Determining the pathophysiology of delirium in the elderly through translational models

 描述（由申请方提供）：谵妄是一种急性波动性注意力和意识障碍，最常见于老年患者和神经系统疾病患者。谵妄与痴呆症的风险增加三倍，依赖和死亡的几率增加一倍有关。尽管谵妄具有深刻和令人担忧的性质，并且衰老相关疾病的患病率日益增加，但目前还没有FDA批准的谵妄治疗方法。尽管流行病学信息已经确定了谵妄的重要危险因素，包括炎症和麻醉，但这些知识尚未转化为令人满意的治疗方法。先前的工作假设谵妄病理生理学的最后共同途径是脑乙酰胆碱缺乏。然而，这一假设并没有在临床前模型中得到严格的检验，并且使用胆碱酯酶抑制剂的多项临床试验导致了令人失望的结果。新的证据表明，多巴胺能系统可能与谵妄有更大的病理生理学相关性，因为D1多巴胺能激动剂可用于加速麻醉苏醒，而补充D2多巴胺能拮抗剂通常用于超说明书治疗多动症。谵妄的综合转化模型可以确定老年人谵妄中涉及的特定诱发风险因素和常见神经网络，在对老年患者进行复杂研究之前验证治疗靶点。我们将整合转化神经科学和老年流行病学的方法，以确定老年人谵妄的病理生理学。我们将翻译一个床边仪器，用于识别谵妄插管，非语言的病人在实验室使用的动物。我们开发了新的设备，使我们能够以多种方式对谵妄相关表型进行实时，同时评估，包括注意力测试，运动活动和脑电图（EEG），这是谵妄唯一敏感和可靠的生物标志物。我们将使用我们的翻译模型和新的设备来确定哪些危险因素在病理生理上足以促成谵妄 在老年受试者中（炎症和镇静）以及多巴胺能系统的哪些组分与谵妄的病理生理学和治疗（D1激动剂和D2拮抗剂）具有最大的相关性。拟议的实验将显着有助于谵妄的病理生理学的理解，通过确定其沉淀因素和神经通路，可以作为治疗目标。GEMSSTAR奖支持的研究和专业发展计划中确定的进一步培训将使主要研究者能够为老龄化的持续转化研究奠定基础，并在实验室研究和床边护理之间建立密切联系。

 DESCRIPTION (provided by applicant): Delirium is an acute and fluctuating disturbance of attention and awareness that is most common in elderly patients and patients with neurologic diseases. Delirium is associated with a threefold increased risk of dementia and doubled odds of dependence and death. Despite the profound and alarming nature of delirium and the increasing prevalence of aging-related diseases, there are currently no FDA-approved treatments for delirium. Though epidemiologic information has identified important risk factors for delirium, including inflammation and anesthesia, this knowledge has yet to translate into satisfactory treatments. Prior work hypothesized that the final common pathway in the pathophysiology of delirium was a deficiency in brain acetylcholine. However, this hypothesis was not rigorously tested in preclinical models and multiple clinical trials with cholinesterase inhibitors have led to disappointing results. New evidence suggests that dopaminergic systems may instead have a greater pathophysiologic relevance for delirium, given that D1 dopaminergic agonists can be used to speed emergence from anesthesia and that complementary D2 dopaminergic antagonists are commonly used off-label for hyperactive delirium. An integrated translational model of delirium could determine specific precipitating risk factors and common neural networks involved in delirium in the elderly, validating therapeutic targets prior to undertaking complex studies in elderly patients. We will integrate methods from translational neuroscience and geriatric epidemiology to determine the pathophysiology of delirium in the elderly. We will translate a bedside instrument used to identify delirium in intubated, nonverbal patients for use with animals at the bench. We have developed new devices that allow us to perform real-time, simultaneous assessments of delirium related phenotypes in multiple modalities, including attention testing, motor activity, and electroencephalography (EEG), the only sensitive and reliable biomarker of delirium. We will use our translational model and novel devices to determine which risk factors are pathophysiologically sufficient to precipitate delirium in aged subjects (inflammation and sedation) and which components of the dopaminergic system have the greatest relevance for the pathophysiology and therapy of delirium (D1 agonists and D2 antagonists). The proposed experiments will significantly contribute to the understanding of the pathophysiology of delirium by determining its precipitating factors and neural pathways that can serve as therapeutic targets. The studies supported by this GEMSSTAR award and the further training identified in the professional development plan will allow the principal investigator to build a foundation for continued translational research in aging, with close connections between bench research and bedside care.