Eyes may hold the answer for early Alzheimer’s detection, treatment method

Presently, diagnosis of Alzheimer’s disease begins with symptoms patients exhibit, namely memory loss. Unfortunately, by the time patients become symptomatic, the disease has already progressed to its later stages. Like age-related macular degeneration, treating Alzheimer’s disease at such an advanced stage is difficult, if not altogether impossible. However, recent advances in Alzheimer’s research have yielded the potential for a method of detecting the disease in its developmental stages, possibly decades before patients become symptomatic.

What is now generally agreed upon by neurologists as being a biomarker of Alzheimer’s disease (AD) is the presence of amyloid beta protein deposits in the brain. Moreover, amyloid also accumulates in the eye, and it has been theorized that if a correlation can be made between the amyloid in the eye and the amyloid in the brain, it would be possible to diagnose AD by looking into the eye.

Retinal Amyloid Index

Acting on this theory, two companies, Cognoptix and NeuroVision, have been developing simple tests to detect amyloid beta plaques in the eye. The Retinal Amyloid Index (NeuroVision), a working title for the test, utilizes a device that looks and functions similarly to a conventional retinal imaging scanner and a curcumin compound, administered orally to the patient, to detect amyloid plaques in the retina, according to Keith L. Black, MD, chairman and professor of the Department of Neurosurgery at Cedars-Sinai Medical Center in Los Angeles, Calif., and co-founder of NeuroVision.

Curcumin, the active ingredient in turmeric, or curry, crosses the blood-brain and blood-retina barrier and binds with high affinity to amyloid beta plaque — particularly amyloid beta 42, which is the most toxic. Curcumin is also a fluorochrome and naturally generates a fluorescent signal, so once bound to the amyloid plaques, the fluorescing curcumin signals are then captured by the retinal imaging device, Black explained during a Google “Solve for X” presentation.

“An increase in fluorescence that we can detect with the retinal imager is directly proportional to the amount of amyloid protein in the back of the eye, which correlates with the amount of amyloid protein in the brain,” Black said in an interview.

Through digital processing of the increased fluorescence and the application of quantitative algorithms, Black and his colleagues have developed a way to heat-map the data and refine it into a quantitative value, a Retinal Amyloid Index number, he said during the online presentation.

The hallmark of AD, according to Black, is the accumulation of amyloid beta proteins in the brain, which may begin about 20 years before a person develops memory loss symptoms.

“Most people, if they’re going to get AD, start developing the pathology hallmarks, such as amyloid deposits, in their 50s,” he said. “It’s the first thing that changes.

“The whole key for having an effective treatment for AD is early detection. You want to prevent those brain cells from being killed or dying in the first place. This test allows us to detect the onset of AD years, maybe even decades, before one develops memory loss. That gives us a much better probability of having an effective treatment for it,” he said.

Black said this test has the potential to be included as part of a routine eye exam for all patients older than 50.

“A PET scan is about a $5,000 test and radioactive,” he said. “With the Retinal Amyloid Index, we’re looking at a $500 test that performs at the micron level of resolution, instead of the millimeter-level performance with a PET scan. It is more sensitive than PET, less costly, noninvasive and safe.”

As far as clinical applications, Black sees two opportunities for the Retinal Amyloid Index. One is early detection, or screening, and the other is clarity of AD diagnosis.

“We think this should be incorporated as a screening test to determine risk, very much like a PSA test for prostate cancer or a mammogram for breast cancer,” he said. “This is the best use. If we can see that they’re starting to accumulate these toxic proteins that can harm or kill brain cells, then we actually have a shot at therapeutic intervention.”

Current AD treatments fail because they are used during the end stage of the disease, according to Black.

“We’re much more likely to develop a therapeutic solution if we can start early,” he said. “This test opens up an exciting new area, where we might see a shift from neurologists being on the front lines of diagnosing AD to now potentially eye care practitioners being the early front-line physicians screening for AD.”

