Have biomarkers for preclinical Alzheimer’s disease been staring us in the face all along, and we just did not see them? Recent studies report a plethora of changes in the eye as Aβ pathology emerges in the brain. Dwindling retinal blood flow, thinning retinal nerve fibers, and retinal Aβ plaques themselves are but a few of the features scientists have proffered as readily detectable AD biomarkers. As disparate studies mount, so does the need for consensus. Thus far, there is little independent confirmation, much less agreement on what works. Peter Snyder of the University of Rhode Island, Providence, is trying to change that. At the AD/PD meeting in Lisbon, Snyder announced an initiative to compare eye-based measures head-to-head, and longitudinally, in people across the disease continuum. If his effort confirms eye-based tests as bona fide AD biomarkers, they could become frontline screens that could be deployed around the world.
- Lots of little studies hint that the eye undergoes changes in the preclinical stage of AD.
- The planned Atlas of Retinal Imaging Study seeks to anoint a gold standard.
- Will optometrists screen for people at risk of cognitive decline?
“For those of us doing research in this field, the dream is that universal and regular vision care with retinal imaging could serve to both preserve physical/social functioning in older adults and detect early signs of cognitive disease,” wrote Alison Abraham of Johns Hopkins School of Medicine in Baltimore.
“Eye-based screening could have a meaningful role in future studies of preclinical Alzheimer’s disease even in an era when we have high hopes for fluid and imaging biomarkers,” noted Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix.
Studies have linked numerous eye changes to AD or cognitive impairment. Many focus on the retina, a disc of nervous tissue at the back of the eye that connects to the brain via the optic nerve. PubMed lists around 100 studies published in the past three years about the retina and AD. For example, the retina can be visualized with ocular coherence tomography. Opthalmologists and optometrists use OCT to identify glaucoma or macular degeneration, and angiography recently has been tacked on to add blood flow measurements. This is called OCT-A.
Zoom in on AD? A peripapillary OCT scan images a region (green circle) of the retina surrounding the entrance to the optic nerve. The analysis renders a linearized image in which each retinal layer can be measured. [Courtesy of Peter Snyder.]
Researchers use OCT to detect Aβ plaques in the retina and attempt to correlate them with cortical Aβ accumulation as per PET scans (Jul 2014 conference news; Sep 2017 news). Others link retinal capillaries to AD. For example, one study reported that the inner fovea—an avascular zone in the middle of the retina where visual acuity is highest—was thinner and wider in cognitively normal people with a positive amyloid PET scan (Aug 2018 news). Another claimed slower blood flow and fewer vessels in the surrounding parafoveal region in people with mild cognitive impairment (Zhang et al., 2019). Using photography, a study found double the odds of mild cognitive impairment or dementia in people whose retina had hemorrhaged than in people without such bleeds (Lee et al., 2019).
Synaptic Sandwich. The retina comprises 10 layers, including eight depicted here. Three neuronal layers (GCL, INL, and OPL) are connected via synaptic layers (IPL, OPL). The retinal nerve fiber layer (RNFL) projects axons into the optic nerve. [Courtesy of Peter Snyder.]
The structure of the retina itself is also implicated in AD. It consists of 10 layers, including three neuronal cell layers sandwiched on either side by synaptic and axonal layers. Studies have come to conflicting conclusions about how the thickness of each layer correlates with AD. Some report that people with AD have fewer ganglion cells—the neurons project their axons into the optic nerve like hairs pulled into a ponytail. Others report a thinner retinal nerve fiber layer (RFNL), which contains those optic nerve-bound axons; alas, it’s unclear exactly where along the retina the RNFL thins, if at all (Danesh-Meyer et al., 2006; Cheung et al., 2015; Garcia-Martin et al., 2016). The list of single-study biomarker suggestions goes on (for review, see Chan et al., 2018).
At AD/PD, Snyder reviewed his own data of one of the few longitudinal studies thus far to examine the relationship between multiple retinal measures and preclinical AD (Santos et al., 2018). He also presented unpublished findings from the same cohort. The researchers enrolled 63 people with a family history of AD who were cognitively normal but reported subjective memory complaints. They measured numerous retinal markers in them at baseline and 27 months later, at which time participants had an Aβ-PET scan. Santos et al. spotted a correlation between a person’s Aβ accumulation and thinning of the RNFL in their macula, a pigmented region near the retina’s center. In Lisbon, Snyder added an analysis of macular pigment optical density (MPOD), a measure of pigment within the macula. Using a combination of lasers to detect pigment, Snyder found that reduced pigment correlated with slippage on cognitive tests, but not with Aβ deposition.
Snyder likened the current landscape of eye-based biomarkers to the pre-ADNI days of neuroimaging. Given the jumble of small studies reporting on a group’s “favorite” single marker, Snyder decided to kick off a larger, longer cohort to track multiple candidate markers across the disease spectrum. Called Atlas of Retinal Imaging in Alzheimer’s Study, ARIAS aims to amass a reference database of retinal changes that track with disease (see clinicaltrials.gov). To be funded by Florida’s BayCare Health System, ARIAS will recruit participants from two hospitals in Tampa, Florida, and from one in Rhode Island.
