ABSTRACT 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.
ABSTRACT While delirium and dementia are the most common causes of cognitive impairment in older adults, their interrelationship is complex and poorly understood. Many questions remain unresolved: Does pre-existing Alzheimer's disease (AD) pathology increase vulnerability to delirium? Does delirium increase cognitive decline in those with AD pathology? Do AD pathology and delirium interact to promote cognitive decline or dementia? Project 1 will investigate the inter-relationship of delirium and long-term cognitive decline (LTCD) with molecular biomarkers of AD pathology according to 3 general components of the new "ATN" (Amyloid−β [Aβ], Tau, Neurodegeneration) descriptive classification scheme for AD biomarkers. We propose the following specific aims: (1) to examine the relationship between baseline cerebrospinal fluid (CSF) AD biomarkers (CSF Aβ42, total tau [t-tau], phospho-tau tau/Aβ42 ratios, and neurofilament light [NFL]), sampled prior to spinal anesthesia, and development of post-operative delirium and cognitive decline over 18-36 months in a new cohort of 400 older persons undergoing joint replacement surgery (SAGES II); (2) to evaluate associations of history of delirium and CSF AD biomarkers (sampled near 4 year follow-up) with LTCD (over a minimum of 8 years) in a probability sample from SAGES I (N=128): 64 patients who developed delirium during the initial hospitalization and 64 who did not develop delirium during the initial or subsequent hospitalizations; and (3) after correlating CSF and plasma levels of novel SiMoA assays of t-tau and NFL obtained at follow-up in the SAGES I probability sample (N=128), to examine the relationship of pre-operative levels of these markers obtained from stored plasma with delirium incidence/severity and LTCD following delirium. We have conducted detailed pilot work ensuring the feasibility of the proposed work, including assuring adequate numbers of available patients and their willingness to participate, and verifying feasibility and tolerability of all study procedures. We have demonstrated adequate statistical power to examine our aims. The success of the proposed work is further assured by a highly skilled interdisciplinary team of study investigators who have been working together for 2-11 years, by the demonstrated attainment of all of the previous aims, and by enrolling a large, complex cohort of over 560 surgical patients along with 119 non-surgical controls during the initial cycle. This project will probe whether fluid biomarkers identify patients who are more vulnerable to delirium, and are most likely to have cognitive decline following delirium. By probing the relationship of delirium and AD biomarkers, we will be well positioned to advance our mechanistic understanding and to develop more effective intervention strategies to forestall LTCD associated with delirium and AD. Moreover, this study may lay the groundwork for identification of potential plasma biomarkers for AD and related dementias (ADRD). If our hypotheses are confirmed, this study will offer compelling support for the importance of prevention of delirium to forestall the progression of cognitive decline in AD/ADRD.
ABSTRACT Given the success, efficiency, and integration achieved in our first cycle, we will retain the previous structure of our Administrative Core (Core A), which will provide the essential administrative management and scientific leadership to facilitate and ensure productivity and integration of effort between all 5 proposed projects and 2 additional cores for the proposed Program Project renewal. We propose the following aims: (1) to provide overall leadership and organization that will ensure regular, ongoing, coordinated scientific interaction, planning, learning and feedback between all cores and projects, and effective and efficient use of shared resources; (2) to monitor timely progress and effectiveness of operations of all cores and projects, jointly holding investigators accountable for products expected on those timelines, and requiring any course corrections, as needed; (3) to convene meetings with the Safety Officer on a quarterly basis, and coordinate preparation of all necessary safety monitoring materials across all projects and cores; and (4) to conduct all reporting activities required by the National Institute on Aging, our Scientific Advisory Board, our safety monitoring process, and institutional review boards. The organizational structure of the Core will include a central Executive Committee, the main decision-making and policy group; Operations Committee, in charge of day-to-day operations; Scientific Working Group, for scientific advancement and productivity in abstracts and papers; Publications Committee, providing oversight and approval of publication requests; Biorepository/Database Committee, providing oversight and approval of requests for data sharing and use of Biorepository specimens; Fiscal Management Committee, tracking all budgets and subcontracts to maintain fiscal accountability; and the Scientific Advisory Board, meeting annually to evaluate and guide the progress of the Program Project. The Core has already demonstrated its success in managing a complex program across multiple sites and holding the leaders accountable for timelines and productivity. The Core established the central infrastructure and successfully enrolled a large and complex cohort of over 560 surgical patients, with high quality data. Demonstrated productivity has included 3 Advisory Board meetings, 5 Annual Scientific Symposia, 73 published manuscripts, an additional 2 publications under review, >90 conference presentations, and >9 related grants and supplements. By bringing investigators together for regular meetings and scientific symposia, and leveraging resources across projects, Core A will be able to ensure productive interactions between investigators, explore cross-linking hypotheses between projects, and create a whole that is greater than the sum of its parts. Importantly, our streamlined approach with efficient centralized enrollment and collection of the primary data and sharing of Core resources, augmented with specialized data from individual projects, permits our expansion to 5 projects. This successful Core with established infrastructure and procedures provides a strong foundation to ensure the success of the Delirium Program Project renewal.
