Summary: Artificially inducing peripheral inflammation in mice triggered the sudden onset of delirium-like cognitive dysfunction, and this was mediated by a disturbance in energy metabolism.
Scientists from Trinity College Dublin have discovered a new link between impaired brain energy metabolism and delirium – a disorienting and distressing disorder particularly common in the elderly and one that is currently occurring in a large proportion of patients hospitalised with COVID-19.
While much of the research was conducted in mice, additional work suggests overlapping mechanisms are at play in humans because cerebrospinal fluid (CSF) collected from patients suffering from delirium also contained tell-tale markers of altered brain glucose metabolism.
Collectively, the research, which has just been published in the Journal of Neuroscience, suggests that therapies focusing on brain energy metabolism may offer new routes to mitigating delirium.
When the body experiences high levels of inflammation – such as during bacterial or viral infections – the way our brains function changes, which in turn affects our mood and motivation. In older patients such acute inflammation can produce a profound disturbance of brain function known as delirium. Despite the disorder being relatively common, the mechanisms by which it arises are poorly understood.
In the new research the scientists found that artificially inducing peripheral inflammation in mice triggered sudden onset cognitive dysfunction, and that this is mediated by a disturbance to energy metabolism.
In these experiments, inflammation left the mice with lower levels of blood sugar (glucose), which the brain requires for maintaining normal function. When the animals were supplemented with glucose, their cognitive performance returned towards normal, despite the continued inflammation.
Professor Colm Cunningham, who leads the Trinity Biomedical Science Institute lab where the work was performed, said: “An important feature of these experiments was that mice with early stages of pre-existing neurodegenerative disease were far more susceptible to dysfunction when these metabolic changes occurred.
“Our collaborators in Oslo also detected evidence of altered brain glucose metabolism in cerebrospinal fluid taken from people experiencing delirium, which argues for overlapping mechanisms in humans and mice. In other words, the signs are that similar processes are at work in people.”
Dr Wes Ely, a critical care physician from Vanderbilt University, who wasn’t involved with the study, added:
“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.”
Given the frequency of delirium during hospitalised members of the elderly population and, given that these episodes can accelerate the progress of underlying dementia treatments are desperately needed.
Professor Cunningham added: “Simply providing glucose to patients is not likely to treat delirium in most cases but collectively our data emphasise that an appropriate supply of both oxygen and glucose to the brain becomes especially important in older patients and in those with existing dementia. Therefore, we believe that focusing on brain energy metabolism may offer routes to mitigating delirium.”
Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium
Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1β (25 µg/kg) but not prevented in IL-1RI−/− mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1β synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.
Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1β trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus “bioenergetic stress” drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.