title: Association of Delirium With Cognitive Decline in Late Life: A Neuropathologic Study of 3 Population-Based Cohort Studies.
abstract: OBJECTIVE
  Delirium is associated with accelerated cognitive decline. The pathologic substrates of this association are not yet known, that is, whether they are the same as those associated with dementia, are independent, or are interrelated.
  
  
  OBJECTIVE
  To examine whether the accelerated cognitive decline observed after delirium is independent of the pathologic processes of classic dementia.
  
  
  METHODS
  Harmonized data from 987 individual brain donors from 3 observational cohort studies with population-based sampling (Vantaa 85+, Cambridge City Over-75s Cohort, Cognitive Function and Ageing Study) performed from January 1, 1985, through December 31, 2011, with a median follow-up of 5.2 years until death, were used in this study. Neuropathologic assessments were performed with investigators masked to clinical data. Data analysis was performed from January 1, 2012, through December 31, 2013. Clinical characteristics of brain donors were not different from the rest of the cohort. Outcome ascertainment was complete given that the participants were brain donors.
  
  
  METHODS
  Delirium (never vs ever) and pathologic burden of neurofibrillary tangles, amyloid plaques, vascular lesions, and Lewy bodies. Effects modeled using random-effects linear regression and interactions between delirium and pathologic burden were assessed.
  
  
  RESULTS
  Change in Mini-Mental State Examination (MMSE) scores during the 6 years before death.
  
  
  RESULTS
  There were 987 participants (290 from Vantaa 85+, 241 from the Cambridge City Over-75s Cohort, and 456 from the Cognitive Function and Ageing Study) with neuropathologic data; mean (SD) age at death was 90 (6.4) years, including 682 women (69%). The mean MMSE score 6 years before death was 24.7 points. The 279 individuals with delirium (75% women) had worse initial scores (-2.8 points; 95% CI, -4.5 to -1.0; P < .001). Cognitive decline attributable to delirium was -0.37 MMSE points per year (95% CI, -0.60 to -0.13; P < .001). Decline attributable to the pathologic processes of dementia was -0.39 MMSE points per year (95% CI, -0.57 to -0.22; P < .001). However, the combination of delirium and the pathologic processes of dementia resulted in the greatest decline, in which the interaction contributed an additional -0.16 MMSE points per year (95% CI, -0.29 to -0.03; P = .01). The multiplicative nature of these variables resulted in individuals with delirium and the pathologic processes of dementia declining 0.72 MMSE points per year faster than age-, sex-, and educational level-matched controls.
  
  
  CONCLUSIONS
  Delirium in the presence of the pathologic processes of dementia is associated with accelerated cognitive decline beyond that expected for delirium or the pathologic process itself. These findings suggest that additional unmeasured pathologic processes specifically relate to delirium. Age-related cognitive decline has many contributors, and these findings at the population level support a role for delirium acting independently and multiplicatively to the pathologic processes of classic dementia.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England2Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, England.
authors.forename: Daniel H J
authors.initials: DH
authors.lastname: Davis
authors.affiliation: Centre for Dementia Prevention, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Graciela
authors.initials: G
authors.lastname: Muniz-Terrera
authors.affiliation: School of Psychology, Social Work and Social Policy, University of South Australia, Adelaide, Australia.
authors.forename: Hannah A D
authors.initials: HA
authors.lastname: Keage
authors.affiliation: Institute of Health and Society, Newcastle University, Newcastle, England.
authors.forename: Blossom C M
authors.initials: BC
authors.lastname: Stephan
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
authors.forename: Jane
authors.initials: J
authors.lastname: Fleming
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, England.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Institute of Health and Society, Newcastle University, Newcastle, England.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Matthews
authors.affiliation: School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee9Tennessee Valley Veterans Affairs Geriatric Research Education Clinical Center, Nashville.
authors.forename: E Wesley
authors.initials: EW
authors.lastname: Ely
authors.affiliation: Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Alasdair M J
authors.initials: AM
authors.lastname: MacLullich
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D060825:Cognitive Dysfunction / Q000473:pathology*; D015331:Cohort Studies; D003693:Delirium / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D008297:Male; D008609:Mental Status Schedule; D016874:Neurofibrillary Tangles / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology