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Trinity Researchers Shed New Light on Delirium

News feed for Trinity College Dublin.

May 02, 2012

Trinity researchers studying the neuropsychiatric syndrome of delirium have uncovered important interactions between inflammation and brain chemistry that may contribute to its onset. The findings have been just published in the Journal of Neuroscience.

Delirium is a common psychiatric syndrome that manifests as sudden and profound disturbance of attention, memory, and behaviour. It is highly prevalent in the elderly and the long-term outcomes for these individuals are very poor, including long-term deterioration of cognitive function leading to permanent institutionalisation. Despite these economic and clinical imperatives there has been little basic research into delirium and the lack of animal models with which to study delirium has contributed to this. Delirium can arise in many situations, for example, after infection or surgery or as the result of changes in medication, particularly those medications targeting the chemical messenger acetylcholine. This has led to different theories of delirium, including the “cholinergic hypothesis”, which proposes that decreased levels or activity of acetylcholine are responsible for the deficits observed, and the “neuroinflammatory hypothesis”, which proposes that inflammation in the brain causes the disturbance of brain function.

Researchers in the School of Biochemistry and Immunology and the Trinity College Institute of Neuroscience, led by Wellcome Trust Senior Research Fellow Dr Colm Cunningham have now published findings that begin to reconcile these two theories of delirium. The findings, published this week in the Journal of Neuroscience, show that inflammation arising in the body as a result of an infection, trigger a robust disturbance of short-term memory but only in animals who already showed destruction of brain cells that normally synthesise the chemical messenger acetylcholine in cholinergic cells. Importantly, neither inflammation nor cholinergic cell loss individually were sufficient to cause this disturbance indicating that these two key factors must interact to produce the delirium-like state. Furthermore, the disturbance could be partially reversed by treatment with donepezil, a drug that slows down the breakdown of acetylcholine. Therefore, systemic inflammation can induce these cognitive impairments only in individuals with so called cholinergic vulnerability.

As well as throwing light on mechanisms relevant to delirium, this novel combination of prior pathology in the cholinergic area of the brain and subsequent systemic inflammation provides a valuable new animal model that can be used to study this distressing and damaging psychiatric condition.

Commenting on the significance of the findings, Dr Cunningham said: “While much has been hypothesised about risk factors and triggers of delirium, this study offers clear evidence for the interaction of two of these factors to produce brain dysfunction and as such it offers potential routes to preventing or treating this devastating condition.”

The research has also been welcomed by Professor Alasdair MacLullich, Professor of Geriatric Medicine at the University of Edinburgh and President of the European Delirium Association:

“Delirium causes enormous suffering and costs billions of pounds, but it is hardly researched and there are no treatments. Dr Cunningham's exciting study provides critical new knowledge on the mechanisms explaining how two causes of delirium well known to clinicians, cholinergic deficiency and inflammation, may combine to produce this devastating syndrome. This is an important step forward and takes the field closer to developing drug treatments.”

Full title of the publication:

Prior Pathology in the Basal Forebrain Cholinergic System Predisposes to Inflammation-Induced Working Memory Deficits: Reconciling Inflammatory and Cholinergic Hypotheses of Delirium

Robert H. Field, Anna Gossen, and Colm Cunningham , Journal of Neuroscience, 2012

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| sharon.campbell@tcd.ie | Last updated: May 2, 2012