Supervisors: Ben Dickie, Harry Pritchard, Axel Montagne (Edinburgh)

Chronic hypertension causes functional and anatomical rarefaction of the cerebral blood vessels and is the main risk factor after age for vascular dementia and stroke. In addition to distributing nutrients and oxygen to brain tissue, the cerebral vasculature also helps to distribute cerebrospinal fluid (CSF) into the brain parenchyma via perivascular channels that surround vessels, a process vital for clearing metabolic waste from the brain. The impact of hypertension on blood vessels (stiffening, remodelling, increased leakiness) has a “knock-on” effect on these perivascular channels, causing backflows, which slow the rate of CSF movement down these channels and into the brain. It is currently unclear which element of hypertensive-induced vascular pathology drives the observed alterations in perivascular flows.  

In this PhD, the student will attempt to further explore the role of vasomotion, or lack thereof, on perivascular flows. The impact of acute and chronic vasoconstriction and reduced cerebral blood flow in the context of hypertension will be studied. Initially studies will be undertaken in naïve mice using arterial pressure myography to determine compounds that robustly vasoconstrict (e.g endothelin-1) or dilate vessels (e.g sodium nitroprusside). Furthermore, we will determine if lower concentrations of these compounds can initiate vasomotion in the cerebral arteries. These compounds will then be utilised in vivo in wild-type mice to study their impact on perivascular flows using both contrast-agent and non-contrast MRI methods. We have previously shown that the BPH/2 mouse model of hypertension has an exaggerated contractile phenotype in the cerebral circulation, and we will determine if the perivascular flow shows similar traits to wild-type mice with a vasoconstrictor. Since vasomotion is driven by cerebral blood flow, it is influenced by both vascular smooth muscle cells and pericytes. To understand the role of pericytes in perivascular flows, pericyte-deficient mice (e.g. Atp13a5) will be studied at basal cerebral blood flow, but also in the presence of vasoconstrictors, dilators, and pharmacologically-induced vasomotion. Following in-vivo studies, mouse brain tissue will be taken and studied via histological techniques including AQP4 staining. Subgroups of mice will be injected with fixable tracers to further study rates of perivascular influx.   

Outputs from this project will reveal the mechanisms that reduce perivascular flow in hypertension, enabling future studies undertake studies that aim to restore perivascular flows in hypertensive mice, and determine the impact on brain health. 

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Supervisors: James Eales, Harry Pritchard, Francesa Chappell (Edinburgh), Joanna Wardlaw (Edinburgh)

Vascular dementia (VaD) is characterised by impaired cerebral blood flow (CBF), that over time leads to a mismatch between energy supply and demand, leading to a loss of neuronal function and the onset of clinical symptoms. Other than large events such as strokes, impaired blood flow to the brain can occur through various mechanisms such as reduced arteriole lumen size, micro-ischaemic events, haemorrhages or capillary stalling. Apart from age, hypertension is the strongest risk factor for VaD, and although recent research has uncovered mechanisms that impair CBF in hypertension models, the pathophysiological links between the two are not well defined.

This project will utilise the resources available in UK Biobank to compare the genetic associations between a panel of blood pressure related traits (SBP, DBP, PP and clinically coded hypertension) with those from cognitive function tests (i.e. fluid intelligence score, as a proxy for dementia) to determine all loci in the genome where the two colocalise. These loci will then be investigated for additional genetic associations with processed magnetic resonance imaging phenotype data, plasma proteomics and a panel of blood metabolites (including cholesterol subtypes and a panel of other blood lipids and lipoproteins). The loci will then be prioritised from most to least evidence of relevance to dementia progression.

In the second half of the project, putative targets of interest – in particular those linked to vessel diameter control – will be investigated using physiological approaches. The validation approach will be tailored according to its functional role, but will involve either pharmacological inactivation or over-activation and short-term knockdown studies in mouse cerebral arteries, the main outcome of interest will be impact on arterial diameter or its control mechanisms.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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