基于定量磁敏感图和ApoE基因检测的原发性开角型青光眼患者脑内铁稳态失衡机制研究

Glaucoma is the leading cause of irreversible vision loss globally. The pathogenetic mechanisms of primary open-angle glaucoma (POAG) is unclear. Therefore, the clinical diagnostic accuracy is low and the prognosis is poor. Increasing evidence shows that POAG is a neurodegenerative disease, and the neurodegeneration is significantly associated with ApoE ε4 and iron deposition. However, is there iron deposition in the brain of POAG? Is it strongly associated with the neurodegeneration? Is ApoE ε4 gene a risk factor for iron deposition? To answer these questions, we hypothesize that there is obvious iron deposition in the brain of POAG patients, which is correlated with disease severity, and ApoE ε4 gene is a risk factor for that. We will imply quantitative susceptibility mapping (QSM) to compare the iron levels in the brains of POAG patients, patients with ocular hypertension and normal controls. Then the correlations between iron deposition in the brain and the disease severity, cognitive conditions, psychiatric conditions and the concentration of ferritin in the serum and cerebrospinal fluid will be analyzed. Moreover, the iron deposition of POAG patients without ApoE ε4 gene and patients with ApoE ε4 will be compared. The results will help to explore the roles of ApoE ε4 gene and unbalance of iron homeostasis in the mechanisms of neurodegeneration of POAG， and to provide evidence for improving early detection of the disease and new treatment strategy.

青光眼是全球首位不可逆致盲性眼病。原发性开角型青光眼（POAG）发病机制不清，误漏诊率高且治疗效果差。越来越多的证据表明POAG是神经退行性疾病，且与ApoE ε4基因及铁沉积异常显著相关。但POAG患者脑内是否存在铁沉积异常？铁沉积异常是否为神经退变的重要致病因素？ApoE ε4基因是否为铁沉积异常的危险因素？据此提出假说：POAG患者相关脑区存在明显铁沉积异常，并且与疾病严重程度相关，而ApoE ε4基因是其危险因素。拟采用定量磁敏感图研究POAG、高眼压症以及正常人脑内铁含量的差异及其与疾病严重程度、精神心理学评分、血清铁蛋白水平和脑脊液铁蛋白水平的相关性，对比无ApoE ε4组及有ApoE ε4组患者脑内铁沉积的差异，揭示铁代谢和ApoE ε4基因在POAG神经退行性改变机制中的作用，为POAG早期准确诊断和开发新的治疗方式提供重要依据。

原发性开角型青光眼（POAG）发病机制不清，误漏诊率高且治疗效果差。越来越多的证据表明POAG是累及视通路内外多个脑区的神经退行性疾病。本研究通过多模态磁共振检查，发现POAG患者初级视皮层、高级视皮层、双侧红核及黑质的结构均发生了改变，并且患者在静息状态下视觉认知相关脑区的工作模式也发生了改变。其中QSM结果显示POAG患者双侧红核及黑质信号不均匀、纹理粗糙度增大。DKI研究结果显示POAG患者顶叶、颞叶、前额叶及扣带回多发灰质微结构损伤，其中AK值敏感性最高，而MK和FA值特异性较高。静息态fMRI研究结果显示高眼压POAG患者（HTG）、正常眼压POAG患者(NTG)及正常受试者的全脑功能连接密度的分布有差异，HTG表现为视觉区减低、额顶叶局部增高，NTG仅有枕叶及颞叶减低区，HTG与NTG相比，HTG额顶叶局部增高，枕叶及颞叶可见零散小片状减低区；而且初级视皮层BA17向高级视皮层BA18、BA19的信息流减少，而高级视皮层向初级视皮层的信息流增加，默认脑网络（DMN）与初级视皮层BA17之间的信息流增加，而高级视皮层BA18、19到DMN的信息流减少，提示POAG患者存在静息状态下视觉认知相关脑区的工作模式改变，而且初级视皮层与一般躯体感觉皮层间的信息流减少。与GCA结果进行相关性分析，研究脑皮层微结构损伤与信息流改变之间的相关性。将DKI指标与fMRI指标联合分析，结果显示左侧BA17→左侧枕中回（MOG）及左侧MOG→左侧BA17的效应连接与左侧BA17的FA值呈正相关，左侧BA17→左侧额中回的效应连接与左侧BA17的AK值呈正相关。左侧MOG→右侧BA17的效应连接与右侧BA17的FA值呈正相关，右侧BA17→右侧MOG的效应连接与右侧BA17的FA值呈正相关。右侧BA17→右侧额上回的效应连接与右侧BA17的AK值呈正相关。本研究进一步证明了POAG累及视通路内外多个脑区，并且可出现脑功能重塑，并且为POAG的诊断和评估提供了潜在的影像学指标。