The OCTAF study is a monocentric, cross-sectional pilot study designed to investigate the relationship between retinal microvascular biomarkers and cognitive impairment in patients with atrial fibrillation (AF). Atrial fibrillation is a highly prevalent cardiac arrhythmia associated not only with stroke and cardiovascular complications but also with an increased risk of cognitive decline, even in the absence of overt cerebrovascular events. Current approaches to detect cognitive impairment are often time-consuming and resource-intensive, highlighting the need for simple, non-invasive screening tools. The retina, often described as a "window to the brain," provides a unique opportunity to assess microvascular health, and Optical Coherence Tomography Angiography (OCT-A) allows detailed, non-invasive visualization of retinal blood flow and structure.

In this study, 40 patients with AF aged 40 years or older will be recruited at UZ Brussels and stratified according to cognitive status using the Montreal Cognitive Assessment (MoCA), with a score below 26 indicating cognitive impairment. Each participant will undergo a standardized evaluation including a questionnaire capturing demographic characteristics and vascular risk factors, a MoCA cognitive test, and OCT-A imaging of the retina and optic nerve head. The imaging will focus on quantifying vessel density in different retinal layers, including the superficial and deep capillary plexuses and radial peripapillary capillaries, as well as measuring the foveal avascular zone area.

The primary objective is to compare these OCT-A parameters between AF patients with and without cognitive impairment. Statistical analyses will be exploratory and performed using regression models to account for potential confounders such as age and cardiovascular risk factors. As a pilot study, the aim is not to establish definitive causal relationships but to assess feasibility, characterize variability, and generate preliminary data that may guide future larger-scale studies. The study is expected to run from late 2025 to September 2026 and will adhere to ethical standards and Good Clinical Practice guidelines. Ultimately, the study seeks to determine whether retinal imaging could serve as a practical and non-invasive tool for early detection of cognitive decline in patients with atrial fibrillation.

The OCTAF study is a monocentric, cross-sectional pilot investigation conducted at UZ Brussels that aims to explore the association between retinal microvascular characteristics and cognitive impairment in patients with atrial fibrillation. Atrial fibrillation is the most common sustained cardiac arrhythmia and represents a growing public health concern, particularly in aging populations. While its association with stroke and thromboembolic complications is well established, increasing evidence indicates that AF is also independently linked to cognitive decline, even in patients without clinically apparent stroke. The mechanisms underlying this association remain incompletely understood but are thought to involve a combination of silent cerebral infarctions, microbleeds, chronic cerebral hypoperfusion, systemic inflammation, and shared vascular risk factors such as hypertension, diabetes, and atherosclerosis. Cognitive impairment in AF patients is clinically significant because it negatively impacts quality of life, treatment adherence, and long-term outcomes, thereby increasing the burden on healthcare systems.

Despite this, routine screening for cognitive impairment in AF patients is not widely implemented, largely due to the complexity, cost, and limited accessibility of conventional neuroimaging and neuropsychological assessments. This has led to growing interest in identifying alternative, non-invasive biomarkers that can facilitate early detection. The retina provides a unique opportunity in this regard, as it shares embryological origin and microvascular characteristics with the brain. The emerging field of oculomics focuses on the use of retinal imaging to detect systemic and neurological diseases. Optical Coherence Tomography Angiography is a particularly promising modality because it enables high-resolution visualization of retinal microvasculature without the need for contrast agents, allowing quantitative assessment of parameters such as vessel density and the foveal avascular zone.

Previous research investigating retinal biomarkers in neurodegenerative conditions such as Alzheimer's disease and mild cognitive impairment has produced inconsistent findings, with some studies reporting reduced vessel density and enlarged foveal avascular zones, while others found no significant differences. Similarly, studies in atrial fibrillation populations have demonstrated alterations in retinal microvasculature compared to healthy controls, including reduced perfusion and structural retinal changes potentially related to ischemia. However, no prior study has specifically examined retinal OCT-A parameters in AF patients stratified by cognitive status, which represents an important gap in knowledge that this study seeks to address.

