PhD Studentships at the VIDA Doctoral Training Centre

Do altered oligodendrocyte-microglia interactions underlie global white matter tract impairments and cognitive decline after focal ischaemic stroke?

Based at The University of Edinburgh

Supervisors: Jill Fowler (University of Edinburgh), Owen Dando (University of Edinburgh), Raj Kalaria (University of Newcastle), Magdalena Sastre (Imperial)

Abstract:

Stroke is a leading cause of death and disability. With the aging population and improved survival rates, more individuals face serious long-term consequences of stroke, including immediate or delayed cognitive impairment and a doubled risk of dementia. Despite its clinical importance, the mechanisms leading to cognitive decline post-stroke are not well understood.

Initially, stroke causes focal cell death and a localised immune response. However, emerging evidence from PET imaging, post-mortem studies, and animal models shows that inflammatory responses extend throughout the brain, impacting remote regions anatomically connected to the primary site of damage. These widespread inflammatory changes are linked to slowly evolving brain pathology, including damage to distant white matter tracts. Clinical imaging studies suggest that this widespread white matter damage is associated with long-term cognitive impairment.

Oligodendrocytes, glial cells located in white matter tracts, myelinate neuronal axons, which facilitates efficient communication and supports axonal health. Our preliminary data indicate that in the long-term response to experimental stroke in mice, a unique subtype of oligodendrocytes, termed ‘disease-associated oligodendrocytes,’ appear in white matter regions remote from the primary lesion and exhibit a distinct inflammation-related gene expression profile. This project aims to explore these disease-associated oligodendrocytes and their interactions with microglia, the brain’s primary immune cells, through a combination of methods in experimental mouse models and human post-mortem tissue.

The first part of the project will involve bioinformatic analysis of single-cell data to examine the heterogeneity of disease-associated oligodendrocytes compared to homeostatic oligodendrocytes. We will utilize specialised bioinformatic tools to investigate ligand-receptor interactions between oligodendrocytes and microglia post-stroke. The second part will combine MRI imaging with spatial transcriptomics to determine the spatial locations of disease-associated oligodendrocytes and their relationships with gene changes in other brain cells.

Lastly, we will analyse human post-mortem tissue from individuals who died months to years after stroke, sourced from the Cognitive Function After Stroke (CogFAST) cohort, which includes cognitive data and neuroimaging. Using immunohistochemistry, we will assess the presence of disease-associated oligodendrocytes and their relationship with white matter integrity and cognitive status post-stroke.

Ultimately, this research aims to clarify the mechanisms underlying cognitive decline post-stroke, exploring whether disease-associated oligodendrocytes and their altered signalling with microglia could serve as potential therapeutic targets for protecting white matter. We also aim to equip students with specialized skills in dementia-related neuroscience, including molecular imaging and computational analysis, within a collaborative environment that advances dementia research and training.

Plasma-to-Brain Tissue Integrated Proteomics to Identify Vascular and Immune system Biomarkers in Alzheimer’s Disease

Based at The University of Manchester

Supervisors: Marilena Hadjidemetriou (University of Manchester), Cath Lawrence (University of Manchester), Barry McColl (University of Edinburgh)

Abstract:

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60-80% of cases. Despite extensive research efforts, the underlying causes of AD remain uncertain, and there is currently no effective cure. By the time symptoms appear, AD pathology is already well-advanced in the brain, with amyloid-beta plaques and neurofibrillary tangles forming 10-15 and 20 years before cognitive symptoms manifest, respectively. Blood-based biomarkers have the potential not only to improve diagnostic workups in primary care but also to enhance patient stratification in clinical trials for new disease-modifying treatments. Recently, the therapeutic landscape has shifted significantly with the FDA’s approval of amyloid-targeting therapies for patients with mild cognitive impairment due to AD and mild AD dementia. This historic development highlights the critical need for minimally invasive biomarker tests that can detect AD in its earliest stages.

