Retinal Imaging of Alzheimer's Disease Pathology

摘要 这项提议的中心目标是探索视网膜中阿尔茨海默病(AD)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的一种新方法。有越来越多的 阿尔茨海默病影响神经感觉视网膜的证据，视网膜是大脑的发育产物，也是唯一的中枢神经系统 可直接获取的组织，可进行高分辨率成像。阿尔茨海默病的视网膜表现出广泛的病理变化 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(RGC)。AD-淀粉样蛋白β蛋白(A-β)斑块和神经原纤维的标志性病理征象 缠结(NFT)由过度磷酸化的tau蛋白(Ptau)组成-长期以来一直在大脑中被描述。 然而，人类AD患者视网膜中的Aβ沉积，包括早期病例，只是最近才出现的 被发现了。进一步的研究发现，在死后AD中发现了Ptau，Aβ样沉积，并升高了Aβ42肽 视网膜。值得注意的是，视网膜节细胞的一种亚型--含有黑素的视网膜节细胞的丢失与积聚有关 这些细胞内部和周围的β。我们小组的初步数据表明血管的表现 淀粉样变性和视网膜炎症(如星形胶质细胞增多症和小胶质细胞增多症)围绕Aβ纤维和神经纤维素样 结构，这是阿尔茨海默病患者视网膜特有的。这些变化似乎在 疾病的发展。为了可视化显示AD的病理，一种非侵入性的视网膜淀粉样蛋白成像方法已经被 为便于重复监测视网膜Aβ沉积而开发，具有高分辨率和活体特异性 转基因AD啮齿动物模型。应用这种视网膜姜黄素成像技术的初步临床试验 证明其有能力定量检测活体AD患者的视网膜Aβ沉积。我们的研究使用这一点 小鼠视网膜淀粉样蛋白光学成像显示追踪视网膜细微变化的可行性 疾病进展过程中的淀粉样斑块，以及对基于免疫的治疗的反应。根据已发布的 并收集了初步数据，提出了以下研究目标：1)确定是否存在 视网膜中淀粉样沉积、血管淀粉样变性、细胞内Aβ寡聚体和节段性病变的分布 对AD和轻度认知障碍(MCI)患者进行检查；2)检查视网膜炎症和变性，以及 评估MCI和AD患者与脑病理和认知状态的可能相关性，以及3) 无创性监测AD活体模型小鼠视网膜Aβ沉积的形成、出现和清除 在疾病进展期间和对免疫治疗的反应中。这些研究的结果很明显 加深对阿尔茨海默病如何影响视网膜的了解，以及视网膜淀粉样蛋白成像是否能可靠地提示 脑部病理或认知状态。考虑到视网膜可获得直接和非侵入性的高分辨率 以此组织为靶点的成像可能为识别新的生物标志物和筛查提供了一种宝贵的方法 促进AD风险的预测、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.