Analysis of amyloid deposits in the retina and implications for use as a biomarker of Alzheimer’s Disease

Abstract

AbstractBackgroundIn humans and the naturally occurring canine model of Alzheimer’s disease (AD), we and others observe amyloid deposits in the retina en face. We have previously shown that detecting the number of amyloid deposits with polarised light, using wide field, dye free retinal imaging, can predict the degree of severity of AD pathology in the brain. But some who take thin, transverse retinal sections find amyloid while others do not. Here, we report the surface area of retinal amyloid deposits in human and the canine model of AD.MethodFormalin‐fixed retinas from 29 individuals with a moderate to high likelihood of AD (with some comorbidities excluded) and 20 canines were flat‐mounted and imaged in florescence and polarized light (Fig 1). The full retina was imaged for 24 human and 16 canine retinas. For 4 canines, in‐vivo blue light fluorescent retinal images were collected before and after injection of an amyloid dye, CRANAD‐28. Deposits visible only after injection were counted. Fluorescence and polarization images were compared post‐mortem in a canine after an injection of CRANAD‐28. Amyloid deposits were segmented using custom methods. The total area of segmented deposits was then divided by the total retinal area imaged.ResultIn retinas from individuals with AD brain pathology, the area of the retinal covered by amyloid deposits was on average 0.01% and correlated with the number of deposits (Fig 2). In vivo (Fig 3), the area of the canine retina covered by amyloid deposits was on average 0.29% (Fig 4). In one ex vivo retina, fluorescent and polarization positive deposits had a concurrence of 93% and the average area of fluorescent deposits (0.14%) was larger than the same deposits imaged in polarimetry (0.08%) (Fig. 5).ConclusionThese findings and our previous report of an almost constant density of amyloid deposits across the retina, should guide in vivo imaging of amyloid in the retina as a biomarker of AD. Across all human and canine retinas, amyloid deposits covered less than 0.6% of the retinal surface. Careful, extensive sampling is needed. The surface area of amyloid deposits is an additional potential biomarker of disease severity.