Progress in developing blood biomarkers has been limited by the extremely low concentrations of AD-associated proteins in the blood, which underscores the need for novel analytical platforms. Our research group has developed the NanoOmics platform, which uses nanotechnology to enable comprehensive analysis of the plasma proteome and the discovery of novel blood biomarkers. NanoOmics utilizes nanoparticles as scavenging agents to isolate disease-specific protein markers in blood that are typically masked by highly abundant molecules. Using the NanoOmics pipeline in a transgenic AD mouse model, we have previously tracked disease-specific protein patterns from asymptomatic stages through plaque formation and cognitive decline. Our preliminary findings show a strong correlation between changes in the blood proteome and AD pathology, even at the preclinical stage.

This PhD project aims to build on the NanoOmics approach by integrating the profiling of blood and brain tissue proteomes to address two major challenges: (i) the clinical need for early diagnostic and disease-monitoring blood biomarkers specific to AD, and (ii) the biological need to elucidate immune and vascular mechanisms involved in AD at a molecular level, both systemically and within brain tissue. The project will combine longitudinal blood-brain integrative proteomic analysis in a transgenic AD mouse model with validation studies using a biobank of matched plasma and post-mortem brain tissue samples from AD patients.

Exploring the role of the astrocyte-leptomeningeal vessel interface in dementia

Based at The University of Edinburgh

Supervisors: Philip Hasel (University of Edinburgh), Ingo Schiessl (University of Manchester), Karen Horsburgh (University of Edinburgh)

Abstract:

Astrocytes are a highly abundant cell type in the central nervous system (CNS). In the past, these cells were described as homogenous ‘brain glue’ that offer structural support for neurons. Recently, large-scale molecular profiling approaches have highlighted their vast heterogeneity in the mammalian CNS in both health and neurodegeneration. We now understand that astrocytes can specialize to circuits and anatomical domains, such as blood vessels, ventricles and the brain surface where they are thought to adjust their functions to local demands. Indeed, we have recently discovered that astrocytes making up the ultimate border of the brain, called glia limitans superficialis (GLS) astrocytes, are highly specialized astrocytes. These GLS astrocytes make up the vertebrate brain surface and are molecular and morphologically unique, selectively expressing the gene Myoc and possessing a flat cell body with processes reaching into the parenchyma. Intriguingly, these GLS astrocytes also form long superficial processes that wrap around blood vessels of the leptomeninges in pial and sub-pial compartments. This ‘extra parenchymal’ border structure is completely unexplored, but we argue that it plays a critical role in the gliovascular-immune interface in the context of neuroinflammation and neurodegeneration. Indeed, neuroinflammation and neurodegeneration are critical risk factors of developing dementia and understanding the GLS-leptomeningeal vessel interface will provide new opportunities for early intervention and treatment.

This project will explore the molecular, cellular and structural properties of the GLS-leptomeningeal vessel interface in health and disease using both long term 2-photon in vivo live cell imaging and molecular biology in astrocyte-reporter mice with the ultimate aim to understand the role of this interface in neuroinflammation and neurodegeneration. The PhD student will be located at the UK Dementia Research Institute in Edinburgh and will receive extensive training in in-vivo 2-photon imaging (Manchester) as well as cell reconstruction and spatial transcriptomics (Edinburgh).

Unblocking blood vessel occlusion in dementia: Mechanisms of thrombi extrusion and removal

Based at The University of Manchester

Supervisors: Shane Herbert (University of Manchester), Katie Murray (University of Manchester), Tijana Matic (University of Edinburgh)

Abstract:

Microthrombi formation and occlusion of brain blood vessels is a surprisingly common feature of the aging brain (>30%) and is recognised as a key contributor to Alzheimer’s disease/dementia. For example, in dementia patients the presence of resulting brain microinfarcts is observed at almost double the number of age matched counterparts and is causally associated with age-related cognitive decline. In particular, the high prevalence of microvessel occlusion in dementia disrupts blood flow to neurones, depriving them of oxygen and significantly worsening the disease symptoms – leading to tissue damage known as vascular dementia. Understanding the endogenous mechanisms of thrombi removal and vessel recanalisation could thus offer valuable insights to inform development of innovative treatments for these debilitating conditions. However, the mechanisms underpinning microthrombi clearance remained largely unclear until the recent discovery by the supervisorial team of the process termed thromboangioplasticity (TAP). During TAP, dramatic local remodelling of endothelial cells (ECs) lining the occluded vessel triggers extension of protrusions that anchor and envelop the thrombi, followed by formation of large abluminal transcellular tunnels that drive thrombus extrusion. Thus, TAP uniquely enables efficient engulfment, compaction and extrusion of thrombi, ultimately restoring normal blood flow. However, how TAP is modulated/dysregulated in dementia still remains unknown.

In this project, we will exploit the power of the zebrafish vertebrate model system for genome editing and high spatiotemporal resolution in vivo live imaging studies to delineate mechanistic events underpinning TAP and their importance to dementia via three core aims:

(1) Firstly, we will define the core cellular events directing TAP in brain microvessels by using in vivo live imaging in zebrafish embryos and fluorescent reporters for EC cytoskeletal dynamics, cell signalling responses and cell-cell junction remodelling.

(2) Next, utilising RNAseq transcriptome analyses of brain ECs undergoing TAP we will define novel key molecular drivers of this process and define their function utilising CRISPR-Cas9-mediated gene knockdown.

(3) Finally, the relevance of these newly identified basic mechanisms of TAP to dementia progression will be explored upon analysis of Alzheimer’s transcriptomic data, with an aim to define core TAP pathways that are perturbed in patient ECs. Moreover, manipulation of dementia-related TAP modulators in vivo will further assess if this recapitulates the increased thrombus presence seen in human disease.

Considering that TAP is critical to haemorrhage cessation, vessel recanalisation and maintenance of tissue function, this project could uncover an entirely novel class of therapeutic targets for tackling dementia.

Lipid-dependent regulation of inflammation in vascular dementia

Based at The University of Manchester

Supervisors: Roy Ng (University of Manchester), David Brough (University of Manchester), Paras Anand (Imperial)

Abstract:

Vascular dementia (VaD) is the second most common type of dementia that is caused by chronic cerebral hypoperfusion (CCH). Neuroinflammation is the major driver of vascular pathology and white matter lesions (WHLs) in CCH. Lipid accumulation has been found in the immune cells in human brains with vascular injuries and WMLs. However, how lipids regulate neuroinflammation in VaD pathogenesis remains unclear.

To elucidate how lipid-dependent inflammation drives and manifests VaD pathology, it is crucial to identify the specific cell type involved and when the inflammatory response is initiated. By using our in-house developed inflammation reporter mice and CCH-induced VaD mouse model, we are well-positioned to address these unanswered questions.

The overarching aim is to understand the association between lipid-dependent regulation of inflammation and VaD pathogenesis. The specific aims of this study include:

1) Characterise the cellular and spatial expression of inflammatory proteins in the brain and vasculature in VaD models.

2) Study the mechanistic association between lipid metabolism and inflammation to identify and develop an optimal therapeutic targeting strategy.

This project will provide exciting new insights into how the brain lipid metabolism is important in regulating neuroinflammation and identify novel therapeutic targets for drug development. The collaborative supervisory team from the University of Manchester and Imperial College London will provide training on in vivo and in vitro disease modelling, cell biology analysis and metabolomic/lipidomic analysis.

Imaging vascular dysfunction in dementia using quantitative MRI

Based at The University of Manchester

Supervisors: Laura Parkes (University of Manchester), David Owen (Imperial), Olivia Jones (University of Manchester), Paul Matthews (Imperial)

Abstract:

Disruption to the brain’s blood supply is a key contributor to dementia. Damage to the inner lining of blood vessels, the endothelium, is a key driver, characterised by i) impaired vasoreactivity resulting in dysfunctional cerebral blood flow (CBF) and hypoxia and ii) a compromised blood-brain barrier (BBB), exposing the brain to blood products, and indicating potentially harmful neuroinflammation. Magnetic Resonance Imaging can measure these physiological processes in vivo in people.

We are seeking a neuroscience student with an interest in neuroimaging or a physics student with an interest in neuroscience with high motivation to undertake a challenging interdisciplinary topic. You will develop MRI measurements of endothelial dysfunction (vasoreactivity and BBB leakage) and evaluate their sensitivity to cognitive impairment in people with cerebral small vessel disease (cSVD).

Vasoreactivity is generally assessed using a hypercapnic gas challenge. However, use of a neural challenge (e.g. visual stimulation) may improve comfort and repeatability and may be more closely related to cognitive impairment. Reactivity to gas/visual challenge will be compared using Arterial Spin Labelling and Quantitative Susceptibility Mapping to quantify changes in CBF and oxygen extraction fraction. The latest advances in simultaneous multi-slice technology, enabling fMRI with sub-second temporal resolution, will capture the dynamics of the vascular response.

