Serum uric acid change, regional brain activity, and cognitive impairment after herpes simplex encephalitis: a prospective two-center cohort study

Background Cognitive impairment is common after herpes simplex encephalitis (HSE). We examined associations of the acute-to-follow-up change in serum uric acid with regional spontaneous brain activity and cognitive status. Methods This prospective two-center cohort included 55 adults with polymerase chain reaction-confirmed HSE and 30 healthy controls. At follow-up, HSE participants underwent neuropsychological testing, serum sampling, and resting-state functional magnetic resonance imaging. Cognitive impairment was defined as a Montreal Cognitive Assessment score below 26 or a memory or executive-function Z-score of −1.5 or lower. The sole primary analysis compared whole-brain fractional amplitude of low-frequency fluctuation (fALFF) between HSE participants with cognitive impairment (HSE-CD) and healthy controls. Secondary analyses used adjusted linear regression, restricted cubic splines and subgroup models and were considered exploratory. Results Twenty-six participants were classified as HSE-CD and 29 as HSE without cognitive impairment (HSE-noCD). Acute-phase urate was lower in HSE-CD ( p = 0.002), whereas follow-up urate ( p = 0.116) and ΔUA ( p = 0.454) did not differ significantly between HSE groups. Compared with healthy controls, HSE-CD had higher fALFF in the right insula and right lingual gyrus and lower fALFF in the right thalamus and left hippocampus. Of nine evaluated regions, these four remained significant after whole-brain voxelwise FWE correction (P_FWE < 0.05). In adjusted exploratory models, ΔUA was negatively associated with right-insular and right-lingual fALFF and positively associated with left-hippocampal fALFF (all nominal p < 0.05). Regional fALFF was also associated with memory and executive performance in selected regions. Spline models of binary regional abnormality and cognitive impairment showed no significant overall or nonlinear associations. Conclusion ΔUA was associated with fALFF in three regions, and regional fALFF was associated with domain-specific cognitive performance after HSE. These exploratory associations warrant independent validation and do not establish causality or a clinical urate threshold.