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J Gerontol A Biol Sci Med Sci. 2019 Sep 24. pii: glz209. doi: 10.1093/gerona/glz209. [Epub ahead of print]

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

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Department of Neurology Memory and Aging Center University of California at San Francisco San Francisco, CA, USA.
Department of Epidemiology and Biostatistics University of California at San Francisco San Francisco, CA, USA.



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.


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.


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).


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


Inflammation; brain aging; cognition; gray matter volume; neuroimaging


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