The Contribution of Late Onset Unexplained Epilepsy to Cognitive Decline and its Interaction with Vascular and Alzheimer's Disease Pathologies

迟发性不明原因癫痫对认知能力下降的影响及其与血管和阿尔茨海默病病理学的相互作用

基本信息

批准号：
10652547
负责人：
Rani Sarkis
金额：
$ 22.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

项目摘要

Project Summary As life expectancy increases, the burden of seizures in the elderly will increase with up to half of the cases with no identifiable cause termed Late Onset Unexplained Epilepsy (LOUE). Large databases have identified patients with LOUE as having a higher risk of dementia and stroke, but studies focusing on individual patients have been limited. There is a current need to identify the factors underlying LOUE, their impact on cognition and its natural history to develop preventive and therapeutic strategies. The first goal of this project is to determine the burden of the two most common aging pathologies in a cohort of LOUE by assessing the burden of small vessel ischemic disease using MRI and blood biomarkers of Alzheimer’s disease (AD), and how they relate to cognition and neurodegeneration. The second goal is to follow the LOUE cohort over a 3-year period to determine whether the burden of the pathologies increases when someone has seizures and leads to accelerated cognitive decline and neurodegeneration. Through a junior investigator grant funded by the American Epilepsy Society, I have started recruiting a cohort of 40 subjects with LOUE for cross-sectional analyses. As part of the proposed K23, I will expand this cohort to 100 subjects and follow it longitudinally. A control group will consist of subjects from the Harvard Aging Brian Study, an NIH funded study following cognitively normal (at enrollment)older adults with clinical assessments, fluid biomarkers, and multimodal neuroimaging, of which my mentor, Dr. Gad Marshall, has been a co-investigator since its inception. Findings from this study can be applied to other diseases where seizures are a common comorbidity such as Alzheimer’s disease. My training will rely on the mentorship of Dr. Marshall (an expert in AD and aging) and Dr. Page Pennell (an expert in epilepsy), as well as an advisory committee of world leaders in the fields of AD biomarkers (Dr. Dennis Selkoe), neuroimaging (Dr. Steven Stufflebeam), neuropsychology (Dr. Rebecca Amariglio), vascular related cognitive impairment (Dr. Anand Viswanathan), and statistical analysis of longitudinal studies (Dr. Joseph Locascio). During the training period, I will gain expertise in neuroimaging analysis, the implementation of longitudinal studies in an elderly cohort, and the statistical analysis of longitudinal data. The institutional resources available through Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, and Harvard School of Public Health are world class and will support my career development in an environment that can foster high impact contributions. Upon successful completion of the project, I will be well positioned to launch a career as an independent investigator examining the interactions of seizures, neurodegeneration, cerebrovascular disease and cognition.

项目概要随着预期寿命的增加，老年人癫痫发作的负担将会增加，其中多达一半的病例患有癫痫发作大型数据库尚未发现可识别的原因称为迟发性不明原因癫痫 (LOUE)。 LOUE 患者患痴呆症和中风的风险较高，但研究重点关注个体患者目前需要确定 LOUE 的潜在因素及其对认知的影响。及其自然史，以制定预防和治疗策略。该项目的第一个目标是确定队列中两种最常见的衰老病理的负担 LOUE 通过使用 MRI 和血液生物标志物评估小血管缺血性疾病的负担阿尔茨海默病 (AD) 及其与认知和神经退行性疾病的关系第二个目标是。跟踪 LOUE 队列 3 年，以确定病理负担是否增加当某人癫痫发作并导致认知能力加速下降和神经退行性变时。由美国癫痫协会资助的初级研究员资助，我已经开始招募 40 人的队列作为拟议 K23 的一部分，我将把这个队列扩大到 100 名受试者。对照组将由哈佛老化布莱恩研究的受试者组成，美国国立卫生研究院 (NIH) 资助的一项研究，对认知正常（入组时）的老年人进行了临床评估、液体生物标志物和多模式神经影像，我的导师 Gad Marshall 博士是其中的联合研究员自这项研究开始以来，其研究结果可应用于癫痫发作常见的其他疾病。合并症，例如阿尔茨海默病。我的培训将依赖于马歇尔博士（AD 和衰老方面的专家）和佩奇·彭内尔博士（AD 和衰老方面的专家）的指导。癫痫专家），以及 AD 生物标志物领域世界领导人的咨询委员会（Dr. Dennis Selkoe）、神经影像学（Steven Stufflebeam 博士）、神经心理学（Rebecca Amariglio 博士）、血管相关认知障碍（Anand Viswanathan 博士），以及纵向研究的统计分析（Dr. Anand Viswanathan） Joseph Locascio）在培训期间，我将获得神经影像分析、实施方面的专业知识。老年队列的纵向研究，以及纵向数据的统计分析。布莱根妇女医院、马萨诸塞州总医院、哈佛大学提供的资源医学院和哈佛大学公共卫生学院是世界一流的，将支持我的职业发展在一个可以促进高影响力贡献的环境中成功完成该项目后，我将完全有能力开启作为独立调查员的职业生涯，研究癫痫发作的相互作用，神经退行性疾病、脑血管疾病和认知。