Delirium as a disorder of brain network disintegration

Abstract

Delirium is a common neuropsychiatric syndrome, characterized by acute change in attention and awareness, as direct consequence of an underlying medical condition. It is affecting 10-50% of the hospitalized elderly. Delirium is a burden for patients and related to negative outcomes, such as long-term cognitive impairment. The development of delirium is usually the result of an interaction of various heterogeneous risk factors. Predisposing risk factors, such as older age or cognitive impairment, cover the baseline vulnerability to delirium. Precipitating risk factors for delirium, such as sedation, determine acute changes that can trigger the syndrome. The underlying mechanism of how (combinations of) these risk factors lead to delirium is unknown. In addition, although several hypothesis exist, the pathophysiology of the clinical syndrome is generally unknown. Nevertheless, previous studies have indicated that the acute state of delirium can be accompanied with alterations in brain (network) activity. Studying the brain network in relation to delirium may therefore give us new insights in this complex clinical syndrome. The aim of this dissertation was to evaluate the hypothesis of delirium as a disorder of brain network disintegration. The hypothesis was tested in three different aspects. Brain network disintegration was evaluated as biological substrate of (1) vulnerability for delirium, (2) the clinical syndrome of delirium and (3) longitudinal changes after delirium.

Taken together, this dissertation may add the following conclusions to the existing literature: 1. Predisposing risk for delirium does not appear to be associated with similar functional network alterations as observed during delirium. 2. Network disintegration can be defined as biological characteristic for the clinical syndrome of delirium. Alterations in functional network efficiency and integration seem to be related to the clinical symptoms of delirium and may recover when delirium resolves. 3. Delirium is associated with a decrease in global connectivity strength of the functional brain network over time. This alteration could be the biological substrate of impaired outcomes of delirium, such as longterm cognitive dysfunction or dementia.

The theory of delirium as a disorder of brain network disintegration does not have to replace other hypotheses on the pathophysiology of delirium. Previous hypotheses indicated neuroinflammation, neurotransmitter disturbances, neuronal aging, oxidative stress or neuroendocrine disturbances as an essential underlying biological mechanism for delirium. It remains to be studied to what extent brain network alterations are associated with these other hypotheses. Presumably, integrating different hypotheses for delirium may be beneficial in elucidating the complex pathophysiology.