Inflammation-mediated regional brain alterations associated with mild cognitive impairment in knee osteoarthritis

Knee osteoarthritis (KOA), a degenerative joint disease marked by chronic pain, is associated with systemic inflammation that may extend to neurocognitive dysfunction. While chronic low-grade inflammation in KOA has been implicated in mild cognitive impairment (MCI), a prodromal stage of dementia, the mediating role of inflammation in brain functional reorganization remains unclear.

This study integrated neuroimaging, inflammatory biomarkers, and machine learning to investigate inflammation-mediated brain functional alterations in 63 KOA patients with/without MCI. Serum levels of pro-inflammatory cytokines (IL-6, TNF-α) and resting-state fMRI data were analyzed using voxel-wise Regional Homogeneity (ReHo) and Amplitude of Low-Frequency Fluctuation (ALFF).

Comparisons across healthy controls, KOA-MCI, and KOA-non-MCI groups identified MCI-linked functional alterations in the medial prefrontal cortex (mPFC), precuneus, and superior temporal gyrus. Mediation analysis revealed that mPFC ReHo significantly mediated the relationship between elevated IL-6 and cognitive decline. Machine learning models incorporating ReHo features from mPFC demonstrated robust classification of MCI status (AUC: 0.87), validated in an external dataset.

Our findings suggest that IL-6-driven mPFC dysfunction is a potential pathway linking KOA-related inflammation to MCI, while highlighting the combined utility of ReHo/ALFF metrics in mPFC, precuneus, and temporal regions as potential neuroimaging biomarkers. This multimodal approach advances understanding of neuroinflammatory mechanisms in osteoarthritis and provides a framework for early detection of cognitive vulnerability in KOA populations.