Circulating inflammatory biomarkers are related to cerebrovascular disease in older adults

Abstract

Objective: This investigation aimed at examining whether circulating inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to cerebrovascular disease (CVD) assessed by MRI.

Methods: The study included nondemented elderly participants of a community-based, multiethnic cohort, who received baseline MRI scans and had CRP (n = 508), ACT (435), and IL6 (N = 357) measured by ELISA. Silent brain infarcts and white matter hyperintensities (WMH) were derived from all available MRI scans at baseline, approximately 4.4 years after blood sample collection for inflammatory biomarkers. Repeated assessments of infarcts and WMH, as well as microbleeds assessment, were performed at follow-up MRI visits around 4.5 years later. Cross-sectional and longitudinal relationship between inflammatory biomarkers and CVD were analyzed using appropriate logistic regression models, generalized linear models, or COX models.

Results: After adjusting for age, sex, ethnicity, education, APOE genotype, and intracranial volume, 1 SD increase in log₁₀IL6 was associated with infarcts on MRI {odds ratio [OR] (95% confidence interval [CI]) = 1.28 [1.02-1.60], p = 0.033}, and 1 SD increase in log₁₀CRP and log₁₀ACT was associated with microbleeds (OR [95% CI] = 1.46 [1.02-2.09], p = 0.041; and 1.65 [1.11-2.46], p = 0.013; respectively). One SD increase in log₁₀ACT was also associated with larger WMH at the follow-up MRI (b = 0.103, p = 0.012) and increased accumulation of WMH volume (b = 0.062, p = 0.041) during follow-up. The associations remained significant after additional adjustment of vascular risk factors and excluding participants with clinical stroke.

Conclusions: Among older adults, increased circulating inflammatory biomarkers were associated with the presence of infarcts and microbleeds, WMH burden, and progression of WMH.

Figure 1. Selection of the study population

Selection of study participants from the neuroimaging study of the Washington Heights/Hamilton Heights Inwood Columbia Aging Project (WHICAP). The study participants were those participants of the WHICAP imaging substudy started in 2004. A total of 769 WHICAP participants received MRI scans including T1-weighted images, FLAIR-weighted images, and proton density and T2-weighted double-echo images, which measured white matter hyperintensity (WMH) and infarcts. Among the 680 nondemented (n = 45 demented) participants who had baseline MRI data available and analyzed by FreeSurfer (n = 44 without FreeSurefer processing), a total of 508 (75%) participants had CRP and 435 (64%) had ACT/IL6 detected (figure 1). For the analysis for IL6, 357 participants were included after excluding 78 participants whose IL6 levels were out of the measurement range. A total of 310 (46% of 680) participants completed repeat MRI scans approximately 4.5 (SD = 0.9) years after their baseline scans, and 230 (74% of 310) of them also received gradient echo (GRE) scans for microbleeds assessment. In total, 235 (76%) had CRP and 204 (66%) had IL6/ACT measured among the 310 participants who received second structural MRI scans, and 171 (74%) had CRP and 145 (63%) had IL6/ACT measured among those who received GRE scans (figure 1). ACT = alpha 1-antichymotrypsin; CRP = C-reactive protein; IL6 = interleukin-6.

Figure 2. Association of circulating concentrations of inflammatory biomarkers and cerebrovascular disease

Association of circulating concentrations of C-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) with infarct and microbleeds status (A.a–A.c) and white matter hyperintensity (WMH) level (B.a–B.c). p Values in the figure were from unadjusted t-test (for infarcts and microbleeds) or from Pearson correlation (for WMH). WMH = white matter hyperintensity. *p < 0.05.