Association of Systemic Inflammatory Markers With Cerebral Small Vessel Disease Progression

BACKGROUND AND OBJECTIVES: Inflammation is an established risk factor in the development of cerebral small vessel disease (CSVD). This study aimed to investigate the associations between neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) with progression of CSVD. METHODS: This prospective cohort study used data from the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events study between 2017 and 2024. Participants were excluded for a history of stroke or cancer or because of missing data on baseline systemic inflammatory markers or follow-up neuroimaging for CSVD. Baseline systemic inflammatory markers were calculated by neutrophils, monocytes, lymphocytes, and platelets count data, and categorized into 4 groups according to the quartiles. The progression of total CSVD burden, using Wardlaw and Rothwell ratings, along with progression of specific MRI markers were assessed between baseline and wave 3 follow-up (∼4.7 years). Assessment of the associations was performed using log-binomial regression models. RESULTS: The median follow-up duration was 4.7 years (interquartile range 4.5-4.8), and 2,267 participants were included. At baseline, the mean age of the participants was 60.4 years, with 50.6% being male. An elevation in NLR was associated with progression of total CSVD burden (Wardlaw: adjusted relative risk [aRR] 1.23, 95% CI 1.08-1.41; Rothwell: aRR 1.29, 95% CI 1.11-1.50) and incident cerebral microbleeds (CMBs) (aRR 1.43, 95% CI 1.16-1.78). High level of MLR was associated with incident lacunes (aRR 1.88, 95% CI 1.28-2.77) and incident CMBs (aRR 1.33, 95% CI 1.08-1.65). High level of SII was associated with progression of total CSVD burden (Wardlaw: aRR 1.15, 95% CI 1.01-1.31; Rothwell: aRR 1.17, 95% CI 1.01-1.35) and incident CMBs (aRR 1.34, 95% CI 1.10-1.64). Linear associations between these markers and progression of CSVD were demonstrated by restricted cubic spline analysis. DISCUSSION: This community-based prospective study demonstrated that elevated NLR, MLR, and SII were associated with progression of total CSVD burden and progression of white matter hyperintensity, incident lacunes, and CMBs over ∼4.7 years, supporting their potential to provide additional context for CSVD preventive considerations. Limitations include study's single-city population and the lack of dynamic changes in inflammatory markers.