Association of inflammatory markers with cerebral small vessel disease in community-based population

Abstract

Background: This study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD).

Methods: A total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed.

Results: At baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05-1.70; cOR 1.28, 95% CI 1.02-1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00-1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25-3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14-2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16-2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08-1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20-2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04-1.39) and small vessel stroke (OR 1.21, 95% CI 1.06-1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p < 0.05).

Conclusions: This community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.

Keywords: Cerebral small vessel disease; Inflammation; Neutrophil count; Neutrophil–lymphocyte ratio; Systemic immune-inflammation index.

Fig. 1

Forest plots for the association of NC, NLR and SII with CSVD. Forest plots show the cORs/ORs for NC and total CSVD burden or presence of CSVD (A, B); the cORs/ORs for NLR (neutrophil-to-lymphocyte ratio) and total CSVD burden or presence of CSVD (C, D); the cORs/ORs for SII (systemic immune-inflammation index) and total CSVD burden or presence of CSVD (E, F). Association for ordinal categorical outcome of total CSVD burden was expressed as cOR, whereas presence of CSVD was expressed as OR. The black lines represent the 95% confidence intervals of cORs/ORs. Multivariable logistic regression model adjusted for traditional risk factors of CSVD in Table 1. NC neutrophil count, NLR neutrophil-to-lymphocyte ratio, SII systemic immune-inflammation index (platelet count × neutrophil count/lymphocyte count), cOR common odds ratio, OR odds ratio. Wardlaw/total CSVD burden: 1 point allocated for presence of lacunes, microbleeds, moderate-to-severe (> 10) perivascular space in basal ganglia, periventricular white matter hyperintensities Fazekas 3 or deep white matter hyperintensities Fazekas 2-3. Rothwell/modified total CSVD burden: 1 point allocated for presence of lacunes, 1-4 microbleeds, frequent to severe (> 20) perivascular space in basal ganglia, moderate white matter hyperintensities (total periventricular + subcortical white matter hyperintensities grade 3-4), 2 points allocated for ≥ 5 microbleeds and severe white matter hyperintensities (total periventricular + subcortical white matter hyperintensities grade 5-6)

Fig. 2

Forest plots for the association of NC, NLR and SII with CSVD imaging markers. Forest plots show the cORs/ORs for NC, NLR, SII and outcomes of WMH, Lacunes, CMBs and BG-EPVS assessed according to Wardlaw and Rothwell grading system, respectively. Association for ordinal categorical outcomes of Modified WMH burden and CMBs assessed according to Rothwell were expressed as cOR, whereas others was expressed as OR. The black lines represent the 95% confidence intervals of cORs/ORs. Multivariable logistic regression model adjusted for traditional risk factors of CSVD in Table 1. NC neutrophil count, NLR neutrophil-to-lymphocyte ratio, SII systemic immune-inflammation index (platelet count × neutrophil count/lymphocyte count), cOR common odds ratio, OR odds ratio. WMH burden was defined as either (early) confluent deep white matter hyperintensities (Fazekas score 2 or 3) or irregular periventricular white matter hyperintensities extending into the deep white matter (Fazekas score 3); modified WMH burden was classified into grade 0: total periventricular + subcortical white matter hyperintensities score 1–2, grade 1: total periventricular + subcortical white matter hyperintensities score 3–4 and grade 2: total periventricular + subcortical white matter hyperintensities score 5–6. Presence of CMBs was defined as presence of cerebral microbleeds; CMBs burden was classified as grade 0: absent, grade 1: 1–4 microbleeds and grade 2: ≥ 5 microbleeds. BG-EPVS (moderate-to-severe) indicated > 10 perivascular space in basal ganglia; BG-EPVS (severe) indicated severe (> 20) perivascular space in basal ganglia

Fig. 3

Mendelian randomization association of genetic determinants of neutrophil count with the risk of CSVD phenotypes. Forest plot shows estimates for the effects of neutrophil count related genetic variants on risk of cerebral small vessel disease phenotypes including white matter hyperintensities volume, lacunar stroke, small vessel stroke and cerebral microbleeds. The results are derived from the random-effects IVW (inverse-variance weighted) Mendelian randomization analysis and presented as odds ratios (95% confidence interval [CI]). Red rows correspond to statistically significant association estimates at a P_FDR (false discovery rate-adjusted p value) < 0.05. CSVD cerebral small vessel disease; SNPs single nucleotide polymorphisms, ORs odds ratios; WMH white matter hyperintensities, CMBs cerebral microbleeds