Biomarkers and Pathogenesis of Perioperative Neurocognitive Disorders - Perioperative neurocognitive disorders (PND) – including postoperative delirium, delayed neurocognitive recovery (dNCR), and postoperative neurocognitive disorders (PNCD) – are associated with increased morbidity and mortality, higher costs of care, and greater risk of developing Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). However, the biomarkers and pathogenesis of PND remain largely undetermined. Consistent with the findings that blood pTau at threonine 217 (pTau217) is a specific biomarker for the early stage of AD, we reported that pre-operative blood pTau217 might serve as a predictor of postoperative delirium in patients. Additionally, blood inflammatory cytokines such as interleukin-6 (IL-6) and C-reactive protein (CRP) are associated with postoperative delirium. Finally, our most recent study identified potential contributions of gut microbiota and their metabolites indole-3-propinoic acid (IPA) and butyric acid to the development of postoperative delirium and cognitive impairment. Thus, the objective of our proposed research is to: (1) identify whether non-brain-derived (BD) pTau217 can be generated in blood, and reveal the up-stream mechanisms (e.g., gut microbiota) and down-stream consequences (e.g., potentiation of inflammation); (2) determine whether the pre- and postoperative blood non-brain-derived pTau217, gut microbiota and the metabolites IPA and butyric acid are biomarkers of PND (primary objective) and enhancers (second objective) of the association between inflammation and PND; and (3) investigate whether specific gut microbiota profile can regulate activity of blood GSK3b (the kinase for Tau phosphorylation) to promote the generation of non-brain-derived pTau217 in blood, which contributes to the pathogenesis of PND. The general hypothesis is that specific gut microbiota dysbiosis-mediated reduction of blood IPA and butyric acid increases blood GSK3b activity to generate higher concentration of non-brain-derived pTau217 in blood, which potentiates the anesthesia/surgery-induced inflammation, leading to PND. We will prospectively enroll 400 adults aged ≥ 65 years who are scheduled for orthopedic surgery under general anesthesia. We will measure pre- and postoperative gut microbiota profile, blood IPA, butyric acid, GSK3b, pGSK3b, BD versus non-BD Tau and pTau217, IL-6 and CRP concentrations using newly developed nanoneedle technology, Single Molecule Array (Simoa), specific antibody (e.g., brain derived-specific Tau antibody) and other methods. We will determine incidence and severity of postoperative delirium, dNCR and PNCD. The proposed studies aim to establish pre- and postoperative blood non-BD pTau217, gut microbiota, blood IPA and butyric acid as biomarkers of PND and enhancers of the association between blood inflammation and PND, and elucidate the underlying mechanism (e.g., increased blood GSK3b activity). The results of our proposed studies will challenge existing practices, guide strategies to prevent and treat PND, and ultimately improve anesthesia and surgical care for older patients, particularly those at increased risk of developing AD/ADRD.
