FOCAL CORTICAL DYSPLASIA TYPE II: FINDINGS OF THE NEUROPATHOLOGICAL, GENETIC AND CLINICAL CORRELATIONS TO TAU PATHOLOGY IN A SURGICAL COHORT OF 54 EPILEPSY PATIENTS

Focal cortical dysplasia (FCD) type II is a common epilepsy-related pathology associated with mTOR-pathway gene variants. Degenerative pathology, including pTau accumulation in dysmorphic neurones (DN) is recognised but the relationship with clinical-pathological-genetic factors and specific neuronal vulnerabilities is less clear. FCD cases from 54 patients were evaluated with neurodegenerative markers (AT8,Abeta,p62), NeuN and in selected cases for Parvalbumin, Calbindin, Calretinin, Somatostatin, Neuropeptide Y, Reelin, Tbr1 and mTOR pathway activation (pS6-240/235) using multiplex immunopanels. Cortical and white matter regions of interest (ROIs) in FCD and perilesional cortex (PC) were defined using QuPath. Cellpose models and pixel-based thresholding enabled spatial localisation, cell morphometry and single-cell analysis of marker co-localisation. 48 cases underwent targeted panel sequencing, UMI-based variant calling and annotation. Key findings included lower NeuN densities overall in FCD compared to PC, particularly in superficial cortex, vulnerability of larger DN for pTau/AT8 and reduced NeuN mean cell size with age and longer duration of epilepsy. AT8 correlated with pS6 neuronal expression. Variable alterations of interneurons (mainly reduction) were noted in FCD compared to PC but limited co-expression of AT8/pS6, whereas Tbr1/AT8 DN were identified. Genetics analysis uncovered likely pathogenic somatic and germline mutations in 20/48 cases including TSC1/2 and a novel FLNA variant in one case but found no clear relationship to tau load. The findings support progressive neurodegenerative changes in DN in FCD with less vulnerability of interneurons. This may relate to mTOR activation but with little evidence from this cohort of a relationship to driver mutations.