Serum neurofilament light in atrial fibrillation: clinical, neuroimaging and cognitive correlates

Emerging evidence suggests that atrial fibrillation is associated with cognitive dysfunction independently of stroke, but the underlying mechanisms remain unclear. In this cross-sectional analysis from the Swiss-AF Study (NCT02105844), we investigated the association of serum neurofilament light protein, a neuronal injury biomarker, with (i) the CHA2DS2-VASc score (congestive heart failure, hypertension, age 65-74 or ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, sex), clinical and neuroimaging parameters and (ii) cognitive measures in atrial fibrillation patients.

We measured neurofilament light in serum using an ultrasensitive single-molecule array assay in a sample of 1,379 atrial fibrillation patients (mean age 72 years, 27% female). Ischemic infarcts, small vessel disease markers and normalized brain volume were assessed on brain MRI. Cognitive testing included the Montreal Cognitive Assessment, Trail Making Test, Semantic Verbal Fluency and Digit Symbol Substitution Test, which were summarized using principal component analysis. Results were analyzed using univariable and multivariable linear regression.

Neurofilament light was associated with the CHA2DS2-VASc score, with an average 19.2% (95% confidence interval [17.2%, 21.3%]) higher neurofilament per unit CHA2DS2-VASc increase. This association persisted after adjustment for age and MRI characteristics. In multivariable analyses, clinical parameters associated with neurofilament light were higher age (32.5% [27.2%, 38%] neurofilament increase per 10 years), diabetes mellitus, heart failure and peripheral artery disease (26.8% [16.8%, 37.6%], 15.7% [8.1%, 23.9%] and 19.5% [6.8%, 33.7%] higher neurofilament, respectively). Mean arterial pressure showed a curvilinear association with neurofilament, with evidence for both an inverse linear and a U-shaped association. MRI characteristics associated with neurofilament were white matter lesion volume and volume of large non-cortical or cortical infarcts (4.3% [1.8%, 6.8%] and 5.5% [2.5%, 8.7%] neurofilament increase per unit increase in log-volume of the respective lesion), as well as normalized brain volume (4.9% [1.7%, 8.1%] higher neurofilament per 100 cm3 smaller brain volume). Neurofilament light was inversely associated with all cognitive measures in univariable analyses. The effect sizes diminished after adjusting for clinical and MRI variables, but the association with the first principal component was still evident.

Our results suggest that in atrial fibrillation patients, neuronal loss measured by serum neurofilament light is associated with age, diabetes mellitus, heart failure, blood pressure and vascular brain lesions, and inversely correlates with normalized brain volume and cognitive function.