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
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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.
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