BBB leakage is assessed using Dynamic Contrast-Enhanced MRI, tracking the passage of the tracer out of the blood into the brain. You will consider different physics-based models of this system and employ them quantify BBB permeability to the tracer. For example, different physiological constraints in different brain regions may require voxel-wise model selection for accurate permeability estimation.

The association between BBB leakage and impaired vasoreactivity will be tested across individuals and across the brain to understand whether they may have a common cause, for example recent evidence suggests they may both be associated with pericyte loss.

Improving endothelial cell function may provide a therapeutic route for cSVD, slowing the onset of vascular dementia. You will join a team at Imperial College London and the University of Manchester currently working together to evaluate the action of a new drug aimed at improving endothelial function. You will analyse the imaging data from this ongoing project to evaluate the changes in endothelial function associated with the drug.  Comparisons with plasma markers of endothelial activation will aid evaluation of the specificity of the imaging measurements.

Investigating Mechanosensitive Ion Channels’ Role in Dementia: Functional and Therapeutic Insights Using Computational and Structural Biology

Based at The University of Manchester

Supervisors: Christos Pliotas (University of Manchester), Theodoras Karamanos (Imperial), Tao Wang (University of Manchester)

Abstract:

Mechanosensitive ion channels play a pivotal role in various biological processes, including cellular signalling, tissue homeostasis, and responses to mechanical stimuli. Channels such as Piezo1, TRPV4, and TREK-1 have gained increasing attention for their potential involvement in neurodegenerative diseases, particularly dementia, where vascular and immune factors are critical. This PhD project aims to investigate the role of mechanosensitive ion channels in dementia, focusing on blood-brain barrier integrity, immune responses, and vascular dysfunction, which are implicated in dementia-related conditions.

We will use a combination of state-of-the-art computational approaches, biophysics and structural biology. Bioinformatics methods will also be applied to analyse gene expression data, identifying dysregulated pathways and molecular networks associated with these human ion channels in dementia. AI-assisted molecular docking and molecular dynamics simulations will be employed to explore ligand interactions with Piezo1, TRPV4, and TREK-1, providing insight into the channels’ pharmacology under mechanical stress and other stimuli known to influence their function. Nuclear Magnetic Resonance (NMR) spectroscopy will be used to investigate protein-drug binding affinity and interactions of the most optimal hits as a result of the AI-assisted computational approaches to be used in this project.

In collaboration with leading researchers in mechanosensitive ion channel biology and NMR techniques, the project will provide a comprehensive analysis of these channels’ immune and vascular contributions to dementia. By combining computational approaches with experimental techniques, the findings will offer valuable insights into novel therapeutic strategies targeting these channels for dementia treatment.

Cerebral microinfarcts in a mouse model of hypertension

Based at The University of Manchester

Supervisors: Harry Pritchard (University of Manchester), Katie Murray (University of Manchester), Alastair Webb (Imperial), Atticus Hainsworth (City St George’s, University of London)

Abstract:

Vascular dementia (VaD) is driven by a reduction in blood flow to the brain. This can occur via multiple mechanisms including narrowing of the cerebral arteries, acute large vessel occlusion or microvascular obstructions that result in cerebral microinfarcts, thought to play a central role in cognitive decline.  These vascular obstructions can result from cardioembolic diseases, such as atrial fibrillation (AF), the most common form of cardiac arrhythmia. AF is often undiagnosed, suggesting it might be more prevalent in the general population then currently thought of. Turbulent and stagnant blood flow in the atria during AF can lead to the formation of microemboli, which can become lodged in the cerebral circulation, impairing cerebral blood flow, resulting in a transient ischemic attack (TIA) or ‘silent’ strokes. The accumulation of these cerebrovascular insults are thought to play a causal role in cognitive decline.