ARIAS seeks 330 participants aged 55 to 80, from cognitively normal people deemed at low or high risk for AD based on family history and ApoE4 status, to people with mild cognitive impairment or mild AD. They will undergo annual eye exams for three years, at which investigators will use OCT and OCT-A to measure the thickness of every retinal layer, blood vessel volume and flow, and macular pigment. They will assess the pupil’s response to light, and sensitivity to contrast, a visual marker that wanes in AD. A subset of participants will wear actigraphy monitors for two weeks to gauge their physical activity and sleep patterns, as connections between the eye and the brain are known to affect sleep. Amyloid PET scans are not in the protocol, but Snyder said many participants have already had one as part of the Imaging Dementia–Evidence for Amyloid Screening (IDEAS) study (see clinicaltrials.gov), and that data can go into ARIAS analyses.
“This longitudinal study in well-characterized (preclinical) AD cases provides a great step forward for retinal imaging as possible biomarker in AD,” commented Jurre den Haan and Philip Scheltens of VU University Medical Center (see full comment below). Longitudinal retinal imaging data from preclinical AD cases from the European Medical Information Framework (EMIF)-AD cohort will soon be published.
Carol Cheung of the Chinese University of Hong Kong believes ARIAS will fill a knowledge gap in the field. Interpreting retinal parameters is tricky because they can be affected by aging, diseases such as hypertension and diabetes, eye size, glaucoma, and other neurological conditions including multiple sclerosis and stroke. “It is likely that AD-related changes in retinal vasculature and neuronal structure present as a spectrum of variants due to involvement of multiple variables,” she wrote.
Maya Koronyo-Hamaoui of Cedars-Sinai Medical Center in Los Angeles agreed that studies such as ARIAS were highly needed to find eye-based biomarkers that could facilitate early AD detection and monitoring of progression. “Moreover, there is a great need to correlate these nonspecific changes in retinal vascular biomarkers and atrophy with retinal AD-characteristic signs (amyloid beta and tauopathy) in these patients,” she added.
Snyder hopes results from ARIAS will form the foundation for a future toolkit of eye-based biomarkers that can be used as a frontline screening tool for preclinical AD. A person who tests positive for eye-based markers could be referred to a neurologist for more standard biomarker tests. OCT tests could theoretically be run in primary care clinics, but Snyder said that adding one more test to the already packed to-do list of these physicians might not be easy. Opthalmologists also have a loaded schedule and perform a variety of procedures. Optometrists, he said, are more likely to welcome Alzheimer screening into their standard care. Not only do they have fewer tests to run on their patients, they may also see AD screening as a way to ensure a steady client base, Snyder said. OCT scanners are cheaper and more widely available around the world than PET scanners.
That said, Delia Cabrera DeBuc of the University of Miami pointed toward even cheaper tools. Last December, she reported that retinal neurons are hypoactive in people with cognitive impairment. She uses a handheld electroretinogram (ERG, see Cabrera DeBuc et al., 2018). The device costs less than $15,000, requires no dilation or manipulation of the eye, and is easier to use than an OCT scanner, which costs around $100,000, Cabrera DeBuc said.
Even with an electroretinogram, Cabrera has seen pushback in primary care settings, where nurses and doctors are crammed for time. She agrees that optometrists’ offices might be a venue for AD screening using OCT, though patients without insurance for vision care would have to pay out of pocket to receive tests there. Therefore, incorporating eye-based AD screening tests into the primary care reimbursement structure would be key to their widespread use, Cabrera DeBuc said. She thinks ARIAS is on the right track, because any retinal AD markers that emerge from it will motivate the health care field to implement screening into primary care.
Snyder is hosting an open workshop May 22–23 in Washington, D.C., where researchers can discuss new data and challenges in the field of retinal imaging, and hash out a way forward. Register by clicking here.
Eye-based biomarkers could hold promise for detecting other neurodegenerative diseases as well. One study found thinning in the retina’s outer photoreceptor layer in people with frontotemporal dementia (FTD) (Kim et al., 2017). This month, Benjamin Kim at the University of Pennsylvania in Philadelphia and colleagues published longitudinal findings from the same cohort. The outer retina continued to diminish, but only in FTD patients predicted to have underlying tau pathology (Kim et al., 2019). This is distinct from the inner layer thinning observed in AD. “This suggests that OCT may help to distinguish FTD from AD. We currently are enrolling patients in an OCT study to directly compare these two groups,” Kim wrote to Alzforum.
Retinal thinning in the rTg4510 mouse model of tauopathy suggests that changes in the eye reflect tau pathology in the brain (Harrison et al., 2019). Retinal changes have also been reported in people with amyotrophic lateral sclerosis (Volpe et al., 2015).—Jessica Shugart
- Alzheimer’s Disease: In the Eye of the Patient?
