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 6

Development of a noninvasive retinal amyloid imaging method using curcumin labeling in live human patients.

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Development of a noninvasive retinal amyloid imaging method using curcum...
(A) Curcumin regimen and retinal imaging protocols in living human subjects (n = 16 AD and CTRLs and n = 2 AMD patients). Oral Longvida curcumin administration for 2 or 10 days. Subjects’ retinas were imaged with modified ophthalmoscopes prior to (day 0, baseline image) and after curcumin intake, per the regimen. (B) Repeated regional fundus imaging in a mild AD patient receiving curcumin for 10 days. Increase of curcumin fluorescent intensity due to retinal amyloid deposits (white spots) is observed from baseline (day 0) through days 1–10. Decreased curcumin signal is observed at day 29 (washout). (C) Spot line profile analysis of curcumin fluorescence from an individual plaque (marked in B by red arrows), showing increased signal at days 1 and 10 versus baseline levels. At day 29, fluorescent signal decays to baseline levels (washout). Representative spot line profile from n = 3 patients. (D) Representative retinal fundus images from a moderate AD patient (top) and their pseudocolor images (bottom); arrowheads mark individual plaques, and circles demarcate a cluster of deposits. Increased spot number and area from baseline image to day 2 and 10 images were quantified by ImageJ analysis (bottom). (B–D) Representative images from all human subjects (n = 16; Supplemental Table 2). (E) Longvida curcumin pharmacokinetic (PK) analyses in living healthy controls receiving curcumin for 10 days (n = 6 subjects; all or a subset analyzed for each time point, as shown). Tissue curcumin levels in red blood cells (RBCs) and free curcumin in plasma peaked at day 10 (P < 0.0001). Group mean and SEM are shown. *P < 0.05, ****P < 0.0001 for comparison between day 0 and days 3, 10, or 30, by 1-way ANOVA and Tukey’s post test. Logarithmic transformation analysis of covariance (subject × day) demonstrated that curcumin levels increased with duration of treatment in RBCs (R2 = 0.654; day: P = 0.001; subject: P = 0.024) and plasma (R2 = 0.559; day: P = 0.003; subject: P = 0.09). (F) A quantitative longitudinal retinal curcumin imaging in a representative healthy control and mild AD patient, both receiving 2-day curcumin regimen. Exponential decay of integrated fluorescent intensity occurred after day 2. Decay rate = 10.4% per day, half-life = 6.3 days, offset IFI = 21.5. Scale bar: 200 μm.