Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms

Abstract

Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease.

Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired.

Design, setting, and participants: A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020.

Main outcomes and measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension.

Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, β = -3.06; P = .007; outer inferior quadrant, β = -2.60; P = .02), outer plexiform layer (outer superior quadrant, β = -3.44; P = .03), and outer nuclear layer (central quadrant, β = -8.61; P = .03; inner nasal quadrant, β = -8.39; P = .04; inner temporal quadrant, β = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied.

Conclusions and relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.

Figure 1.. Retinal Vessel Segmentation and Tortuosity and Fractal Dimension Calculation

A, Representative fundus photograph with conversion to grayscale used for retinal vessel segmentation. B, Noise reduction by elimination of small continuous pixel bodies less than 50-pixel area. C, Vessel branch points were visually confirmed and vessel segments were defined by a continuous line of pixels between branch points. D, Each vessel segment was classified as either an artery or vein by a single trained and masked researcher. Arterial and venous branch points are indicated by the red and blue dots, respectively.

Figure 2.. Estimated Difference in Thickness of Retinal Layers in PSEN1 Carriers vs Controls

Early Treatment Diabetic Retinopathy Study (ETDRS) grids showing estimated difference (regression coefficient) in the thickness of various retinal layers of the PSEN1 carriers compared with the controls. GCL indicates ganglion cell layer; IPL, inner plexiform layer; and RNFL, retinal nerve fiber layer. The left side of each grid represents the nasal retina, and the right side represents the temporal retina (light green, –0.1 to –5.0; dark green, –5.1 to –10.0). ^aP < .05.

Figure 3.. Estimated Difference in Thickness of Retinal Layers in PSEN1 Carriers vs Controls

Early Treatment Diabetic Retinopathy Study (ETDRS) grids showing estimated difference (regression coefficient) in the thickness of various retinal layers of the PSEN1 carriers compared with the controls. INL indicates inner nuclear layer; ONL, outer nuclear layer; and OPL, outer plexiform layer. The left side of each grid represents the nasal retina, and the right side represents the temporal retina (light green, –0.1 to –5.0; dark green, –5.1 to –10.0). ^aP < .05. ^bP < .01.