Project Grant F31AG099465

LOCUS COERULEUS CONTRIBUTIONS TO EPISODIC MEMORY SEGREGATION IN AGING - PROJECT SUMMARY A KEY FOCUS OF ALZHEIMER'S DISEASE (AD) RESEARCH IS DETECTING THE EARLIEST CHANGES IN COGNITIVE FUNCTION AND AD- RELATED PATHOLOGIES. RECENT NEUROIMAGING BIOMARKER RESEARCH HAS IDENTIFIED THE LOCUS COERULEUS (LC) AS A KEY BRAIN REGION WHICH SHOWS EARLY CHANGES DURING AD AND IS ALSO RELEVANT TO UNDERSTANDING SUBTLE COGNITIVE AND AFFECTIVE CHANGES. THE LC IS A SMALL BRAINSTEM NUCLEUS THAT IS ONE OF THE FIRST BRAIN REGIONS TO DEVELOP TAU PRETANGLES. A GROWING BODY OF RESEARCH DIRECTLY IMPLICATES THE LC IN EPISODIC MEMORY ENCODING. SPECIFICALLY, LC INPUTS TO THE HIPPOCAMPUS ARE THOUGHT TO MARK IMPORTANT TRANSITIONAL POINTS (I.E. EVENT BOUNDARIES) THAT ALLOWS CONTINUOUS EXPERIENCES TO BE SEGMENTED INTO DISCRETE AND MEMORABLE EVENTS. DESPITE THESE ADVANCEMENTS, LITTLE TO NO WORK HAS EVALUATED THE LC'S ROLE IN THE USE OF EVENT BOUNDARIES WITHIN AGING AND AD POPULATIONS. ASSESSING LC HEALTH IN THE FACE OF AGE-RELATED TAU PATHOLOGY MAY PROVIDE INSIGHT INTO THE MECHANISMS DIFFERENTIATING INDIVIDUALS WHO REMAIN COGNITIVELY NORMAL AND THOSE WHO EVENTUALLY DEVELOP AD. THIS PROPOSED RESEARCH ADDRESSES THIS GAP BY USING A COMBINATION OF POSITRON EMISSION TOMOGRAPHY (PET), STRUCTURAL MAGNETIC RESONANCE IMAGING (MRI), AND COGNITIVE NEUROSCIENCE METHODS. GIVEN LIMITATIONS OF CURRENTLY DEVELOPED TAU-PET TRACERS, ANALYSES OF TAU BURDEN (WITH RADIOTRACER [18F]MK-6240) WILL FOCUS ON MEDIAL TEMPORAL LOBE REGIONS. TO OBTAIN A MEASURE SPECIFIC TO LC HEALTH AND STRUCTURAL INTEGRITY, A STRUCTURAL MRI SEQUENCE WILL BE USED. THE CURRENT PROPOSAL WILL DEFINE HOW LC STRUCTURAL INTEGRITY AND TAU PATHOLOGY RELATE TO PERFORMANCE ON AN EPISODIC MEMORY TASK. A FOCUS ON INTERACTIONS BETWEEN EVENT BOUNDARY DETECTION AND AGE IS A CENTRAL COMPONENT OF THE PROPOSED RESEARCH GIVEN THE IMPORTANCE OF COGNITIVE STRATEGIES TO MAINTAIN EPISODIC MEMORY IN AGING AND AD, AND THE GROWING APPRECIATION OF THE INTERPLAY BETWEEN LC HEALTH AND GENERAL COGNITION IN BOTH POPULATIONS. AIM 1 WILL DIRECTLY TEST AGE GROUP DIFFERENCES IN THE IDENTIFICATION AND USE OF EVENT BOUNDARIES TO BENEFIT EPISODIC MEMORY. AIM 2 WILL EVALUATE HOW LC STRUCTURAL INTEGRITY AND TAU BURDEN RELATES TO EVENT BOUNDARY IDENTIFICATION AND EPISODIC MEMORY. PRIMARY ANALYSES WITH USE LC STRUCTURAL INTEGRITY AND MEDIAL TEMPORAL LOBE TAU AS PREDICTORS WITH AGE AS A COVARIATE. THIS PROPOSAL WILL PROVIDE THE APPLICANT WITH UNIQUE TRAINING IN (1) COGNITIVE NEUROSCIENCE OF EPISODIC MEMORY, (2) THE ADVANCED ANALYSIS OF AD NEUROIMAGING BIOMARKERS, (3) THE NEUROPATHOLOGY OF AGING AND PRECLINICAL AD AND IN (4) ORAL AND WRITTEN COMMUNICATION AND MENTORSHIP. SPONSORS DR. ANNE BERRY (BRANDEIS UNIVERSITY) AND DR. HEIDI JACOBS (MASSACHUSETTS GENERAL HOSPITAL) HAVE EXTENSIVE BACKGROUNDS AND SUCCESS IN THESE FOUR DOMAINS AND ARE LOCATED AT INSTITUTIONS WITH STRONG TRACK RECORDS FOR TRAINING YOUNG INVESTIGATORS. THIS PROPOSED PROJECT WILL HELP THE APPLICANT PURSUE A CAREER FOCUSED ON DEFINING COGNITIVE AND NEUROBIOLOGICAL UNDERPINNINGS OF DIFFERING AGING TRAJECTORIES.