Retinal Imaging Device May Offer Insight Into Alzheimer's

Pauline Anderson

August 30, 2017

UPDATED September 7, 2017 // A noninvasive retinal imaging device that detects changes in the eye that are indicative of brain amyloid may provide new insight into Alzheimer's disease (AD), new research shows.

The proof-of-concept study showed that the mean retinal amyloid index score was elevated compared with that of healthy control persons. Other evidence showed that amyloid beta (Aβ) deposits were distributed in a particular pattern in the retinas of AD patients.

The study was published online August 17 in JCI Insight.

Surrogate Biomarker?

Although accumulation of neurotoxic Aβ protein can be detected with positron-emission tomography (PET) or by analysis of cerebrospinal fluid (CSF), these approaches are invasive, inconvenient, and costly and thus are impractical for routine screening and follow-up evaluation.

The new technology, developed by investigators at Cedars-Sinai Medical Center in Los Angeles, California, and NeuroVision Imaging LLC, addresses these limitations.

"Findings from this study strongly suggest that retinal imaging can serve as a surrogate biomarker to investigate and monitor Alzheimer's disease," study investigator Maya Koronyo-Hamaoui, PhD, said in a press release.

"Alzheimer's disease risk doesn't have to be a mystery prior to clinical symptoms, and elucidating that risk doesn't need to be expensive, invasive, or time consuming," Dr Koronyo-Hamaoui told Medscape Medical News. "We hope that this device will allow patients and doctors to learn information about AD risk on the molecular level in a matter of minutes."

The experimental technology involves autofluorescence scanning of the retina using a specialized ophthalmic camera and sophisticated image processing software. The technology was unveiled at the Alzheimer's Association International Conference in 2014.

Dr Koronyo-Hamaoui described the "pioneer" discovery by her research team of Aβ protein deposits in the postmortem retina of AD patients and in cases of probable and possible AD. The findings of the original discovery, published in June 2010, were corroborated in follow-up studies that also showed increased Aβ peptides and the appearance of these plaques in the postmortem retina of AD patients.

In another major study published last year, Dr Koronyo-Hamaoui's team and others showed that together with accumulation of Aβ in the postmortem retina of AD patients, there is a degeneration of specific cells in the retina that might be crucial for circadian rhythms. "This may provide a retinal-based explanation for sleep disturbances in AD patients," said Dr Koronyo-Hamaoui.

The new study included 10 AD patients and six healthy control participants. The researchers sought to demonstrate the feasibility of identifying Aβ in the eye using autofluorescence imaging.

As a contrast medium, investigators used curcumin, the main ingredient in the spice turmeric. Curcumin has several properties that make it a good contrast agent. It binds with high affinity to Aβ, has fluorescent properties that enable amyloid plaques to be imaged in the retina, and is safe.

The researchers also report on AD pathology in the retina from a study involving donated eyes and brains of 37 deceased patients, 23 with confirmed AD and 14 control individuals.

Among key findings, the researchers report a 4.7-fold increase in retinal plaque burden in AD patients compared to control persons. In addition, they provide observations regarding geometric distribution and layer location of amyloid pathology in the retina.

The research provides other new insights into the disease's manifestations in the retina and information on the optical imaging system. Research highlights include the following:

  • The first histologic quantitative analysis of retinal plaque clusters, or "hot spots," containing the most toxic forms of Aβ with specific distribution patterns in superior peripheral regions that were previously unexplored

  • A detailed analysis of Aβ deposit types using electron microscopy

  • The first report of certain Alzheimer's-related pathologies in the retina, including vascular amyloid pathology

  • The demonstration of a significant correlation between retinal and brain plaques, and coexistence of neuronal loss

  • The first feasibility study for noninvasively detecting presumed amyloid deposits in retinas of living patients

  • The demonstration of a fully automated calculation quantifying retinal autofluorescence that showed a 2.1-fold increase in patients with Alzheimer's, compared with control persons

Most of the amyloid in the eye is in the retina. Unlike the rest of the eye, the retina is a central nervous system (CNS) tissue, explained Dr Koronyo-Hamaoui. "Therefore, beta-amyloid deposits associated with Alzheimer's disease ― a disease affecting the CNS ― affects the retina."

