RF1NS142613

ASSESSING NOVEL BIOMARKERS FOR COGNITIVE FLUCTUATIONS IN DLB - AGE-RELATED DISEASES, SUCH AS ALZHEIMER DISEASE (AD) AND DEMENTIA WITH LEWY BODIES (DLB), ARE DEFINING PUBLIC HEALTH CONCERNS OF THE 21ST CENTURY AND ARE THE LEADING CAUSE OF DISABILITY WORLDWIDE. NOVEL DISEASE MODIFYING THERAPIES HAVE OPENED A NEW HORIZON FOR MANAGING THESE PROGRESSIVE DISEASES. HOWEVER CLINICAL TRIALS ASSESSING THESE THERAPEUTIC MEDICATIONS ARE BEDEVILED BY SMALL EFFECT SIZES AND SUBSTANTIAL INTERSUBJECT VARIABILITY THAT CHALLENGES EVALUATION OF THEIR EFFECTIVENESS. TO MEET THIS CHALLENGE, ADDITIONAL FACTORS MEDIATING VARIABILITY IN COGNITIVE PERFORMANCE ARE A KEY KNOWLEDGE GAP TO OVERCOME. COGNITIVE FLUCTUATIONS (CFS) ARE INTERMITTENT EPISODES OF DECREASED ALERTNESS, ATTENTION, AND RESPONSIVENESS THAT OCCUR IN SOME PATIENTS WITH DEMENTIA. THE UNPREDICTABLE NATURE OF THESE EVENTS POSES A MAJOR BURDEN FOR PATIENTS AND CAREGIVERS, AS WELL AS COMPLICATING THE MEASUREMENT OF TREATMENT EFFICACY IN CLINICAL TRIALS, PARTICULARLY WHEN THE TREATMENT IS INTENDED TO IMPROVE COGNITION. UNFORTUNATELY, METHODS TO TRACK CFS EFFECTIVELY AND THE PATHOPHYSIOLOGY OF THIS CONDITION ARE POORLY UNDERSTOOD. IN THIS PROPOSAL, WE AIM TO VALIDATE NOVEL BIOMARKERS THAT CAPTURES THE MOST RELEVANT FEATURES OF COGNITIVE FLUCTUATIONS IN AD AND DLB. TOWARDS THIS GOAL, WE WILL PROVIDE A MULTIMODAL CHARACTERIZATION OF THE FREQUENCY AND SEVERITY OF CFS AND THEIR LONGITUDINAL VARIABILITY AT ANNUAL VISITS. THE DEMENTIA WITH LEWY BODY CONSORTIUM (DLBC) COHORT PRESENTS A GOLD STANDARD COHORT FOR DLB BIOMARKER DIAGNOSIS (CSF Α-SYNUCLEIN, AGGREGATION ASSAY), WHILE THE ALZHEIMER’S DISEASE RESEARCH CENTERS (ADRC) PRESENTS COHORTS FOR AD DIAGNOSIS (CSF A-BETA42,40, T-TAU, AND P-TAU181) ALONG WITH AUTOPSY CONFIRMATION. IN THESE COHORTS, WE WILL OBTAIN BOTH CLINICAL (FLUCTUATION SCALES, COGNITIVE VARIABILITY) AND MULTIPLE OBJECTIVE DIGITAL BIOMARKERS (ACTIGRAPHY, EEG, SLEEP, RESTING STATE FUNCTIONAL MRI) TO EVALUATE THE FREQUENCY AND SEVERITY OF CFS AT BASELINE AND LONGITUDINAL VARIABILITY ANNUALLY OVER FOUR YEARS. THIS PROJECT WILL ENABLE US TO HELP DEVELOP APPROPRIATE BIOMARKERS THAT CAPTURE THE MOST RELEVANT FEATURES THAT CAN BE SCALED TO TRACK CFS EFFECTIVELY IN LARGE CLINICAL TRIALS. FURTHER, THIS PROJECT WILL HELP US DEVELOP A MODEL OF THE UNDERLYING NEURAL FEATURES OF CFS TO ENABLE FUTURE TARGETED THERAPIES.

Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University

(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.

93.866 - Aging Research

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

National Institute on Aging (NIA) [HHS - NIH]

Cleveland, Ohio 44195 United States

Single Zip Code

Mechanisms of Cognitive Fluctuations in ADRD Populations (R01 - Clinical Trial Optional) (RFA-NS-25-014)