Systemic Inflammatory Cytokines and Immune-Mediated Microvascular Injury in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis of MRI-Defined Phenotypes

Serum Inflammatory Markers and MRI in Small Vessel Disease

Abstract

Cerebral small vessel disease (CSVD) is increasingly recognized as a chronic immune-mediated microvascular disorder, in which sustained systemic inflammation contributes to endothelial dysfunction, blood–brain barrier (BBB) disruption, and progressive brain injury. Pro-inflammatory cytokines and acute-phase reactants, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), have been implicated in cerebrovascular immune dysregulation; however, their specific associations with magnetic resonance imaging (MRI)–defined CSVD phenotypes remain incompletely understood.

A systematic literature search of PubMed, Embase, Web of Science, the Cochrane Library, CNKI, and Wanfang databases was conducted from inception to December 2025. Observational studies reporting independent associations between circulating inflammatory markers and MRI features of CSVD—including white matter hyperintensities (WMH), lacunar infarction (LI), and cerebral microbleeds (CMB)—were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models based on heterogeneity.

Eighteen eligible studies were included in the meta-analysis. Elevated IL-6 levels were significantly associated with increased risks of LI (OR = 1.53, 95% CI: 1.11–2.11) and CMB (OR = 1.28, 95% CI: 1.06–1.55), reflecting cytokine-driven immune activation and BBB vulnerability. Increased hs-CRP levels were significantly correlated with WMH (OR = 2.19, 95% CI: 1.18–4.07), LI (OR = 1.97, 95% CI: 1.21–3.20), and CMB (OR = 1.67, 95% CI: 1.37–2.04), consistent with chronic low-grade systemic inflammation and endothelial injury. In contrast, conventional CRP showed no significant association with CSVD imaging markers. Elevated fibrinogen levels were specifically associated with WMH (OR = 1.48, 95% CI: 1.21–1.80), suggesting an interaction between inflammatory–coagulative pathways and microvascular white matter damage.

This meta-analysis demonstrates that systemic inflammatory cytokines and acute-phase proteins are closely linked to immune-mediated microvascular injury underlying MRI-defined CSVD phenotypes. IL-6 and hs-CRP, in particular, may serve as accessible immunological biomarkers reflecting chronic vascular inflammation and BBB dysfunction in CSVD. These findings support an immunopathological framework for CSVD and provide evidence for incorporating inflammatory markers into immune-focused risk stratification and early intervention strategies.