The association of mid-to late-life systemic inflammation with white matter structure in older adults: The Atherosclerosis Risk in Communities Study

Abstract

We examined whether the pattern of middle- to late-life systemic inflammation was associated with white matter (WM) structural abnormalities in older adults. A total of 1532 participants (age = 76.5; standard deviations = 5.4) underwent 3T brain magnetic resonance imaging to quantify white matter hyperintensity volume and whole-brain WM microstructural integrity (fractional anisotropy, mean diffusivity). High-sensitivity C-reactive protein (CRP), a marker of systemic inflammation, was measured at 3 visits (21 and 14 years before, and concurrent with, neuroimaging). Participants were categorized into 1 of 6 groups based on their 21-year pattern of low (<3 mg/L) versus elevated (≥3 mg/L) CRP. Compared to the group with low CRP at all 3 visits, the group that transitioned from low to elevated CRP during midlife demonstrated greatest white matter hyperintensity volume and poorest WM microstructural integrity, after adjusting for demographic variables and cardiovascular risk factors. Participants with high CRP at all visits also demonstrated greater WM structural abnormalities, but only after accounting for differential attrition. These results suggest that increasing and persistent inflammation in the decades spanning middle-to late-life may promote WM disease in older adults.

Keywords: Aging; Brain; Diffusion tensor imaging; Inflammation; Magnetic resonance imaging; White matter disease.

Figure 1. Study flowchart and C-reactive protein trajectory grouping

(A) Study design and primary inclusion and exclusion criteria. (B) Participants were assigned to one of six C-reactive protein (CRP) trajectory groups based on CRP levels at Visits 2, 4, and 5. The dotted line denotes CRP levels at each time-point. A line above the tic mark indicates a CRP level ≥3 mg/L.

Figure 2. Late-life white matter hyperintensity volume according to 21-year C-reactive protein trajectory

Estimated late-life total white matter hyperintensity volume according to the trajectory of C-reactive protein levels from mid- to late-life in the (A) primary analysis and (B) after accounting for differential attrition due to death and drop-out using inverse probability of attrition weighting. Models are adjusted for age, sex, race-center, education, cigarette smoking and alcohol use status, BMI, total cholesterol, HDL, hypertension, diabetes, coronary heart disease, previous cancer, inflammatory disease, anti-inflammatory medication use, and APOE ε4 status. *P < .05; ** P < .01 difference between group and the Stable Low (referent) group Abbreviations: IPAW = inverse probability of attrition weighting; WMH = white matter hyperintensity.

Figure 3. Late-life fractional anisotropy and mean diffusivity according to 21-year C-reactive protein trajectory

Estimated late-life total brain (A, B) fractional anisotropy and (C, D) mean diffusivity according to the trajectory of C-reactive protein levels from mid- to late-life in the (A, C) primary analysis of the total sample and (B, D) after accounting for differential attrition due to death and drop-out using inverse probability of attrition weighting. Models are adjusted for age, sex, race-center, education, cigarette smoking and alcohol use status, BMI, total cholesterol, HDL, hypertension, diabetes, coronary heart disease, previous cancer, inflammatory disease, anti-inflammatory medication use, and APOE ε4 status. *P < .05; ** P < .01 difference between group and the Stable Low (referent) group Abbreviations: FA = fractional anisotropy; IPAW = inverse probability of attrition weighting; MD = mean diffusivity.