Epilepsy patients are losing cognitive function faster than their peers, and a protein called tau is building up in their brains like it does in Alzheimer's disease. This project aims to understand why. The problem is that cognitive decline—memory loss, slower thinking—is a common and devastating side effect of epilepsy, yet doctors have no way to predict, prevent, or treat it. Standard epilepsy care focuses on seizures, not the brain shrinkage and tau accumulation that quietly accelerate alongside them. This research fills that gap by linking what shows up on brain scans with what is actually happening in brain tissue. If successful, the work could identify early biomarkers—measurable signs in scans or spinal fluid—that flag which epilepsy patients are heading for cognitive trouble years before symptoms appear. That would allow clinicians to intervene early with existing or future treatments, potentially slowing or halting decline. It could also reveal whether drugs developed for Alzheimer’s tau pathology might work in epilepsy, repurposing therapies across conditions. The project is fundamentally about understanding disease mechanisms, but the payoff is a practical diagnostic tool for a currently invisible problem.
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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.
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