Sapphire II

Cognoptix’s test, the Sapphire II, is based on detecting amyloid plaques in the crystalline lens using a fluorescent ligand marker applied topically in an ointment, according to Paul Hartung, president and chief executive officer of Cognoptix.

“The Cognoptix aftobetin fluorescent ointment is applied at home to the inner eyelid of one eye the evening before the procedure; any blurring dissipates within about 10 minutes,” he said.

The ointment requires three applications, 2 hours apart, according to Carl Sadowsky, MD, medical director of the Premiere Research Institute at Palm Beach Neurology in West Palm Beach, Fla., and clinical professor of neurology at Nova Southeastern University.

“The next day, the patient is seated at the Sapphire II, a desktop unit about the size of a PC, and positioned in a typical ophthalmic chin rest and asked to fixate on a colored spot,” Hartung said.

The operator then aligns to the patient using a joystick with the aid of stereo images, he said.

Sadowsky said the ointment is stimulated with a low-level laser, which causes it to fluoresce.

Fluorescence measurements are automatically taken in the lens, Hartung said, and the instrument produces a numerical score associated with the level of amyloid detected.

“It emits photons, which we capture with the Sapphire II system, and the amount of photons captured is a direct correlation with the amount of amyloid in the lens of the eye,” Sadowsky said.

“A scan of the lens takes less than a second,” Hartung said, “and the entire procedure takes only a few minutes from alignment to completion.”

“It’s much like amyloid imaging in the brain with an amyloid PET scan,” Sadowsky said. “We measure pathology; it’s not diagnostic of AD. It’s an adjunct that you add to your clinical consideration. So if a patient has amyloid in the brain, and they have clinical symptoms of AD, it makes us more confident of the diagnosis.”

According to a Cognoptix press release, Sapphire II identified Alzheimer’s disease patients via the beta amyloid signature in their eyes in a 10-subject proof-of-concept clinical trial, achieving a 200% differentiation factor between a group of five healthy volunteers and a group of five patients diagnosed with probable Alzheimer’s disease.

Sapphire II is currently in phase 1/2 clinical feasibility trials, according to Sadowsky. A pivotal phase 3 study is expected to begin in 2014.

Tests’ potential

“Ocular exams through the years have attempted to diagnose Alzheimer’s at an early age,” Michael Tolentino, MD, director of research at the Center for Retina and Macular Diseases in Winter Haven, Fla., said. “We have looked at optic nerve cupping, pupillary response to tropicamide dilation and ocular muscle movement. While all have been investigated, all have failed to withstand the test of time in terms of sensitivity and specificity, and all were subjective in nature.

“Cognoptix and NeuroVision are trying to objectify the diagnosis,” he said.

According to a Cognoptix press release, there are nearly 100 new Alzheimer’s drugs in various stages of development. The ability of a test like the Sapphire II, or the Retinal Amyloid Index, to easily identify and qualify patients for clinical study inclusion, as well as accurately and inexpensively track disease progression, may give pharmaceutical companies the foundation necessary to identify and document differentiating pharmaceutical product performance attributes in phase 4 studies.

“The next step,” according to Imre Lengyel, PhD, of the University College London Institute of Ophthalmology, “once they find a reliable way to monitor the progression or the appearance of AD very early on, is to see whether any of the drugs have any effect on progression. Since it’s measurable in the eye — if it turns out to be confirmed that it is — they’ll have a means of marking clinical effectiveness in a reliable way.”

Questions

While NeuroVision’s and Cognoptix’s tests, and their ability to detect amyloid beta plaque in the eye, are promising, they are not yet confirmed as accurate, effective and specific.

“Clearly, the specificity of amyloid beta deposition is a very big question because there has been plenty of amyloid beta found in normal patients; it’s not specific for AD patients,” Lengyel said in an interview.

Also, specifically with the Retinal Amyloid Index, curcumin may not only bind with amyloid beta, according to Lengyel.

“It certainly binds to amyloid beta, but it can bind to other molecules, as well,” he said. Therefore, results of a test predicated on using this method could be muddled, he said.

