The contribution of late onset unexplained epilepsy to cognitive decline and its interaction with vascular and Alzheimer's disease pathologies

项目摘要 随着预期寿命的增加，老年人癫痫发作的负担将增加，多达一半的病例 无可识别的原因称为迟发性不明原因癫痫(LOUE)。大型数据库已经确定 LOE患者患痴呆症和中风的风险更高，但研究重点放在个别患者身上 都是有限的。目前需要确定LOE的潜在因素，即它们对认知的影响 以及它的自然历史，以制定预防和治疗策略。 这个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 通过使用MRI和血液生物标记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化的关系。第二个目标是 在三年的时间里跟踪LOUE队列，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减退和神经退化加速时。通过一个 初级研究员资助金由美国癫痫学会资助，我已经开始招募40名 有LUE的受试者进行横断面分析。作为拟议的K23的一部分，我将把这一群体扩大到100人 受试者，并纵向跟踪。一个控制组将由哈佛大学老龄化布莱恩研究的受试者组成， 美国国立卫生研究院资助的一项研究，跟踪研究认知正常(在登记时)有临床评估、体液 生物标记物和多模式神经成像，我的导师盖德·马歇尔博士一直是这方面的联合研究员 从一开始就是这样。这项研究的发现可以应用于其他疾病，在这些疾病中，癫痫发作是常见的 阿尔茨海默病等共病。 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( 癫痫专家)，以及AD生物标记物领域的世界领袖咨询委员会(Dr。 Dennis Selkoe)、神经成像(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)和纵向研究的统计分析(Dr. 约瑟夫·洛卡西奥)。在培训期间，我将获得神经成像分析方面的专业知识， 对一组老年人进行纵向研究，并对纵向数据进行统计分析。体制上的 可通过布里格姆妇女医院、马萨诸塞州综合医院、哈佛大学获得的资源 医学院和哈佛公共卫生学院都是世界一流的，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。在该项目成功完成后，我将 作为一名研究癫痫发作相互作用的独立调查员， 神经退行性变、脑血管疾病与认知。

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.