Circulating immune cells in cerebral small vessel disease: a systematic review

Cerebral small vessel disease (cSVD) refers to all pathologies of the brain's arterioles, capillaries, and venules. cSVD is highly prevalent with ageing and is diagnosed by its characteristic neuro-imaging features. Emerging evidence suggests that circulating immune cells play an important role in cSVD's pathology. However, the specific immune cell populations involved remain poorly understood. This systematic review synthesizes current evidence on circulating immune cells in cSVD and their associations with cSVD features. A systematic search was conducted using PubMed, Embase, and Web of Science databases. All studies investigating the association between peripheral immune cells and imaging features of cSVD were included. Data were extracted on study design, immune cells and cSVD measures, and outcomes. A total of 18 studies were included. Pro-inflammatory monocytes were associated with the severity and progression of cSVD over time. The neutrophil-to-lymphocyte ratio (NLR) showed positive associations with white matter hyperintensities (WMH) and enlarged perivascular spaces. The monocyte-to-HDL ratio (MHR) demonstrated a stronger association than the NLR with WMH, lacunes, and cerebral microbleeds. The lymphocyte-to-monocyte ratio (LMR) was linked to slower WMH progression and lower cSVD prevalence. Key findings highlight a role for pro-inflammatory circulating monocytes, NLR, MHR, and LMR in cSVD patients. These derived ratios serve as more reliable disease predictors than individual blood counts, showing potential as innovative diagnostic and prognostic markers. However, the reviewed studies predominantly employed cross-sectional and retrospective designs, suggesting the need for large-scale, prospective investigations to determine the role of these inflammatory markers in cSVD's pathogenesis.