Retinal Imaging of Alzheimer's Disease Pathology

摘要 本研究的主要目的是探讨阿尔茨海默病（AD）在视网膜中的病理特征 评价视网膜淀粉样蛋白成像作为诊断和监测AD的新方法。人们越来越 证据表明，AD影响神经感觉视网膜，大脑的发育产物和唯一的CNS 可直接用于高分辨率成像的组织。视网膜表现出广泛的病理在AD 患者，包括神经纤维层变薄，血管和血流改变，以及视网膜变性 神经节细胞（RGCs）。AD的标志性病理体征--β淀粉样蛋白（Aβ）斑块和神经胶质瘤 由过度磷酸化的tau蛋白（ptau）组成的缠结（NFT）-早已在脑中被描述。 然而，Aβ沉积在人类AD患者的视网膜中，包括早期病例，直到最近才被发现。 发现了进一步的研究发现，AD患者死后存在ptau、Aβ样沉积和Aβ42肽水平升高 视网膜值得注意的是，RGC的一种亚型（含黑视素的RGC）的丢失与累积有关。 在这些细胞内部和周围的Aβ。我们小组的初步数据表明， 淀粉样变性和视网膜炎症（如星形胶质细胞增生和小胶质细胞增生）周围的Aβ纤维和NFT样 结构，这是特定于AD患者的视网膜。这些变化似乎在 疾病进展。为了可视化AD病理，已经开发了一种非侵入性视网膜淀粉样蛋白成像方法 开发用于在生活中以高分辨率和特异性重复监测视网膜Aβ沉积物 AD的转基因啮齿动物模型。实施这种视网膜姜黄素成像技术的试点临床试验 证实了其定量检测活体AD患者视网膜Aβ沉积的能力。我们的研究使用这个 小鼠模型中的视网膜淀粉样蛋白光学成像证实了追踪视网膜淀粉样蛋白的细微变化的可行性。 淀粉样蛋白斑块在疾病进展过程中，并在响应免疫为基础的治疗。根据已发表的 根据收集的初步数据，提出以下研究目标：1）确定 淀粉样沉积物、血管淀粉样变性、细胞内Aβ寡聚体和tau蛋白病在视网膜中的分布 AD和轻度认知障碍（MCI）患者的视网膜炎症和变性; 2）检查视网膜炎症和变性， 评估MCI和AD患者的脑病理学和认知状态的可能相关性，以及3） 非侵入性监测AD活小鼠模型中视网膜Aβ沉积物的形成、出现和清除， 在疾病进展期间和对免疫疗法的反应中。这些研究的结果表明， 增加对AD如何影响视网膜的理解，以及视网膜淀粉样蛋白成像是否可以可靠地指示 大脑病理或认知状态。鉴于视网膜直接和非侵入性高分辨率的可达性 成像，靶向该组织可能提供一种宝贵的方法来识别新的生物标志物和筛选 人群，以促进AD的风险预测，诊断和监测。

ABSTRACT The central goal of this proposal is to explore pathological hallmarks of Alzheimer’s disease (AD) in the retina and evaluate retinal amyloid imaging as a novel approach for diagnosis and monitoring of AD. There is growing evidence that AD affects the neurosensory retina, a developmental outgrowth of the brain and the only CNS tissue directly accessible for high-resolution imaging. The retina exhibits a wide spectrum of pathologies in AD patients, including thinning of the nerve fiber layer, vascular and blood flow changes, and degeneration of retinal ganglion cells (RGCs). The hallmark pathological signs of AD – amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprised of hyperphosphorylated tau protein (ptau) – have long been described in the brain. However, Aβ deposits in the retina of human AD patients, including early stage cases, were only recently discovered. Further studies have found ptau, Aβ-like deposits, and elevated Aβ42 peptides in postmortem AD retinas. Notably, a loss of a subtype of RGCs, melanopsin-containing RGCs, was associated with accumulation of Aβ inside and around these cells. Preliminary data from our group indicate manifestation of vascular amyloidosis and retinal inflammation (e.g. astrogliosis and microgliosis) surrounding Aβ fibrils and NFT-like structures, which are specific to the retinas of AD patients. These changes appear to be exacerbated during disease progression. In order to visualize AD pathology, a noninvasive retinal amyloid imaging method has been developed to facilitate repeated monitoring of retinal Aβ deposits with high resolution and specificity in living transgenic rodent models of AD. Pilot clinical trials implementing this retinal curcumin imaging technology demonstrate its capacity to quantitatively detect retinal Aβ deposits in living AD patients. Our studies using this retinal amyloid optical imaging in mouse models demonstrate the feasibility to track subtle changes in retinal amyloid plaques during disease progression, and in response to immune-based therapy. Based on the published and preliminary data collected, the following research objectives are proposed: 1) To determine the existence and distribution of amyloid deposits, vascular amyloidosis, intracellular Aβ oligomers, and tauopathy in the retinas of AD and Mild Cognitive Impairment (MCI) patients; 2) To examine retinal inflammation and degeneration, and evaluate possible correlations with brain pathology and cognitive status in MCI and AD patients, and 3) To noninvasively monitor formation, appearance and clearance of retinal Aβ deposits in live mouse models of AD, during disease progression and in response to immunotherapy. Results from these studies stand to markedly increase the understanding of how AD affects the retina, and whether retinal amyloid imaging can reliably indicate brain pathology or cognitive status. Given the accessibility of the retina for direct and noninvasive high resolution imaging, targeting this tissue may provide an invaluable approach to identify new biomarkers and screen populations to facilitate prediction of risk, diagnosis and monitoring of AD.