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.
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
Submitter: Umur Kayabasi | email@example.com
Authors: Umur Kayabasi
Uskudar University/ Istanbul
Published August 31, 2017
I read with great interest the article written by my colleague and friend Yosef Koronyo, PhD and his team. A couple years ago, I had the chance and pleasure to discuss with him their great work and findings.
Screening amyloid beta (AB) in the retina is definitely a major breakthrough in Alzheimer’s disease (AD). Comparing retinal amyloid burden with brain amyloid is even going one step further in the trials for the early diagnosing of AD . Imaging the retina is easy, non-invasive, cheap and does not involve radiation.
But, there are two important questions that come to mind when considering the recent developments in AD studies:
1. Mayo Clinic study of thousands of brains revealed Tau as driver of AD (1) . So, do we need to show Tau protein along with AB in the retina to be able to make correct assumptions about the disease process ?
2. Postmortem studies have demonstrated that people with AD have far more AB plaques in their brains than healthy people. But, roughly 30% of people without any signs of dementia have brains “chock-full” of AB at autopsy (2). So, the presence of AB may not be enough to prove that any patient will develop the disease in the future.
Increased deposition of AB isoforms have been described on photoreceptor outer segments and along the RPE–Bruch's membrane interface in the aging human and mouse retina (3). Another study using immunostaining revealed AB on photoreceptor outer segments all through the retina in humans as an aging process (4). This deposition process may very well be only a sign of aging and not related to AD.
Analyses of drusen components have shown deposition of AB within vesicles in eyes of age related macular degeneration (AMD) patients . We also managed to show AB in drusen of AMD patients (5).
A better approach may be to demonstrate and quantify both proteins in the retina (6,7). We have been able to image Tau aggregates in the retina of live patients.
Tau deposits have been found in the temporal lobe early in the disease, which proves that Tau PET imaging is also necessary to be able to correlate the abnormal protein burden with brain plaques (3).
Recent studies confirmed that combination of Tau and AB aggregates caused the disease. Another proof of this theory is the unsuccessful results of AB aimed therapies in AD. We believe more collaborative work is necessary for the definite answers to the remaining questions.
1. Murray M, et al. Study of Thousands of Brains Reveals Tau as Driver of Alzheimer’s Disease. Mayo Clinic Alumni Association, 2015.
2. Jones DT, et al. Cascading network failure across the Alzheimer’s disease spectrum. Brain. 2016 Feb; 139(2): 547–562.
3. Shah TM, et al. Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer's disease. Mol Psychiatry. 2017 Mar;22(3):353-363.
4. Kam JH,et al. Viewing Ageing Eyes: Diverse Sites of Amyloid Beta Accumulation in the Ageing Mouse Retina and the Up-Regulation of Macrophages. PLoS One. 2010; 5(10): e13127.
5. Kayabasi U, Sahbaz I. Beta Amyloid in Age- Related Macular Degeneration Lesions in a Patient with Alzheimer’s Disease. EC Ophthalmology 7.1 (2017): 18-21.
6. Kayabasi U. Tau in the Retina. EC Neurology 3.5 (2016): 493-499.
7. Kayabasi U. Retinal Examination by OCT to Reveal Neurodegeneration in the Brain. EC Ophthalmology 6.5 (2017): 139- 140.