Delirium is a common, costly, life-threatening, and potentially preventable problem for older persons, yet its pathophysiology remains poorly understood. The development of delirium is considered to be a marker of brain vulnerability; however, its relationship to dementia remains unclear. During the first cycle, we successfully completed 4 projects centered around a cohort of >560 older surgical patients (SAGES I), which documented: an accelerated trajectory of long-term cognitive decline following delirium (Project 1); and important risk markers for delirium, related to inflammation (Project 2), structural dysconnectivity (Project 3), and impairment in global cognitive performance (Project 4). These important findings have paved the way for us to move forward to extend our pathophysiologic understanding through innovative probes of brain vulnerability. We now propose a series of 5 interlinked projects applying innovative approaches to deepen our exploration of pathophysiologic pathways potentially contributing to delirium and its associated cognitive decline. We will examine the role of inflammation with state-of-the-art approaches in Project 2; Alzheimer's disease (AD) biomarkers (cerebrospinal fluid, CSF) in Project 1,and neuroimaging markers in Project 3); and measures of brain plasticity/connectivity (transcranial magnetic stimulation and evoked potentials) in Project 5. These approaches were chosen based on their innovation, potential to probe vulnerability, and ability to advance our mechanistic understanding. Project 4 will identify and validate predictors of complicated delirium, i.e., delirium associated with long-term cognitive decline. All of these studies will utilize both the original SAGES I cohort, and a new prospectively enrolled cohort, SAGES II (N=400), which will include CSF sampling obtained prior to spinal anesthesia. All projects will be supported by our effective infrastructure of 3 cores: Administrative (Core A), Field (Core B), and Data Management and Statistical Analysis (Core C). This Program Project renewal proposal brings together an expert, interdisciplinary group in a supportive environment to address a highly clinically relevant area in an integrated and coordinated fashion. The proposal is truly innovative with novel pathophysiologic approaches, extensive cross-linking aims, and multiple methodologic innovations. Furthermore, the large, well-defined cohort created in the first cycle (SAGES I) presents an unprecedented opportunity to explore long-term the relationship of delirium, cognitive decline, and Alzheimer's disease, lending some urgency to this renewal. The highly integrated nature of all the projects could not be achieved without this program project infrastructure, representing a major strength and source of efficiency. This infrastructure provides the capacity to execute five projects and cross-linking aims, expanding the breadth of our pathophysiologic investigation in far-reaching directions. Ultimately, this project holds tremendous potential to advance our understanding of delirium, its attendant complications, and to develop more effective strategies for prevention and treatment.
Delirium is a common and costly problem in older individuals, which can lead to accelerated cognitive decline, disability, death, and increased healthcare costs in excess of $164 billion/year (US). Delirium reflects increased brain vulnerability, but its mechanisms and relationship to dementia or Alzheimer's disease remain unclear; the proposed Program Project renewal will define the inter-relationship of delirium, cognitive decline, and Alzheimer's disease. Through a series of 5 interlinked projects, we will apply innovative approaches to deepen our understanding of pathophysiologic pathways contributing to delirium, and in particular, complicated delirium (i.e., delirium that is associated with long-term cognitive decline). Ultimately, our results will be used to develop more advanced approaches to identify individuals with vulnerable brains; to develop more effective and targeted interventions for prevention and treatment of delirium, dementia, and Alzheimer's disease; and to predict and measure treatment response in future clinical trials.
|Mudge, Alison M; McRae, Prue; Hubbard, Ruth E et al. (2018) Hospital-Associated Complications of Older People: A Proposed Multicomponent Outcome for Acute Care. J Am Geriatr Soc :|
|Racine, Annie M; Gou, Yun; Fong, Tamara G et al. (2018) Correction for retest effects across repeated measures of cognitive functioning: a longitudinal cohort study of postoperative delirium. BMC Med Res Methodol 18:69|
|Inouye, Sharon K (2018) Delirium-A Framework to Improve Acute Care for Older Persons. J Am Geriatr Soc 66:446-451|
|Racine, Annie M; Fong, Tamara G; Gou, Yun et al. (2018) Clinical outcomes in older surgical patients with mild cognitive impairment. Alzheimers Dement 14:590-600|
|Fick, Donna M; Inouye, Sharon K; McDermott, Caroline et al. (2018) Pilot Study of a Two-Step Delirium Detection Protocol Administered By Certified Nursing Assistants, Physicians, and Registered Nurses. J Gerontol Nurs 44:18-24|
|Racine, Annie M; D'Aquila, Madeline; Schmitt, Eva M et al. (2018) Delirium Burden in Patients and Family Caregivers: Development and Testing of New Instruments. Gerontologist :|
|Vasunilashorn, Sarinnapha M; Fong, Tamara G; Albuquerque, Asha et al. (2018) Delirium Severity Post-Surgery and its Relationship with Long-Term Cognitive Decline in a Cohort of Patients without Dementia. J Alzheimers Dis 61:347-358|
|Kim, Dae Hyun; Mahesri, Mufaddal; Bateman, Brian T et al. (2018) Longitudinal Trends and Variation in Antipsychotic Use in Older Adults After Cardiac Surgery. J Am Geriatr Soc 66:1491-1498|
|Gross, Alden L; Tommet, Doug; D'Aquila, Madeline et al. (2018) Harmonization of delirium severity instruments: a comparison of the DRS-R-98, MDAS, and CAM-S using item response theory. BMC Med Res Methodol 18:92|
|Miao, Huihui; Dong, Yuanlin; Zhang, Yiying et al. (2018) Anesthetic Isoflurane or Desflurane Plus Surgery Differently Affects Cognitive Function in Alzheimer's Disease Transgenic Mice. Mol Neurobiol 55:5623-5638|
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