Midlife systemic inflammation may promote the development of white matter dysfunction

Midlife Systemic Inflammation, Late-Life White Matter Integrity, and Cerebral Small Vessel Disease: The Atherosclerosis Risk in Communities Study

Literature - Walker KA, Power MC, Hoogeveen RC, et al. - Stroke 2017;48: 3196-3202


Older adults often have cerebral small vessel disease (SVD) and white matter (WM) abnormalities, which are associated with cognitive decline and dementia [1,2]. It is not clear whether systemic inflammation contributes to the pathogenesis of these structural brain abnormalities.

In this sub-analysis of the Atherosclerosis Risk In Communities (ARIC) study, the relationships between midlife high-sensitivity (hs)CRP and late-life measures of WM hyperintensity (WMH) volume, deep and periventricular WM microstructure (fractional anisotropy and mean diffusivity [MD]), cerebral infarcts, and cerebral microbleeds (CMBs) were examined in adults without dementia. Since race and APOE ε4 allele status may influence the effect of inflammatory stimuli on vascular function [3,4], the modifying effect of each of these factors was also examined.

ARIC is an ongoing community-based, prospective study, which initially enrolled 15792 adults aged 45 - 65 years, of whom 1978 participants underwent brain MRI. Subjects with poor or incomplete MRI data, or with missing hsCRP or other covariates data, as well as those with dementia, chronic inflammatory diseases, intracranial abnormalities, and race other than white or black, were excluded, leaving 1485 participants for the analysis.

Main results

  • Mean time between hsCRP measurement and MRI was 21 years (SD 0.9). Individuals with high midlife hsCRP levels were more likely women, black, with a lower level of education, with fewer copies of the APOE ε4 allele, with higher levels of vascular risk factors, diagnosed with hypertension, HF and arthritis.
  • In the primary analysis, higher hsCRP levels were only marginally associated with greater WMH volume. However, there was a significant association between each SD increase in hsCRP level and greater WMH volume in participants with ≥1 copy of the APOE ε4 allele (SD: 0.14; 95%CI: 0.01–0.26; P=0.032), but not in APOE ε4-negative participants (SD: 0.03; 95%CI: −0.06 to 0.11; P=0.522).
  • Weighting analyses that account for differential attrition, strengthened the association between higher hsCRP levels and larger WMH volume.
  • Higher midlife hsCRP levels were associated with lower fractional anisotropy and greater MD within deep WM, as well as with lower fractional anisotropy within periventricular WM.
  • There was a significant interaction of race by hsCRP level on MD within the periventricular WM (P interaction=0.011). The association between higher midlife hsCRP and reduced periventricular WM microstructural integrity was significantly stronger among black, compared with white, participants.
  • The associations between hsCRP levels and deep WM microstructural integrity did not differ by race, and there was no evidence for effect modification by APOE ε4 status.
  • After accounting for differential attrition, associations between higher hsCRP levels and reduced periventricular microstructural integrity were strengthened, particularly among white participants.
  • Cortical and lacunar infarcts and CMBs were present on MRI in 10% (n=148), 17% (n=257) and 25% (n=362), respectively. No association of midlife hsCRP levels with cortical or lacunar infarct presence, CMB presence, or SVD composite score was found.


In a sub-analysis of the ARIC study, midlife systemic inflammation was associated with the development of chronic microangiopathic structural WM abnormalities in the elderly. These results provide insight into the temporal relationship between systemic inflammation and brain health and support the hypothesis that systemic inflammation plays a role in the pathogenesis of late-life WM dysfunction.


1. Knopman DS, Griswold ME, Lirette ST, et al; ARIC Neurocognitive Investigators. Vascular imaging abnormalities and cognition: mediation by cortical volume in nondemented individuals: atherosclerosis risk in communities-neurocognitive study. Stroke. 2015;46:433–440.

2. Fu JL, Liu Y, Li YM, et al. Use of diffusion tensor imaging for evaluating changes in the microstructural integrity of white matter over 3 years in patients with amnesic-type mild cognitive impairment converting to Alzheimer’s disease. J Neuroimaging. 2014;24:343–348.

3. Brown MD, Feairheller DL, Thakkar S, et al. Racial differences in tumor necrosis factor-α-induced endothelial microparticles and interleukin-6 production. Vasc Health Risk Manag. 2011;7:541–550.

4. Romero JR, Preis SR, Beiser AS, et al. Lipoprotein phospholipase A2 and cerebral microbleeds in the Framingham Heart Study. Stroke. 2012;43:3091–3094.

Find this article online at Stroke

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