- Retinal Plaques May Enable Noninvasive Screening for AD
- Does Retinal Thinning Reflect Early Alzheimer’s?
Research Models Citations
- Zhang YS, Zhou N, Knoll BM, Samra S, Ward MR, Weintraub S, Fawzi AA. Parafoveal vessel loss and correlation between peripapillary vessel density and cognitive performance in amnestic mild cognitive impairment and early Alzheimer's Disease on optical coherence tomography angiography. PLoS One. 2019;14(4):e0214685. Epub 2019 Apr 2 PubMed.
- Lee MJ, Deal JA, Ramulu PY, Sharrett AR, Abraham AG. Prevalence of Retinal Signs and Association With Cognitive Status: The ARIC Neurocognitive Study. J Am Geriatr Soc. 2019 Feb 1; PubMed.
- Danesh-Meyer HV, Birch H, Ku JY, Carroll S, Gamble G. Reduction of optic nerve fibers in patients with Alzheimer disease identified by laser imaging. Neurology. 2006 Nov 28;67(10):1852-4. PubMed.
- Cheung CY, Ong YT, Hilal S, Ikram MK, Low S, Ong YL, Venketasubramanian N, Yap P, Seow D, Chen CL, Wong TY. Retinal ganglion cell analysis using high-definition optical coherence tomography in patients with mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2015;45(1):45-56. PubMed.
- Garcia-Martin E, Bambo MP, Marques ML, Satue M, Otin S, Larrosa JM, Polo V, Pablo LE. Ganglion cell layer measurements correlate with disease severity in patients with Alzheimer's disease. Acta Ophthalmol. 2016 Feb 19; PubMed.
- Chan VT, Sun Z, Tang S, Chen LJ, Wong A, Tham CC, Wong TY, Chen C, Ikram MK, Whitson HE, Lad EM, Mok VC, Cheung CY. Spectral-Domain OCT Measurements in Alzheimer's Disease: A Systematic Review and Meta-analysis. Ophthalmology. 2018 Aug 13; PubMed.
- Santos CY, Johnson LN, Sinoff SE, Festa EK, Heindel WC, Snyder PJ. Change in retinal structural anatomy during the preclinical stage of Alzheimer's disease. Alzheimers Dement (Amst). 2018;10:196-209. Epub 2018 Feb 7 PubMed.
- Cabrera DeBuc D, Somfai GM, Arthur E, Kostic M, Oropesa S, Mendoza Santiesteban C. Investigating Multimodal Diagnostic Eye Biomarkers of Cognitive Impairment by Measuring Vascular and Neurogenic Changes in the Retina. Front Physiol. 2018;9:1721. Epub 2018 Dec 6 PubMed.
- Kim BJ, Irwin DJ, Song D, Daniel E, Leveque JD, Raquib AR, Pan W, Ying GS, Aleman TS, Dunaief JL, Grossman M. Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration. Neurology. 2017 Oct 10;89(15):1604-1611. Epub 2017 Sep 8 PubMed.
- Kim BJ, Grossman M, Song D, Saludades S, Pan W, Dominguez-Perez S, Dunaief JL, Aleman TS, Ying GS, Irwin DJ. Persistent and Progressive Outer Retina Thinning in Frontotemporal Degeneration. Front Neurosci. 2019;13:298. Epub 2019 Apr 4 PubMed.
- Harrison IF, Whitaker R, Bertelli PM, O'Callaghan JM, Csincsik L, Bocchetta M, Ma D, Fisher A, Ahmed Z, Murray TK, O'Neill MJ, Rohrer JD, Lythgoe MF, Lengyel I. Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia. Acta Neuropathol Commun. 2019 Jan 7;7(1):4. PubMed.
- Volpe NJ, Simonett J, Fawzi AA, Siddique T. Ophthalmic Manifestations of Amyotrophic Lateral Sclerosis (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2015;113:T12-1-15. PubMed.
- Thomson KL, Yeo JM, Waddell B, Cameron JR, Pal S. A systematic review and meta-analysis of retinal nerve fiber layer change in dementia, using optical coherence tomography. Alzheimers Dement (Amst). 2015 Jun;1(2):136-43. Epub 2015 Apr 23 PubMed.
- den Haan J, Balk LJ, Verbraak FD. Ganglion cell layer measurements correlate with disease severity in patients with Alzheimer's disease. Acta Ophthalmol. 2018 Mar;96(2):e265-e266. Epub 2017 Aug 22 PubMed.
- Snyder PJ, Johnson LN, Lim YY, Santos CY, Alber J, Maruff P, Fernández B. Nonvascular retinal imaging markers of preclinical Alzheimer's disease. Alzheimers Dement (Amst). 2016;4:169-178. Epub 2016 Oct 1 PubMed.