Late-onset unexplained epilepsy as a risk factor for cognitive impairment and dementia: Protocol for a multi-center prospective longitudinal observational study (ELUCID).

Background: Late-onset unexplained epilepsy (LoUE), defined as epilepsy onset after age 55 without an obvious cause, is an important risk factor for dementia. Studies have shown that 10-25% of individuals with LoUE develop dementia within three to four years following their first seizure. However, the mechanisms underlying progression from LoUE to dementia remain poorly understood. The goals of the ELUCID study are to identify risk factors associated with development of cognitive decline and dementia in LoUE, and to develop tools to identify patients at high risk for these outcomes and thereby establish a foundation for dementia prevention strategies in this population. Methods and analysis: ELUCID is a multi-center prospective longitudinal observational study that will enroll 600 participants aged 55 or older with LoUE across seven U.S. medical centers. Participants undergo a baseline evaluation that includes a detailed clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood biomarkers. Participants will be followed at six-month intervals to record cognitive and neurological changes, with the primary outcomes of interest being development of mild cognitive impairment and/or dementia. This study aims to establish LoUE disease subtypes based on biomarkers, cognitive trajectories, and imaging features, and to develop a risk stratification tool for predicting risk for cognitive decline and dementia in patients presenting with LoUE. Ethics and Dissemination: ELUCID has obtained IRB approval (# 2023P001566, August 2023), with the MassGeneral Brigham IRB serving as the single IRB of record. All de-identified study data will be made publicly available on completion of the study.