title: Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium.
abstract: BACKGROUND
  Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk.
  
  
  METHODS
  Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 μg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry.
  
  
  RESULTS
  In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology.
  
  
  CONCLUSIONS
  A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Daniel H J
authors.initials: DHJ
authors.lastname: Davis
authors.affiliation: Trinity College Institute of Neuroscience, School of Biochemistry and Immunology, Trinity College Dublin, Republic of Ireland.
authors.forename: Donal T
authors.initials: DT
authors.lastname: Skelly
authors.affiliation: Trinity College Institute of Neuroscience, School of Biochemistry and Immunology, Trinity College Dublin, Republic of Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: Murray
authors.affiliation: Trinity College Institute of Neuroscience, School of Biochemistry and Immunology, Trinity College Dublin, Republic of Ireland.
authors.forename: Edel
authors.initials: E
authors.lastname: Hennessy
authors.affiliation: Department of Clinical Geratology, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Jordan
authors.initials: J
authors.lastname: Bowen
authors.affiliation: Department of Psychology, King's College, London, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Norton
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.affiliation: Department of Geriatrics, Jämsä District Municipal Federation of Health Care, Jämsä, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Rahkonen
authors.affiliation: School of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Sulkava
authors.affiliation: Deparment of Psychology, Durham University, Durham, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sanderson
authors.affiliation: Department of Experimental Psychology, University of Oxford, United Kingdom.
authors.forename: J Nicholas
authors.initials: JN
authors.lastname: Rawlins
authors.affiliation: Department of Experimental Psychology, University of Oxford, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Edinburgh Delirium Research Group, Geriatric Medicine Unit, Edinburgh New Royal Infirmary, Edinburgh, United Kingdom.
authors.forename: Alasdair M J
authors.initials: AMJ
authors.lastname: MacLullich
authors.affiliation: Trinity College Institute of Neuroscience, School of Biochemistry and Immunology, Trinity College Dublin, Republic of Ireland. Electronic address: colm.cunningham@tcd.ie.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D001369:Axons / Q000473:pathology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000523:psychology; D003693:Delirium / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005387:Finland / Q000453:epidemiology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology* / Q000523:psychology; D008070:Lipopolysaccharides; D008137:Longitudinal Studies; D008297:Male; D018782:Maze Learning; D051379:Mice; D011569:Psychiatric Status Rating Scales; D013569:Synapses / Q000473:pathology*; D013788:Thalamus / Q000187:drug effects / Q000473:pathology
chemical_list: D008070:Lipopolysaccharides
keywords: Delirium; ageing; axonal; basal forebrain; cognitive decline; dementia; hippocampus; inflammation; neurodegeneration; neuroinflammation; neuropathology; susceptibility; synaptic; systemic; thalamus