Acute illness, delirium and long-term cognitive decline in later life: causes and consequences - Dunhill Medical Trust PhD Cohort

In older people acute illness commonly triggers delirium, an acute-onset, often reversible syndrome of severe decline in mental functioning [1]. Delirium affects 25% of hospitalised older people, with higher rates in certain populations, e.g. Intensive Care Units (>60%).

It is linked to multiple short-term adverse outcomes including 3-fold 30-day mortality and 2-fold need for new care home admission.

Beyond these early adverse outcomes, delirium is associated with acceleration of existing dementia [2] and a greater than 8-fold increased risk of future dementia [3]. Delirium is also linked with other longer-term adverse outcomes, including frailty and 1-year mortality.

In older people, hospitalisation itself is linked with longer-term cognitive decline, though this relationship is strongest when the acute illness has been complicated by delirium [4].

There is also evidence that acute illness involving inflammation may alter trajectories of cognitive decline in the absence of hospitalisation or without delirium, though these relationships are less well-understood [1].

Neuroscience studies have discovered body-brain links that may play a role in cognitive decline following acute illness [1,5].

Acute peripheral inflammatory signals from diverse sources (infection, surgery, injury) can through several pathways trigger acutely altered behaviour, neuroinflammation and neural injury, particularly in the presence of pre-existing neurodegeneration where microglia and astrocytes are ‘primed’ to produce more pro-inflammatory signals than microglia and astrocytes in healthy brain [5].

Even short-term acute inflammatory signals can lead to accelerated neurodegeneration, paralleling clinical epidemiological observations.

Additional mechanisms of brain injury occurring during acute illness include periods of low blood oxygen and low blood pressure occurring during acute illness, and altered glucose homeostasis in the brain [6].

Taken together, these findings show that in older people acute illness is a determinant of both acute brain injury (commonly manifesting as delirium), and dementia. Yet this is a strikingly under-researched area in both clinical and basic science research.

Better understanding of the relationships between acute illness and cognitive decline has huge potential to improve the health of older people.

Notably, a recent international interdisciplinary consensus statement concluded that ‘… addressing delirium prevention and treatment represents an unparalleled opportunity to make potentially a meaningful impact on the global dementia burden.’ [7] Much requires to be investigated across the spectrum from basic science to clinical studies, including identifying mechanisms, how different types of acute illnesses and physiological derangements affect the risk of future cognitive decline, therapeutic targets, and the experiences of people who experience acute illness followed by long-term cognitive decline.

Aim: We propose an interdisciplinary PhD cohort (the Dunhill Cohort) whose overarching aim is to investigate the relationships between acute illness and cognitive decline in older age thus opening the way to the future development of treatments.

Novelty: We believe that progress in our overarching theme requires a new and explicit focus with a coordinated, interdisciplinary approach that promotes cross-pollination of observations, ideas and methods. Our proposal thus brings together in a new way four collaborating groups with complementary expertise.

This provides a powerful combination of essential capabilities enabling interdisciplinary research on this theme (see the Environment section).

For example, we can perform novel big data studies on relationships between predisposing risk factors (frailty, multimorbidity), delirium, acute illness parameters, markers of inflammation, and long-term cognitive decline. Variables identified can be further investigated in basic science experiments, and potential interventions tested.

Equally, basic science studies of how models of acute illness affect brain health may suggest novel biomarkers that can be investigated in clinical studies. Each student will undergo a 48-month PhD programme.

In Year 1 the students will undergo a range of training and project work before embarking on their main research phase in Years 2-4.

The content of Year 1 will include a translational course for all of the Dunhill Cohort students addressing interdisciplinary elements of the theme, with the remaining content determined by the supervisory team for each student within the regulations for the PhD programme.

Why it is important: Older people hospitalised with acute illness are highly vulnerable to acute brain injury, which has both acute (delirium) and chronic (dementia) consequences. Delirium is extremely common, affecting 1 in 4 hospitalised older people.

It is associated with increased hospital costs but also substantial long-term social (disability, carer burden) and financial costs (increased social care needs) [8]. Though some delirium can be prevented by in-hospital strategies, most (two-thirds) is present at admission. Therefore, the potential impact of research that reduces or prevents brain injury in this context is enormous.

Yet little is known about how acute illness causes brain injury and subsequent cognitive decline.

There are no known effective treatments for delirium, or more broadly for neuroprotective treatments in the context of acute illness.

There is an urgent need to increase explicit and focused interdisciplinary research capacity in this area, to work towards better understanding of prognosis and the development of new treatments which have the potential to reduce long-term cognitive decline. This proposal addresses that need with 5 four-year PhD studentships across the translational spectrum.

References [1] Wilson JE. Delirium. Nat Rev Dis Primers 6;90;doi:10.1038/s41572-020-00223-4 (2020). [2] Fong TG. Delirium accelerates cognitive decline in Alzheimer disease. Neurology 72;1570-1575 (2009). [3] Goldberg TE. Association of delirium with long-term cognitive decline: a meta-analysis. JAMA Neurology 77;1373-1381;doi:10.1001/jamaneurol.2020.2273 (2020). [4] Richardson SJ.

Hospitalisation without delirium is not associated with cognitive decline in a population-based sample of older people-results from a nested, longitudinal cohort study. Age Ageing 50;1675-1681;doi:10.1093/ageing/afab068 (2021). [5] Lopez-Rodriguez AB.

Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1beta drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimer's and Dementia 17;1735-1755;doi:10.1002/alz.12341 (2021). [6] Kealy J.

Acute inflammation alters brain energy metabolism in mice and humans: role in suppressed spontaneous activity, impaired cognition, and delirium. J Neurosci 40;5681-5696;doi:10.1523/JNEUROSCI.2876-19.2020 (2020). [7] Khachaturian AS. International Drive to Illuminate Delirium: A developing public health blueprint for action.

Alzheimer's and Dementia 16;711-725;doi:10.1002/alz.12075 (2020). [8] Caplan GA. The financial and social costs of delirium. Eur Geriatr Med. 11;105-112;doi:10.1007/s41999-019-00257-2 (2020).