PROJECT SUMMARY/ABSTRACT Background: Among older adults, delirium, cognitive decline, and functional decline after surgery are common. These issues may be particularly important in spine surgery patients, in whom my GEMSSTAR study showed a 43% incidence of delirium. In this proposal, I will build the foundation for a research career focused on reducing neurocognitive and functional decline after surgery in older adults, using trial methodology. The training provided by the K23 will be critical for my development in these areas. There are tremendous resources at Johns Hopkins to provide support and collaboration in pursuit of these goals, including established research programs in delirium and cognitive decline after surgery and centers of excellence in aging research. Ultimately, the combination of my education as an anesthesiologist and clinical investigator, in addition to deep training and knowledge of cognitive and functional outcomes resulting from surgery, will make me ideally situated to lead impactful studies that can directly improve postoperative outcomes in older adults. Career Development Plan: I am proposing specific educational goals that address gaps in my current knowledge. First, I will develop expertise in clinical trials through three courses, meetings with my primary co- mentor, Dr. Hogue (anesthesiologist and trialist), and ongoing seminars at the Center for Clinical Trials Research. Second, developing expertise in neurocognitive testing and dementia assessment is crucial, because these will be important outcomes in my future research, and as an anesthesiologist, I have no background in these areas. Expertise will be developed through a year-long course in cognition, the Medical Psychology Lecture Series, and meetings with Dr. Brandt (neuropsychologist), Drs. Albert and Gottesman (experts in dementia), and Dr. Moghekar (expert in cerebrospinal fluid [CSF] biomarkers). I will also participate in dementia diagnosis conferences. Finally, I will develop expertise in functional changes and geriatric issues through attendance at a Frailty Working group, ongoing seminars at the Center on Aging and Health, and in meetings with a primary co-mentor, Dr. Walston (geriatrician and expert in late-life functional decline). The didactic foundation of my educational activities will occur in Year 1, thus providing baseline knowledge to allow me to properly conduct my research proposal. Research Proposal: Reducing the depth of anesthesia in older adults during surgery may be a strategy to reduce postoperative delirium and/or cognitive and functional decline, but weaknesses of prior literature include inability to examine the effects of “light” anesthesia (thus obscuring potential benefits of the intervention), poor generalizability of patients, and post hoc analyses. Thus, while intriguing, the causal role of reducing depth of anesthesia in promoting optimal neurocognitive and functional outcomes in older adults after surgery has not been established. To address these gaps in understanding and with support from a small foundation grant obtained since my original K submission, I am conducting a small pilot trial (n=18 so far) to determine feasibility and safety of an intervention to reduce depth of anesthesia with the goal of reducing delirium. Older adults undergoing spine surgery are being randomized to different depths of anesthesia—light sedation with spinal anesthesia vs. general anesthesia. In Aim 1 of this proposal, I will extend enrollment in this trial (n=75 from ongoing pilot, and n=131 anticipated from this K23), so that with a combined sample size of 206 patients, I can (a) examine feasibility, safety, and potential efficacy of the intervention to prevent delirium and (b) identify clinical characteristics of patients who might derive the most benefit from “light” anesthesia through stratified analyses. In Aim 2, I will determine the feasibility of adding new outcome measures of cognition and function at baseline and 3-month follow-up, and obtain preliminary evidence of the efficacy of the intervention to improve these outcomes. Finally, I propose an exploratory mechanistic Aim 3 to examine if the effect of anesthetic technique on delirium and cognitive decline is modified by baseline levels of cerebrospinal fluid amyloid-β and tau. The feasibility and rationale of each aim is supported by my pilot data. Summary: Promising results from this proposal would support a definitive trial at multiple centers to determine whether reduced depth of anesthesia could reduce cognitive or functional decline after surgery in older adults. The results from such a trial would have the potential to fundamentally alter anesthetic strategies. Examination of CSF may also provide insight into the pathophysiology of cognitive and functional decline. Together with my educational plan, this research will provide me with expertise and data to support my career goal of optimizing neurocognitive and functional outcomes after surgery in older adults.

PROJECT NARRATIVE This proposal will examine the feasibility, safety, and potential efficacy of a novel anesthetic intervention to prevent postoperative delirium, cognitive decline, and functional decline in older adults. Amyloid-β and tau concentrations in the cerebrospinal fluid will also be measured to evaluate any modifying effects on the effects of the anesthetic intervention. The results of this proposal will provide important information on the feasibility, safety, and efficacy of a strategy to improve important postoperative outcomes in older adults after surgery.