Postoperative Delirium and Alzheimer's Disease Related Dementias

术后谵妄和阿尔茨海默病相关的痴呆

基本信息

  • 批准号:
    10565910
  • 负责人:
  • 金额:
    $ 59.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-15 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

Postoperative delirium (POD), a clinical phenomenon different from postoperative cognitive dysfunction, is the most common postoperative complication among older patients and is associated with substantially increased rates of morbidity and mortality, as well as an increased cost of care, and risk of developing Alzheimer's disease and related dementias (ADRD). Specifically, people with ADRD are at an increased risk of developing delirium, and dementia-free patients who experience delirium are at higher risk of developing ADRD. However, the pathogenesis of POD is still largely unknown, and this gap in knowledge impedes current efforts in preventing and treating POD. To further study the POD pathogenesis, we have established a rodent model, called the Confusion Assessment Method (CAM) in mice, to assess the delirium-like behavior in mice. Consistent with the notion that Tau phosphorylation and neuroinflammation are part of ADRD neuropathogenesis and are associated with cognitive impairments, our preliminary studies showed that open abdominal surgery under general anesthesia (anesthesia/surgery) induced neuroinflammation and POD-like behavior in aged mice which had elevated levels of brain phosphorylated Tau (pTau). Thus, the proposed research will extend these studies to define a potential multifactorial model of POD pathogenesis by testing the following hypothesis: anesthesia/surgery-induced neuroinflammation is exacerbated by aging- or AD gene mutation-associated accumulation of brain pTau, leading to neuronal dysfunction and POD-like behavior in mice. We will employ biochemical and genetic tools through both in vivo (mice) and in vitro (neuron and microglia) approaches to accomplish three Specific Aims: 1) We will evaluate the effects of abdominal surgery under anesthesia with 1.4% isoflurane, 3% sevoflurane or 9% desflurane for two hours on plasma and brain levels of IL-6 and pTau, microglia activation, neuronal dysfunction, and POD-like behavior in mice. 2) We will perform in vitro studies to determine the trafficking of neuronal pTau and microglia IL-6, and their effects on each other's generation and consequent neuronal dysfunction, using the neurons and microglia harvested from wild-type, IL-6 knockout and Tau knockout mice. 3) We will assess whether knockout of IL-6 or Tau, anti- inflammatory treatments (naproxen and parecoxib) or Tau phosphorylation inhibitor (lithium) can mitigate the anesthesia/surgery-induced neuronal dysfunction and POD-like behavior in mice. We will include adult wild- type (3 months-old) mice versus age matched (3 months-old) AD transgenic and aged wild-type (18 months- old) mice (with higher pTau levels), and employ a label-free nano-biosensing system for biomolecular analysis (nanobeam technology), calcium imaging, in vitro electrophysiology, microdialysis, and CAM in mice. This proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses. Our efforts could ultimately help to develop prevention and treatment methods towards POD, leading to safer surgical care and better post-operative outcomes for senior and ADRD patients.
术后谵妄(POD)是一种不同于术后认知功能障碍的临床现象

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Zhongcong Xie其他文献

Zhongcong Xie的其他文献

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{{ truncateString('Zhongcong Xie', 18)}}的其他基金

General Anesthesia and Alzheimer's Disease Neuropathogenesis
全身麻醉与阿尔茨海默病的神经发病机制
  • 批准号:
    10119369
  • 财政年份:
    2020
  • 资助金额:
    $ 59.13万
  • 项目类别:
Postoperative Delirium and Alzheimer's Disease Related Dementias
术后谵妄和阿尔茨海默病相关的痴呆
  • 批准号:
    10355518
  • 财政年份:
    2019
  • 资助金额:
    $ 59.13万
  • 项目类别:
Postoperative Delirium and Alzheimer's Disease Related Dementias
术后谵妄和阿尔茨海默病相关的痴呆
  • 批准号:
    10113503
  • 财政年份:
    2019
  • 资助金额:
    $ 59.13万
  • 项目类别:
Administrative Supplement: Postoperative Delirium and Alzheimer's Disease Related Dementias
行政补充:术后谵妄和阿尔茨海默病相关痴呆
  • 批准号:
    10625200
  • 财政年份:
    2019
  • 资助金额:
    $ 59.13万
  • 项目类别:
Postoperative Delirium and Alzheimer's Disease Related Dementias
术后谵妄和阿尔茨海默病相关的痴呆
  • 批准号:
    9912693
  • 财政年份:
    2019
  • 资助金额:
    $ 59.13万
  • 项目类别:
Tau/pTau as Biomarkers of Anesthesia/Surgery-Associated Neurocognitive Outcomes in Children
Tau/pTau 作为儿童麻醉/手术相关神经认知结果的生物标志物
  • 批准号:
    9917802
  • 财政年份:
    2019
  • 资助金额:
    $ 59.13万
  • 项目类别:
Tau/pTau as Biomarkers of Anesthesia/Surgery-Associated Neurocognitive Outcomes in Children
Tau/pTau 作为儿童麻醉/手术相关神经认知结果的生物标志物
  • 批准号:
    9758066
  • 财政年份:
    2019
  • 资助金额:
    $ 59.13万
  • 项目类别:
Tau/P-Tau as Biomarkers of Anesthesia- and Surgery-Induced Cognitive Impairment in a Murine Model
Tau/P-Tau 作为小鼠模型中麻醉和手术引起的认知障碍的生物标志物
  • 批准号:
    9899748
  • 财政年份:
    2016
  • 资助金额:
    $ 59.13万
  • 项目类别:
The Role of Brain Beta-Amyloid and Tau Protein in POD and POCD
大脑 β-淀粉样蛋白和 Tau 蛋白在 POD 和 POCD 中的作用
  • 批准号:
    9130078
  • 财政年份:
    2015
  • 资助金额:
    $ 59.13万
  • 项目类别:
The Role of Brain Beta-Amyloid and Tau Protein in POD and POCD
大脑 β-淀粉样蛋白和 Tau 蛋白在 POD 和 POCD 中的作用
  • 批准号:
    8906008
  • 财政年份:
    2015
  • 资助金额:
    $ 59.13万
  • 项目类别:

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