Dataset Information

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.

SUBMITTER: Armstrong GW

PROVIDER: S-EPMC7662482 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.