Neurovascular dysfunction in delirium superimposed on dementia

Abstract: As many as 20-30% of all COVID-19 patients develop delirium during hospitalization, an estimate that increasesto 60-70% in those that develop severe illness. Delirium is a well-established risk factor for dementia, thus theimpact of the ongoing pandemic on neurodegeneration will be long-lasting. In particular, we hypothesize thatCOVID-19 infection will accelerate the progression and emergence of Alzheimer's Disease Related Dementias(ADRD) in the elderly by increasing both peripheral and central inflammation as well as decreasing the ability ofthe lungs to supply the brain with sufficient oxygen to maintain normal cognitive function. This supplement toRO1AG057525 "Neurovascular dysfunction in delirium superimposed on dementia" seeks to model the systemicimpact of inflammation, akin to the pathology reported in patients with COVID-19 infection, on the central nervoussystem (CNS) by focusing on the neurovascular unit (NVU) and delirium-like behavior as key endpoints from ourparent grant. Furthermore, we have recently reported on the protective effects of our drug in development,URMC-099 on the NVU after orthopedic surgery in mice with ongoing neurodegeneration. We are well-positionedto rapidly evaluate the effects of this therapy after lung injury using methodological approaches established forour parent grant. Our overall objective for this supplement is to determine the impact of the inflammatory milieuon the NVU and cognitive function after lipopolysaccharide (LPS) inhalation as a simplified model of COVID-19-related delirium. The central hypothesis is that inhaled LPS induces platelet aggregation, neutrophil adhesion,and neurovascular hypoxia - key pathologic hallmarks found in patients with COVID-19. We contend that thesesequelae are preventable by treatment with the brain penetrant mixed-lineage kinase (MLK) inhibitor URMC-099. Our hypothesis is based on preliminary data acquired in the applicants' laboratories and will be tested bypursuing 2 specific aims: 1) To implement an inhaled LPS-based lung injury model to translate the clinicalfeatures of systemic COVID-19 infection by quantifying indices of neutrophils, neutrophil extracellular traps(NETs), platelets and cytokine release syndrome as the basis for CNS dysfunction; 2) To define inflammatoryevents at the NVU and related cognitive impairment in mice treated with inhaled LPS and reposition URMC-099to prevent these sequelae. Feasibility for these models and techniques has been established in the applicants'hands. In this innovative approach, real-time in-vivo brain imaging and postmortem analyses will be combinedwith novel behavioral assays to define delirium-like changes in mice. The rationale for the proposed research isthat successful completion will advance our understanding of how COVID-19 affects CNS function and providenew molecular mechanisms of relevance to aging, delirium, neurodegeneration, and the Alzheimer's Diseaseand Related Dementias at-large. Such knowledge is highly significant because COVID-19 infection during thispandemic will impact millions of older adults and at-risk patients in the United States with ongoingneurodegeneration and dementia.