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-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 (GMV) and white matter hyperintensities (WMH). Cognitive outcomes included composites of memory, executive functioning, and processing speed, as well as Mini-Mental State Examination (MMSE) total scores. Longitudinal mixed effects models were employed, 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 GMV (p < .001) and increases in WMH (p = .003). Exploratory analyses suggested that the relation between TNF-α and GMV was curvilinear (TNF-α2 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-α to MMSE scores over time (p = .036) but not the cognitive composites (ps >.05). CONCLUSION Systemic inflammation, as indexed by plasma TNF-α, holds potential as a biomarker for age-related declines in brain health.