Project Summary/Abstract (Description) Lewy bodies are aggregates of misfolded alpha-synuclein (𝛼-Syn), that are seen in dementia-related diseases such as dementia with Lewy bodies (DLB). While the central nervous system (CNS) has been the primary focus of research, an increasing body of evidence suggest peripheral involvement, including that of the gastrointestinal (GI) tract. Recent experiments in rodents and primates have shown gut-to-brain transmission of α-Syn, consistent with clinical observations of GI symptoms in patients manifesting decades before motor and behavioral alterations. This proposal pioneers the use of hyperpolarized magnetic resonance imaging (HP-MRI) as a ‘brain scan’ for early detection of disease, and to assess new therapeutic interventions such as physical activity. HP-MRI is unique in its ability to detect metabolic flux. The overarching hypothesis of this proposal is that gut- to-brain spread of 𝛼-Syn results in metabolic changes, well before development of dementia-related symptoms. We test this hypothesis in mouse models of synucleinopathy. In Aim 1, we directly inject 𝛼-Syn pre-formed fibrils (PFF), that has been shown to traffic from the gut to the brain. We will use HP-MRI to measure alterations in pyruvate metabolism, expecting to detect increased lactate and reduced bicarbonate as 𝛼-Syn aggregates form. Aim 2 explores a related, but separate application of HP-MRI - which is to detect the efficacy of exercise intervention. Physical activity has been extensively study as an intervention to delay cognitive disorders. Here, we hypothesize that HP-MRI can measure a ‘normalization’ of brain metabolism after 𝛼-Syn injection in exercised mice. We also provide a mechanistic explanation, hypothesizing the apelin, an exerkine released after physical activity, promotes autophagy to reduce the burden of 𝛼-Syn aggregation. Together, this proposal delivers new tools and methods, that are ultimately translatable to patients suffering from dementia-related diseases.