Delirium and Dementia in Hospitalised Older People with Acute Illness: Risk Factors, Mechanisms and Prognosis

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Background and Aim Delirium is often precipitated by acute illness (e.g., infection/inflammation) and more likely to occur in older, cognitively-impaired individuals or those with cerebrovascular disease.1-3 Delirium subsequently increases dementia risk4 , thought to reflect the frequent co-association of delirium with systemic infection, itself a risk factor for dementia.5-6 However, the impact of infection on dementia risk appears dependent on the presence of small vessel disease (SVD). Preliminary work by my proposed supervisor found that whereas delirium increased dementia risk irrespective of SVD, infection only increased dementia risk in those with SVD. These findings suggest that SVD may be an important determinant of susceptibility to both delirium and dementia following infection, but the impact of other acute illness factors (e.g., hypotension, hypoxia) may be less dependent on the type of underlying neuropathology. I aim to test this hypothesis by studying multimodal biomarkers (clinical, blood-based, and neuroimaging) in well-phenotyped cohorts of older people hospitalised for acute illness to understand mechanisms underlying i) delirium, and ii) sub-type specific incident dementia on follow-up.Methods Existing Cognitive Frailty cohorts (2010-, >1700 patients). During my Academic Clinical Fellowship in Geriatric Medicine, I assembled data on well-characterised cohorts of acute medicine patients.2 This included data on delirium, pre-existing dementia and objective cognitive deficits alongside other routinely acquired clinical data e.g., demographics, frailty markers, observations, diagnoses, residence and care needs, illness severity and laboratory results. I will now build on this work to obtain routinely acquired brain imaging from up to 5-years prior to admission. Using visual rating scales, I will extract quantified measures of SVD, atrophy and other neuroimaging markers.7-8 To obtain 5-year follow-up for new dementia and dementia subtype, I will use linked mental health data from Oxford Health Foundation Trust and search primary care problem lists. New prospective cohort feasibility study. I will recruit a pilot acute hospital cohort (age>70 years, n=100) with methodology established in our Cognitive Frailty and the Oxford Vascular Study (OXVASC) cohorts. In-person assessment and follow-up to 2-years will enable detailed characterisation of delirium and incident dementia diagnosis using DSM-5 criteria, assessment of delirium subtype, severity and duration; rate of cognitive decline and dementia subtype diagnosis. Participants will be offered home visits or telephone follow-up to maximise participation, supplemented by indirect follow-up using medical records to minimise attrition. This method previously achieved >95% follow-up for dementia to 5-years in OXVASC.9-10. Participants will undergo photon CT-brain imaging at the John Radcliffe Hospital, enabling scan acquisition in only a few seconds whilst providing high-quality enhanced brain grey/white matter differentiation and spatial resolution. This will enable high-quality brain imaging even in confused participants in whom MRI would be impossible. I will use visual rating scales to extract neuroimaging markers and perform research blood sampling to obtain informative biomarkers of immune response and inflammation. Impact My work will help elucidate mechanisms of delirium and dementia in his vulnerable group, thereby aid the development of new treatments and preventive strategies.