AD生物标记OCT-RNFL-C的多维度验证及机制研究

Biomarker is important for early diagnosis and intervention of Alzheimer's disease (AD). In our previous studies, change of retinal nerve fiber layer thickness (RNFL-C) determined by opitcal coherence tomography (OCT) was found to predict cognitive conversion in old adults. RNFL-C was also revealed to correlate with AD-featured cognitive impairment, hippocampus atrophy(determined by 3D-MRI) and elevated p-tau235 level in human cerebrospinal fluid. Thus OCT-RNFL-C was suggested to be a potential AD biomarker. In the proposed studies, we plan to validate RNFL-C against classical AD biomarkers in large-scaled longitudinal study and to verify the clinical effectiveness and feasibility of RNFL-C as AD biomarker. Moreover, we will employ specific AD transgenic mice as well as the corresponding interventional animal models aiming at certain AD neuropathology. We will determine whether RNFL-C is a marker appearing at early stage of AD through comparing time-window of RNFL-C abnormality, hippocampus dysfunction and neurodegeneration in the whole process of AD on the animal models. The effect of certain neuropathological features (e.g., Aß deposition or tau over-expressed) on RNFL-C will be further investigated to determine biological characteristic of RNFL-C in the certain subgroup of AD neuropathology. The results from the above studies would likely establish RNFL-C as a AD biomarker and promote the clinical utilization of RNFL-C in early screening and intervention of AD.

建立有效的生物标记是开展阿尔茨海默病（AD）早期诊断和结局预测的关键。我们前期通过光学相干断层扫描（OCT）发现视网膜的视神经纤维层退化（RNFL-C）可预测AD认知转化，且与AD特征性记忆损害、海马萎缩及脑脊液p-tau水平相关，推测OCT-RNFL-C可作为AD潜在生物标记。本项目拟一方面开展前瞻性临床研究，通过与经典AD生物标记的比对，验证OCT-RNFL-C早期诊断AD的有效性和可行性；另一方面在动物实验中构建不同病理机制的AD动物模型及相应干预模型，观察RNFL-C组织学阳性变化、脑海马功能下降和颅内神经病理改变之间的相关性及“时间窗”；分析特定AD神经病理因素（Aß沉积或tau蛋白过表达）作用下，RNFL-C的特征性病理改变及其分子机制，为将OCT-RNFL-C应用于AD早期筛查和病情监测，以及后期开展的个体化治疗提供依据。

我们前期的研究通过光学相干断层扫描（OCT）发现视网膜的视神经纤维层退化（RNFL-C）可以预测阿尔兹海默症（AD）的认知转化，而且与AD特征性记忆损害、海马萎缩及脑脊液p-tau水平相关，提出OCT-RNFL-C可作为AD潜在生物标记的科学假说。本项目开展前瞻性研究，对手术老人即社区老人开展认知评估。首先引进翻译中文版术后谵妄严重程度评定量表（CAM-S），并对其进行信效度研究。开展随访研究发现，术后谵妄影响长期预后，RNFL变化可作为AD早期生物标记物的神经病理机制，即视网膜神经纤维层厚度的病理改变可投射中枢神经系统的退行性变，为将OCT-RNFL-C应用于AD早期筛查和病情监测，以及后期开展的个体化治疗提供依据。