Project Summary / Abstract Dr. Higginbotham is a promising physician-scientist who aspires to unravel the molecular pathophysiology underlying the cognitive and neuropsychiatric decline of Dementia with Lewy bodies (DLB) and identify novel protein signatures that help monitor and treat these debilitating symptoms. This K23 will advance her goals by providing training and mentorship in the following core competencies: 1) bioinformatics; 2) molecular proteomic techniques; and 3) clinical observational research. Dr. Higginbotham has assembled a mentoring team with unparalleled expertise in these areas and their applications to neurodegeneration research. Her primary mentor, Dr. Allan Levey, is a world-renowned cognitive neurologist who leads a highly productive laboratory with basic and translational expertise in Alzheimer's disease (AD) research. Her co-mentor, Dr. Nicholas Seyfried, is an expert in mass spectrometry (MS)-based proteomics and Director of the Emory Integrated Proteomics Core. She will also work closely with a host of collaborators who will provide key biospecimen and analytical resources. This project will use a systems-based proteomics approach to globally profile the corticolimbic pathophysiology of DLB and identify protein signatures of this dysfunction in cerebrospinal fluid (CSF). The rationale for these experiments stems from a staggering lack of biomarkers that assist in the monitoring and treatment of DLB cognitive and neuropsychiatric decline. While synuclein accumulation in corticolimbic regions correlates strongly to these devastating non-motor symptoms, little is known regarding the complex molecular processes surrounding this pathology. Therefore, efforts to better define the corticolimbic pathophysiology of DLB promise to not only enhance our scientific understanding of disease, but also promote the discovery of novel molecular signatures that advance the clinical management of its cognitive and neuropsychiatric decline. Dr. Higginbotham has spent the last two years optimizing brain-CSF integrative proteomic strategies in AD. This work resulted in the identification of novel CSF AD protein signatures linked to a diverse range of cortical pathophysiology. These exciting analyses comprise much of the pilot data for this proposal and will serve as a template for its experiments in DLB. In Aim 1, Dr. Higginbotham will apply co- expression network analysis to the DLB corticolimbic proteome to identify key disease-associated pathways. She will then use co-immunoprecipitation MS to examine pathological synuclein interactors in disease. In Aim 3, she will measure protein signatures of this brain-based pathophysiology in DLB CSF. Based on preliminary data, Dr. Higginbotham hypothesizes that the cortical and limbic regions of the DLB brain feature altered protein pathways and synuclein interactors involved in cellular metabolism. She also expects this corticolimbic pathophysiology to manifest in the CSF as unique DLB protein sig...