Plasma proteomic biomarkers as mediators or moderators for the association between poor cardiovascular health and white matter microstructural integrity: The UK Biobank study

Abstract

Introduction: The plasma proteome's mediating or moderating roles in the association between poor cardiovascular health (CVH) and brain white matter (WM) microstructural integrity are largely unknown.

Methods: Data from 3953 UK Biobank participants were used (40-70 years, 2006-2010), with a neuroimaging visit between 2014 and 2021. Poor CVH was determined using Life's Essential 8 (LE8) and reversing standardized z-scores (LE8_{z _rev}). The plasma proteome was examined as a potential mediator or moderator of LE8_{z _rev}'s effects on quantitative diffusion-weighted magnetic resonance imaging (dMRI) metrics.

Results: LE8_{z_rev} was significantly associated with deteriorated WM microstructural integrity, as reflected by lower tract-averaged fractional anisotropy (dMRI-FA_mean), (β ± standared error (SE): -0.00152 ± 0.0003, p < 0.001) and higher tract-averaged orientation dispersion (dMRI-OD_mean), (β ± SE:+0.00081 ± 0.00017, p < 0.001). Ten strongly mediating plasma proteins of 1463 were identified, with leptin as the principal driver.

Discussion: Poor CVH is linked to poor WM microstructural integrity measures (lower FA_mean and higher OD_mean), mostly mediated through leptin.

Highlights: Up to 3953 UK Biobank participants were selected for this study. Poor cardiovascular health (CVH) was determined using Life's Essential 8. The plasma proteome was examined as a potential mediator or moderator of poor CVH's effect on dMRI metrics. Ten plasma proteins were identified with strong mediating effects, with leptin being the principal driver.

Keywords: Life's Essential 8; aging; cardiovascular health; diffusion‐weighted magnetic resonance imaging; plasma proteomic biomarkers; white matter microstructural integrity.