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.
Delirium is a dramatic disorder of attention and awareness in elderly patients that is common and associated with increased risks of disability and death. Despite the profound and alarming nature of acute delirium in the elderly, treatments are still severely limited due to an incomplete understanding of its biological basis. This proposal studies the causes and mechanisms of delirium through translational models of aging, with the hope of generating new treatments for this complicated and dangerous clinical condition.
