Abstract

Over the past decade, a surge of evidence has documented various pathological processes in the retina of patients suffering from mild cognitive impairment, Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative diseases. Numerous studies have shown that the retina, a central nervous system tissue formed as a developmental outgrowth of the brain, is profoundly affected by AD. Harboring the earliest detectable disease-specific signs, amyloid β-protein (Aβ) plaques, the retina of AD patients undergoes substantial ganglion cell degeneration, thinning of the retinal nerve fiber layer, and loss of axonal projections in the optic nerve, among other abnormalities. More recent investigations described Aβ plaques in the retina located within sites of neuronal degeneration and occurring in clusters in the mid- and far-periphery of the superior and inferior quadrants, regions that had been previously overlooked. Diverse structural and/or disease-specific changes were also identified in the retina of PD, Huntington’s disease, and multiple sclerosis patients. The pathological relationship between the retina and brain prompted the development of imaging tools designed to noninvasively detect and monitor these signs in living patients. One such tool is optical coherence tomography (OCT), uniquely providing high-resolution two-dimensional cross-sectional imaging and three-dimensional volumetric measurements. As such, OCT emerged as a prominent approach for assessing retinal abnormalities in vivo, and indeed provided multiple parameters that allowed for the distinction between normal aged individuals and patients with neurodegenerative diseases. Beyond the use of retinal optical fundus imaging, which recently allowed for the detection and quantification of amyloid plaques in living AD patients via a wide-field view of the peripheral retina, a major advantage of OCT has been the ability to measure the volumetric changes in specified retinal layers. OCT has proven to be particularly useful in analyzing retinal structural abnormalities consistent with disease pathogenesis. In this review, we provide a summary of OCT findings in the retina of patients with AD and other neurodegenerative diseases. Future studies should explore the combination of imaging early hallmark signs together with structural–functional biomarkers in the accessible retina as a practical means of assessing risk, disease progression, and therapeutic efficacy in these patients.

Highlights

  • Shielded against external injuries, the brain is a concealed central nervous system (CNS) structure that may be uniquely observed through the one exception to its enclosure: the retina

  • Scale bars = 10 μm. (C) Quantitative Nissl neuronal area in Alzheimer’s disease (AD) patients (n = 9) and age- and gender-matched CTRL (n = 8) revealing a significant reduction in AD patients. (D) Quantitative analysis of 12F4-immunoreactive (IR) area of Aβ42-containing plaques in the superior quadrant of retinal flatmounts in a subset of definite AD patients (n = 8) and matched controls (n = 7) showing a significant increase of Aβ42 plaques in AD patients. (E) Schematic of a noninvasive retinal amyloid imaging method using curcumin (Longvida®) to label retinal amyloid β-protein (Aβ) in live human patients

  • White spots marked by red circles are curcumin-positive amyloid plaques detected in the retina of a living AD patient. (F) Scatter bar plot displays retinal amyloid index (RAI) scores, a fully automated calculation of increased curcumin fluorescence representing amyloid deposits in the retina

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Summary

Introduction

The brain is a concealed central nervous system (CNS) structure that may be uniquely observed through the one exception to its enclosure: the retina. In a more recent multisite study, 21 AD patients were compared against 74 agematched controls, revealing a significant (p = 0.038) reduction in average RNFL thickness via OCT imaging.

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