Alzheimer’s Disease in the Retina: Imaging Retinal Aβ Plaques for Early Diagnosis and Therapy Assessment

Abstract

Background: Definite Alzheimer’s disease (AD) diagnosis at early stages is vital for targeting intervention, yet currently unavailable. Noninvasive detection of the pathological hallmark, amyloid-β protein (Aβ) plaques, is limited in the brain. However, the existence of Aβ plaques in the retina, possibly at presymptomatic stages, may improve early detection of AD. Objective: To summarize clinical and preclinical evidence showing that the retina, an accessible part of the central nervous system, displays abnormalities in AD, especially Aβ plaque pathology. The ability to monitor in vivo retinal plaque dynamics in response to immunotherapy is also assessed. Methods: Literature analysis of retinal AD pathology and imaging is provided. In our studies, systemic curcumin is administered to enable monitoring of retinal Aβ plaques in live APP_SWE/PS1_Δ_E9 transgenic mice by optical imaging. Results: Visual and retinal abnormalities, including early manifestation of retinal Aβ plaque pathology, have been documented in AD patients and animal models. In mouse models, retinal Aβ plaques accumulate with age and decrease in response to immunotherapy, consistent with brain pathology. Here, we demonstrate that retinal plaques can be individually monitored in real time following glatiramer acetate immunization. Conclusion: Translation of noninvasive retinal-plaque imaging to humans could eventually facilitate early and accurate AD diagnosis and therapy assessment.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

“…In line with the above findings, numerous studies examining the retinas of sporadic and transgenic animal models of AD have reported Aβ deposits, vascular Aβ, pTau, and paired helical filament-tau (PHF-tau), often in association with RGC degeneration, local inflammation (i.e., microglial activation), and impairments of retinal structure and function (11,39,40,42,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57).…”

“…These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57). Furthermore, several publications, including ours, have reported a positive response to therapy in reducing retinal Aβ plaque burden in transgenic (ADtg) murine models, often reflecting the reaction observed in the respective brains (40,48,51,52,56,60). To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51).…”

“…Furthermore, several publications, including ours, have reported a positive response to therapy in reducing retinal Aβ plaque burden in transgenic (ADtg) murine models, often reflecting the reaction observed in the respective brains (40,48,51,52,56,60). To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51). Curcumin is a natural and safe phytopolylphenol fluorochrome that binds to Aβ fibrils and oligomers with high affinity and specificity (62)(63)(64)(65)(66)(67)(68).…”

Macular Thickness as a Potential Biomarker of Mild Alzheimer's Disease

“…Notably, psychophysical exploration of the parvocellular pathway are affected in AD. 4,5 Our data showed values for the macular RNFL thickness and total macular volume measured by OCT to have highly significant sensitivity and specificity for differentiating mild AD patients from healthy subjects. The most sensitive area was the superior inner macula, followed by the temporal inner macula, with ROCs values of 85% and 80%, respectively.…”

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…These factors might also help to explain why Aβ aggregates are mainly deposited in the brain and cerebral vessel walls, and only rarely in peripheral organs (although detection of Aβ aggregates has been claimed in skin, subcutaneous tissue, intestinal tissues, and heart) [13][14][15] . The aggregation (oligomerization and fibrillogenesis) of Aβ peptides is determined by the relative proportions of Aβ species, their concentrations, the pH, temperature and ionic strength of solution, and incubation time 16 .…”