Shi Haoshen, Koronyo Yosef, Rentsendorj Altan, Fuchs Dieu-Trang, Sheyn Julia, Black Keith L, Mirzaei Nazanin, Koronyo-Hamaoui Maya
Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Front Neurosci. 2021 Sep 22;15:731614. doi: 10.3389/fnins.2021.731614. eCollection 2021.
The retina has been increasingly investigated as a site of Alzheimer's disease (AD) manifestation for over a decade. Early reports documented degeneration of retinal ganglion cells and their axonal projections. Our group provided the first evidence of the key pathological hallmarks of AD, amyloid β-protein (Aβ) plaques including vascular Aβ deposits, in the retina of AD and mild cognitively impaired (MCI) patients. Subsequent studies validated these findings and further identified electroretinography and vision deficits, retinal (p)tau and inflammation, intracellular Aβ accumulation, and retinal ganglion cell-subtype degeneration surrounding Aβ plaques in these patients. Our data suggest that the brain and retina follow a similar trajectory during AD progression, probably due to their common embryonic origin and anatomical proximity. However, the retina is the only CNS organ feasible for direct, repeated, and non-invasive ophthalmic examination with ultra-high spatial resolution and sensitivity. Neurovascular unit integrity is key to maintaining normal CNS function and cerebral vascular abnormalities are increasingly recognized as early and pivotal factors driving cognitive impairment in AD. Likewise, retinal vascular abnormalities such as changes in vessel density and fractal dimensions, blood flow, foveal avascular zone, curvature tortuosity, and arteriole-to-venule ratio were described in AD patients including early-stage cases. A rapidly growing number of reports have suggested that cerebral and retinal vasculopathy are tightly associated with cognitive deficits in AD patients and animal models. Importantly, we recently identified early and progressive deficiency in retinal vascular platelet-derived growth factor receptor-β (PDGFRβ) expression and pericyte loss that were associated with retinal vascular amyloidosis and cerebral amyloid angiopathy in MCI and AD patients. Other studies utilizing optical coherence tomography (OCT), retinal amyloid-fluorescence imaging and retinal hyperspectral imaging have made significant progress in visualizing and quantifying AD pathology through the retina. With new advances in OCT angiography, OCT leakage, scanning laser microscopy, fluorescein angiography and adaptive optics imaging, future studies focusing on retinal vascular AD pathologies could transform non-invasive pre-clinical AD diagnosis and monitoring.
十多年来,视网膜作为阿尔茨海默病(AD)的一个表现部位,受到了越来越多的研究。早期报告记录了视网膜神经节细胞及其轴突投射的退化。我们的团队首次在AD患者和轻度认知障碍(MCI)患者的视网膜中发现了AD关键病理特征,即淀粉样β蛋白(Aβ)斑块,包括血管Aβ沉积。随后的研究证实了这些发现,并进一步确定了这些患者的视网膜电图和视力缺陷、视网膜(p)tau蛋白和炎症、细胞内Aβ积累,以及Aβ斑块周围的视网膜神经节细胞亚型退化。我们的数据表明,在AD进展过程中,大脑和视网膜遵循相似的轨迹,这可能是由于它们共同的胚胎起源和解剖学上的邻近性。然而,视网膜是唯一可行的中枢神经系统器官,可通过超高空间分辨率和灵敏度进行直接、重复和非侵入性的眼科检查。神经血管单元的完整性是维持正常中枢神经系统功能的关键,而脑血管异常越来越被认为是AD认知障碍的早期关键因素。同样,在包括早期病例在内的AD患者中,也描述了视网膜血管异常,如血管密度和分形维数的变化、血流、黄斑无血管区、曲率迂曲和动静脉比。越来越多的报告表明,脑和视网膜血管病变与AD患者及动物模型中的认知缺陷密切相关。重要的是,我们最近发现,视网膜血管血小板衍生生长因子受体-β(PDGFRβ)表达的早期和进行性缺陷以及周细胞丢失与MCI和AD患者的视网膜血管淀粉样变性和脑淀粉样血管病有关。其他利用光学相干断层扫描(OCT)、视网膜淀粉样荧光成像和视网膜高光谱成像的研究,在通过视网膜可视化和量化AD病理方面取得了重大进展。随着OCT血管造影、OCT渗漏、扫描激光显微镜、荧光素血管造影和自适应光学成像的新进展,未来专注于视网膜血管AD病理的研究可能会改变非侵入性临床前AD诊断和监测。