Project Grant F30AG099730

MAPPING SPATIOTEMPORAL METABOLIC CHANGES IN ALZHEIMER'S DISEASE USING ADVANCED WHOLE-BRAIN MAGNETIC RESONANCE SPECTROSCOPIC IMAGING (MRSI) - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) AFFECTS OVER 47 MILLION PEOPLE GLOBALLY, YET CURRENT DIAGNOSTIC APPROACHES FAIL TO DETECT EARLY DISEASE PROCESSES. WHILE AMYLOID PLAQUES AND TAU TANGLES ARE WELL-ESTABLISHED HALLMARKS OF AD, THEY DO NOT FULLY CAPTURE THE DISEASE COMPLEXITY. INCREASING EVIDENCE SUGGESTS THAT NEUROCHEMICAL AND METABOLIC CHANGES OCCUR BEFORE STRUCTURAL BRAIN ATROPHY AND COGNITIVE DECLINE. THESE EARLY ALTERATIONS COULD SERVE AS VALUABLE BIOMARKERS FOR PRECLINICAL DIAGNOSIS AND MONITORING. THIS PROJECT PROPOSES THE USE OF HIGH-RESOLUTION, WHOLE-BRAIN MAGNETIC RESONANCE SPECTROSCOPIC IMAGING (MRSI) TO NON-INVASIVELY TRACK NEUROCHEMICAL CHANGES IN A TRANSGENIC AD MOUSE MODEL. TRADITIONAL MRSI METHODS ARE LIMITED BY LOW SPATIAL RESOLUTION AND LONG SCAN TIMES, WHICH HINDER THEIR TRANSLATIONAL POTENTIAL. OUR ADVANCED IMAGING TECHNIQUE SIGNIFICANTLY REDUCES ACQUISITION TIME WHILE MAINTAINING HIGH DATA QUALITY, ENABLING DETAILED SPATIAL AND TEMPORAL MAPPING OF BRAIN METABOLITES. IN AIM 1, WE WILL IDENTIFY WHERE METABOLIC DISTURBANCES FIRST EMERGE IN THE BRAIN AND HOW THEY RELATE TO HALLMARK PROTEIN PATHOLOGIES SUCH AS AMYLOID-B AND TAU. IN AIM 2, WE WILL ASSESS HOW THESE METABOLIC CHANGES EVOLVE OVER TIME AND HOW THEY CORRELATE WITH COGNITIVE DECLINE USING WELL-VALIDATED BEHAVIORAL ASSAYS. THIS INTEGRATIVE APPROACH COMBINES CUTTING-EDGE IMAGING, HISTOLOGICAL VALIDATION, AND BEHAVIORAL ASSESSMENTS TO PROVIDE A COMPREHENSIVE VIEW OF DISEASE PROGRESSION. THE EXPECTED OUTCOME IS A MORE PRECISE UNDERSTANDING OF WHEN AND WHERE AD-RELATED NEUROCHEMICAL DISRUPTIONS OCCUR, OFFERING NOVEL INSIGHTS INTO PATHOPHYSIOLOGY. ULTIMATELY, THIS WORK MAY TRANSFORM HOW AD IS DIAGNOSED AND MONITORED, ENABLING EARLIER INTERVENTION AND IMPROVED TREATMENT STRATEGIES.