Summary: Triggering peripheral inflammation in mice produced a rapid onset of delirium-like cognitive dysfunction, driven by disruptions in brain energy metabolism.
Source: TCD
Researchers at Trinity College Dublin have identified a clear connection between impaired brain energy metabolism and delirium — a sudden, severe disturbance in attention and cognition that is especially common in older adults and has been observed frequently in hospitalized patients with COVID-19.
Although much of the experimental work was performed in mice, complementary human data indicate similar mechanisms operate in people. Cerebrospinal fluid (CSF) samples from patients with delirium contained markers consistent with altered brain glucose metabolism.
Published in the Journal of Neuroscience, the study points to brain energy metabolism as a promising target for therapies to prevent or reduce delirium.
Delirium and inflammation
When the body mounts a strong inflammatory response to infection or injury, brain function can be altered, affecting mood, motivation and cognition. In older or vulnerable individuals, this acute inflammatory state can trigger delirium — a disorienting and sometimes prolonged decline in cognitive function. Despite its clinical importance, the biological mechanisms that produce delirium have remained poorly understood.
In this study, the authors induced peripheral inflammation in mice and observed a rapid decline in cognitive performance resembling delirium. The key mediator of this dysfunction was a disturbance in energy metabolism: inflammation reduced blood glucose levels and lowered glucose availability in the brain, impairing neural activity and behavior.
Importantly, when the mice received supplemental glucose, their cognitive performance improved even though the inflammatory response persisted, indicating that restoring brain energetics can reverse some of the acute effects of inflammation on cognition.
Professor Colm Cunningham, head of the Trinity Biomedical Sciences Institute laboratory where the research was carried out, emphasized the vulnerability of the aging and degenerating brain: “Mice with early-stage neurodegeneration were far more susceptible to cognitive dysfunction when these metabolic changes occurred.”
He added that collaborators in Oslo found evidence of altered glucose metabolism in CSF taken from people with delirium, supporting the idea that similar bioenergetic disturbances occur in humans as in the animal models.
Dr. Wes Ely, a critical care physician at Vanderbilt University who was not involved in the study, commented that the finding — that animals with neurodegeneration are less resilient to metabolic disruption — mirrors clinical observations in intensive care patients with delirium.
“The finding that the neurodegenerative animals are less resilient to this disturbance of energy metabolism really resonates with what we see in our intensive care unit patients with delirium.”
Delirium is common among hospitalized elderly patients and is associated with worse short- and long-term outcomes, including accelerated cognitive decline. Because of this clinical impact, effective treatments are urgently needed.
Professor Cunningham cautioned that simply giving glucose to every patient is unlikely to cure delirium in most cases, but stressed the clinical implication: “Ensuring adequate delivery of oxygen and glucose to the brain becomes particularly important in older adults and patients with existing dementia. Targeting brain energy metabolism could therefore offer practical ways to reduce the incidence or severity of delirium.”
About this neurology research article
Source:
TCD
Media Contacts:
Thomas Deane – TCD
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The image is in the public domain.
Original Research: Open access. Citation: “Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium” by John Kealy, Carol Murray, Eadaoin W. Griffin, Ana Belen Lopez-Rodriguez, Dáire Healy, Lucas Silva Tortorelli, John P. Lowry, Leiv Otto Watne and Colm Cunningham. Journal of Neuroscience.
Abstract
Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium
Systemic infection triggers a coordinated set of metabolic and behavioral responses known as sickness behavior. While these responses are adaptive, they can impair mood and cognition. In susceptible individuals, acute illness can cause profound cognitive dysfunction such as delirium, yet the underlying biology is not well defined. The researchers used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and examined humans after acute hip fracture to determine whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS produced hypoglycemia in mice; interleukin-1β (IL-1β) produced a similar glucose drop, and LPS-induced reductions in locomotor activity correlated with blood glucose concentrations. Administering glucose improved activity, while blocking glycolysis with 2-deoxyglucose worsened outcomes. In a mouse model of chronic neurodegeneration (ME7), LPS caused acute cognitive deficits selectively in animals with pre-existing degeneration; the same impairments were induced by insulin-driven hypoglycemia and were reversed by glucose. In humans, CSF from hip fracture patients experiencing delirium showed elevated lactate and pyruvate, consistent with altered brain carbohydrate metabolism. Together, these findings indicate that disturbance of energy metabolism drives behavioral and cognitive consequences during acute systemic inflammation.
Significance Statement
Acute systemic inflammation can disproportionately affect vulnerable brains and produce delirium. This study demonstrates that inflammation and certain inflammatory cytokines trigger hypoglycemia, lower CSF glucose and suppress spontaneous behavior; exogenous glucose can mitigate these effects. Equivalent hypoglycemia selectively impairs cognition in animals with neurodegeneration, and patient CSF during inflammatory trauma-induced delirium shows altered glycolytic metabolites. The results support a model in which “bioenergetic stress” — a failure of adequate brain energy supply — underlies systemic inflammation–induced cognitive dysfunction, suggesting that protecting or restoring brain energy metabolism may reduce delirium risk and severity.