Patients in intensive care units are at high risk for long-term health threats including cognitive impairment. The
correlation was only recently revealed after large-scale follow-up cognitive assessments on intensive patient
survivors after their discharge from the hospital. There are testimonials, reviews and calls-to-action on many
critical care websites and in journal issues over the last 2-3 years on this public health crisis. However, the
causative mechanisms that lead to abrupt cognitive impairment are unclear—they are not attributable to age,
gender, relative brain hypoxia, anesthetics and sedatives.
Nosocomial bacteria such as Pseudomonas aeruginosa impair endothelial cell function during the course of
infection that culminates in acute lung injury. Recent studies implicate that after P. aeruginosa infection,
endothelial cells produces and releases cytotoxic amyloids that are transmissible among cells. Having access
to the endothelium of whole blood circulation, these cytotoxic amyloids likely propagate. In fact, the amyloids
are detectable in the blood and cerebrospinal fluid of nosocomial pneumonia patients in intensive care units.
Further, when applied to brain slices, the cytotoxic amyloids derived from endothelium impair neural activity
and synaptic information transfer.
This project takes advantage of vertically integrated approaches, ranging from the use of different bacteria
stains and cultured cells, to in vitro brain slice recordings and in vivo animal behavior studies. The studies are
designs to test the hypothesis that nosocomial pneumonias induce amyloid protein accumulation in CSF,
resulting in LTP suppression and learning deficit. Altogether, studies systematically examine a possible
lung-brain axis, where a primary lung infection induces production of cytotoxic amyloids that spread to the
cerebrospinal fluid and contribute to cognitive impairment. This work addresses a novel mechanism underlying
the end organ dysfunction that is evident during, and in the aftermath of, critical illness. Mechanistic insight
into endothelium-derived cytotoxicity to brain function will reveal novel therapeutic approaches to prevent