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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 1

Schematic diagram of donor eye dissection, retinal isolation, and tissue processing for histological analysis.

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Schematic diagram of donor eye dissection, retinal isolation, and tissue...
(A) Anterior chamber extraction from human donor eyeballs, isolation of whole retinas, and vitreous body removal (n = 37 AD patients and controls, Supplemental Table 1). (B) Preparation of retinal flat mounts and sectioning into 12 geometric regions. (C) Representative segmentation and imaging of regional flat mount stained for Aβ (top right). Region dissection of Aβ-positive areas and preparation of horizontal (en face) and vertical (cross) sections for transmission electron microscopy (TEM) analysis (top left). Microscopic image shows a vertical TEM image with ultrastructure of retinal Aβ plaque in a confirmed AD patient (bottom left). Illustration of paraffin-embedded retinal cross section prepared from Aβ-immunoreactive areas, showing cellular layers (bottom right). P. Pole, posterior pole; O.D., optic disc; M, macula; F, fovea.

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