title: Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1β in delirium after hip fracture.
abstract: OBJECTIVE
  Exaggerated central nervous system (CNS) inflammatory responses to peripheral stressors may be implicated in delirium. This study hypothesised that the IL-1β family is involved in delirium, predicting increased levels of interleukin-1β (IL-1β) and decreased IL-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of elderly patients with acute hip fracture. We also hypothesised that Glial Fibrillary Acidic Protein (GFAP) and interferon-γ (IFN-γ) would be increased, and insulin-like growth factor 1 (IGF-1) would be decreased.
  
  
  METHODS
  Participants with acute hip fracture aged >60 (N=43) were assessed for delirium before and 3-4 days after surgery. CSF samples were taken at induction of spinal anaesthesia. Enzyme-linked immunosorbent assays (ELISA) were used for protein concentrations.
  
  
  RESULTS
  Prevalent delirium was diagnosed in eight patients and incident delirium in 17 patients. CSF IL-1β was higher in patients with incident delirium compared to never delirium (incident delirium 1.74 pg/ml (1.02-1.74) vs. prevalent 0.84 pg/ml (0.49-1.57) vs. never 0.66 pg/ml (0-1.02), Kruskal-Wallis p=0.03). CSF:serum IL-1β ratios were higher in delirious than non-delirious patients. CSF IL-1ra was higher in prevalent delirium compared to incident delirium (prevalent delirium 70.75 pg/ml (65.63-73.01) vs. incident 31.06 pg/ml (28.12-35.15) vs. never 33.98 pg/ml (28.71-43.28), Kruskal-Wallis p=0.04). GFAP was not increased in delirium. IFN-γ and IGF-1 were below the detection limit in CSF.
  
  
  CONCLUSIONS
  This study provides novel evidence of CNS inflammation involving the IL-1β family in delirium and suggests a rise in CSF IL-1β early in delirium pathogenesis. Future larger CSF studies should examine the role of CNS inflammation in delirium and its sequelae.
authors.affiliation: Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Cape
authors.affiliation: Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, UK; Department of Geriatrics, Western General Hospital, Edinburgh, Scotland, UK. Electronic address: roanna.hall@nhslothian.scot.nhs.uk.
authors.forename: Roanna J
authors.initials: RJ
authors.lastname: Hall
authors.affiliation: Department of Medicine, Amsterdam Delirium Study Group, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Department of Geriatrics, Gelre Hospitals, Apeldoorn, The Netherlands.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: van Munster
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: de Vries
authors.affiliation: Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Howie
authors.affiliation: Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearson
authors.affiliation: Department of Trauma and Orthopaedics, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Middleton
authors.affiliation: Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gillies
authors.affiliation: Department of Anaesthetics, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Armstrong
authors.affiliation: Department of Trauma and Orthopaedics, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Tim O
authors.initials: TO
authors.lastname: White
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: Department of Medicine, Amsterdam Delirium Study Group, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sophia E
authors.initials: SE
authors.lastname: de Rooij
authors.affiliation: Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Alasdair M J
authors.initials: AM
authors.lastname: MacLullich
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D003693:Delirium / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000150:complications; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000097:blood / Q000134:cerebrospinal fluid; D006620:Hip Fractures / Q000134:cerebrospinal fluid / Q000150:complications*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications; D007334:Insulin-Like Growth Factor I / Q000134:cerebrospinal fluid; D007371:Interferon-gamma / Q000097:blood / Q000134:cerebrospinal fluid; D053583:Interleukin-1beta / Q000097:blood / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma
keywords: Cerebrospinal fluid; Delirium; Inflammation; Interleukin-1 receptor antagonist; Interleukin-1β