Could optometry unlock secrets to cognitive health? What the research says

November 30, 2021
The 15th century polymath Leonardo da Vinci quipped, “the eyes, the window of the soul.” He couldn’t know the half of it. Only now, with 21st century technology, are researchers unlocking the secrets of the retina—and the brain. The search for retinal biomarkers of neurocognitive disorders is returning results, and optometry may hold a piece of the puzzle.
‘The eyes, the window of the soul’ and a light on our cognitive health?

Excerpted from page 20 of the November/December 2021 edition of AOA Focus.

Elena Biffi, O.D., has charted quite the circuitous if not fateful path to where she is today.

Growing up a ballroom dancer in the shadow of a collapsed Soviet Union, Dr. Biffi emigrated to the United States in the late-90s with her parents and grandparents. Here, she set her mind on optometry school after overhearing medical students in her dance classes. Broken English notwithstanding, Dr. Biffi completed community college, passing biology by translating her textbook into Russian, before graduating summa cum laude from University of Massachusetts on the road to New England College of Optometry (NECO).

“With that I just started learning and going, and I’ve never really stopped since,” Dr. Biffi, now associate professor of optometry at NECO, explains. “Being a doctor in the 21 st century is a career in lifelong learning, and because of it, we have an opportunity to make a lifelong difference.”

But for Dr. Biffi that opportunity to make a difference quickly turned into a purpose. After meeting her husband, Alessandro, a neurologist leading the Aging and Brain Health Research group at Massachusetts General Hospital, Dr. Biffi initiated research into the use of optical coherence tomography (OCT) for retinal diseases. And it wasn’t long before her husband’s research into cerebral small vessel disease (CSVD) and vascular dementia overlapped with her own research. Yet, life was about to take a still more portentous turn.

In 2019, Dr. Biffi’s grandfather, Vladimir, started experiencing gradual but noticeable memory loss. Diagnosed with advanced stage CSVD, her grandfather began wandering from the house and, one night, turned up in the emergency department after struck by a car. Not long after, severe dementia set in, and he couldn’t remember his family.

“That was the point that hit us hard,” Dr. Biffi remembers. “Here my husband and I are, a dementia expert and an OCT expert, and we didn’t see this coming. The transformation happened so fast that in one year, he went from fully functioning to a nursing home and not recognizing his great grandchildren.”

“We couldn’t save my grandfather, but perhaps we can save many more lives in the future and improve the quality of life for many more individuals with this research.” -Elena Biffi, O.D. Poignantly, Vladimir’s passing in 2020 further emboldened his granddaughter’s research into an emerging area of study: retinal imaging for the early diagnosis of age-related brain disorders. While vascular dementia is the second most common cause of progressive cognitive impairment, lessons learned here stand to inform the greater spectrum of neurocognitive disorders, including one that frequently coexists but is uniquely different—Alzheimer’s disease (AD).

But just how cutting-edge is this idea of looking at the retina for neurocognitive disorders? Consider that a PubMed search for the words “retina” and “Alzheimer” returned no results in 2000, seven in 2001 and over 1,200 in 2019. That same year, the Alzheimer’s Association convened an international, interdisciplinary think tank, with optometry’s representation via the AOA, to fully lean into research identifying retinal biomarkers for neurological change. And today, clinicians may be within only a few years of actionable screening recommendations, specifically for AD.

As for Dr. Biffi’s research with OCT and CSVD—for which she received AOA’s Investigator-Initiated Research Award—this moment could herald a paradigm shift for the detection of neurocognitive diseases, and optometry stands to play a significant part.

“If we can utilize noninvasive technology to detect changes with vasculature and neurons, we have the ability to potentially diagnose these diseases much earlier than we can now,” Dr. Biffi says.

The brain-eye connection

The key is the retina. By its very nature, these layers of nervous tissue inside the eyeball is an extension of the brain itself, distinctive in that it’s the only central nervous system (CNS) tissue not protected by bone. As noted in a 2020 study in Alzheimer’s & Dementia, the retina also shares much of the structural and pathogenic pathways with the CNS, such as cerebral microvasculature and neural cells.

But the eyes also contain elements of the peripheral nervous system, too, with eye movement based on the firing and wiring of cranial nerves III, IV and VI, notes, Jaci Theis, O.D., AOA Vision Rehabilitation Committee member. So, the eyes and retinal health intrinsically hold clues for cognitive, cardiovascular and neurological function.

“Ocular health and neurological health are intimately tied together, and I think the eyes contain a great deal of information in regard to systemic and neurological health, in which case they could be a proxy for specific conditions,” Dr. Theis says.

