Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts ( n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.

中文翻译：

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血管生成标志物的性别二态性差异与人类的大脑衰老轨迹有关


异常的血管生成可能导致认知障碍的发展，并代表预防痴呆的治疗靶点。然而，大多数针对血管生成和认知障碍的研究都集中在模式生物上。为了测试血管生成与人类认知衰老的相关性，我们在来自深度表型纵向人类队列 （n = 435;女性 = 207，年龄 = 74 ± 9） 的合并双中心样本中评估了血管生成的循环血液标志物与大脑衰老轨迹的关联使用认知评估、生物样本、结构脑成像和临床数据。血液标志物包括参与血管生成和血管功能的配体，如碱性成纤维细胞生长因子 （bFGF）、血管内皮生长因子家族成员 （VEGFA、VEGFB 和 VEGFC） 和胎盘生长因子 （PlGF），此外还有它们的受体 VEGF 受体 1 （VEGFR1） 和酪氨酸激酶与免疫球蛋白和 EGF 同源结构域 2 （Tie2）。机器学习和传统统计数据揭示了血浆血管生成生长因子与大脑衰老结果（包括执行功能和灰质萎缩）的性别二态性关联。具体来说，血管生成的标志物与年轻女性（非男性）较高的执行功能和较少的脑萎缩相关，这种关联方向性在 75 岁左右发生逆转。较高浓度的 bFGF 已知对多种细胞类型的多效性作用，可预测女性和男性的良好认知轨迹。来自多中心数据集的独立样本 （MarkVCID;n = 80;女性 = 30;年龄 = 73 ± 9） 用于外部验证这些发现。 总之，该分析证明了血管生成与人脑衰老的关联，对血管性认知障碍和痴呆具有潜在的治疗意义。