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

Background: Central nervous system levels of tumor necrosis factor-alpha (TNF-alpha), 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-alpha and typical brain aging is understudied. We hypothesized that within-person increases in systemic TNF-alpha would track with poorer brain health outcomes in functionally normal adults. Methods: Plasma-based TNF-alpha 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-alpha concentrations significantly increased over time (p < .001). Linear increases in within-person TNF-alpha 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-alpha and gray matter volume was curvilinear (TNF-alpha(2)(p) = .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-alpha 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-alpha, holds potential as a biomarker for age-related declines in brain health.