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

## TL;DR

Elevated plasma GFAP and NLRP3 levels are linked to cognitive impairment after small subcortical strokes, partly due to white matter damage.

## Contribution

Identifies plasma GFAP and NLRP3 as early biomarkers of cognitive decline after stroke, mediated by periventricular white matter hyperintensities.

## Key findings

- Plasma GFAP and NLRP3 levels are significantly higher in recent small subcortical infarct patients.
- Higher GFAP and NLRP3 levels correlate with worse cognitive scores and more periventricular white matter hyperintensities.
- Periventricular white matter hyperintensities mediate up to 28.1% of the association between these proteins and cognitive impairment.

## Abstract

To assess whether early plasma inflammatory proteins identify SVD‐related stroke patients at high risk of cognitive impairment and to examine imaging‐mediated effects.

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.

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.

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.

Ischemic stroke, recent small subcortical infarcts, induce systemic inflammation, leading to elevated levels of circulating inflammatory proteins. Through blood–brain barrier disruption, these proteins may gain access to the central nervous system and amplify microvascular injury and white matter degeneration, which directly and indirectly lead to cognition impairment.