ABSTRACT The pathophysiology of delirium and the mechanisms underlying its epidemiological association with long-term cognitive decline (LTCD) remain largely unknown. This important gap limits development of preventive and disease-modifying therapies. To address this gap, we conducted the “Biomarker Discovery for Delirium” project within the P01 “Interdisciplinary Study of Delirium and Its Long Term Outcomes”. Our results support a model for delirium in which a predisposing, pre-inflammatory state results in a heightened inflammatory response to surgery, leading to blood-brain barrier breakdown, microglial activation and neuro-inflammation, resulting in neuronal injury and death. This model is intriguing, as inflammation could be the mechanism underlying the epidemiological link between delirium, LTCD, and Alzheimer's Disease and Related Dementias (ADRD). For the P01 renewal, Delirium, Dementia, and the Vulnerable Brain: An Integrative Approach, our project will leverage banked specimens from the first cycle's Successful Aging after Elective Surgery study (SAGES I), which enrolled and followed 560 participants undergoing major scheduled surgery, and collected plasma at 4 time points relative to surgery. We add banked specimens from the Healthier Postoperative Recovery study (HiPOR), which enrolled 242 participants undergoing total joint replacements under spinal anesthesia using a similar protocol to SAGES I, with the additional collection of preoperative cerebrospinal fluid (CSF). Further, we will collect new blood and CSF samples from a probability sample of 128 SAGES I participants, and from a new cohort of 400 older patients undergoing total joint replacement under spinal anesthesia (SAGES II). We will use two state-of-the-art approaches, SOMAscan, a next generation proteomics platform, to discover new inflammatory proteins (Aim 1), and CyTOF, a single-cell mass cytometry platform, to characterize circulating immune cells that regulate inflammation (Aim 2). We will also extend our prior work by examining CSF in addition to plasma, and by quantifying a novel inflammatory index (Aim 3). Using these techniques, we will compare inflammatory proteins and cells in patients who do and do not develop delirium, and in those who have slower and faster rates of LTCD following delirium. Importantly, we will also independently validate all SOMAscan and CyTOF results using standard laboratory methods. Our current Project represents the next in a series of systematic studies extending important findings from the first P01 cycle, and leading to more detailed understanding of the full inflammatory protein profile associated with delirium and LTCD, including markers in the CSF, plus origins of the inflammatory response from immune cells. The Aims also represent an initial step toward development of blood and CSF protein, and cytometry-based biomarker panels to refine prediction of delirium and LTCD. Importantly, the proposed work will improve our understanding of the pathophysiology of delirium and its association with ADRD, ultimately leading to targeted interventions to improve outcomes of hospitalized older adults with vulnerable brains.
CORE B ABSTRACT The Program Project (P01) entitled “Delirium, Dementia and the Vulnerable Brain: An Integrative Approach” seeks to define the complex relationship of delirium, dementia, and brain vulnerability through a series of five, interrelated projects, each of which examines a unique aspect of vulnerability. The Field Core will support all of the projects and has the following Specific Aims: Aim 1: To perform assessments on the original Successful Aging after Elective Surgery (SAGES I) cohort free of dementia at baseline (N=560), ensuring the highest possible participant retention and completeness of study variables. Activities include: 1) For the entire SAGES I cohort, completing two waves of long-term follow-up interviews: the first wave (years 1-3) will ensure a minimum of 5 years of follow-up, and the second wave (years 3-5) will ensure a minimum of 8 years of follow-up; 2) Inviting 128 SAGES I participants, probability sampled based on their index admission delirium status and frequency matched by age and baseline cognitive status, to return to the hospital for a detailed evaluation, including cerebrospinal fluid (CSF) collection via lumbar puncture (LP) for Alzheimer's Disease (AD) and inflammatory biomarker measurement, phlebotomy for plasma AD and inflammatory marker measurement, magnetic resonance imaging (MRI) studies, and transcranial magnetic stimulation (TMS)-electroencephalography (EEG) studies. Aim 2: To accrue a new cohort, called SAGES II, of 400 patients undergoing total hip or knee replacements under spinal anesthesia at two academic medical centers, Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women's Hospital (BWH), and to follow this cohort for 18 months with extended follow-up to 36 months. Activities related to the SAGES II cohort include: 1) identifying, approaching, and enrolling eligible patients with a goal of achieving the highest possible participation; 2) performing baseline assessments prior to surgery, in-hospital assessments for delirium daily throughout the index hospitalization, and follow-up assessments at 1, 2, 6, 12, 18, months after surgery, with extended follow-up at 24 and 36 months; 3) providing specialized support for each of the component projects by collecting CSF and blood samples for AD and inflammatory biomarker measurement, and referring patients for MRI, TMS, and EEG studies. Aim 3: To hire, train, and monitor the activities of all field staff, ensuring coordination of all aspects of the SAGES I and II cohort studies including study participant safety, and high quality data collection. Through execution of these Aims, the Field Core will play an essential role in all aspects of the Program Project, which will define the complex relationship of delirium, dementia, and brain vulnerability. The Field Core has been highly successful in achieving all of its Aims in the first funding cycle. In the renewal, we will implement the same principles and procedures, employ many of the same leaders and field team staff members. This continuity ensures a very high likelihood of continued success.
