Exploration of Eye Imaging for Identification of Preclinical Alzheimer Disease

Rajendra Apte, MD, PhD, Washington University School of Medicine, Paul A. Cibis Distinguished Professor of Ophthalmology, Professor of Developmental Biology and Medicine, Director of Translational Research and Jeffrey Fort Innovation fund

Rajendra Apte, MD, PhD

A new study suggests that cognitively healthy individuals with preclinical Alzheimer disease have retinal microvascular abnormalities as well as architectural alterations and that these changes occur at earlier stages of disease than previously demonstrated.

The study, conducted by investigators at Washington University, was initiated to determine if optical coherence tomographic angiography (OCTA) can detect early retinal alternations in cognitively normal study participants with preclinical Alzheimer disease diagnosed by criterion standard biomarker testing.

“This was a pilot study that examined biomarker positive preclinical Alzheimer patients.” This is a very well characterized cohort. By advanced neuropsychometric testing, they have no dementia. But, they are positive for amyloid deposits in the brain or tau protein by PET or LP or positive for both,” Rajendra Apte, MD, PhD, Paul A. Cibis Distinguished Professor of Ophthalmology, Professor of Developmental Biology and Medicine, Director of Translational Research and Jeffrey Fort Innovation fund, Washington University School of Medicine, told NeurologyLive. “Prior studies have shown that being biomarker positive is strongly associated with development of clinical Alzheimer in the future. Prior studies have also shown that in autopsy eyes of patients with advanced Alzheimer disease, there is evidence of retinal ganglion cell degeneration in the retina with associated optic neuropathy. In addition, in patients with mild or more severe cognitive impairment, studies with optical coherent tomography, light-based imaging and precursor to the OCTA, showed thinning of some retinal layers suggesting retinal neurodegeneration reflective of brain findings. But, this has never been previously shown in a cognitively normal, biomarker positive preclinical Alzheimer population.”

The case-control study included 30 participants recruited from the Charles and Joanne Knight Alzheimer Disease Research Center. All participants received a complete neuro-ophthalmic examination which included standard assessment of Snellen visual acuity, color perception using Ishihara color plates, ocular motility, intraocular pressure, refractive status and examination of the anterior segment and dilated fundus and determined that all participants were cognitively normal. Additionally, participants underwent PET and/or cerebral spinal fluid testing to determine biomarker status. Data were collected from 58 eyes of 30 participants, 16 women (53%) and 14 men (47%), with a mean age of 74.5 and an age range of 62—92 years from July 1, 2016 through Sept. 30, 2017 and analyzed from July 30, 2016 through Dec. 31, 2017.

Main outcome measures included the total and temporal retinal nerve fiber layer thickness; ganglion cell layer thickness; macular volume; inner, outer and total foveal thickness; total macular, foveal and parafoveal vascular density; and foveal avascular zone (FAZ).

Fourteen of the participants had biomarkers positive for Alzheimer disease and consequently a diagnosis of preclinical Alzheimer disease (mean [SD] age, 73.5 [4.7] years), while the 16 participants without biomarkers were used as the control group (mean [SD] age, 75.4 [6.6 years). Researchers determined that the FAZ was larger in the biomarker-positive group in comparison to the control group (mean [SD], .364 [.095] vs. .275 [.060] mm²; P = .002). The mean inner foveal thickness was found to be smaller in the biomarker-positive group (66 [9.9] vs. 75.4 [10.6] μm; P = .03).

The results concluded that individuals with biomarker-positive, preclinical Alzheimer disease may have retinal vascular and architectural alteration apparent before onset of clinically identifiable cognitive symptoms. OCTA may allow quick, inexpensive and noninvasive screening for those with preclinical Alzheimer disease based on FAZ enlargement unless the findings are related to confounding factors unrelated to FAZ enlargement.

“We demonstrated that there was significant thinning especially in the very center of the retina, around the fovea, in the inner layers of the retina. This is novel as this noninvasive OCT was able to detect these changes prior to any evidence of dementia,” concluded Apte. “The fovea, which is responsible for your most precise vision, has an avascular zone around it normally. In our cohort, with OCTA we found that this FAZ was significantly enlarged. This could have significant clinical implications as vascular degeneration and atrophy has been demonstrated in the brain in Alzheimer disease. Why this occurs in the retina so early prior to any onset of symptoms is unclear...could this be damage to capillaries, deposition of material etc.? Further studies are needed.”

This finding and establishment of the molecular basis of the enlarged FAZ in biomarker-positive patients needs to be confirmed in longitudinal studies in larger cohorts to best determine the value in identifying preclinical Alzheimer disease.

“Given the small size of the cohort and the cross-sectional nature of the study, we need to substantiate these findings in the future. As therapeutic strategies are designed early in disease, and if our findings are validated, the eye could be a biomarker for therapeutic response should these changes in the vasculature be reversible,” Apte concluded.

Recruitment has proceeded in order to evaluate individuals with biomarker-positive mild cognitive impairment and more severe Alzheimer disease, as well as to follow up on individuals with biomarker-positive findings for longitudinal evaluation of changes in retinal vasculature.

Asked about future plans, Apte addressed questions that researchers aim to answer in future longitudinal studies, “We hope to follow biomarker-positive patients with serial testing by PET and LP and neuropsychometric testing. We will correlate the findings of OCTA with progression to dementia. Would it be possible to stratify progression of disease by the eye findings? E.g. does an increased FAZ put you at a higher risk for developing dementia early as opposed to the biomarker-positive patients who have a normal FAZ on OCTA? We would need to create a normative FAZ database and establish a floor for what’s associated with progression at faster rates.”

REFERENCE

O’Bryhim B, Apte R, Kung N, et al. Association of Preclinical Alzheimer Disease With Optical Coherence Tomographic Angiography Findings. JAMA Ophthalmology. 2018.

doi

:10.1001/jamaophthalmol.2018.3556.