Nonvascular retinal imaging markers of preclinical Alzheimer's disease

Abstract

Introduction: In patients with Alzheimer's disease (AD) and mild cognitive impairment, structural changes in the retina (i.e., reduced thicknesses of the ganglion cell and retinal nerve fiber layers and inclusion bodies that appear to contain beta-amyloid protein [Ab]) have been previously reported. We sought to explore whether anatomic retinal changes are detectable in the preclinical stage of AD.

Methods: A cross-sectional study (as part of an ongoing longitudinal cohort study) involving 63 cognitively normal adults, all of whom have a parent with AD and subjective memory complaints. We compared neocortical amyloid aggregation (florbetapir PET imaging) to retinal spectral domain optical coherence tomography (SD-OCT) markers of possible disease burden. Retinal biomarkers, including the number and surface area of retinal inclusion bodies and the thickness of retinal neuronal layers, were compared across groups with high vs. low neocortical beta-amyloid load.

Results: The surface area of inclusion bodies increased as a function of cortical amyloid burden. Additionally, there was a trend toward a selective volume increase in the inner plexiform layer (IPL; a layer rich in cholinergic activity) of the retina in Aβ+ relative to Aβ- participants, and IPL volume was correlated with the surface area of retinal inclusion bodies.

Discussion: These initial results suggest that retinal imaging may be a potential cost-effective and noninvasive technique that can be used to identify those at-risk for AD. Layer-specific changes in the IPL and their association with surface area of inclusion bodies are discussed as a possible reflection of early inflammatory processes associated with cholinergic disruption and concurrent Ab accumulation in the neocortex.

Keywords: Acetylcholine; Alzheimer's disease; Biomarkers; Cholinergic hypothesis; Inner plexiform layer; OCT; Optical Coherence Tomography; Preclinical AD; Retina.

Fig. 1

Inclusion bodies (circled in red ellipses) identified via BluePeak autofluorescence (BAF) imaging in a high neocortical amyloid-beta load (Aβ+) cognitively normal older adult.

Fig. 2

Magnitude of difference between low neocortical amyloid-beta load (Aβ−) and high neocortical amyloid-beta load (Aβ+) cognitively normal older adults on each retinal neuronal layer and the number of inclusion bodies (“0” line represents Aβ− cognitively normal older adults group) (error bars represent 95% confidence intervals).

Fig. 3

Relationship between surface area of inclusion bodies and amyloid-beta (Aβ) burden (dotted lines represent 95% confidence intervals).

Fig. 4

Relationship between surface area of inclusion bodies and the volume of the inner plexiform layer (A) and the outer plexiform layer (B) (dotted lines represent 95% confidence intervals).