Monday, March 31, 2025
3/31/2025
Late-onset Unexplained Epilepsy as a Risk Factor for Dementia - Project Summary / Abstract Late-onset unexplained epilepsy (LoUE), defined as epilepsy starting after age 55 with no clearly identified cause, has emerged as a significant risk factor for Alzheimer’s disease and related dementias (AD/ADRD). Individuals presenting with LoUE have no prior history of dementia. Yet, LoUE is associated with a 2-3x increased risk of developing dementia, and up to 25% of LoUE develop dementia within 4 years after their first seizure. We have little understanding of the mechanisms underlying dementia in LoUE; no tools to predict which individuals with LoUE are at highest risk for developing dementia; and no treatments to prevent dementia in LoUE. 30-40% of LoUE may harbor AD pathology and/or occult cerebrovascular disease, and we hypothesize that these pathologies drive much of the increased dementia risk in LoUE. Yet, other pathologies and mechanisms are also possible and need to be identified. Our long-term goal is to develop a precision medicine approach to preventing dementia in LoUE, in which individualized risk assessment and disease subtyping can specifically inform a patient’s dementia prognosis and guide targeted therapies to reduce dementia risk. The ELUCID study (NINDS R01 NS130119) is a multi-center, prospective, longitudinal observational study of LoUE, focused on identifying risk factors and mechanisms that lead to dementia in LoUE, and developing predictive tools for dementia risk-stratification in LoUE. We will enroll 600 participants with LoUE, who will undergo a baseline evaluation with clinical history, cognitive testing, brain MRI, overnight EEG, and blood draw, and will be followed longitudinally with interval history every 6 months and annual cognitive testing. Our specific aims are: 1) To establish an unbiased framework for identifying mechanisms leading to dementia in LoUE, we will organize LoUE into disease subtypes based on: (a) associated neuropathology; (b) clinical phenotype; and (c) cognitive trajectory; 2) To advance mechanistic understanding of dementia in LoUE, we will identify epilepsy-related, neuropathologic, neurophysiologic, and structural features associated with development of dementia in LoUE; and 3) To enable prognostication of dementia in LoUE, we will develop practical clinical tools to forecast an individual’s risk of developing dementia after presenting with LoUE. The ELUCID study will measure blood-based biomarkers relevant to AD/ADRD, including: plasma AB42/40 and p-tau217, and APOE and LRRK2 G2019S genotyping. In the proposed administrative supplement, we will acquire additional blood-based biomarkers relevant to AD/ADRD, focused specifically on neuronal injury, vascular health, and neuroinflammation. These will include: neurofilament light; glial fibrillary acidic protein; lipid panel; hemoglobin A1C; Mesoscale Discovery V-plex Angiogenesis Panel; and Mesoscale Discovery S-Plex Proinflammatory Panel 1. Addition of these biomarkers will greatly enrich our dataset, enhancing our ability to characterize LoUE sub-types, identify mechanisms underlying dementia in LoUE, predict dementia outcomes, and guide future therapeutic development to prevent dementia in LoUE.
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