A sophisticated eye scanner might detect early signs of Alzheimer’s disease, at least according to a paper in the August 23 JAMA Ophthalmology. Researchers led by Gregory van Stavern and Rajendra Apte, both at Washington University, St. Louis, studied the architecture of the retina in normal adults. They detected thinning of the tissue and a dearth of teeny blood vessels in its center in people who had tested positive for brain amyloid. The finding hints that a simple eye test could help diagnose prodromal AD. “Though this was a small study and very preliminary, it is certainly telling us that we can detect retinal changes in the preclinical stage of Alzheimer’s disease,” van Stavern told Alzforum.
Others have previously reported changes to the retinal architecture in people already diagnosed with AD or with mild cognitive impairment (Cheung et al., 2014; Golzan et al., 2017). Van Stavern and colleagues wondered how early in disease such changes occur. First author Bliss Elizabeth O’Bryhim and colleagues recruited 30 cognitively normal older adults from the Knight Alzheimer’s Disease Research Center at WashU and examined their eyes by optical coherence tomographic angiography. OCT-A, now commonly available, combines the structural information on the eye obtained from tomography with measures of blood flow and microvasculature structure.
The volunteers, 16 of them women, were between 62 and 92 years old. The average age was 75. Seven had had positive florbetapir PET scans, while 10 had low cerebrospinal fluid Aβ42 levels. O’Bryhim found that the inner fovea was thinner in the Aβ-positive than -negative volunteers. A small depression in the middle of the retina, the fovea is where a person’s visual acuity is highest. It is normally devoid of blood vessels, and this foveal avascular zone was wider in amyloid-positive people, as well. The findings suggest that vascular and structural alterations in the retina occur in AD patients before the onset of symptoms, said van Stavern.
Maya Koronyo-Hamaoui, Cedars Sinai Medical Center, Los Angeles, said the study was novel and could have important implications. “It’s so exciting to see that changes in OCTA could be described so early on in disease,” she said. Koronyo- Hamaoui was not involved in this study. While others in the field agreed the results were enticing, they also noted some limitations, as did the authors themselves. Mojtaba Golzan, University of Technology Sydney, wrote to Alzforum that a major challenge for retinal scanning in preclinical AD is the occurrence of ocular comorbidities. “Glaucoma, diabetic retinopathy, and macular degeneration are all well-known ocular conditions that alter the retinal structure and microcirculation,” she wrote. People with these conditions were excluded from the study.
Nevertheless, van Stavern sees potential for an early noninvasive test that would be simpler than PET scans or lumbar taps. He thinks the foveal thinning might be a sign of neurodegeneration and the widening of the avascular zone might be more specific to AD, since Aβ is known to aggregate in blood vessels.
He said that larger cohorts and longitudinal analyses are needed to prove any connections. Cecilia Lee, Washington University, Seattle, agreed. “Longitudinal studies of larger cohorts are needed to confirm who progresses from preclinical AD to clinical manifestation of AD (versus who remains resilient), and to evaluate longitudinal changes in retinal imaging markers using OCTA,” she wrote (see full comment below). Just recently, other researchers used OCT to document thinning of the retina in Parkinson’s disease, for example (Aug 2018 news).
Koronyo-Hamaoui thinks a combination of OCT and scans for retinal protein aggregates is the way to go. “The real opportunity I see here is to combine measurements that show vascular changes, which appear to happen very early on, with more specific amyloid or tau analysis,” she said. She has reported finding retinal plaques in AD patients and has founded a company, NeuroVision, to develop a retinal scanning test (Sep 2017 news). In a JAMA Ophthalmology editorial accompanying the paper, Christine Curcio, University of Alabama, Birmingham, noted that O’Bryhim and colleagues scanned only the very center of the retina, i.e., the macula. “Thus, obtaining imaging and histopathology data from the same affected retinal regions and layers in AD remains a priority for this line of research,” she wrote.
Others are not so convinced that amyloid plaques occur in the retina. “It’s unfortunate that people cite very limited studies of the retina compared to rigorous studies we have done by histology,” Koronyo-Hamaoui told Alzforum. She claimed to have data showing amyloid, tau, vascular amyloid, and inflammation in the retina. “All the signs you see in the brain you find in the retina,” she said.
Jurre den Haan from VU Medical Center, Amsterdam, noted that a major problem in this field is lack of agreed-upon tests. “I advocate for a multidisciplinary international workgroup to standardize retinal studies in terms of phenotyping, imaging, and postmortem protocols,” he wrote (see full comment below). “This could finally make studies from different labs comparable, and thus advance this emerging field of research.”—Tom Fagan
- Cheung CY, Ong YT, Ikram MK, Ong SY, Li X, Hilal S, Catindig JA, Venketasubramanian N, Yap P, Seow D, Chen CP, Wong TY. Microvascular network alterations in the retina of patients with Alzheimer's disease. Alzheimers Dement. 2014 Mar;10(2):135-42. Epub 2014 Jan 15 PubMed.
- Golzan SM, Goozee K, Georgevsky D, Avolio A, Chatterjee P, Shen K, Gupta V, Chung R, Savage G, Orr CF, Martins RN, Graham SL. Retinal vascular and structural changes are associated with amyloid burden in the elderly: ophthalmic biomarkers of preclinical Alzheimer's disease. Alzheimers Res Ther. 2017 Mar 1;9(1):13. PubMed.
No Available Further Reading
- O'Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Association of Preclinical Alzheimer Disease With Optical Coherence Tomographic Angiography Findings. JAMA Ophthalmol. 2018 Nov 1;136(11):1242-1248. PubMed.