Systemic Tumor Necrosis Factor-Alpha Trajectories Relate to Brain Health in Typically Aging Older Adults

Abstract

Background: Central nervous system levels of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, regulate the neuroinflammatory response and may play a role in age-related neurodegenerative diseases. The longitudinal relation between peripheral levels of TNF-α and typical brain aging is understudied. We hypothesized that within-person increases in systemic TNF-α would track with poorer brain health outcomes in functionally normal adults.

Methods: Plasma-based TNF-α concentrations (pg/mL; fasting morning draws) and magnetic resonance imaging were acquired in 424 functionally intact adults (mean age = 71) followed annually for up to 8.4 years (mean follow-up = 2.2 years). Brain outcomes included total gray matter volume and white matter hyperintensities. Cognitive outcomes included composites of memory, executive functioning, and processing speed, as well as Mini-Mental State Examination total scores. Longitudinal mixed-effects models were used, controlling for age, sex, education, and total intracranial volume, as appropriate.

Results: TNF-α concentrations significantly increased over time (p < .001). Linear increases in within-person TNF-α were longitudinally associated with declines in gray matter volume (p < .001) and increases in white matter hyperintensities (p = .003). Exploratory analyses suggested that the relation between TNF-α and gray matter volume was curvilinear (TNF-α 2p = .002), such that initial increases in inflammation were associated with more precipitous atrophy. There was a negative linear relationship of within-person changes in TNF-α to Mini-Mental State Examination scores over time (p = .036) but not the cognitive composites (all ps >.05).

Conclusion: Systemic inflammation, as indexed by plasma TNF-α, holds potential as a biomarker for age-related declines in brain health.

Keywords: Brain aging; Cognition; Gray matter volume; Inflammation; Neuroimaging.

Figure 1.

Curvilinear relationship of within-person changes in TNF‐α to total GMV. To visualize the quadratic effect, the mixed-effects model was refit with all predictors centered except the within-person terms. Predicted values from that model were then plotted, thus displaying the curve of a subject with a typical (average) trajectory in the present sample. The x-axis depicts within-person change in TNF‐α (pg/mL) whereas the y-axis depicts corresponding total GMV values (L). As illustrated by the curve, initial increases in inflammatory status were associated with more precipitous GMV decline, which eventually plateaued. GMV = Gray matter volume; TNF‐α = Tumor necrosis factor‐alpha.

Figure 2.

Linear relationship of within-person changes in TNF‐α to WMH. The x-axis depicts within-person change in TNF‐α (pg/mL) whereas the y-axis depicts corresponding WMH volumes (logarithmically transformed to meet assumptions of normality) with 95% confidence intervals. As illustrated in the graph, increases in TNF‐α over time were significantly associated with increases in WMH burden. TNF‐α = Tumor necrosis factor‐alpha; WMH = White matter hyperintensity.