It's not yet known whether some patients have amyloid in the eyes but not in the brain, and vice versa, said Dr Koronyo-Hamaoui.

As a developmental outgrowth of the central nervous system that shares many of the brain's characteristics, the retina may offer a "unique opportunity" to easily and conveniently detect and monitor Alzheimer's disease, Keith L. Black, MD, chairman of NeuroVision, chair of the Department of Neurosurgery, and director of the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai, said in a release.

"We know that Alzheimer's begins as many as 10 or 20 years before cognitive decline becomes evident, and we believe that potential treatments may be more effective if they can be started early in the process. Therefore, screening and early detection may be crucial to our efforts to turn the tide against the growing threat of this devastating disease."

But what good is detecting amyloid ― in the eye or the brain ― if the disease cannot be reversed? "There is currently a large body of research developing therapies for Alzheimer's disease," said Dr Koronyo-Hamaoui. "Our hope is that by informing patients of their disease risk, lifestyle changes and eventually therapies will prevent or alleviate the disease."

Cautious Optimism

Commenting on the findings for Medscape Medical News, David Knopman, MD, a neurologist at the Mayo Clinic, Rochester, Minnesota, who is involved in research in late-life cognitive disorders, including dementia, expressed cautious optimistic.

"The Koronyo report offers some exciting but tentative evidence that visualization of amyloid in the eyes of living persons might be predictive of levels of brain amyloid. The authors show pathologically that they can visualize beta amyloid in the retina," said Dr Knopman.

The article, he added, also provides "very preliminary evidence" for visualizing Aβ in living people using the authors' proprietary curcumin.

"The ocular pathology was carefully described and is very convincing, and the living human data on the ocular imaging is also excellent."

However, Dr Knopman stressed that these comparisons are "a long way" from being clinically useful.

He pointed out that in the pathologic demonstration, the authors show differences between normal individuals who are known to be free of evidence of AD and those who died with AD.

"In the case of the antemortem comparisons of controls and persons with clinically diagnosed AD dementia, there were too few subjects, poor age-matching, and inadequate characterization of the AD dementia patients."

Conclusions from such sources cannot be extrapolated to the clinical setting, in which some elderly normal individuals are known to harbor excess Aβ, said Dr Knopman. "In fact, about 30% of cognitively normal people over age 70 have elevated beta amyloid by PET imaging."

The weaknesses of a proof-of-concept demonstration such as the current report "are understandable," and the demonstrations form "a strong rationale" for conducting a fully powered clinical trial, said Dr Knopman.

If ocular imaging could be proved through rigorous clinical testing to correlate well with brain beta-amyloidosis, and if it is less expensive and less burdensome to perform than PET imaging or CSF examinations, "there is genuine value for this technique."

However, Dr Knopman added, "Ultimately, it is likely to be at best a screening tool for elevated brain beta-amyloid, and like beta-amyloid PET or CSF assays of beta-amyloid, it will not correlate with disease severity, and there will be a large overlap with cognitively normal people."

He reiterated that elevations in levels of brain Aβ is not synonymous with AD. "Elevated brain beta-amyloid is necessary but not sufficient to make a diagnosis of Alzheimer's."

Funding for the study was provided by the National Institutes of Health/National Institute on Aging, the Saban Family Foundation, and the Marciano Family Foundation. Dr Koronyo is a scientist and inventor at NeuroVision. Dr Koronyo-Hamaoui is cofounder, inventor, and scientist at NeuroVision. Dr Knopman has disclosed no relevant financial relationships.

JCI Insight. Published online August 17, 2017. Full text

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