In many neurological diseases, the eyes are often the first site to manifest a disorder. For example, Dr. Theis points to patients with abnormal eye movements in neurological conditions—myasthenia gravis, multiple sclerosis (MS) and Parkinson’s disease (PD)—that when promptly identified can help confirm or lead to a diagnosis with a patient’s neurologist. Such is the case, Dr. Theis counts numerous occasions where neurology referred patients for eye movements suspicious of MS or PD, but unsure of diagnosis due to limitations in standard diagnostic neuroimaging, e.g., CT scan or MRI.

“One of the advantages of the neurosensory retina is that it is an easily accessible tissue through the pupil, as compared to the brain, which allows for the opportunity in noninvasive, high-resolution imaging devices like electroretinography, visual evoked potential, OCT, OCT-Angiography (OCT-A), hyperspectral imaging and more,” Dr. Theis says. “Thus, as we get to understand the link between the neuropathology of many neurological conditions and the retina, the role of optometry in early detection and co-management of neurodegenerative disease will expand.”

A new approach akin to diabetes care

Not might but will expand, Dr. Theis emphasizes. In fact, optometry may be at an inflection point not unlike where the profession was thirty years’ ago with another disease: diabetes. It wasn’t until 1991 that the U.S. Centers for Disease Control and Prevention (CDC) first recognized optometry’s utility in the team approach to diabetes care, largely based upon AOA’s advocacy and doctors’ accessibility and competence assessing the effects of uncontrolled hyperglycemia.

In the decades since, optometry concretized its role in regular diabetes care with the clinical utility of the regular, dilated eye exams, and further solidified itself among the pharmacy, podiatry, optometry and dentistry (PPOD) model of integrated care (read more about diabetes care in, “lorem ipsum dolor sit amet,” on page XX). The same could be true of where the profession is heading with neurocognitive care.

Such parallel is the subject of a 2020 paper penned by Michael R. Dueñas, O.D., AOA chief public health officer, and Peter J. Snyder, Ph.D., vice president of research at The University of Rhode Island and a leading researcher in the field of retinal imaging and AD. Titled, “Alzheimer’s team care approach—akin to diabetes—in the development, validation and population assessment of retinal biomarkers for disease,” the paper argues that with emerging evidence of retinal biomarkers for AD detectable via OCT, combined with the profession’s accessibility and already established care for this at-risk population, optometry could hold the crucial piece of an early-diagnosis puzzle.

“With the emerging research of retinal imaging and Alzheimer’s disease, optometry, through the AOA’s advocacy, made sure to be on the starting line of the track,” Dr. Duenas says. “Through optometry’s advanced training and advanced diagnostic medical equipment, we have been expertly examining the eye-brain, cardiovascular and endocrine systems of our patients for some time now. For AD, this is our patient cohort—one that we see regularly.

“It is time once again for optometry to run skillfully and embrace our essential involvement in patient and population health by identifying cognitively normal individuals with high risk of preclinical AD, thereby helping overcome AD altogether. We are on the track and the shoe fits perfectly, so let’s wear it and run fast. The impact will be as great or greater than that for diabetes.”

And that’s no exaggeration. Large numbers of Americans are living with preclinical AD. In fact, 46.7 million had preclinical AD (amyloidosis, neurodegeneration or both) in 2017 by one estimate in Alzheimer’s & Dementia. Such is the case, this preclinical stage is a window of opportunity when disease development may be detectable and the earliest intervention may allay irreversible damage.

Amyloid positron emission tomography (PET) neuroimaging and cerebrospinal fluid (CSF) assays provide great sensitivity and specificity as far as diagnostic biomarker tests go; however, they are invasive, costly and have limited availability. Blood-based biomarkers are fast becoming a possibility, but additional strategies are needed to identify and follow these at-risk patients over time. Hence, retinal imaging’s potential.

Windows to the brain

In 2019, the Alzheimer’s Association sponsored a workshop of 90 leading researchers from nine countries to hold a first-ever “think tank” meeting on the current status and future efforts to study early detection and monitoring of AD and mild cognitive impairment (MCI) through in vivo, noninvasive retinal imaging. Alongside this international team, the AOA, through Dr. Duenas’ representation, is helping identify a path to expediting development of retinal biomarkers for AD and tracking disease progression.

This isn’t some ‘pie in the sky’ work, either—the results are there and its much closer to reality than one would think.

“I’ve been doing this research for over 10 years now and we do have very good data,” says Dr. Snyder, the neuroscientist who organized the conference and is co-leading a research consortium at the nerve-center of this research. “We’re showing convergent results across laboratories for a couple of key biomarkers that are easy to industrialize.

“I’m optimistic. I think we’re going to have good tools for practicing clinicians within 3 to 5 years.”

To be certain, Dr. Snyder says the next decade will see researchers get to the point of making something completely turn-key, where a module can be integrated into existing clinical systems to create a binomial decision, i.e., either a patient is showing an at-risk trajectory or not. But what exactly are these retinal changes of interest?