Microemboli lodged in the vasculature can be removed from the lumen by a highly co-ordinated process of vessel remodelling to remove thrombi and re-establish blood flow (Grutzendler et al, 2014). Recent unpublished work from the Murray lab has characterised this co-ordinated multicellular process and identified previously unknown cellular and molecular mechanisms that regulate this vascular plasticity and are central to reestablishing blood flow after occlusion. However, this process has not been studied in the context of disease, especially hypertension (a risk factor in the development of AF and VaD). Work from the Pritchard lab has shown that in a mouse model of hypertension (BPH/2), the cerebral arteries have a smaller lumen diameter and may contribute to a reduction in cerebral blood flow. However, it is unclear whether hypertension-induced vascular changes impair the ability of vessels to remove occlusive microemboli and reestablish perfusion, and thus whether this represents a novel target to reduce the burden of vascular dementia

This VIDA PhD studentship determines if the cerebral circulation in the hypertensive mice has an impaired ability to remove microemboli from the vessel lumen and its overall effect on cerebral blood flow and cognition, compared to its normotensive counterparts. Furthermore, we will explore what impact clinically approached anti-hypertensive treatments will have on the speed and efficiency of the vasculature to remove emboli and assess the downstream consequences vessel survival, cognition and overall tissue health.

Systematic evidence-based approach to identifying and tailoring inflammation modulating treatments to improve clinical outcomes including cognition for patients with intracerebral haemorrhage

Based at The University of Edinburgh

Supervisors: Neshika Samarasekera (University of Edinburgh), Malcolm Macleod (University of Edinburgh), Charis Wong (University of Edinburgh), Stuart Allan (University of Manchester)

Abstract:

Background – 40% patients die in the first month after intracerebral haemorrhage (ICH) and of those who survive 30% will develop dementia with dementia risk linked to ICH severity and underlying small vessel disease including cerebral amyloid angiopathy. Finding an effective ICH treatment could improve outcomes including the risk of developing dementia after ICH.  We have shown that brain swelling (peri-haematomal oedema) increases in the first two weeks after ICH and this tends to occur most in ICH in the lobes of the brain rather than ICH in other locations, which may be linked to cerebral amyloid angiopathy. Brain swelling is a biomarker of neuroinflammation and is associated with clinical outcome.

Drug repurposing accelerates the identification of effective treatments and we have developed systematic evidence-based approaches to guide drug repurposing in clinical trials of MND. We will use similar approaches to identify potential inflammation modulating treatments for improving outcomes after ICH.

Aim – To develop a framework to identify, evaluate, and prioritise repurposed inflammation-modulating drugs to improve clinical outcomes after ICH including reducing the risk of post-ICH cognitive impairment and dementia. We would aim to match information on potential candidate drugs with clinical features such as ICH location, to tailor drug selection to a given patient. We have a CSO funded feasibility study for an ICH platform trial – PLINTH | The University of Edinburgh and this will enable drug selection for a platform trial where a trial arm meeting predefined futility endpoints can be replaced with a new trial arm testing a different drug without interrupting study recruitment.

Methods– We will create a systematic online living evidence summary of inflammation modulating drugs tested in human and animal models.  We will integrate automated processes to continuously gather, synthesise and summarise all existing evidence from a research domain, and report the resulting content as interrogatable databases via interactive web applications.  We will summarise the information for each drug and present the evidence to an expert panel for shortlisting.

Patient and public involvement – We sought the opinion of ICH survivors on studying inflammation.39 patients, carers, and members of the public responded to questions about the design. 87% strongly agreed that, “studying inflammation after brain haemorrhage is a priority.”  We presented an outline of the proposed research to members of our patient group Patient Reference Group | Centre for Clinical Brain Sciences (ed.ac.uk). They supported it because they thought it was a good way of finding a treatment which improves outcomes for people with ICH.

The associations and impact of brain mineral deposition as a marker of vascular dysfunction and inflammation in neurovascular diseases

Based at The University of Edinburgh

Supervisors: Joanna Wardlaw (University of Edinburgh), Maria del C. Valdés Hernández (University of Edinburgh), Fatemeh Geranmayeh (Imperial), Roberto Duarte Coello (University of Edinburgh), Blanca Díaz Castro (University of Edinburgh)

Abstract:

