Cortisol and inflammation in delirium and long-term cognitive decline after hip fracture
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Hall2016.doc (5.233Mb)
Date
02/07/2016Author
Hall, Roanna Jane
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Abstract
Delirium, or “acute confusion” is a common and serious acute neuropsychiatric
syndrome mainly affecting older people. It is associated with multiple adverse
outcomes, including an increased risk of developing dementia and increased
mortality. The underlying mechanisms of delirium are poorly understood, and there
are currently no specific treatments. This thesis investigated the roles of the
hypothalamic-pituitary adrenal axis and inflammation in the pathophysiology of
delirium, persistent delirium and cognitive decline following delirium. It investigated
whether levels of cortisol in blood and cerebrospinal fluid (CSF) are elevated in
delirium, with elevated pro-inflammatory and reduced anti-inflammatory cytokines.
It also investigated whether there is loss of cortisol diurnal rhythm (in saliva) with
elevated afternoon cortisol levels. The thesis investigated whether any
hypercortisolaemia was sustained during the year after delirium, and whether this
was associated with deterioration in cognition during the year after hip fracture.
Finally, it also tested whether there are high levels of a marker of central nervous
system damage (S100B) and of a dementia marker (tau) in CSF in delirium.
A prospective observational cohort study was conducted in N=108 patients aged over
60 who had sustained a hip fracture, in whom 40% developed delirium. Participants
gave informed consent or if they lacked capacity to give informed consent, this was
given by their next of kin. Participants were assessed regularly for delirium,
according to DSM IV criteria, during the two weeks after hip fracture. A sample of
CSF was collected during the spinal anaesthetic performed for the operation to repair
their fracture. Samples of blood and saliva were collected during the two weeks after
the hip fracture operation. Participants were visited three, six and twelve months
after their hip fracture for further delirium assessment, and a cognitive test battery
was completed. Further samples of blood and saliva were collected at these visits.
The study found evidence of high levels of cortisol and of S100B in CSF in those
with active delirium, but there were no differences in levels of tau or cytokines in
CSF. Those with delirium had elevated serum cortisol during the perioperative
period, and elevated afternoon salivary cortisol, suggesting flattening of cortisol
diurnal rhythm with failure to reach the normal diurnal nadir. After adjusting for
confounders in a multivariate logistic regression analysis, serum cortisol was still
predictive of delirium, but salivary cortisol AM:PM ratio had a trend towards
significance. Those who had persistent delirium features in the months after hip
fracture had significantly higher serum cortisol three months after hip fracture. There
was a change in serum inflammatory profile in those with delirium, with a shift
towards a pro-inflammatory state. Testing the study hypotheses surrounding
cognition after delirium was very challenging, due to patient attrition and other
factors. Some participants showed a trajectory of cognitive improvement, which was
probably due to resolution of delirium during the year after hip fracture. Those with
resolved delirium had deficits in verbal and visual memory. This study has improved
understanding of the mechanisms of delirium, suggested further avenues for research
and identified possible new therapeutic targets.