Mediation Effect of Brain Volume on the Relationship Between Peripheral Inflammation and Cognitive Decline

Abstract

Background: Studies have reported the associations between inflammation, brain volume, and cognition separately. It is reasonable to assume peripheral inflammation may contribute to cognitive decline through brain volume atrophy. Objective: To examine the associations between peripheral inflammation, brain volume, and cognition among adults, and to investigate whether brain volume atrophy mediates the inflammation-cognition relationship Methods: We retrieved 20,381 participants with available data on peripheral inflammation, brain volume, and cognition from the UK Biobank cohort. Cognitive function was assessed by performance on cognitive tasks probing various cognitive domains. Brain volumes were measured by magnetic resonance imaging (MRI). Multivariable linear models were used to investigate the associations between three peripheral inflammatory indexes (C-reactive protein, systemic immune-inflammatory index, neutrophil-to-lymphocyte ratio), brain volume, and cognition. Mediation analyses were conducted to assess the potential mediating effect of brain volume atrophy. All results were corrected for multiple comparisons using the false-discovery rate (FDR). Results: Peripheral inflammation was inversely associated with grey matter volume (GMV), white matter volume (WMV), and cognition after adjusting for potential covariates. For instance, CRP was associated with the GMV of left parahippocampal gyrus (β= –0.05, 95% confidence interval [CI]: –0.06 to –0.04, p FDR =1.07×10 - 16) and general cognitive factor (β= –0.03, 95% CI: –0. –0.04 to –0.01, p FDR = 0.001). Brain volume atrophy mediated the inflammation-cognitive decline relationship, accounting for 15–29% of the overall impact. Conclusion: In this cohort study, peripheral inflammation was associated with brain volume atrophy and cognitive decline. Brain atrophy may mediate the inflammation-cognitive decline relationship.

Peripheral inflammation and neurocognitive impairment: correlations, underlying mechanisms, and therapeutic implications

“…A recently published Mendelian randomization study ( Zhuo et al, 2023 ) based on a sample of 20,381 cases pointed to a causal relationship between high levels of peripheral inflammation levels and cognitive deterioration, which may be mediated by atrophy of brain volume (gray and white matter) under the influence of inflammation. The study demonstrated that peripheral C-reactive protein (CRP) levels correlated with gray matter volume in the left para hippocampal gyrus (β = −0.05, 95% confidence interval (CI): −0.06 to −0.04, pFDR = 1.07*10 −16 ) and cognitive performance (β = −0.03, 95% CI: −0.04 to −0.01, pFDR = 0.001).…”