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In the Pipeline-Alzheimer's Disease: Retinal Amyloid Imaging Shines a Light on Alzheimer's Disease

Robinson, Richard

doi: 10.1097/01.NT.0000527859.81394.7c
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Researchers found increased deposits of amyloid-beta in the retinas of Alzheimer's disease cases confirmed post-mortem compared with healthy controls. The study provides a proof of concept for using noninvasive retinal imaging to detect Alzheimer's disease pathology.

Amyloid plaques accumulate in the retina and can be detected noninvasively in people with Alzheimer's disease (AD), according to a study in the August 17 issue of the Journal of Clinical Investigation Insight.

The plaques were imaged using curcumin, a substance derived from plants, which is ingested orally and binds tightly to aggregated amyloid-beta (Abeta) protein, the principal component of amyloid plaques. The technique potentially provides a unique window into the brain for diagnosing the disease and tracking response to plaque-lowering therapies, independent experts said.

The new work was led by Maya Koronyo-Hamaoui, PhD, associate professor of neurosurgery and biomedical sciences at Cedars-Sinai Medical Center in Los Angeles. It builds on her previous research, published in 2010, showing for the first time that Abeta plaques could be detected post-mortem in the retinas of AD patients, work that has since been independently replicated in other labs.



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In the new study, she and her colleagues first quantified the distribution and burden of retinal plaques in 23 confirmed AD patients and compared them to tissue from 14 non-AD healthy controls. Retinal tissue was stained with a variety of antibodies and compounds that react to Abeta and examined with light, fluorescent, and electron microscopy.

“We found there is a marked difference between cognitively normal individuals and those with a diagnosis of Alzheimer's disease,” Dr. Koronyo-Hamaoui said. Using a fluorescent antibody, the researchers found that the total area of Abeta-42-containing amyloid plaques was 4.7 times as high in patients as in controls (p=0.0063).

Under the transmission electron microscope, the team saw “fibrils, protofibrils, and even forms that look like oligomers,” she said, which may be more toxic that the plaques themselves. “The plaque ultrastructure we find in the retina is very similar to what we find in the brain,” with a dense central core, but the average size was about 10 percent to 15 percent of that typically seen in the brain.

Plaques were not uniformly scattered across the retina, she noted. Instead, they were concentrated in the peripheral regions of the superior quadrant and to a much lesser extent in the central retina in the temporal quadrant. This distribution correlates with the relative lack of visual acuity impairment in AD patients, versus patients with glaucoma or age-related macular degeneration, in which pathology is more centrally located. The team observed a more than 20 percent loss of neurons in three different retinal layers compared to controls.

Previous research has shown that AD patients do have visual impairments, Dr. Koronyo-Hamaoui noted, affecting color discrimination, motion recognition, and contrast sensitivity. “We believe these may be explained by the retinopathy we find,” she said. In addition, disturbances of the sleep-wake cycle may be linked to degeneration of the light-sensing cells in the retina.





The team also found that the burden of amyloid pathology in the retina and in the brain of the individual patient was tightly correlated. “In a small sample quantitatively analyzed for Abeta burden in the retina and the brain, we find that when a patient has a higher amount in the brain, we see a higher amount in the retina, and vice versa,” Dr. Koronyo-Hamaoui said. The correlation to retinal pathology was strongest for the primary visual cortex, the entorhinal cortex, and the hippocampus, with a weaker correlation for the neocortex.

Finally, the team, together with the company Neurovision, conducted a pilot trial of curcumin as a fluorescent dye to reveal Abeta in 10 living patients, with a mean age of 76 years and six controls with a mean age of 53 years.

Curcumin is extracted from the root of the turmeric plant, a common curry spice. It binds to aggregated Abeta with high affinity and specificity, Dr. Koronyo-Hamaoui said, and has been developed by her team to noninvasively detect retinal Abeta deposits in mouse models of AD.

Patients received either a two- or 10-day course of a modified form of curcumin, and were then imaged with a modified version of a standard ophthalmic instrument. The images obtained were used to calculate a “retinal amyloid index,” derived from a combination of the number, area, intensity, and distribution of fluorescing spots. The procedure took about 20 minutes, and would likely take less time outside the research setting, Dr. Koronyo-Hamaoui said. Curcumin in both blood and retina begins to decline after dosing is stopped, she added.

Curcumin staining clearly revealed amyloid deposits in the retina of AD patients at levels much higher than in controls. Patients had about twice as many spots as controls, and their retinal amyloid index was more than twice as high.

“This is the first time the ability to quantitate Abeta deposits in the retina noninvasively has been demonstrated,” she said. “It's the proof of concept.”

Dr. Koronyo-Hamaoui and several authors of the study are founding members of Neurovision Imaging, which markets retinal imaging technology. Several authors are founding members of Optimized Curcumin Longvida, which markets the modified curcumin used in the study.

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“By far the biggest impact of this work is on early diagnostics,” said Allan Levey, MD, PhD, professor and chairman of the department of neurology at Emory University and director of the Emory Alzheimer's Disease Research Center, in Atlanta, who was not involved in the study. “It may also provide an inexpensive way to tell whether treatments that attack Abeta are reducing accumulation of the protein” [NeuroVision has provided Dr. Levey with payment of travel-related expenses in work unrelated to the current study.]

Jaime Grutzendler, MD, professor of neurology and neuroscience and director of the Center for Experimental Neuroimaging at Yale University, said: “The research team has done what I think is the best job so far in characterizing amyloid in human retina.”

The curcumin imaging looks promising, he said, but he cautioned that autofluorescence increases as the brain ages, raising the question of whether the patients in the study, who were older than controls on average, may have had an elevated level of signal independent of Abeta accumulation.

One potentially important application of retinal imaging, should it be validated in future studies, may be to monitor response to therapy, said Dr. Levey. Positron emission tomography (PET) imaging of brain Abeta currently has challenges tracking small changes, he noted. If the retinal alternative proves to be accurate and sensitive to change, it could provide an important alternative, especially since it could be administered more frequently and with less expense.

Even more importantly, Dr. Grutzendler said, is whether amyloid deposits occur in the retina earlier than they do in the brain. If so, he said, the deposits could potentially be predictive of who will develop Alzheimer's disease.

“Because accumulation of pathology in the brain begins 20 or more years before symptoms begin, the field has been focused on presymptomatic treatment to maximize the chances of success,” Dr. Levey said. “But a major challenge with implementing this approach is the ability to identify those at risk very early.”

“PET imaging with amyloid and tau is very promising, but it isn't feasible for large-scale public health use, so what's urgently needed is a very simple, cheap, reliable way to help us improve our predictive ability for who is going to get Alzheimer's disease during the presymptomatic period. That's the big gap, and that's where the retinal imaging appears to show some promise.”

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•. Koronyo Y, Biggs D, Barron E, et al Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease JCI Insight 2017;2(16). pii: 93621.
    •. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, et al Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model http:// Neuroimage 2011; 54 Suppl 1:S2404–217; Epub 2010 Jun 13.
      © 2017 American Academy of Neurology