Determining the pathophysiology of delirium in the elderly through translational models

通过转化模型确定老年人谵妄的病理生理学

• 批准号: 9122271
• 负责人: Eyal Yaacov Kimchi
• 金额: $ 13.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122271
• 关键词: Acetylcholine; Acute; Affect; Aging; Agonist; Anesthesia procedures; Animal Model; Animals; Attention; Award; Awareness; Biological; Biological Markers; Biological Neural Networks; Brain; Caring; Cessation of life; Cholinesterase Inhibitors; Clinical; Clinical Trials; Complex; Data; Delirium; Dementia; Dependence; Development Plans; Devices; Diagnosis; Disease; Dopamine Agonists; Dopamine Antagonists; Elderly; Electroencephalography; Employee Strikes; Endotoxins; Epidemiologic Studies; Epidemiology; FDA approved; Foundations; Functional disorder; Gerontology; Haloperidol; Health; Impairment; Inflammation; Injection of therapeutic agent; Isoflurane; Knowledge; Label; Methods; Modality; Modeling; Motor Activity; Nature; Neural Pathways; Neurologic; Neurology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Precipitating Factors; Prevalence; Prevention; Principal Investigator; Rattus; Research; Risk; Risk Factors; Sedation procedure; Speed; System; Testing; Therapeutic; Time; Training; Translating; Translational Research; Work; age related; aged; base; clinically relevant; disability; economic impact; improved; instrument; novel; older patient; pre-clinical; research study; response; social; therapeutic target; tool; translational neuroscience

 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.

 描述（由适用提供）：del妄是一种急性和波动的注意力和意识，在古老的患者和神经疾病患者中最常见。 del妄与增加痴呆症的风险增加三倍，依赖和死亡的几率增加了一倍。尽管del妄的性质深远，与衰老有关的疾病的患病率不断增加，但目前尚无与FDA批准的del妄的治疗方法。尽管流行病学信息已经确定了del妄的重要风险因素，包括感染和麻醉，但这些知识尚未转化为满意度治疗。先前的工作假设，del妄的病理生理学的最终共同途径是脑乙酰胆碱的缺乏。但是，在临床前模型中并未对该假设进行严格的检验，并且具有胆碱酯酶抑制剂的多个临床试验导致了令人失望的结果。新的证据表明，鉴于D1多巴胺能拮抗剂可用于加快麻醉的紧急情况，并且互补的D2多巴胺能拮抗剂通常使用非标签用于超级活跃的Delirium，因此多巴胺能系统可能与del妄具有更大的病理生理相关性。 del妄的综合翻译模型可以确定较旧的del妄的特定降水危险因素和常见的神经元网络，在对基本患者进行复杂的研究之前，在较老的治疗靶标中验证了治疗靶标。我们将整合来自转化神经科学和老年流行病学的方法，以确定基础del妄的病理生理学。我们将翻译一种用于识别插管的非语言患者del妄的床头仪器，可在长凳上与动物一起使用。我们开发了新的设备，使我们能够以多种方式进行实时，同时评估相关表型，包括注意力测试，运动活动和脑电图（EEG），这是妄想的唯一敏感且可靠的生物标志物。我们将使用翻译模型和新型设备来确定哪些危险因素在病理学上足以使ir妄沉淀 在老年受试者（炎症和镇静）中，多巴胺能系统的哪些组成部分与del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。提出的实验将通过确定可以用作治疗靶标的降水因素和神经途径来显着有助于理解妄想的病理生理学。该GEMSSTAR奖和专业发展计划中确定的进一步培训的研究将使主要研究人员能够为衰老的持续转化研究建立基础，并在基准研究与床旁护理之间进行密切联系。