With an increase in the number of aged people, it is predicted that cognitive decline will be one of the most demanding healthcare problems in the near future for both patients and their providers, consuming a growing fraction of healthcare resources. Post-operative cognitive dysfunction or decline (POCD) is one of the most common post-operative complications in older patients, and is associated with substantially increased morbidity, mortality, and cost of care. However, the pathogenesis of POCD is still largely unknown, and this gap in knowledge impedes further studies of POCD. Neuroinflammation includes microglia activation and increases in pro-inflammatory cytokines such as tumor necrosis factor (TNF)-?, interleukin-6 (IL-6), and IL-1 in the brain. -Amyloid protein (A) is th key component of senile plaques in Alzheimer's disease (AD) patients, and A levels are elevated in the brains of AD patients as well as older adults. Consistent with the notion that neuroinflammation and A accumulation are associated with cognitive dysfunction, and that surgery without general anesthesia can also lead to POCD in humans, our Preliminary studies in mice have shown that open abdominal surgery under local anesthesia induced neuroinflammation, A accumulation, and neurobehavioral deficits. Thus, the proposed research will extend these studies to define a potential multifactorial model of POCD pathogenesis by testing the hypothesis that: surgery-induced neuroinflammation will interact with the gene mutation- or aging-induced elevation of A levels, leading to impairment of learning/memory and attention/executive function. We will employ chemical and genetic tools through both in vitro (neurons) and in vivo (mice) approaches to accomplish three Specific Aims: 1) We will evaluate the time- dependent effects of the surgery on plasma levels of TNF-?, IL-6, and IL-1; the brain levels of TNF-?, IL-6, IL- 1, phosphorylated eukaryotic translation initiatin factor 2? (eIF2?-P), -site APP-cleaving enzyme (BACE)1, A, microglia activation, and amyloid plaques; and postoperative behavioral changes in mice. 2) We will dissect the pathways contributing to A accumulation following surgery-induced neuroinflammation by investigating the effects of TNF-?, IL-6, and IL-1 on eIF2?-P-associated A generation pathway and potential CD33 (a newly suggested Alzheimer's disease gene)-associated A degradation pathway. 3) We will assess whether the knockout of TNF-?, IL-6 or IL-1 receptor, anti-inflammatory, or anti-A accumulation treatment can inhibit the surgery-induced neurotoxicity. We will include wild-type and younger (9 month-old) mice versus age matched AD transgenic and older (18 month-old) mice (with higher baseline A levels), and employ Western blot, ELISA, immunohistochemistry, RT-PCR, microdialysis, RNAi, the Fear Conditioning Test, and an intra-dimensional/extra-dimensional digging task. This proposal aims to investigate an understudied topic in an innovative system by testing novel hypotheses. Our efforts would ultimately lead to safer surgical care and better post-operative outcomes for senior patients.

Public Health Relevance

Post-operative cognitive dysfunction or decline (POCD), one of the most common post-operative complications in geriatric patients, is associated with substantially increased morbidity, mortality, and cost of care. However, its pathogenesis is largely unknown. The proposed research will characterize surgery-induced neurotoxicity, investigate the underlying mechanisms, and define its role in POCD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG041274-05
Application #
9233886
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Wagster, Molly V
Project Start
2012-09-01
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
5
Fiscal Year
2017
Total Cost
$352,873
Indirect Cost
$138,019
Name
Massachusetts General Hospital
Department
Type
Independent Hospitals
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Miao, Huihui; Dong, Yuanlin; Zhang, Yiying et al. (2018) Anesthetic Isoflurane or Desflurane Plus Surgery Differently Affects Cognitive Function in Alzheimer's Disease Transgenic Mice. Mol Neurobiol 55:5623-5638
Shen, Shiqian; Lim, Grewo; You, Zerong et al. (2017) Gut microbiota is critical for the induction of chemotherapy-induced pain. Nat Neurosci 20:1213-1216
Zhang, Ce; Zhang, Yiying; Shen, Yuan et al. (2017) Anesthesia/Surgery Induces Cognitive Impairment in Female Alzheimer's Disease Transgenic Mice. J Alzheimers Dis 57:505-518
Ni, Cheng; Li, Cheng; Dong, Yuanlin et al. (2017) Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway. Mol Neurobiol 54:3591-3605
Lu, Han; Liufu, Ning; Dong, Yuanlin et al. (2017) Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice. Anesthesiology 127:961-975
Liang, Feng; Zhang, Yiying; Hong, Wooyoung et al. (2016) Direct Tracking of Amyloid and Tu Dynamics in Neuroblastoma Cells Using Nanoplasmonic Fiber Tip Probes. Nano Lett 16:3989-94
Culley, Deborah J; Flaherty, Devon; Reddy, Srini et al. (2016) Preoperative Cognitive Stratification of Older Elective Surgical Patients: A Cross-Sectional Study. Anesth Analg 123:186-92
Peng, Mian; Zhang, Ce; Dong, Yuanlin et al. (2016) Battery of behavioral tests in mice to study postoperative delirium. Sci Rep 6:29874
Zimering, Jeffrey H; Dong, Yuanlin; Fang, Fang et al. (2016) Anesthetic Sevoflurane Causes Rho-Dependent Filopodial Shortening in Mouse Neurons. PLoS One 11:e0159637
Dong, Yuanlin; Xu, Zhipeng; Huang, Lining et al. (2016) Peripheral surgical wounding may induce cognitive impairment through interlukin-6-dependent mechanisms in aged mice. Med Gas Res 6:180-186

Showing the most recent 10 out of 45 publications