Late-onset Unexplained Epilepsy as a Risk Factor for Dementia

迟发性不明原因癫痫是痴呆症的危险因素

• 批准号: 10739517
• 负责人: Alice D Lam
• 金额: $ 295.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739517
• 关键词: Acceleration; Affect; Age; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Big Data; Biological Markers; Biometry; Blood Vessels; Brain; Cerebrovascular Disorders; Clinical; Clinical Trials; Cognitive; Data; Data Set; Dementia; Development; Elderly; Electroencephalography; Enrollment; Epilepsy; Evaluation; Family; Foundations; Future; Goals; Impaired cognition; Incidence; Individual; Knowledge; Learning; Longitudinal, observational study; Machine Learning; Magnetic Resonance Imaging; Measurement; Modeling; Neurodegenerative Disorders; Neuropsychology; Outcome; Participant; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasma; Population; Prevention; Prognosis; Recording of previous events; Research; Risk; Risk Assessment; Risk Factors; Risk Reduction; Seizures; Severities; Site; Testing; Therapeutic; Thick; Work; brain magnetic resonance imaging; clinical care; clinical phenotype; clinical risk; cognitive testing; comorbidity; dementia risk; demographics; design; disorder subtype; epileptiform; high risk; improved; insight; interest; lifestyle factors; machine learning method; mixed dementia; neural network; neuroimaging; neuropathology; neurophysiology; novel; outcome prediction; precision medicine; prevent; prognostication; prospective; risk stratification; sleep physiology; targeted treatment; tau Proteins; therapeutic development; tool; unsupervised learning

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.

项目总结/摘要 迟发性不明原因癫痫（Late onset unexplained epilepsy，LoUE），定义为55岁以后开始的癫痫， 阿尔茨海默氏病和相关痴呆症（AD/ADRD）的一个重要危险因素。LoUE 在美国，每年有5万名新患者受到影响，随着老年人口的增长，很快还会有更多的患者受到影响。 患有LoUE的人没有痴呆症的既往史。然而，LoUE与2- 3倍的增加相关， 有发生痴呆的风险，高达25%的LoUE在首次癫痫发作后4年内发生痴呆。我们 对LoUE中痴呆的潜在机制知之甚少;没有工具来预测哪些个体 LoUE患者的风险最高;并且没有治疗方法来预防LoUE中的痴呆症。30-40%的LoUE可能携带AD 病理学和/或隐匿性脑血管疾病，我们假设这些病理学驱动了大部分的 LOUE中痴呆风险增加。然而，其他病理和机制也是可能的，并且需要考虑。 鉴定我们的长期目标是开发一种精确的医学方法来预防LoUE中的痴呆症， 哪种个性化的风险评估和疾病亚型可以明确地告知患者的痴呆症 预测和指导靶向治疗以降低痴呆风险。我们假设严格的数据驱动的 基于临床特征、生物标志物和认知结果的LoUE表型分型，将促进 了解LoUE中的痴呆症，并加速治疗开发以降低痴呆症风险。的目标 这项建议的目的是阐明导致LoUE痴呆的危险因素和机制， LoUE中痴呆风险分层的工具。为了实现这些目标，我们将开展一项前瞻性的、多方面的工作， 中心，LoUE的纵向观察性研究，重点是了解机制和预测 LoUE中AD/ADRD的结局。我们将在3年内在7个研究中心招募600名LoUE受试者。 参与者将接受基线评估，包括临床病史、认知测试、脑MRI、夜间EEG， 和血浆AD生物标志物，并将每6个月和每年对间隔史进行纵向随访 认知测试我们的具体目标是：1）建立一个公正的框架，以确定机制 导致LoUE中的痴呆，我们将根据以下因素将LoUE组织成疾病亚型：（a）相关 神经病理学;（B）临床表型;和（c）认知轨迹; 2）促进对 在LoUE痴呆中，我们将识别癫痫相关的神经病理学、神经生理学和结构特征 与LoUE中痴呆的发展相关;和3）为了使LoUE中痴呆的诊断成为可能，我们 将开发实用的临床工具来预测一个人患痴呆症的风险， LoUE。这项研究将是第一项大规模的LoUE研究，将确定其与AD/ADRD的关系， 有足够的能力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，这将有助于设计有效和信息丰富的临床 在LoUE中进行痴呆症预防试验。