Identification of Retinal Biomarkers in Alzheimer's Disease Using Optical Coherence Tomography: Recent Insights, Challenges, and Opportunities

Abstract

This review will highlight recent insights into measuring retinal structure in Alzheimer's disease (AD). A growing body of evidence indicates that disturbances in retinal blood flow and structure are related to cognitive function, which can severely impair vision. Optical coherence tomography (OCT) is an optical imaging technology that may allow researchers and physicians to gain deeper insights into retinal morphology and clarify the impact of AD on retinal health and function. Direct and noninvasive measurement of retinal morphology using OCT has provided useful diagnostic and therapeutic indications in several central nervous system (CNS) diseases, including AD, multiple sclerosis, and Parkinson disease. Despite several limitations, morphology assessment in the retinal layers is a significant advancement in the understanding of ocular diseases. Nevertheless, additional studies are required to validate the use of OCT in AD and its complications in the eye.

Keywords: Alzheimer’s disease; central nervous system diseases; ganglion cell layer; optical coherence tomography; retinal nerve fiber layer.

Figure 1

OCT’s spatial-temporal resolution vs. those of conventional clinical technologies. Magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission computed tomography (SPECT), magneto-electroencephalography (MEG), electroencephalography (EEG), optical coherence tomography (OCT).

Figure 2

Capabilities of ocular imaging showing the retinal layer thickness measurements for the retinal nerve fiber layer (RNFL, top row), ganglion cell layer and inner plexiform layer complex (GCL + IPL, middle row), and the ganglion cell complex (GCC consisting of the RNFL + GCL + IPL, bottom row) in each 10 × 10 grid cell within a macular area of 6 × 6 mm. Images were obtained with a 3D OCT-2000 unit (software version 8.11, Topcon Corp., Tokyo, Japan). The horizontal OCT B scans (right column) reveal the corresponding boundaries (green lines) of the inner retinal layers. The scanned macular area (7 × 7 mm) is shown on the left column. Image was taken with permission from Cunha et al. [20].

Figure 3

Capabilities of ocular imaging revealing drusen-like regions in the peripheral retina along with pigment dispersion noted in subjects with mild and more severe cognitive impairment. The red arrows indicate the location of the drusen and white spots observed at extramacular locations. The areas enclosed by the orange rectangles indicate the locations where pigment dispersion was observed. Abbreviations: mild cognitive impairment (MCI), oculus sinister (OS), oculus dextrus (OD).

Figure 4

Multi-variate regression analysis results obtained after investigating the association between the NFL and GCIPL layer thicknesses (i.e., GCL + IPL complex) to the disease categories of the participants: control, mild cognitive impairment (MCI) or Alzheimer’s disease (AD) by using a quasi-least squares technique, adjusted for multiple comparisons. In this analysis, a total of 17 regional thickness measurements for both NFL and GCIPL were used. Also, note that areas in the macula were statistically significantly thinner (red) or thicker (green). (Image was taken with permission from Lad et al. [26]).

Figure 5

Magnetic resonance images (MRI) and fundus images from a supposedly healthy subject (male, 51 years old) with discrete focal lesions in the brain without visible or detectable ocular manifestations. TOP: MRI images showing mild to moderate white matter (WM) disease in the MRI image. The images show discrete focal lesions in anterior and posterior WM, focal confluence in posterior WM, and periventricular caps. BOTTOM: Fundus images annotated (see black arrows) showing arterio-venous crossings. The arterio-venous crossings are frequent in the average healthy population. (Image Courtesy of Valia Rodriguez at Aston University, personal communication).