Acute hospitals have seen unprecedented demographic changes, where older age, frailty and cognitive impairment now characterise the majority of health service users. Delirium is very common in this setting, and adverse outcomes are well described. However, studies investigating cognitive outcomes after delirium in unselected samples have been lacking. This thesis had four objectives: (1) To estimate the prevalence of delirium in the general population (2) To assess the association of delirium with cognitive outcomes (3) To investigate how these associations relate to underlying dementia pathology (4) To develop novel methods for retrospectively ascertaining delirium.

Methods: Data from three population-based neuropathology cohort studies were used: Vantaa 85+; Cambridge City over-75s Cohort (CC75C); MRC Cognitive Function and Ageing Study (CFAS). (1) To ascertain the prevalence of delirium in the general population, a measure of delirium was developed using data recorded in standardised interview schedules, with criterion validity evaluated through the association with mortality and dementia risk. (2) The association with cognitive outcomes was tested in a series of logistic regression models, where delirium was the exposure and dementia (or worsening dementia severity) was the outcome. In addition, the association with change in Mini-Mental Status Examination (MMSE) score was assessed using random-effects linear regression. (3) In brain donors from all three cohorts, the independent effects of delirium, dementia pathology, and their interaction, were investigated using the same approach. (4) A chart-based method for deriving a retrospective diagnosis for delirium was developed, validated against bedside psychiatrist diagnosis. Vignettes from the medical record were abstracted and delirium status decided by expert consensus panel.

Results: (1) Age-specific prevalence in CFAS increased with age from 1.8% in the 65-69 year age group to 13.5% in the ≥90 age group (p<0.01 for trend). (2) Delirium was consistently associated with adverse cognitive outcomes: new dementia (OR 8.7, 95% CI 2.1 to 35); worsening dementia severity (OR 3.1, 95% CI 1.5 to 6.3); faster change in Mini-Mental Status Examination (MMSE) score (1.0 additional points/year, p<0.01) (3) In the neuropathology analyses, decline attributable to delirium was -0.37 MMSE points/year (p<0.01). Decline attributable to dementia pathology was -0.39 MMSE points/year (p<0.01). However, the combination of delirium and dementia pathology resulted in the greatest decline, where the interaction contributed a further -0.16 MMSE points/year (p=0.01), suggesting that delirium worsened cognitive trajectories in dementia, but through distinct pathophysiological pathways not accounted for by Alzheimer’s, vascular or Lewy body pathology. (4) The chart abstraction method yielded a sensitivity of 0.88 and specificity 0.75 for ‘possible delirium’, with lower sensitivity (0.58) and higher specificity (0.93) for ‘probable delirium’ (AUC 0.86, 95% CI 0.82 to 0.89).

This thesis adds to the small body of work on delirium in prospective studies, with the first ever analyses conducted in whole populations. The findings suggest new possibilities regarding the pathology of cognitive impairment, positioning delirium and/or its precipitants as a critically inter-related mechanism.