Alterations in Serum RAGE/NF-κB Pathway Expression Levels and Their Association with Cognitive Function in Wilson's Disease Patients with Mild Cognitive Impairment postprint

Abstract: Background　Wilson's disease（WD）is associated with elevated inflammatory levels and closely linked to cognitive impairment. Studies suggest that activation of the receptor for advanced glycation end products（RAGE）/nuclear factor kappa B（NF-κB）signaling pathway is a critical inflammatory mechanism mediating cognitive dysfunction，yet its expression in serum of WD patients with mild cognitive impairment（MCI）remains unclear. Objective　To investigate changes in serum RAGE/NF-κB pathway expression and their impact on MCI in WD patients. Methods　A total of 23 WD patients with MCI（WD-MCI group）hospitalized at the Encephalopathy Center of the First Affiliated Hospital of Anhui University of Chinese Medicine from January 2024 to January 2025 were enrolled. Age-，sex-，and education-matched healthy controls （n=23）were recruited. Cognitive function was assessed using the Mini-Mental State Examination（MMSE），Hopkins Verbal Learning Test（HVLT），Boston Naming Test-Second Edition（BNT-2），Clock Drawing Test（CDT），Trail Making Test-A（TMT-A），and Instrumental Activities of Daily Living Scale（IADL）. Serum RAGE levels and NF-κB p65 mRNA expression were measured using enzyme-linked immunosorbent assay（ELISA）and qRT-PCR，respectively. Differences in cognitive scores，serum RAGE levels，and NF-κB p65 mRNA expression between groups were compared. Pearson or Spearman correlation analysis evaluated associations between RAGE/NF-κB p65 mRNA levels and cognitive scores. Results　Compared with controls，the WD-MCI group showed significantly lower MMSE，HVLT，BNT-2，and CDT scores，and higher TMT-A and IADL scores（P<0.05）. Serum RAGE levels and NF-κB p65 mRNA expression were elevated in the WD-MCI group（P<0.05）. Correlation analysis revealed that serum RAGE levels and NF-κB p65 mRNA expression negatively correlated with MMSE（r=-0.866，-0.729），HVLT（r=-0.721，-0.728），BNT-2（rs=-0.381，-0.382），and CDT（rs=-0.788，-0.709）scores，and positively correlated with TMT-A（r=0.774，0.524）and IADL（rs=0.433，0.376）scores（P<0.05）. Conclusion　WD patients exhibit increased serum RAGE/NF-κB pathway activity，which is significantly associated with mild cognitive impairment.