Project Grant R21AG086721

HYPERPOLARIZED MR-PET FOR EVALUATING MITOCHONDRIAL FUNCTION AND AVAILABILITY IN AN ALZHEIMERS DISEASE MODEL - PROJECT SUMMARY/ABSTRACT METABOLIC DYSFUNCTION IS A PROMINENT CONTRIBUTOR TO THE DEVELOPMENT OF ALZHEIMER'S DISEASE (AD), EVIDENCED BY BRAIN GLUCOSE HYPOMETABOLISM OBSERVED DECADES PRIOR TO THE DEVELOPMENT OF AD SYMPTOMS. DESPITE OCCURRING EARLY IN DISEASE AND PRIOR TO OR EXCEEDING TO BRAIN VOLUME CHANGES, REDUCED METABOLIC DEMAND IS OFTEN ASSUMED TO BE DUE TO THE LOSS OF NEURONS. HOWEVER, RECENT STUDIES INDICATE THAT COMPLEX ALTERATIONS TO MITOCHONDRIAL FUNCTION IN BOTH NEURONS AND GLIAL CELLS MAY BE THE CULPRIT. MITOCHONDRIA IS THE POWERHOUSE IN CELLS TO GENERATE ENERGY AND KEEP METABOLIC CYCLES TURNING THROUGH OXIDATIVE PHOSPHORYLATION (OXPHOS), WHICH IS DRIVEN BY THE ELECTRON TRANSPORT CHAIN (ETC) CONSISTING OF FIVE ENZYME COMPLEXES IN THE INNER MITOCHONDRIAL MEMBRANE. AS THE GATEWAY TO THE ETC, MITOCHONDRIAL COMPLEX-I (MC-1) IS RESPONSIBLE FOR RECYCLING NAD AND TRANSLOCATING PROTONS TO PRODUCE ATP DOWN THE ETC. IN MURINE MODELS OF AD, DISRUPTION OF MITOCHONDRIAL ACTIVITIES CAUSED BY TAU AND AB PATHOGENIC AGGREGATES HAVE BEEN IDENTIFIED MUCH EARLIER THAN THE FORMATION OF NEUROFIBRILLARY TANGLES AND AMYLOID PLAQUES. RECENT STUDY IN EARLY AD PATIENTS SHOWED THAT MC-1 RELATED ENERGY FAILURE MAY PRECEDE GLYCOLYSIS RELATED HYPOMETABOLISM IN REGIONS WITH PATHOLOGICALLY CONFIRMED EARLY NEURODEGENERATION IN AD. THE MC-1 DYSFUNCTION IN EARLY AD PRESENTS AN OPPORTUNITY FOR THE DEVELOPMENT OF NEW THERAPIES AT EARLY ENTRY POINTS DURING AD PROGRESSION. INDEED, PARTIAL INHIBITION OF MC-1 HAS BEEN EXPLOITED AS A NOVEL STRATEGY FOR AD IN MANY CLINICAL TRIALS, AS EMERGING DATA SUGGEST THAT IN RESPONSE TO ENVIRONMENTAL STRESS, MITOCHONDRIA INITIATE AN INTEGRATED STRESS RESPONSE SHOWN TO BE BENEFICIAL FOR HEALTHY AGING AND NEUROPROTECTION. THIS STRATEGY IS COUNTERINTUITIVE FROM THE CONVENTIONAL REMEDIES OF ENHANCING MITOCHONDRIAL FUNCTION TO AID IN HEALTHY AGING. REGARDLESS OF THE TREATMENT STRATEGIES, A NON-INVASIVELY TECHNIQUE TO MONITOR RESPONSE TO METABOLIC-TARGETING THERAPIES IS AN UNMET NEED. [18F]FDG PET ONLY MEASURES GLUCOSE UPTAKE AND DOES NOT DIFFERENTIATE GLUCOSE PHOSPHORYLATION VS. OXPHOS. METHODS TO NON-INVASIVELY IMAGE BOTH THE MC-1 AVAILABILITY AND METABOLIC FUNCTION IN VIVO WILL REVOLUTIONIZE HOW WE STUDY MITOCHONDRIAL HEALTH IN AD. IN THIS EXPLORATORY STUDY, WE WILL EVALUATE THE FEASIBILITY OF TWO NOVEL SCANNING TECHNIQUES IN AD MODELS TO 1) IMAGE THE AVAILABILITY OF MC-1 USING 1[18F]BCPP-EF PET TRACER WHICH SPECIFICALLY BINDS TO MC1 RECEPTORS AND TO 2) ASSESS THE MC-1 METABOLIC ACTIVITY USING HYPERPOLARIZED MR SPECTROSCOPY TO OBSERVE THE METABOLIC CONVERSION OF [2-13C]PYRUVATE TO [5-13C]GLUTAMATE, A PROCESS OCCURRING IN MITOCHONDRIA THAT UTILIZES NAD REGENERATED BY MC-1. THE SUCCESS OF THESE TECHNIQUES WILL REPRESENT A SIGNIFICANT DEPARTURE FROM THE CURRENT APPROACH OF EX VIVO ANALYSES. BY COMPLETING THE PROPOSED STUDY, WE WILL HAVE OBTAINED IMPORTANT FEASIBILITY DATA FOR FUTURE DEVELOPMENT OF A HYPER-PET IMAGING TECHNIQUE TO ASSESS BOTH THE AVAILABILITY AND METABOLIC FUNCTION OF MC-1 SIMULTANEOUSLY AND NON-INVASIVELY IN AD ANIMAL MODELS AND AD PATIENTS IN THE FUTURE.