留正性高唤醒图片和负性低唤醒图片的EEM效应，男性患者则保留负性高唤醒图片的EEM效应。健康老年人群中性激素与脑神经血管耦合及认知能力之间存在显著相关性，且可通过调节具体脑区的神经血管耦合影响认知能力。我们的研究揭示了AD进程中性别差异的神经机制，为临床实现AD性别特异的预防、诊断、干预、治疗提供了潜在的理论依据，具有重要的临床应用价值。