Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study

Abstract

Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study.

Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later.

Results: Each SD increase in midlife inflammation composite score was associated with 1,788 mm³ greater ventricular (p = 0.013), 110 mm³ smaller hippocampal (p = 0.013), 519 mm³ smaller occipital (p = 0.009), and 532 mm³ smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently.

Conclusions: Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

Figure 1. Association between number of elevated inflammatory markers, brain volume, and episodic memory

Number of elevated inflammatory markers, predicted brain volumes, and episodic memory. Covariate-adjusted predicted brain volumes and delayed word recall test scores among participants with 0, 1–2, and ≥3 elevated inflammatory markers. Inflammatory marker levels were classified as elevated if they were ≥75th %tile based on the study sample. (A) Total brain volume, (B) Alzheimer disease signature region volume, (C) ventricular volume, (D) occipital lobe volume, (E) hippocampal volume, (F) delayed word recall score.

Figure 2. Association between midlife inflammation and late-life brain volume stratified by baseline age

Predicted values of Alzheimer disease (AD) signature region volume across levels of the inflammation composite score using a covariate-adjusted regression.