MCI空间导航障碍中内嗅-CA3/1及其高级皮层环路损害的神经机制

Getting lost is a frequent feature of the early stage of Alzheimer disease (AD) and mild cognitive impairment (MCI), which seriously affecting the quality of daily life, therefore the exploration of neural mechanism of spatial navigation impairment and then early intervention is particularly important. In rodents, the grid cells in entorhinal cortex and place cells in hippocampal CA3/1 are both vital in acuurate spatial navigation. Rencently, the Nobel Prize has been awarded for this discovery, underlying the importance of their existence. In our previouse studies, we also found activation of key brain regions such as entorhinal - CA3/1, parietal cortex - striatum in human brain by task fMRI based on the virtual navigation test. The entorhinal cortex and hippocampus is the earliest involved pathological structure in AD, but the relationship between these key brain regions and spatial navigation impairment remains unclear. In our preliminary experiments, we found the atrophy of pyramidal cells and reduction of NAA metabolism in CA3/1, the damage in the perforant pathway, allo- and ego-centric navigation impairment in amnestic-MCI with hippocampal atrophy. Therefore, we will combine the neuro-psychology, spatial navigation test, ultra high resolution magnetic resonance imaging and advanced algorithm to investigate the characteristics of pattern recognition of imaging parameters for key brain regions related with spatial navigation impairment in different subtypes of MCI, and to explore the biological markers for predicting MCI progression to AD. Results from this project are important for enriching the theory of neural mechanisms of spatial navigation and promoting early diagnosis and treatment of dementia.

迷路和走失是阿尔茨海默病(AD)和轻度认知障碍(MCI)的常见表现，严重影响生活质量，因此，探索空间导航障碍神经机制从而早期干预尤为重要。诺贝尔奖重大发现是大鼠空间导航任务由内嗅皮层网格细胞和海马CA3/1位置细胞协调完成。我们预试验也发现虚拟导航引起人脑内嗅-CA3/1、顶叶-纹状体等关键脑区激活。内嗅皮层和海马是AD早期病理部位，但这些关键脑区损害与空间导航障碍的关系尚不清晰。我们前期用多水平研究(结构-代谢-白质-功能)发现：伴海马萎缩的遗忘型MCI中CA3/1锥体细胞萎缩，NAA代谢降低，穿通通路损害，环境和自我导航功能均受损。所以，本项目将采用神经心理学、空间导航行为学、超高分辨磁共振及先进算法，结合横向研究和纵向随访，深入分析不同亚型MCI中空间导航关键脑区影像学参数的模式识别特征，探寻预测MCI向AD转化的生物学标志物，对丰富空间导航神经机制理论和促进痴呆早期诊治有重要意义。

迷路和走失是阿尔茨海默病(AD)和轻度认知障碍(MCI)的常见表现，严重影响生活质量，因此，探索空间导航障碍神经机制从而早期干预尤为重要。诺贝尔奖重大发现是大鼠空间导航任务由内嗅皮层网格细胞和海马CA3/1位置细胞协调完成。我们预试验也发现虚拟导航引起人脑内嗅-CA3/1、顶叶-纹状体等关键脑区激活。内嗅皮层和海马是AD早期病理部位，但这些关键脑区损害与空间导航障碍的关系尚不清晰。本项目采用了神经心理学、空间导航行为学、超高分辨磁共振及先进算法，结合横向研究和纵向随访，深入分析不同亚型MCI中空间导航关键脑区影像学参数的模式识别特征。本项目建立了超过500人的认知障碍行为学和脑影像数据库，发现空间导航环路的结构和功能受损对空间导航功能损伤的意义，并通过海马亚区功能连接等指标实现了高风险MCI患者的自动识别，另外，我们探究了风险基因、糖尿病等风险因素的认知障碍的影响，同时，基于本项目我们优化了功能磁共振数据采集、分析和任务设计范式的标准，从多个方面探寻预测MCI向AD转化的生物学标志物，对丰富空间导航神经机制理论和促进痴呆早期诊断奠定了基础。