Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease

了解阿尔茨海默病中 tau 蛋白病理学与小胶质细胞介导的炎症之间的动态相互作用

基本信息

  • 批准号:
    10317631
  • 负责人:
  • 金额:
    $ 114.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract The etiology, mechanism and progression of Alzheimer’s Disease (AD), and the relationship of AD pathology to clinical manifestations, are not fully understood. Emerging studies suggest that inflammation and microglial activation is an important contributor to AD pathogenesis and progression. The association between tau and microglia is especially critical, since tau is most closely associated with AD. The conventionally accepted sequence of this interaction is that misfolded tau, which is pro-inflammatory, causes microglial activation, leading to dendritic pruning and eventually neuronal cell death. However, it is recently emerging that microglial activation can itself cause tau aggregation and subsequent propagation. Therefore the causality of these interactions is controversial, and requires much needed elucidation in humans in vivo. The goal of this proposal is to understand the interaction and causal sequencing between tau, neurodegeneration, microglia and systemic inflammation in governing the etiology and progression of human AD. This proposal involves a series of principled statistical and mathematical model-based tests that will uncover these relationships, for the first time, directly in patients. This proposal involves a new prospective longitudinal study of 100 AD spectrum patients acquiring brain MRI and PET imaging of activated microglia using a new generation TSPO ligand called DPA-713 and tau-PET imaging using a relatively novel ligand, MK6240. The same imaging protocol (MRI, DPA-713 and MK6240 PET) will be repeated at 18- and 36-month follow up time points. All subjects will have amyloid neuritic plaque density measured at baseline using florbetaben PET. Next this proposal involves developing and testing a model of microglial inflammation-tau interaction via mathematical models to determine whether regional microglia-mediated neuroinflammation measured by DPA-PET is higher in AD spectrum patients or in cognitively normal older adults; and whether regional microglial activation is predictable directly from tau and/or amyloid. Finally, this proposed research includes testing a network spread model of tau and microglia. Mounting animal data implicate a trans-neuronal transmission mechanism of tau through brain networks. Using a network diffusion model of disease spread, this proposal will further investigate the role of microglia in tau progression directly in humans. Since tau and microglia provide complementary signal about evolving pathology, this proposal will determine whether combining imaging studies that measure both biomarkers will result in a uniquely powerful and predictive test of AD progression. Given the rapidly evolving understanding of the role of microglia and systemic inflammation in dementias, the current proposal is timely, topical and necessary for advancing human dementia research. If successful, it will give the first validated spatiotemporal model of the causal interactions between pathology and neuroinflammation in AD, catalyzing future advances in prognostication and targeted anti-inflammatory therapies.
项目总结/文摘

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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Ajay Gupta其他文献

Ajay Gupta的其他文献

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{{ truncateString('Ajay Gupta', 18)}}的其他基金

Development of a dry powder inhalation product against Respiratory Syncytial Virus based on an endogenous anionic pulmonary surfactant lipid
基于内源性阴离子肺表面活性剂脂质的抗呼吸道合胞病毒干粉吸入产品的开发
  • 批准号:
    10697027
  • 财政年份:
    2023
  • 资助金额:
    $ 114.16万
  • 项目类别:
Quantitative susceptibility mapping for stroke risk prediction of vulnerable carotid plaques
用于预测易损颈动脉斑块中风风险的定量敏感性图
  • 批准号:
    10446087
  • 财政年份:
    2022
  • 资助金额:
    $ 114.16万
  • 项目类别:
Quantitative Susceptibility Mapping for Stroke Risk Prediction of Vulnerable Carotid Plaques
用于预测易损颈动脉斑块中风风险的定量敏感性图
  • 批准号:
    10609912
  • 财政年份:
    2022
  • 资助金额:
    $ 114.16万
  • 项目类别:
Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease
了解阿尔茨海默病中 tau 蛋白病理学与小胶质细胞介导的炎症之间的动态相互作用
  • 批准号:
    10622513
  • 财政年份:
    2021
  • 资助金额:
    $ 114.16万
  • 项目类别:
Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease
了解阿尔茨海默病中 tau 蛋白病理学与小胶质细胞介导的炎症之间的动态相互作用
  • 批准号:
    10471976
  • 财政年份:
    2021
  • 资助金额:
    $ 114.16万
  • 项目类别:
MRI Detection of CarotId Plaques as a mecHanism for Embolic strokes of undeteRmined source (MRI DECIPHER)
颈动脉斑块的 MRI 检测作为不明原因栓塞性中风的机制(MRI DECIPHER)
  • 批准号:
    10204095
  • 财政年份:
    2019
  • 资助金额:
    $ 114.16万
  • 项目类别:
A Machine Learning Approach For CTA-based Plaque Characterization and Stroke Risk Prediction in Carotid Artery Atherosclerosis
基于 CTA 的颈动脉粥样硬化斑块表征和中风风险预测的机器学习方法
  • 批准号:
    9904175
  • 财政年份:
    2019
  • 资助金额:
    $ 114.16万
  • 项目类别:
MRI Detection of CarotId Plaques as a mecHanism for Embolic strokes of undeteRmined source (MRI DECIPHER)
颈动脉斑块的 MRI 检测作为不明原因栓塞性中风的机制(MRI DECIPHER)
  • 批准号:
    10661676
  • 财政年份:
    2019
  • 资助金额:
    $ 114.16万
  • 项目类别:
MRI Detection of CarotId Plaques as a mecHanism for Embolic strokes of undeteRmined source (MRI DECIPHER)
颈动脉斑块的 MRI 检测作为不明原因栓塞性中风的机制(MRI DECIPHER)
  • 批准号:
    10449116
  • 财政年份:
    2019
  • 资助金额:
    $ 114.16万
  • 项目类别:
Parallel Algorithms for Big Data from Mass Spectrometry based Proteomics
基于质谱的蛋白质组学大数据并行算法
  • 批准号:
    9301702
  • 财政年份:
    2017
  • 资助金额:
    $ 114.16万
  • 项目类别:

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利用纳米材料高速振荡构建亲和传感器
  • 批准号:
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    2023
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