Staff Writer

Current brain imaging techniques are unable to visualize small vessels, but researchers have taken a systematic look at what could be the next best thing: retinal images. Vascular disease has long been known to contribute to cognitive decline in older adults, but a recent study published in the journal Neurology aimed to define that relationship more precisely.

In a longitudinal study, researchers found that people who presented with moderate to severe retinopathy in fundus photographs at about age 60, were much more likely to having thinking and memory problems by age 80. The researchers have incorporated more precise retinal imaging technology in a subset of patients in the study in an effort to understand even better how well the retina functions as a window into the brain.

Microvascular changes

"We know that vascular disease contributes to cognitive decline in older adults. So, we were really trying to get an idea of the relative contribution of microvascular disease. That would be the very, very small blood vessels and, unfortunately, with current standard-of-care imaging techniques like MRI, we can't see those very small vessels," Jennifer Deal, an assistant scientist at the Johns Hopkins Bloomberg School of Public Health, told BioWorld MedTech.

"But what's really unique and so wonderful about the eye is that it's anatomically and physiologically related to what's going on in the brain. So we think that by actually looking at the back of the retina, we can visualize those very small blood vessels and that gives us kind of an idea of what's going on in the brain," she continued. "So, that was really our goal. We wanted to try to estimate what the contribution of vascular disease might be to cognitive decline in older adults."

A prior study had looked at a similar question in this study population, but this time around researchers were able to examine all the patients rather than a sub-group and to have a longer time period of follow-up. With the larger population and longer follow-up, the results were heightened with the relationship between retinopathy at age 60 and later cognitive issue found to be even stronger than it had been previously.

In a longitudinal study of 12,317 people, about three years into the study when the participants had an average age of 60, a fundus photograph was taken with a retinal camera. At that time, 11,692 people had no signs of retinopathy, while 365 people displayed signs of mild retinopathy and another 256 people showed moderate to severe damage.

Those patients with moderate to severe retinopathy at about age 60 were found to have had much bigger drops in scores on memory and thinking tests that had been conducted over time through at least about age 80.

The scores of these patients declined by 1.22 standard deviation units over 20 years. In contrast, people who had healthy eyes had a decline of 0.91 standard deviation units. When adjusted for missed tests, the difference between the two groups was found to be 0.57 standard deviation units.

The association of cognitive decline with prior retinopathy, and the microvascular problems in the brain that this indicates, is actually stronger than the association with diabetes. A prior study using the same methods found that the difference in cognitive decline scores between healthy adults and those with diabetes was equal to 0.21 standard deviation units. Diabetes is known to be associated with cognitive decline, so the fact that microvascular issues are an even stronger indicator is significant.

OCT advances

"If our study results can be confirmed, differences in retinal integrity could provide reasonable estimates of how much small blood vessel damage in the brain is contributing to cognitive decline," said Deal.

Confirmation is expected to come with the inclusion of a subset of patients that are examined with a more precise kind of imaging of the eye: optical coherence tomography (OCT). Deal anticipates that the use of OCT could lead to the clinical use of a retinopathy diagnosis as a predictor of the risk of cognitive decline.

"Another type of eye imaging, OCT, may be more sensitive than the retinal fundus photography that we used. So, we're very interested in thinking about the association between OCT measures and what's going on in the brain with cognitive decline, as well. It may be that, eventually, that could be something that could be useful for clinical practice, just because it does have more sensitivity than the fundus photograph," said Deal.

Summed up the study, "Retinopathy was associated with accelerated rates of 20 year cognitive decline. These findings support the exploration of more sensitive measures in the eye such as optical coherence tomography angiography, which may provide surrogate indexes of microvascular lesions relevant to cognitive decline in older adults."

Biomarker complications

This research did not address any specific diseases related to cognitive decline, such as dementia or Alzheimer's disease. But Deal expects that OCT retinal images could offer a preclinical biomarker for dementia. Microvascular disease in the brain has been found on autopsy in dementia patients. Alzheimer's disease is one kind of dementia.

With its latest updated guidance on the topic, the FDA is encouraging drug developers to target Alzheimer's disease patients via biomarkers before they develop symptoms. The theory is that symptomatic patients are too far along in the disease process to be aided by drug candidates. But early identification of an at-risk population, without any accompanying meaningful treatments to offer those patients, carries its own risks as well when it comes to patient treatment.

"Any time when you think about screening in a population, we have to demonstrate the validity of the tool. We need to know who actually has the disease and to be able to correctly identify people who don't have the disease. So, we need to do both. And, ideally, we would have some sort of intervention," noted Deal.

She concluded, "If we were able to screen someone and tell them that they have a disease, but we are not able to do anything for them, that can be tough. That's why groups like the United States Preventive Services Task Force have not recommended for dementia screening in routine clinical care."

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