Epileptic Hippocampus in Alzheimer's Disease

The major goals of the study are to 1) characterize hippocampal activity in patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and AD who have suspected hippocampal epileptic activity based on scalp EEG recordings from IRB # 21-001603; 2) study the efficacy of brivaracetam to suppress epileptic activity and pathological high frequency oscilations (pHFOs) during hippocampal depth electrode and scalp EEG in patients with MCI and AD; and 3) investigate the effects of brivaracetam on cognition in an open-label pilot study.

This is a prospective, single-center, open-label, pilot study. Individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) who show epileptic activity as part of an overnight EEG from study IRB#21-001603 or as a part of a clinical EEG will be eligible. After informed consent, participants will undergo hippocampal depth electrode placement and full scalp electroencephalogram (EEG) recordings to characterize epileptic hippocampal activity and pathological high frequency oscilations (pHFOs). During recordings, the investigators will determine whether brivaracetam, given intravenously, suppresses epileptic activity/high frequency oscillations. After recordings are completed, investigators will test whether brivaracetam, in oral tablets, improves cognition over the course of 1 year. Participants will include men and women 45-70 years of age who meet criteria for MCI due to AD and mild AD. Clinical diagnoses will be made by a panel of experts. The target enrollment for the 5-year period is 25 participants. The ratio of males to females is nearly equal, given previous experience of the investigators in finding subclinical epileptiform activity in both males and females with AD. The findings may lead to better characterization of neural network dysfunction in Alzheimer's disease and identify subpopulations with subclinical epileptiform activity or seizures and cognitive impairments who could benefit from antiseizure therapies. This study also has the potential of advancing our knowledge of the pathophysiology of Alzheimer's disease.

If epileptic activity or pHFOs are identified during an overnight EEG from study Biomarkers in Neurodegenerative Disease (UCLA IRB#21-001603) or through a clinical study, the investigators will offer the opportunity to be part of this research study. Consenting and study overview will be conducted by the investigators. If accepted into the study, participants will undergo a magnetic resonance venography (MRV), magnetic resonance angiography (MRA) and a gadolinium-enhanced MRI a couple of weeks prior the hippocampal implantation of one or two depth electrodes. A coagulation blood draw will be collected prior to the surgery during one of the neuroimaging visits. Before the surgical procedure, participants will complete cognitive testing with one of the investigators. The Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Stroop Interference naming, and Virtual Route Learning Test (VRLT) will be collected. If coagulation levels come back normal and the participants are in good health, they will undergo general anesthesia and a neurosurgeon will implant one to two depth electrodes in the hippocampus. A Leksell stereotactic frame will be attached to the head to guide localization and a CT angiography will be collected to guide the surgical procedure. Participants will go to the Intensive Care Unit and spend the night there while their recovery is being monitored.

The next day, a scalp EEG will be placed to record brain activity for six days and five nights in conjunction with the hippocampal depth electrode(s) already implanted. On nights four and five, participants will undergo intravenous administration of brivaracetam to study its effects on hippocampal epileptic activity. Investigators will determine whether brivaracetam 25 mg IV suppresses the number of epileptic events and pHFOs by >50%, which is analogous to preclinical investigations with this drug in AD models. If the 50% suppression is reached, the same dosage will be repeated the following night to ensure reproducibility. If the 50% suppression is not reached, then the dosage of brivaracetam will be increased to 50 mg the following night. On day six, the depth electrode will be removed using local anesthesia. Participants will stay at the hospital one more day for recovery and will be discharged on day seven.

Participants will take brivaracetam twice a day for 1 year and will come back the University of California, Los Angeles (UCLA) at 3 months, 6 months, and 1 year to complete cognitive testing (ADAS-cog, Stroop Interference naming, and VRLT) and receive additional brivaracetam supplies. During the follow-up visits, blood samples will be collected to study plasma biomarkers of neurodegenerative diseases. Participants will conclude their participation after 1 year.