IL-6, PF-4, sCD40 L, and homocysteine are associated with the radiological progression of cerebral small-vessel disease: a 2-year follow-up study

Abstract

Background: Endothelial dysfunction (ED) is involved in the pathogenesis of cerebral small vessel disease (SVD), however, it is not clear if specific biomarkers related to ED are associated with radiological progression of SVD.

Methods: A single-center, prospective cohort study was conducted among consecutive, adult patients with SVD. Logistic regression was used to analyze the association of each baseline biomarker (highest vs lowest tertile) and the MRI radiological outcome after 2 years. The mean Z-score for vascular inflammation (VI) combined soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble platelet selectin (sP-selectin), CD40 ligand (sCD40 L), platelet factor-4 (PF-4) and homocysteine; Z-score for systemic inflammation (SI) combined high-sensitivity C-reactive protein (hsCRP), interleukin-1α and -6 (IL-1α and IL-6, respectively) and tumor necrosis factor-α (TNF-α).

Results: The study group comprised 123 patients (age, mean±SD: 72.2±8 years, 49% females), with lacunar stroke (n=49), vascular dementia (n=48), and vascular parkinsonism (n=26). Moreover, 34.9% patients experienced radiological progression, 43% had progression of isolated white matter lesions (WMLs), 23.2% had new lacunes, and 34.8% had both WMLs progression and new lacunes. After adjustment for confounders (age, sex, blood pressure, MRI lesions load), the PF-4 (OR; 95% CI 5.5; 1.5-21), sCD40L (4.6; 1.1-18.6), IL-6 (7.4; 1.48-37), Z-score for VI (4.5; 1.1-18.6), and, marginally, homocysteine (4.1; 0.99-17) were associated with the risk of any radiological progression; further, homocysteine (2.4; 1.4-14), Z-score for SI (2.1; 1.2-14) and, marginally, IL-6 (6.0; 0.95 -38) were related to the development of new lacunes; PF-4 (7.9; 1.6-38) and, marginally, the Z-score for VI (4.2; 0.9-19.5) were correlated with the risk of WMLs progression. Additional adjustment for clinical SVD manifestations did not significantly alter the results.

Conclusion: The data supports the concept that ED modulates the radiological progression of SVD and WMLs and lacunes are associated with different inflammatory markers.

Keywords: IL-6; PF-4; cerebral small-vessel disease; homocysteine; radiological progression; sCD40 L.

Figure 1

MRI axial T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) images at the level of lateral ventricles showing progression of deep white matter lesions at the 2-year follow-up (A, initial scan; B, follow-up).