Biological basis of post-delirium cognitive decline

项目总结： 妄想症是一种临床综合征，其特征是发生急性和可逆性的精神功能障碍。 在代谢异常、手术或感染后的老年人。阿尔茨海默病(AD)患者 更容易发展为精神错乱，尽管最初的急性症状得到缓解，但经常 认知功能减退的预期速度加快，长期效果不佳。精确的机械装置 对慢性神经退行性变过程的恶化负有责任的人知之甚少， 阻碍治疗干预措施的发展。这项应用旨在探索复杂的神经免疫 相互作用，并确定进行性精神错乱后认知衰退的机制。具体来说，我们 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 在全身感染/炎症期间受损，导致神经变性加剧。我们 假设在急性全身性炎症期间对关键细胞靶点的分子操作将保留 神经保护的小胶质细胞起作用，减少神经退行性变，改善长期认知结果。 我们已经开发了一套复杂的工具来在体内测试这些假说，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/药物操作和行为表型。这个项目将大大改善我们的 了解小胶质细胞在AD中的作用，有可能发现新的治疗靶点 防止精神错乱后进行性认知能力下降。

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.