Iron is involved in oxygen transport, DNA synthesis, cell division, metabolism, and neurotransmission.  However, an excess of iron in brain tissue can lead to oxidative stress damage to biomolecules, and cellular dysfunction. With age, iron and other minerals like calcium, accumulate ‘physiologically’ in deep brain structures, but with a wide variation in the amount: we previously found in older people that excess mineral deposition, which is visible and quantifiable by magnetic resonance imaging (MRI), is associated with cerebral small vessel disease (SVD) on MRI, worse cognitive decline, and increased risks of other neurodegenerative diseases, but the mechanisms are unknown. On pathology, the iron has been associated with blood-brain barrier (BBB) leakage and inflammation, both of which are features of SVD, the commonest cause of vascular dementia. For example, in neuro-immune disorders, dystrophic microglia may be accompanied by iron-laden, perivascular macrophages, suggesting a role of inflammation in iron accumulation. Insoluble mineral deposition has been also observed in perivascular astrocytes, as well as increased perivascular fibrinogen, both implicating BBB disturbance. However, these studies relied on post-mortem tissue, were typically small and reflect end stage disease.

In this project, we will use in vivo MRI from several large longitudinal cohort studies (n~1400) in Edinburgh and London with MRI data on iron, SVD features, and most also with BBB function, to assess relationships of brain iron deposition to SVD features, cognitive and clinical measures, MRI measures of BBB leakage, blood markers of inflammation, and disease progression, with tissue samples available for some subjects. Analysis of MRI-detected iron, BBB leakage, and SVD severity, with blood and cellular biomarkers of vascular and neurodegenerative diseases, longitudinal clinical, cognitive, and demographic data, in four large cohort studies, will help determine the vascular and inflammatory associations and impact of brain iron deposition in neurovascular disease. Secondarily it will identify patterns of iron deposition that may indicate increased risk of vascular dementia. Iron deposition is easily seen on commonly-used clinical MRI sequences meaning that the findings will translate readily to clinical practice and research. The student will learn about imaging in vascular and neurodegenerative diseases including AI techniques, neuroanatomy, a range of MRI image analysis methods, how to manage large data samples, clinical observational and biomarker methods, state of the art statistical analysis, tissue histology, and benefit from training provided by the DPUK and DRI, including Vascular Theme ECR Network, and the two host institutions.

Defining interactions between PDE5 and endothelin-1 inhibition underlying cerebrovascular dysfunction in small vessel disease

Based at Imperial College London

Supervisors: Alastair Webb (Imperial), Oliver Warrington (Imperial), Atticus Hainsworth (City St George’s, University of London), Alicja Rudnicka (City St George’s, University of London).

Abstract:

Cerebral small vessel disease (cSVD) causes 30% of ischaemic stroke, 80% of haemorrhagic stroke and 40% of dementia but has no effective treatment. It is associated with abnormal endothelial function in the brain, manifest as reduced blood flow to the brain and reduced reactivity of blood vessels to stimulation, such as by inhalation of carbon dioxide. Our recent OxHARP clinical trial demonstrated that treatment with the vasodilator sildenafil (a PDE5 inhibitor) improved both cerebral blood flow and cerebrovascular reactivity in patients with small vessel disease, but that this effect was significantly reduced in patients with higher levels of endothelin-1. Endothelin-1 is the most potent cerebral vasoconstrictor, is elevated in acute stroke, and its antagonism reduces progression of small vessel diseases in other organs such as the kidney. Its potential as a treatment for cerebral small vessel disease is currently under investigation. However, understanding which interventions are applicable in which patients, which biomarkers predict response to treatment and whether combination treatment may be beneficial is essential for translation to clinical practice.

This 4-year PhD training program will test the differential role of these antagonistic pathways in the cerebrovascular dysfunction evident in small vessel disease. The successful candidate will use data and samples from previous studies (OxHARP; pig model of inducible endothelin-1, Hainsworth BHF PG/20/10397); carry out cerebrovascular function testing with MRI and transcranial ultrasound within ongoing physiological prospective cohorts in cSVD (the ACCESS@ICL cohort) and planned phase-2, randomised, crossover design clinical studies of the effect on cerebrovascular haemodynamics of PDE5 inhibition and endothelin-1 inhibition in patients with cerebral small vessel disease. They will compare whether fluid biomarkers in each target pathway interact with baseline cerebrovascular function (cerebral blood flow, cerebrovascular reactivity, blood-brain barrier permeability); tissue injury due to excess ET-1 activity (pig model); prediction of the physiological response to treatment in interventional studies; and whether these markers reflect response to treatment.

