ABSTRACT Early detection of Alzheimer’s disease (AD) remains a critical unmet clinical need. Poly(ADP-ribose) polymerase- 1 (PARP-1) is a DNA repair enzyme that regulates the expression of pro-inflammatory factors. Microglia, the primary inflammatory cells of the brain, are intimately associated with amyloid plaques in the brains of patients with AD. It has been shown that the response of microglia to neuroinflammation is mediated by PARP-1 and that PARP-1 inhibition or knockout in transgenic AD mice has a beneficial effect on cognitive dysfunction, synaptic damage, and microglial activation. To date, however, there have been no studies that have investigated a radiolabeled PARP-1 imaging agent for determining PARP-1 expression in AD mice and correlating the imaging findings with AD pathology. The parent R01 for this Supplement application focuses on the development of radiolabeled PARP-1 inhibitors that can be used as tracers for non-invasive positron emission tomographic (PET) imaging of recurrent glioma. Here, we propose that similar inhibitors can be used to non-invasively track neuroinflammation related to AD pathology. We hypothesize that radiolabeled PARP-1 inhibitors will demonstrate specific uptake and retention in a mouse model of AD, compared with age-matched controls. Using in vivo PET imaging as a readout, we further hypothesize that these radiolabeled inhibitors will effectively measure changes in PARP-1 expression in cohorts of aged AD mice and that PARP-1 levels will correlate with the extent of disease progression. The aim of the proposal is to correlate the specific binding of a radiolabeled PARP-1 analog with Aβ plaques in the brains of AD mice. PET imaging data will be supported by, and correlated with, MR imaging results from an established pipeline of 1H MRI experiments aimed at assessing brain anatomy and physiology. This application will be led by a quality team of experts specializing in MR imaging (Dr. Joel Garbow); PET imaging (Dr. Buck Rogers); radioligand development and labeling (Dr. Dong Zhou); A plaque biology in AD (Dr. John Cirrito), autoradiography (Dr. Jinbin Xu); and focused ultrasound (Dr. Hong Chen). If successful, our approach will demonstrate the feasibility of non-invasive imaging of PARP-1 as an early marker of AD and provide the preliminary data for a subsequent R01 application.