PROJECT SUMMARY / ABSTRACT Dementia with Lewy bodies (DLB) is a clinical syndrome characterized by the presence of Lewy body disease (LBD), but additional Alzheimer's disease (AD)-related pathology is also common in patients with DLB. Although the impact of each of these two pathologies on the clinical disease progression is not fully understood, many DLB patients may benefit from treatments that target both AD and LBD-related pathological processes. To prepare for these clinical trials in DLB, we need robust and reliable biomarkers that can track disease progression, particularly the progression of both LBD- and AD-related pathologies. We propose multi-modal imaging biomarkers of pathological processes commonly present in patients with DLB to detect disease progression. We propose to establish a longitudinal cohort of patients with DLB and acquire clinical and multi-modal imaging biomarker data to model the longitudinal imaging biomarker changes with respect to clinical disease progression in DLB. In Aim 1, we propose to determine whether LBD-related dopaminergic loss on SPECT, and AD pathophysiology measured with higher amyloid-? deposition on PET and AD-signature atrophy on MRI is associated with the rate of clinical disease progression, cognitive decline and survival in DLB; In Aim 2, we will determine whether these longitudinal changes in imaging biomarkers and clinical outcomes, and their associations are modified by genetic, sex- based, and cerebrovascular disease-related features. In Aim 3, we will determine the pattern of a tau ligand AV-1451 uptake in DLB compared to controls and its relationship to the rate of change in imaging biomarkers and clinical disease progression. Finally, we will determine the pathologic basis of the biomarker changes in DLB in autopsied patients, which is the gold standard for validating imaging biomarkers in Aim 4. In addition to these aims that focus on hypothesis testing, we will respond to RFA-NS- 16-022 by collecting whole blood, plasma, serum, CSF, and urine samples, clinical and harmonized neuroimaging data longitudinally; DNA and peripheral blood mononuclear cells from a prospective cohort of DLB patients, and submit them to the PDBP.