Abstract: Older people require specific care when undergoing an operation, principally because events around surgery and anesthesia can precipitate delirium. The prevalence of postoperative delirium depends on type of surgery, but an overall postoperative incidence of 17% is a reasonable estimate. The pathophysiological mechanisms that underpin postoperative delirium and its sequelae have yet to be systematically studied. Certain pathways may account for the development of delirium itself, while others may drive longer-term cognitive outcomes such as progression of dementia. The degree to which these interrelate, are separate or shared is completely unknown. One approach to investigate the neural basis of delirium has been to use CSF samples obtained through regional anesthesia. We propose investigating the neural basis of delirium by using CSF samples obtained in the course of spinal anesthesia, combining biomarkers with clinical and demographic information. Our preliminary data indicates arginine metabolism may be a predictor of delirium in CSF. In this study we aim to extend on our previous work, and accurately quantify all arginine related metabolites and complement this data set with protein expression levels for this metabolic cascade. Our goal is to develop a comprehensive picture of arginine metabolism in CSF and correlate these results with current pathophysiological biomarkers of Alzheimer?s disease. Further, having extended our biochemical coverage of arginine metabolism, we will develop novel biomarkers capable of predicting those patients at greatest risk of developing delirium and subsequent cognitive decline. Having defined the biochemical signature of delirium, it will be important to determine which patients later developed dementia and/or significant neurodegeneration following surgery. Therefore, we will complete a long term follow up of our original patients to determine who developed Alzheimer?s disease or one of its related dementias and correlate those findings with our results. Moreover, and to ensure the validity of our delirium biomarker panel, we will prospectively recruit participants undergoing planned joint replacement surgery at Beaumont Health (>4,000 at Beaumont Royal Oak, 2018), perform pre-operative clinical and cognitive assessments and postoperative delirium screening. Having access to such a large and diverse patient population will provide the us with an optimal, independent validation set. In summary, our overarching goals for this proposal are to: (i) develop an existing collaboration with the largest CSF-delirium repository to date (n=358) in order to extend on current findings; (ii) develop new biomarker panels; (iii) perform a long term follow up of our initial cohort and (iv) validate our findings in a large and diverse US based population.