Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease
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
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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Clinical Research and Public Health 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 3

Congo red–positive amyloid fibrils and Gallyas silver–stained neuritic-like plaques found in retinas of AD patients.

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Congo red–positive amyloid fibrils and Gallyas silver–stained neuritic-l...
(A) Amyloid deposits stained with Congo red detected in flat-mount retinas of AD patients (top left, n = 3). Birefringence (apple-green) of Congo red–stained retinas under polarized light indicates presence of amyloid fibrils (bottom left). Scale bar: 25 μm. Congo red–positive amyloid plaques in AD patient retinas (right). Scale bar: 100 μm. Two intersecting blood vessels surrounded (along blood vessels and perivascular) by extensive Congo red–positive staining; matched control retina was negative (data not shown). Background blue counterstain is Toluidine blue. (B–E) Gallyas silver stain in Paraffin-embedded retinal cross sections from AD patients (n = 12) and matched CTRLs (n = 8). Scale bar: 20 μm, unless indicated otherwise. (B) Age-matched controls exhibited intact retinal tissue that lacked major protein aggregates. (C) AD-associated neuropathologies in the retina (red arrowheads), notably observed in the ganglion cell layer (GCL). A compact plaque near a blood vessel (bv; left). A classic Aβ plaque and compact deposits (middle); a higher-magnification image is shown in the inset. Neuritic components of senile plaques in GCL (right); a higher-magnification image is shown below (scale bar: 10 μm). (D) Retinal deposits in GCL near and surrounding a blood vessel. (E) Intracellular/soma-positive silver stain aggregates and nuclear-dominant silver stain (red arrowheads) are observed in GCL and INL (scale bar: 5 μm).