Immunovascular interactions in postoperative delirium superimposed on dementia (DSD).

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ABSTRACT Systemic inflammation triggered by surgical trauma can negatively impact brain function, particularly in older adults and/or frail patients with pre-existing dementia. One frequent neurologic complication for these patients is delirium, an acutely debilitating change in brain function that precedes an adverse prognosis. Indeed, patients that develop delirium superimposed on dementia (DSD) have significiantly worse outcomes with mortality rates as high as 92% two years after surgery, compared to a 7% post-surgical mortality in patients without dementia or delirium. Damage to the blood-brain barrier (BBB), a key interface that regulates neuroimmune interactions between the periphery and the brain, may play a role in DSD. Using a clinically-relevant mouse model of delirium- like behavior as a result of orthopedic surgery, we have identified a prominent role for the innate immune response in promoting BBB dysfunction, and neuroinflammation. Notably, BBB breakdown has been reported in many neurodegenerative conditions, including Alzhemeir’s disease (AD) as well as during aging via altered transcellular permeability and trafficking of blood-derived factors into the brain parenchyma. Yet, the mechanisms by which surgery impacts the BBB and the specific role(s) of vascular dysfunction in DSD remain unknown. Our overall objective is to identify postoperative mechanisms for BBB dysfunction in DSD. Our central hypothesis is that systemic factors impair structure and function of discrete brain vasculature and BBB leading to neuroinflammation, neurodegeneration, and delirium-like behavior in AD mice after surgery. We propose two Specific Aims: 1) to characterize how the postoperative systemic milieu impacts the BBB using organ-on-chip technology comprised of μSiM (microphysiologic system with nanoporous silicon membranes) populated with human iPSCs; and 2) to define cellular and molecular mechanisms mediating DSD-induced vascular dysfunction after surgery. Feasibility for these models and techniques has been established in the applicants’ hands. In this innovative approach, organ-on-chip technology will complement unbiased spatial profiling of vascular changes in the brain of dementia-prone mice with delirium-like behavior. The rationale for the proposed research is that successful completion will expand our understanding of how surgery affects the blood-brain interface, and will provide new molecular mechanisms of relevance to delirium, and neurodegeneration. Such knowledge is highly significant because it will implement new technologies to investigate immune-vascular interactions and inform the advancement of safe therapies to limit postoperative neurocognitive complications in vulnerable patients.