R01NS130119

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.
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.

The General Hospital Corporation

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Massachusetts United States

State-Wide

Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) (PA-20-272)

Amendment Since initial award the End Date has been extended from 05/31/28 to 02/28/29 and the total obligations have increased 99% from $2,959,470 to $5,883,988.