Twins Assessment Followed by Larger Study of OCTA in Detection of Alzheimer’s Disease
By Dilraj S. Grewal, MD, and Sharon Fekrat, MD
As the incidence of Alzheimer’s disease (AD) continues to increase, the need for an accurate yet rapid and less invasive diagnostic screening method becomes more pressing. Current diagnostic modalities for AD have limitations. Magnetic resonance imaging and positron emission tomography are costly, cerebral spinal fluid testing is invasive, genetic markers such as serum amyloid have suboptimal specificity and sensitivity, neuropsychological evaluation is complex and time-consuming, and access to neurology specialists varies. Several research groups, including our group at Duke University (Stephen P. Yoon, Atalie C. Thompson, MD, MPH, Bryce W. Polascik, Cynthia Dunn, James R. Burke, MD, PhD, and others), are currently exploring how OCT angiography (OCTA) and other imaging methods may fill this need.
Neurodegenerative changes and microvascular remodeling are recognized as important factors in the pathogenesis of mild cognitive impairment (MCI) and AD. Previous clinical and histologic studies have suggested that the neurodegenerative process, which affects the brain, may also affect the retina of AD patients. Neuronal loss measured as decreased retinal nerve fiber layer thickness and ganglion cell layer thickness has been correlated with cognitive impairment in AD. Prior research using fundus photographs has demonstrated that AD patients have narrower venular caliber, decreased arteriolar and venular fractal dimension, and increased arteriolar and venular tortuosity. However, such visible vascular changes may be a relatively late indicator of target organ damage. Because OCTA can be used to assess the retinal microvasculature with unprecedented detail, it may detect areas of vascular impairment that mirror AD-related cerebrovascular changes and aren’t visible on fundus photographs or examination. Such changes in the retinal microvasculature may serve as early non-invasive surrogate biomarkers for the diagnosis of AD.
Earlier this year, we published findings from our assessment of 96-year-old female monozygotic twins, one who has advanced AD and one who is cognitively normal. OCTA showed the twin with AD to have significantly reduced vessel density in the superficial capillary plexus compared with her sister, indicating that marked changes occur in the retinal microvasculature of individuals with AD independent of the aging process.1 Also, we recently completed a large prospective study comparing OCTA findings in individuals with AD, individuals with MCI, and cognitively intact controls. Results suggest that vessel density and perfusion density assessed with OCTA may be useful biomarkers for AD screening in symptomatic individuals and for distinguishing between MCI and AD.2 The study involved 70 eyes from 39 AD subjects, 72 eyes from 37 MCI subjects, and 254 eyes from 133 cognitively intact control subjects. Based on OCTA, AD eyes had significantly decreased vessel density and perfusion density in the superficial capillary plexus compared with MCI eyes and cognitively intact controls. However, no significant difference in vessel density or perfusion density in the superficial capillary plexus was seen between MCI eyes and controls. The area of the foveal avascular zone did not significantly differ between the groups. In addition, vessel density and perfusion density in the 3-mm ETDRS grid correlated with Mini-Mental Status Examination (MMSE) scores.
Much work remains to be done to establish these OCTA metrics as biomarkers for Alzheimer’s, but the potential impact on early detection as well as clinical trials of treatments for this devastating disease is exciting. We look forward to reporting results from our planned future studies, which will collect longitudinal data for assessing change over time in AD, assess changes in genetically predisposed individuals, and expand evaluation of OCTA across a spectrum of neurodegenerative diseases.
1. Grewal DS, Polascik BW, Hoffmeyer GC, Fekrat S. Assessment of differences in retinal microvasculature using OCT Angiography in Alzheimer’s Disease: A twin discordance report. Ophthalmic Surg Lasers Imaging Retina. 2018;49(6):440-444.
2. Yoon SP, et al. Retinal microvascular and neurodegenerative changes in Alzheimer’s disease and mild cognitive impairment compared to controls. Ophthalmology Retina. Article in Press.
Dr. Grewal is a vitreoretinal surgeon, uveitis specialist, and associate professor of ophthalmology at the Duke Eye Center in Durham, NC.
Dr. Fekrat is a vitreoretinal surgeon and professor of ophthalmology at the Duke Eye Center in Durham, NC.