Amyloid in the Retina Correlates With Alzheimer's Brain Changes

The eyes may offer a window into the brain when it comes to build-up of amyloid, a key hallmark of Alzheimer's disease (AD).

Elevated amyloid deposits in the proximal mid-periphery (PMP) of the superotemporal retinal region in patients with mild cognitive decline were previously correlated with decreased hippocampal volume.

Additional research suggests retinal beta amyloid (Aβ) deposition correlates with, and may even precede, cerebral Aβ deposition.

Dr Maya Koronyo-Hamaoui

Retinal amyloid screening could be an easy, inexpensive tool to detect the earliest signs of AD, study investigator Maya Koronyo-Hamaoui, PhD, associate professor of neurosurgery and biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California, told Medscape Medical News. "I hope this is a game changer," she added.

The study was published online September 28 in Alzheimer's and Dementia.

Living Patients

Koronyo-Hamaoui's team and others previously found deposits of Aβ in the retinas of mouse models and of patients with AD at autopsy.

The researchers have now developed analytical software and used an iPad-controlled ophthalmic device to examine amyloid in regions of the retina of living patients.

The study included 34 participants — 18 women and 16 men with a mean age of 65 years. Most (97%) were White, with only one Black subject. Subjects were matched for sex and age.

Participants underwent neuropsychiatric evaluation and structural brain MRI. Researchers collected data on total intracranial volume (ICV), hippocampal volume (HV), and inferior lateral ventricle volume (ILVV).

Researchers stratified patients based on Clinical Dementia Rating (CDR) and Montreal Cognitive Assessment (MOCA) scores. MOCA scores of ≤ 26 were considered indicative of cognitive impairment and a score >26 normal cognition. A CDR score of 0.5 indicated questionable dementia, 1 mild cognitive impairment (MCI), and 2 moderate cognitive impairment.

Based on their neuropsychological reports, most participants (n = 22) had amnestic MCI, three had probable AD, one had possible frontotemporal dementia, and eight had normal cognitive scores.

Koronyo-Hamaoui noted that individuals with amnestic MCI are considered to be in the early clinical stage of AD.

All participants received a 4-day supply of curcumin powder, bottles of a liquid nutritional shake with which to mix the powder, and vitamin E capsules 400 IU to enhance bioavailability.

Considered safe by the US Food and Drug Administration (FDA), curcumin has high specificity and affinity for amyloid, especially Aβ 42, and displays natural fluorescence in tissue, said Koronyo-Hamaoui.

Several hours after patients took the last curcumin mixture, researchers used a confocal scanning ophthalmoscope to obtain retinal images using blue light for excitation of curcumin emission.

Direct Connection to the Brain

The retina, which is directly connected to the brain, is the only central nervous system tissue accessible for high-resolution and noninvasive imaging, the investigators note.

The researchers imaged the superior retina in each eye, and processed the high-resolution images using the novel investigational software.

They segmented the region of interest (ROI) into three sub-regions. These included the proximal mid-periphery, the posterior pole (PP), and the distal mid-periphery (DMP).

They quantified retinal amyloid count (RAC), or the number of plaques, and total retinal amyloid area (RA), which indicates the burden or overall load of amyloid, in the target ROI and the three sub-regions.

There is a "tight correlation" between the number of amyloid "spots" and the larger size of these plaques, "especially in cognitively impaired individuals," said Koronyo-Hamaoui.

Results showed RAC significantly and inversely correlated with hippocampal volume (P = .04). Associations were particularly notable in the proximal mid-periphery. The PMP retinal amyloid count and area were significantly greater in patients with MOCA score < 26 (P = .01).

The proximal mid-periphery showed significantly more RAC and area in subjects with amnestic MCI and AD compared with those who were cognitively normal (P = .04).

"We found that the proximal mid-periphery had a very nice correlation that could predict hippocampal loss," said Koronyo-Hamaoui. Among other findings, the study also showed HV and ILVV were significantly different between the three levels of CDR scores.

That proximal mid-periphery RAC in the superotemporal quadrant correlated significantly with hippocampal volume and Clinical Dementia Rating and "supports a possible association between RAC and AD stage," the investigators note.

A Tau Signal?

There were not enough participants to detect statistical differences between retinal amyloid in males and females, "but we know that women have more pathology in general," said Koronyo-Hamaoui.

The researchers were not able to examine the correlation between retinal amyloid with brain amyloid as they didn't have access to positron emission tomography imaging and didn't want to expose patients to an invasive procedure, she noted.

However, another of her studies showed a correlation between Aβ in the retina and the brains of mice.

Researchers believe retinal amyloid affects eyesight, even very early on in AD.

"There are a lot of reports showing functional changes that are related to retinal pathology," which can involve impairment in such things as color vision and contrast sensitivity, said Koronyo-Hamaoui.

Emerging evidence suggests amyloid are in areas of the eye other than the retina, including the lens, she added.

It may also be possible to detect tau tangles, another hallmark sign of AD, in the retina, she said. "We hope that over time, we could develop a tau signal in retina during life."

Koronyo-Hamaoui believes the retina is ideal "as a kind of tool to diagnose and monitor neurodegenerative disease and, so far, appears to mirror very well what's happening in the brain."

Looking ahead, Koronyo-Hamaoui believes that neurologists or ophthalmologists could carry out this simple, noninvasive 10 to 20 minute screening test.

Once a certain predefined retinal amyloid threshold is met, doctors and patients would "keep an eye on" this, much as they might for high triglycerides or blood glucose levels, she said.

This could mean closer follow-up or "additional steps" such as a brain MRI, and lifestyle changes, she said.

Future larger studies should determine the potential of retinal amyloid as a biomarker of early AD, the investigators note.

The Eyes May Have It

Commenting on this research for Medscape Medical News, Heather Snyder, PhD, vice president of medical and scientific operations at the Alzheimer's Association, said it "adds to the growing body of evidence showing Alzheimer's disease brain-related changes may be detected through the eyes."

While the study was carried out in a small population, "it's exciting to see this type of research moving forward in living people," said Snyder.

The next step, she said, is to conduct this research in a much larger population.

Investigating retinal imaging as a screening tool is part of the "global quest" for an easier way to detect and diagnose AD, said Snyder.

Being able to detect abnormal accumulation of amyloid in the eye may allow clinicians to identify the disease at earlier stages, even before symptoms appear, when it may be most treatable and preventable, she said.

A retinal amyloid screening tool promises to be more accessible, less expensive, and less invasive than the current screening methods using PET scans or lumbar punctures, added Snyder.

The Alzheimer's Association, she noted, has been advancing retinal imaging technology for some time. In 2019, it convened a workshop on advancing the technology for clinical trials and diagnostic purposes. Koronyo-Hamaoui's team was part of the organizing committee for that event.

Koronyo-Hamaoui is a cofounding member of NeuroVision Imaging Inc. She is a coinventor of US patents related to retinal imaging and Alzheimer's disease.

Alzheimer's Dement. Published online September 28, 2020. Full text

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