Progressive degeneration of the fornix beyond normal aging in temporal lobe epilepsy: A 10-year longitudinal diffusion imaging study.

OBJECTIVE: Temporal lobe epilepsy (TLE) is increasingly recognized as a network disorder involving widespread structural abnormalities beyond the seizure focus. However, it remains unclear whether white matter alterations in TLE reflect static injury or progressive degeneration beyond normal aging. We aimed to characterize long-term trajectories of limbic microstructural alterations in patients with unilateral TLE using longitudinal diffusion tensor imaging. METHODS: Sixteen patients with unilateral TLE and 15 age- and sex-matched healthy controls underwent diffusion tensor imaging at baseline and approximately 10-year follow-up. Fractional anisotropy (FA) alterations were assessed using tract-based spatial statistics. Longitudinal tract-specific changes were further evaluated using mixed-design ANOVA and correlation analyses with disease duration. Cognitive performance was assessed using the Mini-Mental State Examination and Montreal Cognitive Assessment. RESULTS: Over 10 years, patients with TLE showed significant FA reductions in the fornix and corpus callosum (PFWE < 0.05), whereas healthy controls showed no significant longitudinal changes. The most pronounced alterations involved the fornix body and columns, with significant Group × Time interactions in the unadjusted analyses and a robust interaction in fornix Cluster 1 after age adjustment; an age-adjusted interaction was also observed in the corpus callosum. Greater longitudinal fornix FA decline was associated with longer disease duration (r = 0.570, P = 0.021) and remained significant after adjustment for age (partial r = 0.503, P = 0.046). Exploratory analyses also showed a nominal association between reduced fornix FA and poorer orientation performance (r = 0.592, unadjusted P = 0.016), although this association did not survive FDR correction. SIGNIFICANCE: TLE shows progressive white matter degeneration beyond normal aging, with preferential involvement of the fornix. Greater longitudinal fornix FA decline with longer disease duration supports preferential vulnerability of hippocampal output pathways.