Discovery of Novel Ophthalmic Imaging Biomarkers for Neurodegenerative Disease

Abstract

AbstractBackgroundThe retina is increasingly investigated as a site of Alzheimer’s Disease (AD) manifestation, with amyloid β (Aβ) plaques being found in the retina of AD and mild cognitively impaired (MCI) patients, however functional changes in the retina are poorly understood. Retinal imaging techniques can be utilized for neurodegenerative biomarkers, since the retina is the only CNS organ available for noninvasive tracking.MethodRetinal imaging techniques were using to compare the retina of wild‐type (WT) or AD transgenic mice containing the APP: Swedish and Indiana mutation expressed under the prion promoter (TgCRND8) at 20 and 30 weeks of age (n = 10 mice per genotype). Optical coherence tomography (OCT) for retinal thickness assessment, Fundus Autofluorescence Imaging (FAF) for aggregate visualization, and electroretinogram (ERG) for retinal neuronal electrical activity were performed. Aβ ELISA was also performed on retina and cortex to evaluate amyloid burden correlation.ResultMean retinal insoluble Aβ 1‐42 was significantly elevated in TgCRND8 mice relative to WT at 23 weeks (35 vs 4.2 pg/mL, P<0.05) and 42 weeks (77.9 vs 7.5 pg/mL, P<0.05), and correlated with insoluble cortical brain Aβ 1‐42 (Pearson’s r = 0.847, P = 0.001). Total retinal thickness was significantly higher in TgCRND8 mice relative to WT (233 µm vs 225 µm, P<0.01). Specifically, the retinal nerve fiber layer (RNFL) was thicker in TgCRND8 mice (28.5 vs 22.9 µm, P<0.01). FAF imaging revealed significant autofluorescent aggregate detection in TgCRND8 mice both in the RNFL (94.3 vs 59.8 spots, P<0.01) and outer plexiform layer (OPL) (87.8 vs 49.3 spots, P<0.01). Lastly ERG revealed reduced b wave amplitude in TgCRND8 mice relative to WT (197.45 vs 457.9 µV, P<0.001) and photopic negative response (PhNR) wave amplitude (8.2 µm vs 25.7 457.9 µV, P<0.001). These values are indicative of dysfunctional bipolar and retinal ganglion cell electrical activity.ConclusionTgCRND8 mice have functional changes in retina thickness, FAF lipofuscin deposition, and ERG, which may prove invaluable as biomarkers for pre‐clinical AD diagnosis, monitoring and drug efficacy trials.