Plasma GFAP and NLRP3 Associate with Cognitive Impairment After Recent Small Subcortical Infarct via Periventricular White Matter Hyperintensity

AIM: To assess whether early plasma inflammatory proteins identify SVD-related stroke patients at high risk of cognitive impairment and to examine imaging-mediated effects. METHODS: This single-center retrospective study (April 2020-August 2024) enrolled patients with MRI-confirmed recent small subcortical infarct (RSSI) and healthy controls. GFAP and NLRP3 levels were measured by ELISA. MRI markers of small vessel disease-including white matter hyperintensities (WMH), lacunes, perivascular spaces, and microbleeds-were evaluated. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and functional outcome by the modified Rankin Scale (mRS) at 3 months. Associations were analyzed using correlation, regression, and mediation analyses. RESULTS: A total of 108 RSSI patients and 47 controls were included (mean age 57.9 ± 10.5 years; 64.1% male). RSSI patients had significantly higher plasma GFAP and NLRP3 levels (p < 0.05). Both proteins were inversely associated with total MoCA scores and cognitive subdomains, but not with 3-month mRS. GFAP and NLRP3 correlated positively with periventricular WMH (PWMH). Mediation analysis showed that PWMH accounted for 23.88%-28.10% of the association between plasma protein levels and cognitive impairment. CONCLUSIONS: Elevated plasma GFAP and NLRP3 are associated with post-stroke cognitive impairment in RSSI, partially mediated by PWMH. These biomarkers may help identify patients at risk of early cognitive decline.