Weekman Erica M, Rogers Colin B, Sudduth Tiffany L, Wilcock Donna M
Stark Neurosciences Research Institute, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Sanders Brown Center on Aging, Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA.
J Neuroinflammation. 2025 Jan 30;22(1):23. doi: 10.1186/s12974-025-03332-7.
Over recent years, the retina has been increasingly investigated as a potential biomarker for dementia. A number of studies have looked at the effect of Alzheimer's disease (AD) pathology on the retina and the associations of AD with visual deficits. However, while OCT-A has been explored as a biomarker of cerebral small vessel disease (cSVD), studies identifying the specific retinal changes and mechanisms associated with cSVD are lacking. Using our model of hyperhomocysteinemia-induced cSVD, we aimed to identify the effects of cSVD on visual sensitivity and cognition, retinal glial and vascular cells, and neuroinflammatory and cardiovascular gene expression changes. We placed C57Bl6/SJL mice on a HHcy-inducing diet, a model that has been well characterized to have vascular pathologies in the brain similar to pathologic cSVD. After 14 weeks on diet, mice underwent the Visual-Stimuli 4-arm Maze to identify visual deficits. Whole mount retinas were stained for vessels, microglia and astrocytes to identify glial and vascular changes. Finally, neuroinflammatory and cardiovascular gene expression was measured using NanoString's nCounter system. Ultimately, HHcy led to visual changes that specifically affected the reaction to blue and white light, slightly decreased vascular volume and significantly decreased interaction of microglia with the vasculature, as well as downregulation of inflammatory and vascular genes. These changes provide novel insights and reproduce some prior observations. These studies highlight retinal changes in association with cSVD and serve as a precaution when interpreting vision-dependent cognitive testing of cSVD models.
近年来，视网膜作为痴呆症的潜在生物标志物受到了越来越多的研究。许多研究探讨了阿尔茨海默病（AD）病理对视网膜的影响以及AD与视觉缺陷的关联。然而，虽然光学相干断层扫描血管造影（OCT-A）已被探索作为脑小血管疾病（cSVD）的生物标志物，但缺乏识别与cSVD相关的特定视网膜变化和机制的研究。利用我们高同型半胱氨酸血症诱导的cSVD模型，我们旨在确定cSVD对视觉敏感性和认知、视网膜神经胶质细胞和血管细胞以及神经炎症和心血管基因表达变化的影响。我们将C57Bl6/SJL小鼠置于诱导高同型半胱氨酸血症的饮食中，该模型已被充分表征为在大脑中具有与病理性cSVD相似的血管病变。饮食14周后，小鼠接受视觉刺激四臂迷宫试验以识别视觉缺陷。对整个视网膜进行血管、小胶质细胞和星形胶质细胞染色，以识别神经胶质细胞和血管变化。最后，使用NanoString的nCounter系统测量神经炎症和心血管基因表达。最终，高同型半胱氨酸血症导致视觉变化，具体影响对蓝光和白光的反应，血管体积略有减少，小胶质细胞与血管系统的相互作用显著减少，以及炎症和血管基因的下调。这些变化提供了新的见解并重现了一些先前的观察结果。这些研究突出了与cSVD相关的视网膜变化，并在解释cSVD模型的视觉依赖性认知测试时起到了警示作用。
