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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 Research and Public Health 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 2

Burden and distribution of Aβ deposits in postmortem retinas of AD patients.

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Burden and distribution of Aβ deposits in postmortem retinas of AD patie...
(A) Representative micrographs from flat-mount retinas of definite AD patients (n = 8) and age- and sex-matched non-AD controls (CTRLs; n = 7) at varying ages, stained with anti-Aβ42 mAb (12F4) and the standard peroxidase technique (plaques visible as dark brown spots). Scale bar: 20 μm. Human donor number, sex (male [M] or female [F]), and age in years (y) are shown (for additional details on donor eyes and brains, see Supplemental Table 1). High-magnification images display diverse morphology of Aβ aggregates, including diffuse, compact, and “classical” mature plaques. Scale bar: 10 μm. (B) AD patients brain sections and their respective retinal flat mounts stained with 12F4 mAb. Retinal plaques are generally smaller but similar in morphology to brain plaques (arrowheads). Retinal Aβ deposits are apparent inside blood vessels (bv), perivascular, and along the vessel walls (purple arrowheads). Scale bar: 20 μm. (C) Correlation analyses using Pearson’s correlation coefficient (r) test between retinal 12F4+-plaque burden and cerebral plaques (Gallyas silver or thioflavin-S staining), including mean plaque burden from 7 brain regions (see Methods), primary visual (PV) cortex (Ctx.) only, and entorhinal Ctx. only, in a subset of AD patients and CTRLs (n = 8). (D) Anti-Aβ antibody and Longvida curcumin (Cur) fluorescent staining of Aβ deposits in cortical and retinal tissues from the same patient subset. Sudan black B (SBB) was applied to quench autofluorescence. Retinal Aβ plaques positive for 6E10 single staining. Colocalization of curcumin and 6E10 in cortical and retinal Aβ plaques, showing patterns unique to each staining method. Scale bar: 10 μm (left retina and brain); 5 μm (right retina). (B and D) Representative paired retinal and brain samples from n = 5 AD patients and n = 2 controls. (E) Distribution of plaques in large retinal regions (n = 16 AD patients and controls), using fluorescent-based (top; scale bar: 5 μm) and peroxidase-based (bottom; scale bar: 20 μm) staining. (F) Qualitative geometric hot spot regions for retinal Aβ deposits found in AD patients (S, superior; T, temporal; I, inferior; N, nasal; cumulative data from multiple experiments). (G) Quantitative 12F4-immunoreactive (IR) area of Aβ42-containing plaques (geometric regions ST1-3) in a subset of definite AD patients (n = 8) and age- and sex-matched controls (n = 7). Group mean and SEM are shown. **P < 0.01, unpaired 2-tailed Student’s t test.

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