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; First 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

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 8

Increased retinal amyloid index in AD patients — a proof-of-concept human trial.

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Increased retinal amyloid index in AD patients — a proof-of-concept huma...
(A–D) Representative automated image-processing sequence after repeated fundus image acquisition at day 0 (Baseline) and day 2, showing retinal superior temporal region in an AD patient. (A) Collection of Z-stack scanning laser ophthalmoscope (SLO) fundus images. Each, at baseline and on day 2, underwent illumination correction, alignment of baseline to day 2, and contrast enhancement. (B) Pseudocolor image for visualization. (C and D) Multistep automated postacquisition image processing. (E–G) Threshold defining increased curcumin fluorescent signal in left eye superior hemisphere (LS) and calculation of retinal amyloid index (RAI) scores in a mild AD patient and age-matched CTRL. (E) Blue lines are 1:1 reference, and green lines represent the threshold level, determined at 500 counts and above (red spots are above the threshold). (F) Color-coded spot overlay images. Red spots are above threshold and considered curcumin-positive amyloid deposits, green spots exceed 1:1 reference but not threshold, and blue spots fall below reference. (G) Heatmap images with red spot centroids (left). Day 2 combined overlay images show heatmaps with regions of interest (right). The same automated image processing and analysis was applied on all human subjects. (H) Significant Pearson’s r correlation between RAI scores and retinal spot number in all data set (n = 16 living subjects, see Supplemental Table 2). (I) RAI scores in comparison between AD patients (n = 10) and non-age-matched CTRLs (n = 6) (left) and a comparison of RAI scores in an age-matched subgroup of AD patients (n = 6) and CTRLs (n = 5, see Table 1) (right). Group mean and SEM are shown. **P < 0.005, ***P < 0.0005, unpaired 2-tailed Student’s t test. (J) Pearson’s r correlation analysis of RAI scores and age. (K) RAI and MMSE cognitive scores in AD patient group. Scale bar: 800 μm (A–D); 400 μm (F and G).