Retinal Thinning Tied to Cognitive Decline

Damian McNamara

June 26, 2018

Thinning of the eye's retinal nerve fiber layer (RNFL) appears to be a strong predictor of cognitive decline, new research shows.

Investigators found healthy individuals with RNFL thinning were twice as likely to develop cognitive decline as their counterparts with normal eyes.

"We have identified a link between thin RNFL and cognitive problems," study author Paul Foster, MBMS, PhD, professor of glaucoma studies & ophthalmic epidemiology at UCL Institute of Ophthalmology & Moorfields Eye Hospital in London, United Kingdom, told Medscape Medical News.

"This is the largest study of its kind and the first to identify that future decline in cognitive function is associated with a thinner RNFL in a large, healthy community-based cohort," the researchers noted.

Based on these findings the researchers propose that RNFL could now be used as an indicator of impaired cognition and may eventually be used to screen for future risk.

The study was published online June 25 in JAMA Neurology.

Twofold Increased Risk

The findings are consistent with those from several previous studies of individuals with established disease. For example, the RNFL was thinner among people with early Alzheimer's disease than in healthy, age-matched controls in one study (Neurosci Lett. 2007;420:97-99). Other researchers reported similar findings in Parkinson's disease (Brain. 2016;139:2827-2843)  and Lewy body dementia (J Alzheimers Dis. 2013;34:659-664).

Other research suggests the RNFL is thinner on optical coherence tomography (OCT) among individuals with early cognitive impairment, but most of these studies were small, cross-sectional case series and case-control studies, the investigators note.

For the current study the investigators assessed OCT findings among 32,038 participants in the UK Biobank study. They analyzed the thickness of the RNFL, the innermost layer of the retina, in a subgroup of 1251 (3.9%) participants who had complete data at follow-up.   

All participants were free of neurodegenerative disease at baseline. These UK residents ranged in age from 40 to 69 years. About 54% were women and more than 90% were white.

OCT was initially done in 2009 and 2010 and was repeated between 2012 and 2013. At the same time points, participants underwent neurocognitive testing that assessed prospective memory, pairs matching, reaction time, and numeric and verbal reasoning.

Individuals with thinner RNFL results at baseline tended to have worse overall baseline cognitive performance. The same result was observed in individual cognitive tests, with worse performance at each thinner quintile of RNFL measurement.

Compared with those in the thickest RNFL quintile, people in the thinnest group were 11% more likely to fail at least one cognitive test at baseline (P = .01).

In terms of absolute numbers, 475 people in the thinnest RNFL quintile failed at least two cognitive tests compared with 267 in the thickest quintile. This was also a significant difference (P < .001).

At follow-up, again compared with participants with the thickest RNFLs, those in the two thinnest quintiles were nearly twice as likely to fail one or more cognitive tests (odds ratio, 1.92; P < .001).

At 3 years, for each thinner quintile of RNFL, researchers found an 18% increased risk for cognitive decline.

The researchers assessed cognitive deficit risk by using a multivariate analysis that controlled for age, sex, race/ethnicity, Townsend Deprivation

Index, educational attainment, refractive error, and intraocular pressure.

OCT in the Clinic

Use of OCT to measure and monitor retinal layers is attractive because the technology is quick, noninvasive, and widely available, the investigators note.

"OCT is now the 'industry standard' for diagnosis and management of age-related macular degeneration, diabetic retinopathy, and glaucoma — the big chronic degenerative eye diseases globally," Foster said.  

About a half-day of training is required to start using OCT, he said. Most health technicians can master use of the technology rapidly, he added. In addition, neurologists could offer OCT devices in the clinic, so "this testing does not need to be solely in the ophthalmic or optical sector."

Despite the study's significant findings, it remains too early to use RNFL testing for widespread screening, Foster said. One reason is that the World Health Organization and other organizations stipulate that screening "implies that there is a treatment or lifestyle modification which can be prescribed or advised which manifestly benefits the condition," and this is not the case with dementia.

However, in the meantime, he added that clinicians can recommend increased physical and mental activity and encourage social interaction to their patients.

"There is a link between poorer vision and hearing and cognitive decline, so advising a hearing and vision assessment would be useful," he said.

Some controversy remains in the literature, with some arguing against using the retina to reflect generalized neurodegenerative disease.

For example, Van Koolwijk and colleagues noted that the association between RNFL thickness and cognitive function is insufficient to explain variance in cognitive test results (Invest Ophthalmol Vis Sci. 2009;50:4576-4580).

"In response to Van Koolwijk et al, it would be unlikely for any screening test to be used in isolation," Foster and colleagues write.

In contrast to most previous research, the investigators said, "Our results are more representative of a premorbid population, further strengthening the principle of an association between a thin RNFL and cognitive decline."

Most participants were white, middle class, and educated, which may limit the generalizability of the results.

"However, we believe that the associations that we have identified are unlikely to be the result of an intrinsic bias in the data, and therefore we feel the overall conclusions are valid for populations of Western European descent."

Future research could examine the underlying mechanisms that link RNFL thickness with specific cognitive domains.

"We are working on calculations of the sensitivity and specificity (ie, false-negatives and false-positives) of the eye and vision tests that may help identify increased risk of cognitive decline," said Foster.

Results of such research could help inform how widespread such screening could be in the future.

"Exciting" Findings

Commenting on the findings for Medscape Medical News, Justis Ehlers, MD, an ophthalmologist at Cleveland Clinic's Cole Eye Institute in Ohio, said the study provides important supporting information for the link between the brain and retina and links brain function to retinal anatomy.

"This supports further research for possible retinal biomarkers of neurodegenerative disorders, particularly with OCT," he said.
He added that it is "important to note that only 3.9% of those patients tested at baseline had follow-up testing, which is a significant loss to follow-up."

Also commenting on the study for Medscape Medical News, Esther Seunghee Oh, MD, PhD, associate director of Johns Hopkins Memory and Alzheimer's Treatment Center and associate professor of medicine at Johns Hopkins in Baltimore, Maryland, said the link between retinal thinning and cognitive decline is "exciting" on several levels.

"First, RNFL is a fairly noninvasive biomarker that may be used as a companion screening tool to identify those who may be at risk for future cognitive decline. Secondly, this is more evidence that sensory pathways —  for example vision, hearing, et cetera — may be closely linked with neurodegenerative disease processes. Still, caution needs to be exercised, as these types of associations do not mean that there are casual associations," she said.

The Eranda Foundation, the UCL Overseas Research Scholarship and Graduate Research Scholarship programs, and the Richard Desmond Charitable Trust via Fight for Sight, London, supported the study. Foster receives personal fees from Allergan, Carl Zeiss, Google/DeepMind, and Santen, as well as grant support from Alcon. Ehlers and Oh have disclosed no relevant financial relationships.

JAMA Neurol. Published online June 25, 2018. Abstract

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