This PhD will test the core hypothesis that PDE5 and ET-1 have antagonistic effects on cerebrovascular function in cSVD, that overactivity of either pathway impairs monotherapy targeting the antagonistic pathway and therefore that combined treatment has the potential for synergistic effects. The successful candidate will acquire global research skills through the Doctoral Training Centre, and specific skills in data handling, epidemiology and statistical analysis, and highly-focused expertise in testing cerebrovascular physiology with both ultrasound and MRI imaging analysis.

The role of type 2 diabetes, retinal vasculopathy and inflammation in post-stroke cognitive decline

Based at City St George’s University of London

Supervisors: Liqun Zhang (City St George’s, University of London), Craig Smith (University of Manchester), Philip Benjamin (City St George’s, University of London), Alicja Rudnicka (City St George’s, University of London)

Abstract:

Most dementia has a vascular component. The prevalence of dementia is brought forward by 25 years in those with stroke compared with those without. Type II diabetes is an independent risk factor for stroke, especially ischemic stroke. Diabetes is associated with an increased risk of post-stroke dementia, independent of the stroke severity.

Pre-clinical and clinical data have shown that inflammation plays a key role in both the acute and chronic phases of ischemic stroke, including the development of dementia. In patients with type II diabetes, chronic hyperglycaemia causes chronic low-grade inflammation. This disrupts the balance of pro- and anti-inflammatory responses, resulting in more severe acute ischemic brain damage. Inflammation after a stroke can last for months or even years, resulting in neurodegeneration. Diabetic retinopathy is an early diabetes complication, driven by inflammation. Individuals with diabetic retinopathy have 34 % higher risk of incident dementia.

Despite promising results of anti-inflammation treatments in preclinical studies, studies of functional clinical outcome after stroke have been inconclusive. There are few studies on the role of inflammation in post-stroke cognitive dysfunction/dementia, and very few in high-risk diabetic stroke patients.

The aims of this PhD project are i) to examine pro- and anti-inflammation blood biomarkers during the course of clinical ischaemic stroke in patients with or without type II diabetes, ii) to explore the temporal patterns of inflammation in acute ischemic stroke and post-stroke cognitive decline, iii) to correlate these inflammation markers with clinical imaging findings and retinopathy biomarkers. Focusing on diabetic patients, this study will provide evidence of type II diabetes related inflammation in post stroke cognitive decline, identify strategies for early screening and intervention to prevent dementia.

St George’s University Hospital is a major comprehensive stroke centre in southwest London with high ethnic diversity of patient population, especially Asian patients of high prevalence in type II diabetes. St George’s University Hospital has an established and experience clinical stroke research team. University of Manchester has an international reputation in vascular inflammation and translational neuroscience. The studentship will link these two expert centres and provide training in setting up clinical study, lab skills, vascular and neuroimaging, cognitive assessment, data-analytics, statistics, with a potential of long-term clinical / academic development.

Skills acquisition

The studentship will link these two expert centres and provide training in setting up clinical study, lab skills, vascular and neuroimaging, cognitive assessment, data-analytics, statistics, with a potential of long-term clinical / academic development.

The programme also benefits from built in opportunities for placements with leading industrial partners, and bespoke training plans including schemes to develop teaching, mentoring, and grant writing skills.

Entry requirements

Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in a biomedical science or medicine. Experience in neuroscience and/or immunology is desirable.

Application process

The following documents should be submitted to stgeorgesphd@sgul.ac.uk no later than Friday 20 December 2024, 23.59 GMT:

• Personal statement about your reasons for applying for this studentship (maximum one page)
• Curriculum Vitae (maximum two pages)
• Two references. Applicants should arrange for two relevant referees to submit letters of reference via email before the deadline. 

Interested candidates must first make contact with the Primary Supervisor Dr Liqun Zhang prior to submitting a formal application, to discuss their interest and suitability for the project. Informal enquiries can be sent via email to liqun.zhang@stgeorges.nhs.uk

Interviews will likely take place in March 2025. Candidates will be asked to give an eight-minute presentation on a previous/on-going research project that showcases skills and knowledge, followed by questions on the presentation and the application.