Yosef Koronyo1, David Biggs2, Ernesto Barron3, David S Boyer4, Joel A Pearlman5, William J Au6, Shawn J Kile6, Austin Blanco2, Dieu-Trang Fuchs1, Adeel Ashfaq7, Sally Frautschy8, Gregory M Cole8, Carol A Miller9, David R Hinton10, Steven R Verdooner2, Keith L Black1, Maya Koronyo-Hamaoui1,11. 1. Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 2. NeuroVision Imaging LLC, Sacramento, California, USA. 3. Doheny Eye Institute, Los Angeles, California, USA. 4. Retina Vitreous Associates Medical Group, Beverly Hills, California, USA. 5. Retinal Consultants Medical Group, Sacramento, California, USA. 6. Sutter Neuroscience Institute, Sacramento, California, USA. 7. David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 8. Departments of Neurology and Medicine, University of California, Los Angeles, Los Angeles, California, USA; Geriatric Research Education and Clinical Center, Los Angeles, California, USA; and Veterans Greater Los Angeles Healthcare System, Los Angeles, California, USA. 9. Department of Pathology Program in Neuroscience, Keck School of Medicine, and. 10. Departments of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 11. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
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.
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. ADpatients 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 ADpatients 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 ADpatients 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-lipidcurcumin 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 ADpatients 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.
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