Ophthalmologists on the Frontline of Neurologic Diagnosis?

Laird Harrison


July 23, 2018

Someday not too long from now, an ophthalmologist may invite a patient into her office for a ,bit of bad news. "Remember the last time you were here? I said I noticed some changes in your eyes that I wanted to follow. Well, the changes have continued and I think you'd better be evaluated by a neurologist."

What changes? It could be thinning of the retinal fiber layer. Or perhaps it's the deposition of beta-amyloid or alpha-synuclein. It could be various signs of impaired vision or abnormal papillary reaction, tortuosity of blood vessels, or some combination thereof.

In recent years, such ocular findings have increasingly been linked to neurological disorders including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Huntington disease, and frontotemporal dementia.

It's too early yet to say exactly when or to what degree ophthalmologists will be able to catch signs of neurological disorder. But just as the poet considers the eye a window into the soul, increasingly scientists are using the eye as a window into the brain. And since the advent of optical coherence tomography (OCT) and other advanced ocular imaging techniques, researchers are increasingly confident they will lead to earlier diagnosis and treatment.

"It's an exciting area, and a lot is being done," says Eleonora Lad, MD, PhD, an associate professor of ophthalmology at Duke University in Durham, North Carolina.

Why the Retina? 

Cased inside its shell of bone, the brain is difficult to observe, even with magnetic resonance imaging or positron emission tomography.

"It's expensive, inconvenient and takes a lot of time," says Imre Lengyel, PhD, a senior lecturer at Queen's University Belfast, United Kingdom.

But the retina, an embryonic outgrowth of the brain, shares many of its features, including neurons, glial cells, connected vasculature, and a blood barrier. For decades, researchers have theorized that any degeneration of the brain would be reflected there.

Evidence supporting this approach arrived in 1986 when the dissection of the optic nerves of patients who had died of Alzheimer disease showed that the nerves' axons had degenerated, while there were no signs of this deterioration in people of a similar age who didn't have Alzheimer's.[1] Subsequent research into Alzheimer's revealed loss of retinal ganglion cells and thinning of the retinal nerve fiber layer. But this type of damage could be indicative of a wide range of neurological disorders. Only in recent years have researchers begun to distinguish signs in the retina that appear indicative of specific diseases.[2]

Alzheimer Disease

In 2011, Maya Koronyo-Hamaoui, PhD, an associate professor in neurosurgery and biomedical sciences at Cedars-Sinai Medical Center in Los Angeles, California, and her colleagues reported that they could see amyloid plaques, the hallmark of Alzheimer disease, in retinas from Alzheimer's patients by staining the plaques with curcumin. The plaques were not visible in people of the same age who didn't have Alzheimer's.[2]

Koronyo-Hamaoui acknowledges that the presence of plaque doesn't prove someone has Alzheimer disease. "You can find people with brain imaging who have the plaques but they don't have the symptoms," she said. "You don't know if they will develop it or they have other elements that will protect them from the decline."

And the findings remain controversial. Other researchers, using slightly different techniques, have not been able to find amyloid plaques in Alzheimer's patients.[3] One reason for the discrepancy could be differences in where the researchers looked.

"The studies concentrating on the macula were very much inconclusive," says Lengyel. "But when you look at the periphery, which is 80% of the retina, you do find changes taking place."

Using ultra-widefield retinal scanning laser ophthalmoscope, his team found hard drusen in the retinal periphery of 14 out of 55 people with Alzheimer's, compared with only two out of 48 people without the disease.[4]

These extracellular deposits, common in age-related macular degeneration, are similar to amyloid plaques found in Alzheimer disease, he says.

"For decades people have been looking at these deposits and comparing them. Amyloid beta is detectable in these deposits. Processes that are associated with amyloid plaque are present in and around the drusen. It doesn't mean that they are the same but there are many similar mechanisms that are probably part of these depositions."

As researchers study these images in larger numbers of patients over a longer period of time, Lengyel hopes they will not only be able to use them in measuring the progression of Alzheimer disease but also learn something about the causes of the disease.

"Normally drusen should be cleared out of the body and the fact that they are developing indicates there is some sort of metabolic change in the body," he says. This theory fits with the evidence that nutrition and physical activity can reduce the risk for Alzheimer's, he notes.

