Irish-based scientists find new link between delirium and brain energy disruption

Scientists from Trinity College Dublin have discovered a new link between impaired energy metabolism in the brain and delirium, a disorienting and distressing disorder common in older people – and 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 collected from patients suffering from delirium “also contained tell-tale markers of altered brain glucose metabolism” – the biochemical process that provides the fuel for physiological brain function.

Collectively, the research, which has been published in the latest issue of the Journal of Neuroscience, “suggests 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 as is the case with Covid-19 – the way our brains function changes, which in turn affects 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.

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Energy metabolism

In their research, the TCD scientists found artificially inducing peripheral inflammation in mice triggered sudden onset cognitive dysfunction, and that this is mediated by a disturbance to energy metabolism in the brain.

In these experiments, inflammation left the mice with lower levels of blood sugar (glucose), which the brain requires for maintaining normal function, according to Prof Colm Cunningham who leads the Trinity Biomedical Science Institute lab where the work was performed.

When the animals were given glucose, their cognitive performance returned towards normal, despite the continued inflammation.

Simply providing glucose to patients is not likely to treat delirium in most cases, Prof Cunningham added.

“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.

“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,” he added.

"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," Prof Cunningham said.

Dr Wes Ely, a critical care physician from Vanderbilt University in the US, who was not involved with the study, said: "The finding...really resonates with what we see in our intensive care unit patients with delirium."

Given the frequency of delirium among hospitalised older people and these episodes can accelerate progress of underlying dementia, “treatments are desperately needed”, he said.