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.