Findings on retinal nerve fiber thinning, too, have proved confusing, with some studies reporting thickening rather than thinning. One possible explanation is that the effects of the disease produce a changing pattern, Lad says. "It appears that the changes are dynamic: first thickening from gliosis, then thinning," she says. "These changes are parallel to what occurs in the brain."

Parkinson Disease

Researchers looking for signs of Parkinson disease in the retina have found similar changes. While they have reported contradictory results on the thinning of the retina nerve fiber layer, a recent meta-analysis concluded that people with Parkinson's did have thinner circumpapillary nerve fiber layers on average. The changes were most consistently found in the temporal quadrant, with findings in other quadrants appearing to vary with the type of OCT used.[5]

People with Parkinson's often experience visual deficits such as abnormal contrast sensitivity, motion perception, visual acuity, color vision, and visual hallucinations. These changes have been attributed to dopaminergic loss, a key factor in the etiology of Parkinson's. But dopaminergic neurons and their interconnecting plexus are below the ganglion cells, and the processes of dopaminergic amacrine cells do not directly synapse onto ganglion cells. A recent spectral-domain optical coherence topography study showed thinning of the prenerve fiber layer and a thinner, broader foveal pit in Parkinson's patients. The retinal changes appear to progress with the disease.[5]

And other teams of researchers have been able to spot alpha-synuclein in the retinas of people with Parkinson's. Although the function of this protein remains unknown, it is a major constituent of Lewy bodies, the protein clumps that are a hallmark of the disease.[6]



Additional Neurodegenerative Conditions

Huntington Disease

Although the average overall retinal nerve fiber layer did not appear to differ, some researchers have found that the temporal quadrant was significantly thinner in people with Huntington disease than in people without the disease. Thinner central and inferior macular choroidal thickness has also been found in this disease.[6]

Multiple Sclerosis

Not only is the retinal nerve fiber layer thinner on average in patients with multiple sclerosis, but some findings suggest patterns unique to types of the disease. Patients with secondary progressive multiple sclerosis showed thinner retinal nerve fiber layers in the superior and temporal quadrants and diminished macular volume compared with controls. But in patients with primary progressive multiple sclerosis, the difference was only significant in the temporal quadrant.[6]


At least one team of researchers has found a thinner nerve fiber layer in the nasal quadrant of the left eye when compared with healthy control patients. They hypothesized that the central nervous system involvement was asymmetric.[7]

Frontotemporal Dementia

Researchers have also reported a thinner outer retina in patients with frontotemporal dementia. The patients also had a thinner outer nuclear layer than controls, but had similar thicknesses for inner retinal layers. The researchers found a correlation between outer retina thickness and the minimental state examination, a test for cognitive impairment.[8]

Looking to Retinal Screening's Future

Not only more advanced imaging techniques but also machine learning may help make sense of the patterns that are emerging from these studies. "Ideally, someday we will have a software patch that is available with commercial OCT devices that will say this patient has this much risk of developing Alzheimer's," Lad says.

Still, whether these signs could ever add up to an actual diagnosis remains to be seen. "These changes are unlikely to be a diagnostic tool, but they will be alerting the patient and clinician to potential problems that then need to be followed up," Lengyel says.

The changes in the eye could come years, perhaps decades, sooner than patients experience the symptoms that would normally trigger a neurological exam.

"To look at those specific indications through the retina is very exciting because it will allow us to identify populations at risk for the disease," says Koronyo-Hamaoui says. "Looking at the brain to identify those molecular changes will allow the opportunity to clinically intervene, or to monitor the response to therapy."

Even if signs in the eye are definitively correlated to Alzheimer disease, it would be hard to justify screening everyone because no treatment is yet available that can stop the progression of this most common neurological disease, Lad acknowledges.

But even without such a treatment, getting an early diagnosis could have benefits, she says. "It would be helpful for the patients to know that they will be affected so they can plan for their care and perhaps change their living environment."

Meanwhile, researchers hope their findings will serve yet another purpose, Lenygel says. By monitoring signs in the eyes, they could more easily track the effects of experimental therapies, perhaps speeding the development of therapies to stop these devastating diseases in their tracks.


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