Increasing evidence links neuro-inflammation to Alzheimer's Disease, post-operative cognitive decline and delirium (acute brain failure). Delirium, which may accelerate cognitive decline possibly mediated by inflammatory mechanisms, often occurs following major physiologic disruptions including medical illness and surgery. Scheduled (elective) surgery presents a unique opportunity to study and intervene upon the cognitive trajectory of older adults because of the ability to measure both cognitive function and biomarkers before and after surgery. Anti-inflammatory drugs may be effective treatments to prevent cognitive decline following surgery. However, for a successful anti-inflammatory treatment trial to be designed, we need to improve our ability to identify patients at high-risk for post-operative decline, and to identify biomarkers that will be reliable and clinically valid indicators to help us track level of inflammation. Thus, this study will first focus on identifying patients at high-risk for postoperative delirium with long-term cognitive decline. We will develop a predictive model for long-term cognitive decline following delirium utilizing a large existing dataset of patients who underwent elective surgery. Risk markers that we will consider include broad clinical, neuropsychological, neuroimaging, and blood-based biomarkers. In a second step, we will identify plasma, cerebrospinal fluid (CSF), and neuroimaging biomarkers ([11C]-PBR28 PET) of inflammation to allow for accurate and early detection of neuro-inflammation, to identify potential new therapeutic targets in inflammatory pathways, and eventually to monitor treatment response. For this step, we will assemble a new sample of patients undergoing major orthopedic surgery under spinal anesthesia, and assess the relationships of blood, CSF, and imaging biomarkers of inflammation preoperatively and at one month after hospital discharge. This proposed project, specifically targeting the role of inflammation in delirium and long-term cognitive decline, is innovative and holds great promise to accelerate anti-inflammatory treatment interventions with the goal of reducing delirium and long-term cognitive decline following surgery.