According to Tolentino, the AD process appears to be related to the deposition of amyloid beta, the appearance of which is followed by an inflammatory tangling of neuronal and inflammatory cells, neurofibrillary tangles (NFT). However, there is still much uncertainty associated with the role of amyloid beta in AD.

“The eye is the window to the brain and, as such, if amyloid is found in the eye, then likely it is going to be found in the brain; however, it is unclear whether amyloid beta is an end result of an underlying process leading to the formation of NFTs or if amyloid beta is causative of NFTs,” Tolentino said.

Health care burden

No one misunderstands the importance of being able to treat AD. From a financial perspective, with an increasing number of older Americans reaching Alzheimer’s age, and with the medical community unable to effectively treat the disease, an enormous strain is being exerted on the U.S. health care system — what Black has called a “health care tsunami.”

According to Black, about one in eight individuals aged older than 65 currently living in America has AD, and in 2012, $200 billion was spent on health care specifically for AD patients.

“If no treatment is developed, Alzheimer’s alone will bankrupt the health care system in a very short period of time,” he said during his online presentation.

“The only thing that we need to do is to slow down the slope of the curve,” he said.

In an average AD patient, cognitive decline begins at age 30, with the disease setting in at 50, and finally the patient starts having memory loss at 70, according to Black.

“Just slowing down this curve so that you get memory loss at 105 could potentially eliminate the clinical phase of the disease for most people in the population,” he said. “A solution like that would not only save trillions of health care dollars, but could potentially give us the ability to live out our senior lives with a higher quality.”

AD and AMD

“There are many molecular-level cellular and genetic correlations between AD and AMD, which suggests that there might be some kind of connection between the two diseases,” Lengyel said.

As such, research is currently being done to investigate the correlations between AD and AMD in several laboratories.

Lengyel’s research focuses on drusen in the back of the eye.

“We started to explore the relationship between extracellular deposit formation in the development and progression of both diseases,” he said. “Specifically, we looked at the formation of drusen, which contains amyloid beta deposits, in the back of the eye. Using ultra widefield imaging (Optomap, Optos), we found that drusen formation at the peripheral retina might aid clinical diagnosis in AD patients.”

Tolentino is involved in a study sponsored by Pfizer that is testing an interventional therapy, an antibody designed to attack amyloid beta, which is found in eyes with AMD as well as AD, he said.

“Attempting to clear amyloid beta from the eyes may slow down the process of AMD in dry AMD patients,” and may have a positive effect on AD patients, as well, Tolentino said.

Retinal venules

Optical coherence tomography has demonstrated retinal nerve fiber layer thinning in patients with AD, correlating to earlier histologic studies, and has shown that these changes tend to occur in the superior quadrant, according to Nyssa Connell, OD, MS, FAAO, who specializes in primary care and low vision at the Advanced Low Vision Clinic of the Veteran’s Affairs Boston Healthcare System.

“Current research involves the use of newer, higher-resolution spectral-domain OCT to detect retinal nerve fiber layer abnormalities and compare them to those that occur with other optic nerve pathologies such as glaucoma,” Connell said. “Because of its ability to provide higher resolution than earlier time-domain OCT, SD-OCT also offers the potential of evaluating changes in specific layers of the retina.

“It may also have the potential to detect early changes over time,” she said, “but this has yet to be shown.”

Connell is currently part of a team using OCT imaging to search for retinal irregularities that could be correlated to AD.

“Based on previous research showing AD patients had thinner retinal venules than age-matched controls, we expected to find thinner retinal venules in people without dementia but with risk factors for AD, including worse performance on certain memory tests. We actually did not find this,” Connell said. “Instead, we showed a strong correlation between retinal arteriolar diameter and some tests of executive function, which is typically affected in early vascular dementia.

“While this was a new finding and one we did not expect, it makes sense in retrospect, because the ophthalmic artery is anatomically close to the blood supply for the parts of the brain responsible for executive function,” she said. – by Daniel R. Morgan

Editor’s note: This article originally appeared in the August 2013 edition of Ocular Surgery News’ sister publication, Primary Care Optometry News.