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Precision Medicine DTP - Delirium as an acute brain injury in hospital inpatients: can clinical features and biomarkers predict outcomes?


Project Description

Additional Supervisor - Dr Matthew Reed

Background

Delirium is a severe medical emergency that is triggered by acute medical illness, drugs, trauma or surgery. It is extremely common, affecting no less than 1 in 7 patients in hospital, with higher rates in certain settings, e.g. 1 in 2 in intensive care units. Delirium is more common in older people, especially those with dementia.

People with delirium have profound cognitive impairment, altered level of consciousness, and psychosis (Marcantonio 2017). Many delirium survivors describe terrifying delusions such as being imprisoned or poisoned, and hallucinations such as seeing animals or monsters.

Delirium is associated with several-fold risk of long-term cognitive decline including new-onset dementia and also acceleration of existing dementia (Davis et al 2017). It also has many other adverse associations including post-traumatic stress disorder, loss of independence, and higher mortality. Delirium is therefore an important and yet under-appreciated form of acute brain injury.

Yet the nature of the injury and how variations in delirium phenotype and aetiology relate to outcomes remains strikingly under-researched.

An inflammatory aetiology in some delirium is supported by animal studies: in the presence of chronic neurodegeneration, peripheral administration of lipopolysaccharide (a model of peripheral infection, a common trigger of delirium) causes acute cognitive deterioration and also acceleration of neurodegeneration (Cunningham & MacLullich 2013). In humans, multiple small studies have shown associations between blood and cerebrospinal fluid inflammatory biomarkers and delirium (Watne et al 2018).

The use of electronic records plus standardised methods of assessment for delirium means that there are now exciting new opportunities to study delirium at unprecedented scale. These include investigating the influence of presumed aetiology (eg. inflammatory vs metabolic vs drug causes), physiological parameters, clinical blood test results, novel biomarkers of brain injury eg. neurofilament light using wastage samples, and neuroimaging data in relation to outcomes including new or accelerated neurodegeneration. The supervising team has recently demonstrated in routine care (N=25000 local records) that delirium is strongly predictive of outcomes such as mortality.

Aims

(1) To establish fully the ascertainment of delirium (using the 4 ‘A’s Test (4AT)) together with relevant linked data (blood tests, physiological data, outcomes) from electronic healthcare records in NHS Lothian.

(2) To test the primary hypothesis that in patients with delirium, worse outcomes (eg. 30-day mortality) are associated with evidence of an inflammatory aetiology (derived from analysis of presumed cause and from biomarkers).

(3) To test secondary hypotheses that delirium is associated with (i) abnormal physiological parameters such as hypoxia and hypotension, and (ii) increased atrophy on CT scans (in a subset, using locally-established techniques).

(4) To explore associations between novel biomarkers in wastage clinical blood samples, e.g. neurofilament light, and (i) delirium diagnosis, and (ii) outcomes following delirium.

Training outcomes

This project will provide training in extracting data from healthcare records, and quantitative skills (complex multivariate statistics for data linkage and prediction using multi-domain digital health records) in relation to a very common medical emergency. The student will gain experience in neuroimaging analysis and depending on experience and interest will have the option to participate in ward-based delirium assessment and/or biomarker assays. The student will also gain detailed knowledge of ethical and governance issues relating to working with healthcare data. In addition to mandatory teaching, training will be provided in Edinburgh via the Farr institute, Edinburgh Neuroimaging, Edinburgh Data Epidemiology Network, and the Applied Ageing Network. In Glasgow the student will undergo training and support in complex multivariate statistical design (Dr David McAllister). The PhD training will yield an individual able to use clinical datasets to analyse complex longitudinal clinical problems in relation to biomarkers; these skills will be applicable to multiple clinical areas.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2020

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. Cunningham C, Maclullich AM. At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response. Brain Behav Immun. 2013 Feb;28:1-13.

2. Davis DH, Muniz-Terrera G, Keage HA, Stephan BC, Fleming J, Ince PG, Matthews FE, Cunningham C, Ely EW, MacLullich AM, Brayne C; Epidemiological Clinicopathological Studies in Europe (EClipSE) Collaborative Members. Association of Delirium With Cognitive Decline in Late Life: A Neuropathologic Study of 3 Population-Based Cohort Studies. JAMA Psychiatry. 2017 Mar 1;74(3):244-251.

3. Marcantonio ER. Delirium in Hospitalized Older Adults. N Engl J Med. 2017 Oct 12;377(15):1456-1466.

4. Hall RJ, Watne LO, Cunningham E, Zetterberg H, Shenkin SD, Wyller TB, MacLullich AMJ. CSF biomarkers in delirium: a systematic review. Int J Geriatr Psychiatry. 2018 Nov;33(11):1479-1500.

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