PROJECT SUMMARY Bioenergetic dysfunction is likely an early, critical component of neuropathogenesis of the second-most common neurodegenerative dementia, Dementia with Lewy Bodies (DLB). However, it has been difficult to elucidate the specific patterns and mechanisms of bioenergetic dysfunction, such as mitochondrial respiratory dysfunction, glycolytic failure, or failure of energy reserves in vivo in the neuropathogenesis of this disease. Elucidating the different mechanistic pathways of metabolic dysfunction involved in DLB pathogenesis, and determining the temporal sequence and pattern of these events, will be critical to developing targeted therapies. Capitalizing on our combined expertise and our advancements in neuroimaging methodologies, we have the capacity to combine a new PET radioligand that quantifies brain mitochondrial Complex I, with both fluorodeoxyglucose (FDG)-PET to assess glycolytic energy metabolism, and ultra-high field strength 7T 31P-MRS for assessment of ATP and other high-energy phosphate bioenergetic metabolites. Utilizing this multimodal neuroimaging, along with extensive clinical characterization, we will determine mitochondrial respiratory and glycolytic contribution to ATP dysregulation across the clinical spectrum via evaluation of control, at-risk, prodromal, and clinically established DLB. We will address the following aims: 1) characterize specific mitochondrial respiratory chain dysfunction in the brain as DLB pathogenesis progresses from at-risk to established disease; 2) dissect specific bioenergetic pathways contributing to ATP dysregulation in DLB; 3) analyze the relationship between brain mitochondrial and bioenergetic dysfunction and changes in cognitive function and peripheral measurements of bioenergetics; and 4) explore differences in bioenergetic pathway dysfunction between DLB and Alzheimer’s disease.