Title: Exaggerated Immune Ageing and Pro-inflammatory Immune to Brain Communication in Delirium Pathophysiology
Funder: Dunhill Medical Trust

Abstract: Background Delirium is common, disproportionately affects older people and leads to increased mortality and dementia (Pendlebury et al. 2015). The pathophysiology is poorly understood and there are no treatments. Infection is a common trigger of delirium and the immune response is therefore thought to be key in the pathophysiology. Changes occur to the immune system with ageing and frailty, termed immunesenescence. Monocytes are vital in the innate immune response and their function is compromised with age, with a more pro-inflammatory phenotype (Hearps et al. 2012). A key rodent model of delirium has suggested a role for monocytes in pathophysiological immune to brain communication and subsequent neuroinflammation (Andonegui et al. 2018). Hypothesis Exaggerated immunesenescence, and specifically enhanced monocyte pro-inflammatory function, is associated with an increased vulnerability to delirium, drives pathophysiology through pro-inflammatory immune to brain communication, and can be rescued with targeted pharmacological intervention Objectives 1. To measure markers of monocyte immunesenescence and pro-inflammatory status in blood from older people that went on to have an episode of delirium and those that did not over a 2-year follow-up. 2. To measure monocyte phenotype, cytokine production and migration in older people with infection, admitted to hospital with and without delirium. 3. To measure pro-inflammatory and anti-inflammatory factors and biomarkers of blood brain barrier integrity in older people with infection, admitted to hospital with and without delirium. 4. To investigate, ex vivo, the effect of repurposed drugs on the immune response in monocytes from older people with infection admitted to hospital with and without delirium. Populations 1. Older people (≥70 years) living in the community who did and did not develop delirium over a 2-year period. 2. Older people (≥70 years) admitted to hospital with infection, with and without delirium. Outcome and Impact This project will contribute to our understanding of the mechanisms of immune system ageing and their role in the pathophysiology of delirium, a common age-related disease. I will identify biomarkers to highlight those at risk of delirium and target prevention strategies in the future. Through investigating exaggerated monocyte immunesenescence, and specifically the role of pro-inflammatory monocytes in immune to brain communication and delirium pathophysiology, I will identify target pathways and trial repurposed drugs ex-vivo, providing proof of concept data for phase II trials. This research will contribute to developing an effective treatment for delirium with the potential to ameliorate poor outcomes and reduce future health and social care requirements.

Lay abstract: Delirium is a common condition that affects 20% of older people admitted to hospital. People with delirium have difficulty in holding their attention, thinking clearly and may have upsetting hallucinations. Delirium can be very distressing for patients, carers and healthcare staff. People who get delirium are more likely to die when they come into hospital, be discharged to a new care home and to develop dementia. Unfortunately, we currently have no treatments. This is because we do not understand the biological processes happening in the body to cause delirium. Delirium is commonly triggered by infection or surgery and we suspect the response of immune cells (cells that protect the body from infection) are important in why some people get delirium. Immune cells communicate with the brain during infection and we think that differences in this communication may cause delirium. We know delirium is more common in older people and that there are changes in how these immune cells respond with age. We think that people who have an exaggerated ageing immune cell response, are more likely to develop delirium. I will look at blood samples from older people before they get delirium to see if differences in factors produced by immune cells can predict which people will develop delirium. I will also recruit older people admitted to hospital with infection, with and without delirium, and take a blood sample to find out whether their immune cells are responding differently. I will ask for consent whenever possible. However, if people are unable to give their consent due to delirium, I will ask a relative or healthcare worker, not connected to the research, on their behalf. Finally, these experiments will help us find possible targets in the immune system for future treatments. I will test these drugs on immune cells in the lab. I already have some drugs that I plan to test. This study will improve our understanding of what causes delirium, a common age-related disease. By testing how immune cells respond to different drugs we hope we can find some future treatments. This study would provide us with the evidence needed to plan future trials of treatments in patients. We hope that by developing future treatments for delirium we can reduce the number of people who need to live in a care home or who go on to develop dementia as a result of delirium.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL