Biological basis of post-delirium cognitive decline

谵妄后认知能力下降的生物学基础

• 批准号: 9456085
• 负责人: Jaime Grutzendler
• 金额: $ 285.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456085
• 关键词: Abeta synthesis; Acceleration; Acute; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Axon; Bacterial Infections; Behavioral; Biological; Calcium; Chronic; Clinical; Cognitive; Complex; Data; Delirium; Dendrites; Deposition; Double-Stranded RNA; Elderly; Functional disorder; Growth; Hour; Image; Immune; Immunologic Factors; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Injury; Interleukin-1; Lead; Lipopolysaccharides; Mediating; Metabolic; Microglia; Molecular; Molecular Conformation; Nerve Degeneration; Neuroimmune; Neurons; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Patient risk; Peripheral; Phagocytosis; Pharmacology; Phenotype; Play; Poly I-C; Prevention; Process; Psyche structure; Resolution; Role; Senile Plaques; Structure; Syndrome; Systemic infection; TLR3 gene; TLR4 gene; TNF gene; Testing; Therapeutic Intervention; Viral; Virus Diseases; abeta deposition; abeta toxicity; acute symptom; amyloid peptide; behavior test; beta-site APP cleaving enzyme 1; brain cell; cellular targeting; cytokine; improved; in vivo; in vivo calcium imaging; in vivo imaging; inhibitor/antagonist; mental function; mental state; neurophysiology; neurotoxic; neurotoxicity; new therapeutic target; optical imaging; prevent; therapeutic development; therapy development; tool

PROJECT SUMMARY: Delirium is a clinical syndrome characterized by acute and reversible disturbance in mental function that occurs in the elderly following metabolic abnormalities, surgery or infection. Individuals with Alzheimer's disease (AD) are more prone to developing delirium and despite resolution of the initial acute symptoms, frequently suffer an acceleration in the expected rate of cognitive decline with poor long-term outcomes. The precise mechanisms responsible for the exacerbation of the chronic neurodegenerative processes are poorly understood, significantly impeding the development of therapeutic interventions. This application aims to explore complex neuro-immune interactions, and identify mechanisms underlying progressive post-delirium cognitive decline. Specifically, we will explore newly discovered neuroprotective functions of microglia and test the hypothesis that such functions become impaired during systemic infection/inflammation, leading to exacerbation of neurodegeneration. We hypothesize that molecular manipulation of key cellular targets during acute systemic inflammation will preserve the neuroprotective microglia functions, reduce neurodegeneration and improve long-term cognitive outcomes. We have developed a sophisticated set of tools to test these hypotheses in vivo, including longitudinal high- resolution optical imaging of amyloid plaques, microglia and neurons, as well as calcium imaging, molecular/pharmacological manipulations and behavioral phenotyping. This project will significantly improve our understanding of the role of microglia in AD and has the potential to uncover novel therapeutic targets for the prevention of post-delirium progressive cognitive decline.

项目概要： 谵妄是一种临床综合征，其特征是急性和可逆的精神功能障碍， 老年人在代谢异常、手术或感染后。阿尔茨海默病（AD）患者 更容易发展为谵妄，尽管最初的急性症状得到了缓解， 认知能力下降的预期速度加快，长期结果不佳。精确的机制 导致慢性神经退行性过程恶化的原因知之甚少， 阻碍了治疗干预的发展。该应用旨在探索复杂的神经免疫 相互作用，并确定进行性谵妄后认知下降的潜在机制。我们特别 将探索新发现的小胶质细胞的神经保护功能，并测试这种功能的假设， 在全身性感染/炎症期间受损，导致神经变性恶化。我们 假设在急性全身性炎症过程中，对关键细胞靶点的分子操作将保留 神经保护性小胶质细胞发挥功能，减少神经变性并改善长期认知结果。 我们已经开发了一套复杂的工具来测试这些假设在体内，包括纵向高， 淀粉样斑块、小胶质细胞和神经元的分辨率光学成像，以及钙成像， 分子/药理学操作和行为表型。该项目将大大改善我们的 了解小胶质细胞在AD中的作用，并有可能发现新的治疗靶点， 预防谵妄后进行性认知衰退。