Late-onset Unexplained Epilepsy as a Risk Factor for Dementia

项目摘要/摘要 迟发性不明原因癫痫(LOUE)，定义为55岁以后开始且无明确诊断的癫痫 原因，已成为阿尔茨海默病和相关痴呆症(AD/ADRD)的重要风险因素。路易 在美国，每年有50,000名新患者受到影响，随着老年人口的增长，还将很快影响更多的人。 出现LOE的个体以前没有痴呆症的病史。然而，LUE与2-3倍的增加有关 患痴呆症的风险高达25%的儿童在首次癫痫发作后4年内患上痴呆症。我们 对路易斯安那州痴呆的潜在机制知之甚少；没有工具来预测哪些人 患有LOE的人风险最高；LUE患者没有预防痴呆症的治疗方法。30%-40%的患者可能患有AD 病理和/或隐匿性脑血管疾病，我们假设这些病理导致了大部分 路易斯安那州患痴呆症的风险增加。然而，其他病理和机制也是可能的，并且需要 已确认身份。我们的长期目标是开发一种精准医学方法来预防路易斯安那州的痴呆症。 哪种个性化风险评估和疾病亚型可以具体告知患者痴呆症 并指导有针对性的治疗，以降低痴呆症风险。我们假设严格的、数据驱动的 基于临床特征、生物标记物和认知结果的LUE表型将促进机制研究 了解路易斯安那州的痴呆症，并加快治疗开发，以降低痴呆症的风险。目标 这项建议的目的是阐明导致路易斯安那州痴呆的危险因素和机制，并发展 用于痴呆症风险分层的工具。为了实现这些目标，我们将开展前瞻性的、多层次的 LOUE的中心、纵向观察研究侧重于了解机制和预测 LOUE患者AD/ADRD的转归。我们将在3年内在7个地点招募600名LOE参与者。 参与者将接受基线评估，包括临床病史、认知测试、脑核磁共振、过夜脑电、 和血浆AD生物标志物，并将每6个月和每年进行一次间歇史的纵向跟踪 认知测试。我们的具体目标是：1)建立一个不偏不倚的确定机制的框架 导致LUE的痴呆，我们将根据以下因素将LUE分为疾病亚型： 神经病理学；(B)临床表型；和(C)认知轨迹；2)促进对 在LUE中，我们将确定癫痫相关、神经病理学、神经生理学和结构特征。 与路易斯安那州痴呆症的发展有关；以及3)为了能够预测路易斯安那州的痴呆症，我们 将开发实用的临床工具来预测个人在呈现 路易。这项研究将是第一次大规模研究，将确定其与AD/ADRD的关系，并已 有足够的力量得出直接影响临床护理的结论。这项研究还将建立 基础知识和风险分层工具，将有助于设计高效和信息丰富的临床 路易斯安那州预防痴呆症试验。

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). LoUE afflicts 50,000 new patients in the U.S. each year and will soon affect many more as our elderly population grows. 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; 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. We hypothesize that rigorous, data-driven phenotyping of LoUE based on clinical features, biomarkers, and cognitive outcomes, will advance mechanistic understanding of dementia in LoUE and accelerate therapeutic development to reduce dementia risk. The goals of this proposal are to elucidate the risk factors and mechanisms that lead to dementia in LoUE and to develop tools for dementia risk-stratification in LoUE. To accomplish these goals, we will carry out a prospective, multi- center, longitudinal observational study of LoUE focused on understanding mechanisms and predicting outcomes of AD/ADRD in LoUE. We will enroll 600 participants with LoUE across 7 sites over 3 years. Participants will undergo a baseline evaluation with clinical history, cognitive testing, brain MRI, overnight EEG, and plasma AD biomarkers, 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 presentation with LoUE. This study will be the first large-scale study of LoUE that will define its relationship to AD/ADRD and have sufficient power to draw conclusions that will directly impact clinical care. This study will also establish foundational knowledge and risk-stratification tools that will facilitate the design of efficient and informative clinical trials for dementia prevention in LoUE.