Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are the two most common postoperative complications in older adults, and increase perioperative morbidity, mortality, and cost of medical care. However, at the present time, both POD and POCD are clinical phenomena and their pathogenesis is largely unknown. This gap in knowledge has impeded the progress of research to develop targeted interventions for POD and POCD. We have shown that low pre-operative A/Tau ratio in cerebrospinal fluid (CSF), a biomarker of Alzheimer's disease, may identify individuals at high risk of POD and POCD. However, the direct association between brain A, Tau, and neuroinflammation (e.g., microglia activation) levels with POD/POCD remains to be investigated. Our co-investigator Dr. Johnson has developed the innovative technology of measuring brain Tau [(F-18)T807] and A (Pittsburgh compound B) levels by using positron emission tomographic imaging. We have developed methods to assess POD/POCD and to measure CSF levels of A and Tau. Taken together, the proposed research is aimed at establishing a system/protocol that will help us for a potential larger scale study to investigate the association of brain, CSF, and plasma A and/or Tau levels, and brain microglia activation level, with the incidence and severity of POD and POCD. Our overall hypothesis is that high pre-operative brain A and Tau levels, and high postoperative neuroinflammation represent markers of brain vulnerability under perioperative stress, leading to POD and POCD. We will employ bed-side cognitive tests, bench-side enzyme-linked immunosorbent assays, and brain imaging to accomplish two Specific Aims: (1) to conduct a pilot study determining the feasibility and safety of our system/protocol in 24 participants; (2) to obtain preliminary effect size estimates of the association of brain A, Tau, and/or microglia activation levels with POD/POCD in the recruited 24 participants. The outcomes from the proposed studies will provide crucial information in regard to a future definitive study, including: (1) eligible:recruit ratio; (2) retetion rates; (3) safety; and (4) preliminary effect sizes for the associations of interest. The results fom our pilot study will guide us in determining whether we should apply for the R01; and if so, how many participants are needed. The proposed studies are highly innovative and significant, because the anticipated results would lead to an R01 study, which could illustrate that high brain A, Tau, and/or microglia activation levels are associated with POD and POCD. These findings would suggest that we should avoid or treat perioperative factors (e.g., anesthetic isoflurane, hypothermia, and severe inflammation) which may cause A accumulation, Tau phosphorylation, and/or neuroinflammation, leading to POD and POCD. Ultimately, the proposed R21-supported system/protocol study and the future R01-supported confirmative/ definitive research could lead to better anesthesia and surgery care for older adults.

Public Health Relevance

Post-operative delirium (POD) and Post-operative cognitive dysfunction (POCD) increase peri- operative morbidity, mortality and cost of medical care. However, the pathogenesis of POD and POCD is largely unknown. The proposed research will establish a system/protocol to employ clinical cognitive tests, biochemistry analysis and brain imaging to determine the role of brain -amyloid, Tau and microglia activation in the pathogenesis of POD and POCD in humans, which would ultimately lead to a better anesthesia and surgery care for patients, especially geriatric patients.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Wagster, Molly V
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Massachusetts General Hospital
United States
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