Supplementary Material for: Biomarkers Related to Endothelial Dysfunction and Vascular Cognitive Impairment: A Systematic Review

<b><i>Introduction:</i></b> The damage in the endothelium and the neurovascular unit appears to play a key role in the pathogenesis of vascular cognitive impairment (VCI). Although there have been many advances in understanding the physiopathology of this disease, several questions remain unanswered. The association with other degenerative diseases and the heterogeneity of its clinical spectrum establish a diagnostic problem, compromising a better comprehension of the pathology and halting the development of effective treatments. The investigation of biomarkers is an important movement to the development of novel explicative models and treatment targets involved in VCI. <b><i>Methods:</i></b> We searched MEDLINE considering the original research based on VCI biomarkers in the past 20 years, following prespecified selection criteria, data extraction, and qualitative synthesis. <b><i>Results:</i></b> We reviewed 42 articles: 16 investigated plasma markers, 17 analyzed neuropathological markers, 4 studied CSF markers, 4 evaluated neuroimaging markers (ultrasound and MRI), and 1 used peripheral Doppler perfusion imaging. <b><i>Conclusions:</i></b> The biomarkers in these studies suggest an intrinsic relationship between endothelial dysfunction and VCI. Nonetheless, there is still a need for identification of a distinctive set of markers that can integrate the clinical approach of VCI, improve diagnostic accuracy, and support the discovery of alternative therapies.

**<i>引言：</i>** 内皮细胞与神经血管单元（neurovascular unit）的损伤在血管性认知障碍（vascular cognitive impairment, VCI）的发病机制中发挥关键作用。尽管学界对该疾病的病理生理学认知已取得诸多进展，但仍有诸多问题尚未得到解答。其与其他退行性疾病的关联，以及临床谱系的异质性，共同构成了诊断难题，不仅阻碍了对该病理机制的深入认知，更掣肘了有效治疗手段的研发。对生物标志物（biomarkers）的探索，是构建新型阐释模型与发掘VCI相关治疗靶点的重要路径。**<i>方法：</i>** 本研究检索了MEDLINE数据库中近20年来基于VCI生物标志物的原创研究，遵循预先设定的筛选标准、数据提取流程与定性综合分析方法完成研究筛选与整合。**<i>结果：</i>** 本研究共纳入42篇文献：其中16篇聚焦血浆标志物研究，17篇分析了神经病理标志物，4篇针对脑脊液（CSF）标志物展开探索，4篇评估了神经影像标志物（超声与磁共振成像MRI），另有1项研究采用了外周多普勒灌注成像技术。**<i>结论：</i>** 上述研究中的生物标志物提示，内皮功能障碍与VCI之间存在内在关联。但目前仍需筛选出一套特异性标志物组合，以适配VCI的临床诊疗流程、提升诊断准确率，并助力新型治疗方案的开发。