The OCTAF study will recruit 40 patients diagnosed with atrial fibrillation from the outpatient cardiology clinic at UZ Brussels. Eligible participants must be aged 40 years or older, have a confirmed diagnosis of AF, possess adequate medical records, and provide informed consent. Patients with a history of stroke or thromboembolic events, significant ocular disease, recent ocular surgery, systemic conditions affecting retinal microvasculature such as diabetes or severe organ failure, neurodegenerative or psychiatric disorders, or poor-quality OCT-A imaging will be excluded in order to minimize confounding factors. The study is designed as a pilot, and therefore the sample size is chosen to allow estimation of variability and feasibility rather than to achieve statistical power for hypothesis testing.

All participants will attend a single study visit at the Ophthalmology Department. During this visit, they will first complete a standardized questionnaire to collect demographic information, including age, sex, height, weight, and educational level, as well as data on cardiovascular risk factors such as hypertension, hyperlipidemia, smoking, alcohol consumption, and medication use, including anticoagulant therapy. Cognitive function will then be assessed using the Montreal Cognitive Assessment, a brief screening tool that evaluates multiple cognitive domains including memory, attention, executive function, language, visuospatial abilities, and orientation. The test takes approximately ten minutes to complete, and a score below 26 is considered indicative of cognitive impairment, with an adjustment of one point for individuals with lower educational attainment. The MoCA test is administered prior to retinal imaging to avoid interference from pupil dilation, which can temporarily impair visual performance and potentially affect test results.

Following cognitive assessment, participants will undergo OCT-A imaging using the AngioPlex Elite Zeiss system. Imaging will focus on the foveal region and the optic nerve head, and automated segmentation software will be used to analyze different vascular layers, including the superficial capillary plexus, deep capillary plexus, and radial peripapillary capillaries. Quantitative parameters will include vessel density in these layers and the area of the foveal avascular zone. All images will be reviewed by experienced clinicians to ensure quality prior to analysis. These measurements will serve as the primary variables of interest in evaluating the relationship between retinal microvascular health and cognitive status.

Data will be collected and managed using a secure electronic data capture system, REDCap, which allows for real-time data entry, audit trails, and controlled access. Statistical analyses will be exploratory in nature and conducted using R software. Continuous variables will be summarized using appropriate descriptive statistics depending on their distribution, while categorical variables will be presented as frequencies and percentages. Comparisons between patients with and without cognitive impairment will be performed using regression-based models that allow adjustment for potential confounding variables such as age, sex, and cardiovascular risk factors. Special consideration will be given to the fact that both eyes are imaged, and appropriate methods will be used to account for within-subject correlation, such as selecting a single eye for primary analysis or applying mixed-effects models. Interobserver reliability for OCT-A measurements may also be assessed using statistical measures such as Cohen's kappa or intraclass correlation coefficients.

As a pilot study, the primary goal is not to draw definitive conclusions but to evaluate feasibility, assess variability in OCT-A parameters, estimate the prevalence of cognitive impairment in the AF population, and generate preliminary effect sizes that can inform the design of future, adequately powered studies. The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and all applicable regulatory requirements. Ethical approval will be obtained prior to initiation, and all participants will provide informed consent. Data confidentiality will be strictly maintained. Participants identified as having possible cognitive impairment based on the MoCA will be advised to seek further evaluation through their general practitioner.

Inclusion Criteria:

• > 40 years old
• AF confirmed by cardiologist
• signed informed consent

Exclusion Criteria:

• history of stroke or thromboembolic event
• recent history of ocular surgery
• ocular diseases (severe cataract, glaucoma, macular degeneration, corneal ulcer, optic neuropathies)
• history of any systemic illness that may impact structure and microvasculature of the retina such as diabetes, hyperthyroidism, rheumatic disease, severe kidney injury, liver failure, advanced malignancy,
• OCT-A images of insufficient quality (due to artifacts)
• history of AF ablation
• major depression or other psychiatric/ neurodegenerative disorders