The role of cerebrospinal fluid complement activation in delirium and post-intensive care unit long-term cognitive impairment
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PROJECT SUMMARY/ABSTRACT This K23 application outlines a career development plan that will advance Dr. Michael Devinney on his pathway to becoming an extramurally funded, independent critical care physician-scientist. His long-term career goal is to discover underlying mechanisms that contribute to delirium and its sequelae such as post-ICU cognitive impairment and Alzheimer's Disease and related Dementias (ADRD). Delirium is a syndrome of disrupted attention and consciousness that occurs in ~20% of the >19 million older surgery patients and ~50% of the >5 million intensive care unit (ICU) patients in America every year. Delirium is also associated with increased risk for long-term cognitive impairment and ADRD, yet there are no FDA- approved drugs to prevent delirium, due to a major gap in our understanding of the mechanisms that drive delirium. One possible mechanism that may underpin delirium (and subsequent post-ICU long-term cognitive impairment) is neuroinflammation. Surgical trauma and critical illness induce systemic complement activation and blood-brain barrier dysfunction, which could cause activated complement factors to enter the brain. These activated complement proteins then can cause synaptic tagging for phagocytosis, which can disrupt the neural connectivity necessary for human cognition. Indeed, complement-dependent synapse loss leads to memory deficits in mouse ADRD models, and patients with ADRD have increased cerebrospinal fluid (CSF) C3 levels. However, few, if any, studies have investigated the role of CSF complement activation in delirium and post-ICU long-term cognitive impairment. In this proposal, Dr. Devinney will determine the role of CSF complement activation in postoperative delirium, ICU delirium, and post-ICU long-term cognitive impairment. To do so, he will leverage a unique perioperative CSF biorepository, and also recruit a prospective cohort of 120 older ICU patients that will undergo CSF sampling, delirium assessments, and 6-month post-discharge cognitive testing and dementia assessments. CSF complement activation will be measured with immunoassays, and unbiased proteomics will be used to characterize CSF complement levels and to discover other novel pathways involved in these disorders. CSF ADRD biomarkers will also be measured in both cohorts. Dr. Devinney has co-designed a career development plan and a research proposal with his cross-disciplinary mentorship team to accomplish the following short-term objectives: 1) Obtain expertise in the molecular role of complement in synaptic dysfunction and ADRD 2) Develop a thorough understanding of the practical and ethical considerations of ICU research, 3) Acquire the skills needed to lead larger studies of older ICU patients, and 4) Gain expertise in the staging of ADRD. These objectives will be accomplished through formal training, workshops, experiential learning, and focused mentorship. Thus, this K23 award will allow Dr. Devinney to acquire the outlined research skills, knowledge, and experience to continue his pathway towards independence.
