视网膜淀粉样病变与阿尔茨海默病的概念验证成像试验
Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease.
作者信息
Koronyo Yosef, Biggs David, Barron Ernesto, Boyer David S, Pearlman Joel A, Au William J, Kile Shawn J, Blanco Austin, Fuchs Dieu-Trang, Ashfaq Adeel, Frautschy Sally, Cole Gregory M, Miller Carol A, Hinton David R, Verdooner Steven R, Black Keith L, Koronyo-Hamaoui Maya
机构信息
Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
NeuroVision Imaging LLC, Sacramento, California, USA.
出版信息
JCI Insight. 2017 Aug 17;2(16). doi: 10.1172/jci.insight.93621.
BACKGROUND
Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits.
METHODS
Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients.
RESULTS
Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031).
CONCLUSION
The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.
FUNDING
National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.
背景
以高特异性和敏感性对阿尔茨海默病（AD）进行无创检测，可极大地促进对高危人群的识别，以便进行更早、更有效的干预。AD患者表现出多种视网膜病变，包括标志性的淀粉样β蛋白（Aβ）沉积。
方法
对确诊的AD患者和对照组（n = 37）的视网膜平片和横断面进行分析，以研究视网膜Aβ斑块的负担、分布、细胞层和结构。在一项概念验证性视网膜成像试验（n = 16）中，确定了淀粉样探针姜黄素制剂，并建立了在活体患者中进行视网膜淀粉样成像的方案。
结果
组织学检查发现，与匹配的对照组相比，AD患者存在经典的和神经炎性样Aβ沉积，视网膜Aβ42斑块增加（4.7倍；P = 0.0063），神经元丢失（P = 0.0023）。视网膜Aβ斑块反映了脑病理学特征，尤其是在初级视觉皮层（P = 0.0097至P = 0.0018；Pearson相关系数r = 0.84 - 0.91）。视网膜沉积物常与血管相关，并出现在上象限的热点周边区域和最内层视网膜层。透射电子显微镜显示视网膜Aβ组装成原纤维和纤维。此外，在活体患者中证明了使用固体脂质姜黄素和改良的扫描激光检眼镜对视网膜淀粉样沉积物进行成像的能力。构建了视网膜淀粉样指数（RAI）的全自动计算方法，这是一种对姜黄素荧光增加的定量测量方法。对RAI评分的分析显示，AD患者与对照组相比增加了2.1倍（P = 0.0031）。
结论
AD中视网膜淀粉样病变的几何分布和负担增加，以及在活体患者中无创检测离散视网膜淀粉样沉积物的可行性，可能会带来一种用于大规模AD诊断和监测的实用方法。
资助
美国国立衰老研究所奖（AG044897）以及萨班家族基金会和马尔恰诺家族基金会。
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