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Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease
Yosef Koronyo, … , Keith L. Black, Maya Koronyo-Hamaoui
Yosef Koronyo, … , Keith L. Black, Maya Koronyo-Hamaoui
Published August 17, 2017
Citation Information: JCI Insight. 2017;2(16):e93621. https://doi.org/10.1172/jci.insight.93621.
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Clinical Medicine Neuroscience Ophthalmology

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

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Abstract

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.

Authors

Yosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, Maya Koronyo-Hamaoui

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Figure 5

Ultrastructures of Aβ deposits in human AD retina.

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Ultrastructures of Aβ deposits in human AD retina.
Transmission electron...
Transmission electron microscopy (TEM) analyses of vertical (cross; A–C) and en face (horizontal; D) retinal sections from definite AD patients (n = 3; experiments repeated 3 times). Retinas were prestained with anti-Aβ42 mAb (12F4) and a high-sensitivity immunoperoxidase-based system and DAB substrate chromogen. (A) TEM image showing ultrastructure of Aβ plaque (pl), fibrils (fib), and protofibrils (pfib) near a blood vessel (bv) in vertical sections. Scale bar: 1 μm. Higher-magnification image (right), indicating presence of 10- to 150-nm-wide Aβ fibrils as well as protofibrils and Aβ deposits (abd; scale bar: 50 nm). (B) Fibrillar Aβ ultrastructure surrounded by multiple Aβ deposits. Scale bar: 200 nm. (C) Aβ plaque-like structure, marked by an asterisk and bordering red line, in close proximity to basement membrane (bm) of a blood vessel (scale bar: 0.5 μm). Higher-magnification image showing Aβ plaque-like area, with structures resembling paranuclei containing annular oligomers (arrowhead; scale bar: 40nm). (D) TEM images of en face sections demonstrating retinal Aβ plaque ultrastructures, with radial fibrillar arms emanating from a central dense core found in the innermost retinal layers. Darker black signal represents condensed Aβ aggregate core. Scale bar: 0.5 μm.

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