Researchers at the Complutense University of Madrid (UCM) have used an advanced noninvasive imaging technique and customized software to identify and map changes in the thickness of different layers of the eye’s retina in patients with mild Alzheimer’s disease (AD). The results showed that changes in retinal thickness, including both thinning and thickening in some layers, may indicate neural degeneration and inflammatory processes that might help diagnose the neurodegenerative disorder before symptoms develop.

The study findings also support the notion that the retina has features in common with the brain, and this parallel, combined with the accessibility of the retina for study using noninvasive techniques, means that the retina could represent a promising source of biomarkers for investigating and potentially diagnosing Alzheimer’s disease.

“In recent years, ground-breaking studies have used the eyes as a window onto the brain to detect the changes that occur during the early stages and progression of Alzheimer’s disease,” explained Elena Salobrar-García, PhD, a scientist at the Ramon Castroviejo Ophthalmology Research Institute at the Complutense University of Madrid and co-author of the study, which is published in Scientific Reports.

“The novelty of our results is that in the early stage of the disease represented by our patient sample, neural layer thinning systematically predominated over thickening, as regards both percentage of thinned surface and neural volume lost,” added Luis Jáñez, PhD, a researcher at the Knowledge Technology Institute at the Complutense University of Madrid and first author of the study, which is titled, “Spatial analysis of thickness changes in ten retinal layers of Alzheimer’s disease patients based on optical coherence tomography.” Interestingly, the Madrid-based team’s report publishes within days of a study by researchers at the University of California (UC) San Diego, which indicated that pupillary dilation during cognitive testing may represent a low-cost method for screening individuals at genetic risk for AD before the start of cognitive decline.

The retina represents an “attractive source of biomarkers,” as it shares many features with the brain, and this has particular relevance for brain disorders such as AD, Salobrar-García and colleagues explained. “The brain is the main tissue affected in AD, and the retina is the only neuronal tissue that can be analyzed noninvasively in AD. Increasing evidence suggests that retinal analysis can provide insights into brain pathology.” Studies of retinal changes in the very early stages of AD have also indicated that the volume of brain structures involved in AD is related to retinal thickness and eyesight. “This suggests that AD-associated neuronal damage and deposits may occur in the retina before they occur in the brain, implying that retinal analyses could allow AD detection during the asymptomatic preclinical period.”

For their study the team combined an advanced method of optical coherence tomography (OCT) with specially designed software to map and compare the thickness of 10 different retinal layers, in 19 patients with mild AD—who were selected from 2124 clinical histories at the San Carlos Hospital Clinic Geriatric Service in Madrid—and 24 age-matched control volunteers. The 10 retinal layers analyzed included the nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), inner segments/outer segments layer (IS/OS), outer segment layer (OSL), outer segment PR/RPE complex (OPR), and retinal pigment epithelium layer (RPE).

Retinal layers in one of the patients participating in the study. [Knowledge Technology Institute, UCM]
A three-dimensional image of a square region measuring 6×6 mm was obtained for each participant’s retina, using the OCT technique. “With OCT, a light beam can sweep this area of the retina in 2.5 seconds. This frequently used technique is noninvasive, very fast, and low-cost,” Salobrar-García indicated.

While recent decades have witnessed great improvements in OCT technology, the system used for the reported studies represents another step ahead, the authors indicated. Existing commercial methods give the mean thickness of each retinal layer in geometrically predetermined areas, whereas the new method evaluated a 6×6 mm2 square at the pixel level, and avoided any averaging out that might mask clinically relevant differences. “Our spatially unconstrained analysis of retinal layers allows us to identify which layers are truly affected by the disease,” they wrote.

Using this technique the retinal layers were automatically segmented, and the thickness at each scanned point was measured, and corrected for tilt. “ … the present study is the first, to our knowledge, to apply local tilt correction,” they added. The investigators also developed software specifically for the study, which allowed them to analyze the huge amount of data gathered from measuring the thickness of each retinal layer at 262,144 points distributed over a grid of 512 columns and as many rows. “Using statistical techniques based on Gaussian random field theory, we determined for the first time the exact shape, size, and location of the areas affected by the disease in each retinal layer,” added Jáñez. “Our analysis also applies spatial standardization and correction for distortions coming from OCT techniques and from individual differences, before data are combined for analysis, the investigators stated.

Internal nuclear layer centered on the fovea. [Knowledge Technology Institute, UCM]
The results showed that all 10 layers exhibited AD-related thinning over a relevant percentage of their surface. Thinning reached statistical significance at various locations in NFL, GCL, IPL, INL, OSL, and total retina. All the layers except INL and OS also showed thickened regions. … “the first changes appear in the macular zone, which is the most sensitive area and controls central vision and color perception,” noted José Manuel Ramírez, director of the Ramon Castroviejo Institute.

“The results of our study represent a breakthrough for the diagnosis and follow-up of Alzheimer’s disease and confirm that the retina is a good biomarker,” the researchers concluded. “Our findings are consistent with histopathological studies of human eyes suggesting that changes in retinal thickness may be a consequence of neuronal degeneration and inflammatory processes caused by AD-specific accumulation of retinal deposits that precede the appearance of deposits in the brain.”

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