GRN heterozygous mutations cause progranulin-deficient frontotemporal dementia, an ensemble of age-associated neurodegenerative syndromes presenting predominantly with behavioral abnormalities. Previous investigations suggest neuronal ceroid lipofuscinosis-like features in the retina. Their influence on retinal layer volumes, clinical relevance and utility as biomarkers remains unknown.

We performed optical coherence tomography (OCT) and scanning laser ophthalmoscopy cross-sectionally in 23 GRN haploinsufficient subjects (GRN; age [years, mean+SD]: 62±11, gender [male, N(%)]: 11(48), mean Clinical Dementia Rating(CDR)=0.5; CDR=0.0 for 9 subjects) and 85 healthy controls (HCs) (age [years, mean+SD]: 69±15, gender [male, N(%)]: 42(49)), investigating qualitative and quantitative retinal changes. Mixed-linear effects were used to study the relationships between OCT findings and cognitive performance including design fluency (DF), lexical fluency (LF) and semantic fluency (SF).

Eight GRN eyes (17%) of five subjects (22%) had drusen-like depositions detectable on OCT. Quantifying macular layers, GRN eyes had a thicker outer plexiform layer (OPL, 0.33±0.05mm³, p<0.001), thinner outer nuclear layer (ONL, 0.66±0.07mm³, p=0.019) and thinner retinal pigment epithelium (RPE,0.15±0.02mm³, p=0.039) compared with HC eyes (OPL: 0.30±0.03mm³, ONL: 0.69±0.07mm³, RPE: 0.16±0.01mm³), but no differences in inner retinal layers (replicated without eyes with drusen). GRN subjects with ONL volume<median at baseline, had a faster decline of DF (B=-0.054, SE=0.018, p=0.004), LF (B= - 0.076, SE=0.025, p=0.003) and SF (B=-0.110, SE=0.033, p=0.001) during follow-up compared to subjects with ONL volume≥median. Drusen, OPL and RPE at baseline were not associated with subsequent changes in executive function. Retinal autofluorescence and magnet resonance imaging are pending.

GRN-haploinsufficiency is associated with retinal phenotypes, including drusen and outer retinal layer thinning, suggestive of photoreceptor degeneration. Only ONL volume showed a prognostic value for future cognitive function changes and thereby might be useful as a biomarker.