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.

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  1. O’Bryhim et al. evaluated retinal microvasculature of 14 patients with preclinical stages of AD and 16 controls using optical coherence tomography angiography (OCTA). Preclinical AD was defined by positive biomarkers (PET imaging for PiB or F-AV-45 compound or CSF analysis for Aβ42) with normal cognition. All participants had a Clinical Dementia Rating score of zero (cognitively normal) and were free from confounding eye conditions such as glaucoma, age-related macular degeneration, retinal laser therapy.

    The following OCTA parameters were analyzed in a total of 58 eyes: the thickness of nerve fiber and ganglion cell layer, inner and outer foveal thickness, vascular density, macular volume, and the area of the foveal avascular zone (FA). The authors found that the FAZ was larger and the inner fovea was thinner in participants with preclinical AD than controls.

    The study results are exciting and point to the potential of ophthalmic imaging in AD screening in the future. 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.

    View all comments by Cecilia Lee

  2. With interest we read the article of O’Bryhim and colleagues assessing the retina for possible non-invasive biomarkers in preclinical AD, adding to the literature changes in microvasculature as a possible early sign of retinal involvement in AD pathology. Great to see that the urgency of AD research on patient-friendly biomarkers has also reached the ophthalmological scientific community and that currently used AD biomarkers are being integrated in a retinal imaging study. We agree with the authors‘ caution in interpreting these results. With individual layer segmentation and different vascular parameters available in different anatomical regions of the retina, large amounts of parameters are derived from OCT imaging. Caution should therefore be taken in (over)interpreting findings of a selection of these parameters without correction for multiple testing. Future studies are needed to assess the reproducibility of these interesting findings.

    Given the discrepant findings between different studies assessing retinal involvement in different stages of AD (retinal layer thinning measured with OCT, microvasculature changes on OCT/fundus photography/OCT-A, and amyloid deposition in postmortem and in vivo studies), there is a need for  studies assessing cohorts in the light of the ATN criteria and taking important confounders for retinal changes into account (Jack et al., 2016). These confounders include age and age-related diseases such as diabetes mellitus, glaucoma, and age-related macular degeneration.

    We (in our center and in collaboration with UCL Dementia Research Center) are currently working on correlating retinal measurements with established AD biomarkers (atrophy on MRI, amyloid, and tau in CSF/on PET) in cohorts of patients in different stages of AD (preclinical, SCD, and AD/PCA) taking the above confounders in account. Hopefully these data can help separate disease from aging effects and unravel the precise role of retinal biomarkers for diagnosis, prognosis, and therapeutic read-out in AD.

    Lastly, I advocate for a multidisciplinary international workgroup aiming to standardize retinal studies in terms of phenotyping, imaging, and postmortem protocols. This could help improve comparability between different studies and advance this emerging research field further.

    References:

    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2;87(5):539-47. Epub 2016 Jul 1 PubMed.

    View all comments by Jurre den Haan

  3. Due to a physiological and embryological connection between the eye and the brain, eye imaging, or more specifically scanning, the retina, the light-sensitive layer of the eye, in preclinical Alzheimer’s disease has gained momentum over the past few years. Many studies have utilized current techniques optimized in ophthalmology to investigate the association between retinal changes and signs of AD pathology in the brain. Optical Coherence Tomography (OCT), a noninvasive eye imaging test, uses light wave to reconstruct the structure of the retina. OCT angiography (OCTA) is a functional extension of OCT that is capable of visualising the microcirculation of the retina. O’Bryhim et al. have employed OCTA to study retinal alterations in preclinical AD and control participants. They use results from brain amyloid imaging and/or analyzing levels of amyloid in the cerebrospinal fluid (CSF) to determine an individual’s disease status.

    Results demonstrate specific retinal vascular and structural changes that occur in the preclinical AD group and not in the control group. While these are very exciting findings, there are a number of limitations that need to be addressed prior to establishing the validity of such biomarkers in preclinical AD screening. First, a consistent method to demonstrate preclinical AD presence needs to be used. This study uses two different brain-imaging tracers and/or analysis of the CSF to establish disease presence. A recent study has shown CSF analysis to be superior to brain imaging to determine amyloid-positivity (Lewczuk et al., 2017). Second, a significant proportion of cognitively normal individuals will have positive amyloid imaging with no other symptoms of cognitive impairment (Chételat et al., 2013). As such, a battery of tests including laboratory, imaging, and neuropsychology should be used to determine disease status. Third, a major challenge in using retinal scanning for preclinical AD screening is eliminating local ocular comorbidities. Glaucoma, diabetic retinopathy, and macular degeneration are all well-known ocular conditions that alter the retinal structure and microcirculation. While the study presented has excluded such patients, further longitudinal studies are required to determine the specificity of retinal screening for preclinical AD assessment. Finally, a larger sample size and group is required to draw a meaningful interpretation.

    Collectively, it appears that retinal scanning, taken with other established markers for AD, has merit in establishing the presence of AD. Whether retinal scans alone can be used to determine preclinical AD status needs further longitudinal studies to determine their potential in successfully sub-groupings in mild cognitive impairment—those who have AD-like changes, and those who don’t.

    References:

    Lewczuk P, Matzen A, Blennow K, Parnetti L, Molinuevo JL, Eusebi P, Kornhuber J, Morris JC, Fagan AM. Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer's Disease. J Alzheimers Dis. 2017;55(2):813-822. PubMed.

    Chételat G, La Joie R, Villain N, Perrotin A, de La Sayette V, Eustache F, Vandenberghe R. Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease. Neuroimage Clin. 2013;2:356-65. Epub 2013 Mar 5 PubMed.

    View all comments by Mojtaba Golzan

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