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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 4

Aβ deposits associated with neuronal loss are detected in the retinas of AD patients.

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Aβ deposits associated with neuronal loss are detected in the retinas of...
(A and B) Paraffin-embedded retinal cross sections from superior quadrants of AD patients (n = 12) and matched CTRLs (n = 8) stained with anti-Aβ42 mAbs (12F4) and peroxidase-based labeling (brown). Hematoxylin counter stain for nuclei (violet). (A) Retinas of controls were clear of Aβ immunoreactivity. (B) Retinas of AD patients contained a multitude of Aβ deposits (arrowheads), especially in the ganglion cell layer (GCL). Marked loss of retinal cells apparent in the GCL, inner nuclear layer (INL), and outer nuclear layer (ONL); areas of nuclei loss are indicated by asterisks. Scale bar: 20 μm. Higher-magnification images are shown. Intracellular cytoplasmic Aβ (top; arrow). Aβ deposits near and inside blood vessel walls (middle; bv; arrowheads); these vascular and perivascular deposits are frequent in GCL. Scale bar: 10 μm. A compact multicore Aβ deposit found in GCL (bottom; scale bar: 5 μm). (C) Nissl staining of retinal cross sections from a definite AD patient and matched CTRLs (n = 17 subjects; experiment repeated 3 times). Altered Nissl neuronal staining is observed in AD patients; changes in cytoplasmic staining patterns (chromatolysis) that could associate with neuronal loss are observed in retinal GCL, INL, and ONL. Scale bar: 20 μm. (D) Quantitative Nissl neuronal count and total area in a subset of AD patients (n = 9) and age- and sex-matched CTRLs (n = 8). Percentage change compared with CTRLs is in red. Group mean and SEM are shown. *P < 0.05, **P < 0.01, unpaired 2-tailed Student’s t test. (E–G) Representative images from n = 8 AD patients and n = 8 matched CTRLs; fluorescent images from AD patient retinas showing curcumin-positive Aβ deposits colocalized with various anti-Aβ mAbs (4G8, 6E10, 12F4), recognizing diverse N′- and C′-terminus epitopes within the Aβ sequence (arrowheads). (E) Aβ deposits detected in the ONL, above the outer limiting membrane (OLM), and in the GCL near and inside blood vessel walls (left, arrowheads; scale bar: 20 μm). Colocalization of curcumin and 4G8 in a retinal Aβ plaque near DAPI nuclear staining demonstrates each unique staining pattern (right; scale bar: 5 μm). (F) Intracellular/somatic Aβ immunoreactivity (arrow) and colocalization of 6E10 with curcumin (arrowheads; left; scale bar: 10 μm). Compact multicore Aβ deposits (right; scale bar: 5 μm. (G) Curcumin-positive Aβ deposits colocalized with the anti-Aβ mAbs (12F4) in the GCL/IPL (arrowheads). Scale bar: 10 μm.

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