Epilepsy and neurodegeneration : disease mechanisms and early detection

Cognitive decline represents a significant and debilitating co-morbidity for patients with epilepsy which is poorly understood with an urgent clinical need for diagnostic, preventative and treatment strategies.

Large epilepsy MRI datasets confirm progressive cortical atrophy and white matter abnormalities ; age-accelerated Tau protein accumulation has been reported in surgical resections, correlating with cognitive decline.

We propose a comprehensive evaluation of mixed neurodegenerative processes integrating cross-sectional and longitudinal MRI, DWI, DCE-MRI and Tau-PETimaging with quantitative neuropathology measurements of cortical, white mater atrophy and vascular pathology and pTau in resected surgical specimens in the context of cognitive impairment and genetic risk.

We aim to characterise tau forms in surgical and post-mortem cohorts compared to Alzheimer's disease and other tauopathies.

In prospective surgical cohorts, Tau-PET will be correlated with CSF markers, tissue levels using autoradiography and extent of cortical atrophy with high resolution in-vivo 7T and ex-vivo 9.4T MRI.

In addition, cellular drivers for tau accumulation, as MTOR and seizure activity, will be explored through human slice culture experiments with gene-expression analysis and the kinetics of tau incorporation through SILK studies and mass spectroscopy of tissues.

These studies will elucidate pathomechanims of cognitive impairment, identify early disease-stage biomarkers enabling prediction and preventative strategies.