Amyloid beta plaques and neurofibrillary tau tangles have been found in the retina of patients with AD, and Dr. Snyder and others posit this is associated with a “pathological cascade” of structural changes. A thinning retinal nerve fiber layer (RNFL) is one obvious change, yet research is still out on what quadrant is most involved and at what stage of disease progression is this change most rapid. The foveal avascular zone (FAZ) is another—the weight of evidence shows enlargement of the FAZ early in the disease, but with high individual variability. Work in Dr. Synder’s lab (principally by vision physiologist Edmund Arthur, O.D.) suggests enlargement of the capillary free zone (pCFZ)—a space observed between both retinal arterioles and veins, and the surrounding microvasculature, which is posited to reflect the distance that oxygen and nutrients must diffuse to reach the neural retina—could serve as a useful metric for neurodegenerative disease. So, too, a thinning ganglion cell layer (GCL) could be associated with MCI but could also be dependent on stage of disease with preclinical enlargement due to inflammation followed by a reduction in volume with disease progression, Dr. Snyder says.

“What does this all mean for the practicing clinician? There’s a lot of individual variability, making single cross-sectional examinations of individual patients problematic for a few of these metrics, so we are still refining the choice of measures, considering instrumentation issues, and developing reliable clinical protocols,” Dr. Snyder says. “There are some substantial signal processing issues to work through, but we are making great progress. I think it might be about 3 to 5 years to iron out these kinks before we can provide biomarkers that you can hang your clinical hats on.”

But the question on some doctors’ minds: how specific are retinal biomarkers as opposed to just being sensitive? That’s a two-part answer, Dr. Snyder says. If you’re using a marker as a screening marker in a large population, it’s always better to be more sensitive than specific. That said, we know there are many diseases that affect the retina in similar ways to AD. So, rationally combining a retinal screening marker with other cost-effective markers to increase specificity for AD, such as blood-based markers, may be the optimal solution, Dr. Snyder says.

In dealing with a disease—AD, in this instance—that has a 20- or 30-year prodromal period, both Drs. Snyder and Duenas suggest that doctors of optometry are particularly-well positioned, especially as they embrace the medical side of eye care.

“As we age as a society, the optometrist is in the best position to see the broadest sampling of older and aging adults, and that’s because of those normal [age-related] changes occurring that require the need for corrective lenses and eye care on a regular basis,” Dr. Snyder says.

Adds Dr. Duenas: “We’re in the right place at the right time, seeing the right people with the right training to make the right kind of impact.”

The right stuff

To put words in Dr. Duenas’ mouth: ‘with the right equipment, too.’ In addition to other imaging, the proliferation of OCT in many optometry practices has given doctors unprecedented access to structural information in an easy, noninvasive manner. Whereas OCT-SD (spectral domain) provides that quantitative data of specific retinal layers, newer OCT-A also offers an in vivo-look at the retinal microvasculature. Hence, Dr. Biffi’s ongoing research into CSVD and vascular dementia.

Similarly, Dr. Biffi’s research looks to many of the same biomarkers as AD—RNFL and GCL thickness, for instance—as well as key functional changes that affect the perfusion of blood vessels, i.e., blockages or thicker density. Ultimately, evidence correlates perfusion density in the retina with MRI-measured CSVD in the brain, potentially providing a chance to detect and intervene against ischemia or hemorrhaging. It’s a new era of interdisciplinary care.

“Just think, 30 years ago we didn’t have smartphones and here, today, we’re talking about technology that can discover these biomarkers,” Dr. Biffi says deferentially. Likewise, 30 years ago, Dr. Biffi couldn’t understand the chain of events set into motion by her family’s—and grandfather, Vladimir’s—decision to move to America. Today, his memory is a driving force for a consequential moment in neurocognitive care.

“We’re right at the beginning of being able to screen—on a large scale—millions of people that we as optometrists see regularly for routine exams.”

Who’s at risk for Alzheimer’s disease?

There’s not a single cause for AD; however, there are risk factors based on emerging evidence. The Alzheimer’s Association notes some non-modifiable risk factors, including: 

  • Age, the greatest risk factor for AD or dementia. Most individuals are >65 years of age.
  • Family history, those with close family with AD are more likely to develop it.
  • Genetics, AD genes are in both risk and deterministic categories.

However, individuals may be able to proactively take steps to mitigate other factors, including: 

  • Head injury, there is a link to future risk of dementia.
  • Cardiovascular health, there is a link to brain health.
  • Healthy aging, research suggests a healthy lifestyle, i.e., diet, exercise, and avoiding tobacco or too much alcohol, may reduce risk of AD or other dementias.

For more information, visit alz.org.

Access AOA member resources on brain injury, vision rehab

The AOA Vision Rehabilitation and Brain Injury committees developed resources to help doctors of optometry address these unique areas of patient care.
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