PROJECT SUMMARY (ABSTRACT) The World Health Organization includes dementia and epilepsy among the top four primary diseases of the brain. Our research proposal concerns the fact that patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS), the most common drug resistant form of epilepsy, have an increased risk of developing dementia, and that more patients with Alzheimer Disease (AD) have epileptogenic abnormalities than previously suspected. Whereas classical MTLE begins in childhood and is characterized by unilateral HS with CA2 sparing, we are seeing an increasing number of patients with adult onset MTLE, more diffuse HS, and contralateral involvement. Furthermore, hippocampal specimens resected to treat drug resistant MTLE are more likely to contain plaques and tau than age matched controls. On the other hand, not only are 10-22% of patients with AD known to have overt epilepsy, but also there is increasing evidence that a much greater percentage have subclinical seizures, or epileptiform EEG abnormalities. In order to investigate the relationship between seizures and cognitive decline in MTLE and AD, we are proposing to carry out reiterative translational retro- and prospective studies in patients with adult onset MTLE, and prospective studies on patients with AD and mild cognitive impairment (MCI), as well as a rat model of AD with epileptic seizures. Our Specific Aims are: 1a: In patients with AD and MCI who exhibit epileptic activity and HFOs on overnight scalp EEG, perform hippocampal depth electrode recordings over 5 days to further characterize EEG and HFOs and perform hippocampal and neocortical SPM of MRI, for comparison with MTLE and rat data. (in the near future we will also be able to use MEG). 1b: Carry out pathological analysis of hippocampal specimens for tau and plaques from subjects with MTLE who undergo surgical resection in Aim 1a for correlation with electrophysiology, imaging, age of onset, and cognitive testing. 2a:In a rat model of AD with epilepsy, monitor EEG, HFOs, LFPs, and MUA, and perform hippocampal and neocortical SPM of MRI, for comparison with data already obtained from intrahippocampal kainate (IHKA) rats. Correlate disturbances in hippocampal-prefrontal cortex connectivity with development of cognitive disfunction. 2b: In the same rat model, perform electrophysiological and behavioral testing before and after treatment with brivaracetam and compare effects with animals in Aim 2a. electrophysiological activity will identify patients with MCI and AD who will benefit from antiseizure therapy. 3a: In the same patients with AD and MCI as Aim 1a, perform hippocampal depth recordings of epileptic activity and HFOs before and after low-dose brivaracetam. 3b: In patients with AD and MCI from Aim 1a, who show epileptogenic electrophysiological features, perform cognitive testing before and after one month of treatment with brivaracetam. Long-term goals: Based on the results of these studies, ...