Abstract
Sepsis is a life-threatening condition, the incidence of which is significantly increased in elderly patients. One of the long-lasting effects of sepsis is cognitive impairment defined as a new deficit or exacerbation of preexisting deficits in global cognition or executive function. Normal brain function is dependent on moment-to-moment adjustment of cerebral blood flow to match the increased demands of active brain regions. This homeostatic mechanism, termed neurovascular coupling (NVC, also known as functional hyperemia), is critically dependent on the production of vasodilator NO by microvascular endothelial cells in response to mediators released from activated astrocytes. The goal of this study was to test the hypothesis that sepsis in aging leads to impairment of NVC responses early after treatment and that this neurovascular dysfunction associates with impairments in cognitive performance and vascular endothelial dysfunction. To test this hypothesis, we used a commonly studied bacterial pathogen, Listeria monocytogenes, to induce sepsis in experimental animals (males, 24 months of age) and subjected experimental animals to a standard clinical protocol of 3 doses of ampicillin i.p. and 14 days of amoxicillin added to the drinking water. NVC responses, endothelial function and cognitive performance were measured in septic and age-matched control groups within 14 days after the final antibiotic treatment. Our data demonstrate that sepsis in aging significantly impairs NVC responses measured in somatosensory cortex during whisker stimulation, significantly impairs endothelial function in isolated and pressure cannulated aorta rings in response to acetylcholine stimulation. No significant impairment of cognitive function in post-sepsis aged animals has been observed when measured using the PhenoTyper homecage based system. Our findings suggest that sepsis-associated endothelial dysfunction and impairment of NVC responses may contribute to long-term cognitive deficits in older sepsis survivors.
Highlights
Sepsis is a life-threatening condition, the incidence of which is significantly increased and the outcomes are dramatically worsened in elderly patients (Angus et al, 2001; Martin et al, 2003; Lagu et al, 2012; Corrales-Medina et al, 2015)
One of the long-lasting effects of sepsis is cognitive impairment defined as a new deficit or exacerbation of preexisting deficits in global cognition or executive function (Calsavara et al, 2018a)
One mouse from the experimental group was euthanized per recommendations of attending veterinarian for conditions not associated with experimental sepsis protocol and were removed from analysis
Summary
Sepsis is a life-threatening condition, the incidence of which is significantly increased and the outcomes are dramatically worsened in elderly patients (Angus et al, 2001; Martin et al, 2003; Lagu et al, 2012; Corrales-Medina et al, 2015). The incidence of sepsis in older adults is likely even higher than reported because many elderly dying patients with infection are not documented as having “sepsis” as they often receive palliative care rather than being sent to the ICU for aggressive treatment (Starr and Saito, 2014). Sepsis in elderly patients is one of the most expensive conditions treated in the US hospitals, the costs for which are exceeding $60 billion per year (Andrews and Elixhauser, 2006; Wier and Andrews, 2006). It is established that a number of sepsis survivors experience residual physical and psychological effects long after treatment and discharge from the hospital (Iwashyna et al, 2010; Calsavara et al, 2018a). Clinical data demonstrate that nearly 35% of elderly develop post-sepsis cognitive deficits in the magnitude comparable to individuals with moderate traumatic brain injury or mild Alzheimer’s disease (Pandharipande et al, 2013)
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