Inflammation is increasingly implicated as a risk factor for
dementia,
stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. We systematically reviewed the existing literature on the associations between markers of
inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health,
cerebrovascular disease, or
cognitive impairment. Based on distinctions made in the literature, markers of
inflammation were classified as systemic
inflammation (e.g.
C-reactive protein,
interleukin-6,
fibrinogen) or vascular
inflammation/endothelial dysfunction (e.g.
homocysteine,
von Willebrand factor,
Lp-PLA2). Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular
inflammation, especially amongst
stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD. Conversely, cross-sectional findings on systemic
inflammation were mixed, although longitudinal investigations demonstrated that elevated levels of systemic inflammatory markers at baseline predicted subsequent SVD severity and progression. Importantly, regional analysis revealed that systemic and vascular
inflammation were differentially related to two distinct forms of SVD. Specifically, markers of vascular
inflammation tended to be associated with SVD in areas typical of hypertensive arteriopathy (e.g., basal ganglia), while systemic
inflammation appeared to be involved in CAA-related vascular damage (e.g., centrum semiovale). Nonetheless, there is insufficient data to establish whether
inflammation is causal of, or secondary to, SVD. Findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated
neurodegenerative diseases.