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Cerebral small vessel disease (SVD) is the breakdown of the small blood vessels of the brain, leading to many cases of stroke and dementia. The pathophysiology of SVD is largely unknown, although several mechanisms have been suggested. One such mechanism is the role of increased blood flow pulsatility into the brain, caused by vessel stiffening, leading to damage of the microvasculature. Magnetic resonance imaging (MRI) allows us to non-invasively measure blood flow and velocity using a technique called phase contrast-MRI - traditionally used with 2D slices across the vessel(s) of interest. An advanced form of phase-contrast MRI, known as 4D flow, has emerged in recent years that allows for a volume of data to be acquired, containing velocity information in all directions. However, to keep scan times practical when collecting this amount of data, spatiotemporal resolution has to be sacrificed. The main aim of this thesis was to assess 4D flow's capabilities, including comparing it to the more well-established 2D method in healthy volunteers, patients, and phantom experiments, so as to better understand its role in investigating SVD. Another aim was to learn more about the role of flow and pulsatility in SVD development in patients using data acquired in the longitudinal Mild Stroke Study 3 (MSS3). Firstly, I systematically reviewed studies that have assessed the human brain using 4D flow. Across 61 relevant studies, I found a general consensus for the current use of the technique in this context. I then optimised the Siemens prototype 4D flow sequence (N = 11 healthy volunteers), testing different parameters to find the combination that best balanced scan quality and duration. I then assessed the test-retest repeatability and intra-rater reliability of both 2D and 4D methods (N = 11 healthy volunteers), as well as differences between them. Following this, I performed the same 4D-2D comparison on SVD patients (N = 10). Absolute flow measurements using 4D flow were shown to have moderate repeatability and reliability, while flow pulsatility measurements showed acceptable repeatability and reliability. Furthermore, 2D arterial pulsatility was measured higher than with 4D, while 4D often measured higher flow rates than 2D. 4D flow was shown to be feasible when used on SVD patients, with no noticeable issues caused by potential patient movement. Flow data analysis from the longitudinal SVD study MSS3 showed that intracranial pulsatility is associated with cross-sectional SVD lesion volume but not longitudinal lesion growth, with stronger associations seen in the arteries of the neck compared to the venous sinuses.

Cardiovascular disease is the commonest complication of kidney disease. The risk of cardiovascular disease increases as estimated glomerular filtration rate (eGFR) declines and is highest in patients with advanced chronic kidney disease (CKD) on dialysis or with a kidney transplant - termed 'kidney failure'. Despite this, patients with kidney disease have been excluded from most cardiovascular trials over the last three decades. Given this systematic disenfranchisement of patients with kidney disease, our understanding of the diagnosis, incidence, treatment, and outcomes of cardiovascular disease in these patients is limited. My aim was to use large-scale, contemporaneous regional and national routinely-collected, linked Scottish healthcare data to illustrate, update, and address CKD-related disparities in the diagnosis, treatment, outcomes, and temporal trends of cardiovascular disease in patients with kidney disease. First, I performed a pre-specified secondary analysis of a stepped-wedge, cluster-randomised controlled trial to evaluate the implementation of a high-sensitivity cardiac troponin I assay on the diagnosis, management, and outcomes of patients with and without kidney impairment identified as having myocardial injury or infarction. In 46,927 consecutive patients presenting to hospital with suspected acute coronary syndrome, 19% had kidney impairment. As kidney function declined, the frequency of elevated cardiac troponin concentrations increased six-fold, but the proportion diagnosed with type 1 myocardial infarction halved. Implementation of high-sensitivity cardiac troponin testing increased the diagnosis of type 1 myocardial infarction in both patients with and without kidney impairment. Following implementation, rates of coronary angiography, revascularisation and the prescription of evidencebased treatments increased in patients with normal kidney function, but not in patients with kidney impairment. Despite the identification of more patients at risk, rates of myocardial infarction or cardiovascular death at one year were unchanged in patients with kidney impairment following implementation of high-sensitivity cardiac troponin testing. Second, I performed a retrospective, national data-linkage study to assess temporal trends in the incidence, treatment and outcomes myocardial infarction and stroke in patients with kidney failure in Scotland over the past 20 years. Amongst 16,072 patients with kidney failure, there were 1,992 and 996 incident episodes of myocardial infarction and stroke between 1996 and 2016. During this period, the incidence of myocardial infarction and stroke decreased by ~1.5-fold in patients with kidney failure. When compared with the general population, patients with kidney failure had a ~5 times higher overall incidence of myocardial infarction and a ~3 times higher overall incidence of stroke. Since 2009, there has also been a ~3-fold increase in the prescription of antiplatelet therapy following incident stroke and a ~1.5-fold increase in the prescription of dual antiplatelet therapy following incident myocardial infarction. Finally, although 1-year cardiovascular case fatality has improved substantially following myocardial infarction and stroke in patients with kidney failure over the past 20 years in both sexes and across all kidney replacement therapy modalities, overall outcomes for these patients remain poor. Third, I performed a nationwide data-linkage study comparing the clinical characteristics, microbiology, and long-term outcomes of infective endocarditis in patients with and without kidney failure in Scotland over the past three decades. One-fifth of patients with kidney failure died within 30 days of their incident infective endocarditis hospitalisation, half died within one year, and two-thirds within three years. Compared to those without kidney failure, patients with kidney failure were twice as likely to die within one year of hospitalisation and more than three times as likely to die within three years. Fourth, I investigated how infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) modified existing short- and medium-term cardiovascular risk in ~37,000 patients with and without CKD. In patients with CKD, those with COVID-19 had a higher risk of cardiovascular and all-cause death than those without COVID-19 throughout follow-up, but especially within 30 days of SARS-CoV-2 testing. During this early period, patients with CKD and COVID-19 had a more than two-fold increased risk of cardiovascular death - and a more than four-fold increased risk of all-cause death - than patients with CKD who tested negative. Compared to patients without CKD, those with CKD were also more likely to test positive. Following a positive test, patients with CKD had higher rates of cardiovascular complications - including hospitalisations and cardiovascular death - than those without CKD. Moreover, the risks of cardiovascular, COVID-19-related, and all-cause death increased as kidney function declined. My findings highlight the power and potential of contemporaneous routinelycollected, linked healthcare data to define and address established CKDrelated disparities in cardiovascular disease and outcomes. Moreover, my results will provide an evidence base for public health policy and inform planning of healthcare resource allocation for all patients with kidney disease. My future work will focus on using high-fidelity routinely-collected data to improve the cardiovascular risk stratification of patients with kidney failure listed for kidney transplantation and to comprehensively define how age, sex, and socioeconomic status interact to influence the development, treatment, progression, and outcomes of cardiovascular and kidney disease.

Introduction: This work investigates the hypothesis that combined biomechanical and radiomic features (mechano-radiomics) from magnetic resonance (MR) images can help evaluate carotid plaque vulnerability better than conventional MR methods. Hemodynamic forces have long been associated with the destabilization of developed plaques near regions of complex blood flow e.g., the carotid bifurcation, which results in high wall shear stress. High structural stresses within the artery wall caused by the blood flow are directly associated with risk of plaque rupture. Radiomics is an emerging technique to evaluate tissue heterogeneity. Whilst extensively investigated in oncology, there is limited application of these techniques in MR carotid plaque characterisation. Radiomic features may provide better phenotyping of carotid plaques. Mechanics and radiomic analysis were compared against stenosis measurements and morphological plaque characteristics such as the volume of lipid core, intra-plaque haemorrhage (IPH) and calcification. Methods: Two-dimensional, multi-contrast carotid MR images of 110 patients from the CARE-II multi-centre carotid imaging trial (ClinicalTrials.gov Identifier: NCT02017756) were used to perform the analysis - 55 for the radiomics analysis, and 87 for the 3D modelling of the carotids. Standard radiomic analysis was used to compute over 100 radiomic features derived from each of the multi-slice 2D image stacks. The 2D images were pre-segmented into five plaque components and incorporated into the 3D models. Finite element analysis (FEA) was performed to quantify the wall structural and shear stresses under patient-specific physiological conditions. Radiomic feature analysis was related to patient outcome (culprit or non-culprit lesion) using logistic regression, and the radiomic predictive power was combined with MR-identified plaque components and stenosis measurements to assess the improvement over conventional MR methods. The vessel wall structural and shear stresses were compared between culprit and non-culprit carotid arteries. The robustness of the long-held opinion that culprit carotid arteries (cause of plaque rupture and subsequent TIA or stroke) are associated with higher wall stresses was investigated over a range of material properties. Results: Combining radiomics biomarkers with a conventional model comprised of geometric and plaque compositional metrics had higher predictive performance over the conventional model alone (area under the curve (AUC) of 0.819±0.002 and 0.689±0.019 respectively, p=0.014). Features within the Grey Level Co-occurrence Matrix (GLCM), Grey Level Dependence Matrix (GLDM) and Grey Level Size Zone Matrix (GLSZM) sub-types were found to be particularly useful in identifying textures which could identify vulnerable carotid plaques. In the mechanics analysis, the patient cohort was stratified against the degree of stenosis. In the group with mild to moderate stenosis (< 70%), the maximum stress-P1 was consistently higher at critical locations relating to plaque rupture. Locations at the fibrous cap, plaque shoulder and the bifurcation region were considered to evaluate the critical stress. The hypothesis of higher stress on the culprit side was proved to be robust to different material parameters. Evaluations of wall shear stress and wall curvature in three dimensions were also predictors of the culprit side. Discussion and Conclusions: The results of show that MR radiomics improves upon conventional MR methods for distinguishing culprit and non-culprit plaques. Mechanics adds value by providing a dynamic analysis which combines the 3D artery geometry with patient-specific blood pressures. Recommendations are made for which multi-slice radiomic features should be used in terms of robustness to variations in carotid segmentations and their predictive ability. Radiomic analysis helps identify texture features of vulnerable plaque phenotypes, such as lipid-rich necrotic core or calcification distribution, while biomechanical analysis proved that over different material properties, the stress was found to be higher on culprit sides at critical locations which included the carotid bifurcation and multiple atherosclerotic plaques. A mechano-radiomic model for assessing the vulnerability of carotid plaque is then proposed to obtain the maximum benefit from both a mechanics and radiomic analysis.

Stroke associated pneumonia (SAP) occurs in 8%-14% of people admitted with a stroke. Prevalence of SAP varies considerably across the world, with various frequencies reported among registries and observational studies; however, there is no evidence explaining how SAP varies across stroke units nor what the potential reasons for this variation are. There is also no evidence suggesting how SAP variation affects clinical outcomes. This thesis aims to fill these gaps in knowledge by focusing on 4 different aspects: - to describe the variation of SAP across England and Wales and determine how much of the variation can be accounted by clinical characteristics; - to describe the relationship between SAP and specific stroke care processes in the pre-hospital, hyperacute and acute phases; - to explore the different characteristics used by clinicians to initiate antibiotics in SAP; - to explore the relationship between SAP and clinical outcomes. The first study of this thesis was a registry based cohort study that analysed SAP variation across stroke units in England and Wales, using individual patient level registry data. Median SAP prevalence was 8.5% (IQR 6.1-11.5%). SAP probability was calculated for each stroke unit, as well as variance. The mean and variance of predicted SAP probability decreased from 0.08 (0.68) to 0.05 (0.63). This suggests that patient characteristics account for 5% of the observed variation of SAP across stroke units in England and Wales. The second study of the thesis was also a registry based cohort study that analysed the relationship between timings of certain stroke care processes and the development of SAP across stroke units in England and Wales. Increased times to arrival at a stroke unit, increased time to assessment by a specialist doctor and increased time to assessment by a physiotherapist were associated with increased odds of SAP. Shorter times to thrombolysis were associated with lower odds of SAP. The third study of the thesis was a cross-sectional survey of UK stroke clinicians exploring the different characteristics and thresholds clinicians use to diagnose and initiate antibiotics for suspected SAP. It was an online survey conducted from December 2019 to February 2020. I found that clinicians use known factors such as inflammatory criteria for diagnosis and antibiotic initiation. I also found that the thresholds for each of these factors varied between clinicians, suggesting a lack of standardisation of SAP diagnosis and antibiotic initiation. The final study of the thesis was a registry based cohort study analysing the relationship between SAP and clinical outcomes. I focused on patients whose length of stay in hospital was > 7 days. By focusing on this specific population, potential confounding due to stroke severity on clinical outcomes was mitigated. SAP was consistently associated with increased risk of longer length of stay in hospital with an incidence rate ratio of 1.27 (95% CI 1.25 to 1.30), worse functional outcome at discharge with an odds ratio of 2.9 (2.9 to 3.0) and increased risk of in-hospital mortality with a hazard ratio of 1.78 (1.74 to 1.82). The work presented in this thesis has demonstrated how SAP has important variation across stroke units in England and Wales, and that there are modifiable factors that could be contributing to this observed variation. It has also confirmed the adverse association between SAP and clinical outcomes in real-world stroke unit care. This thesis is the platform for future work to develop a new intervention or tool to reduce the burden of SAP in the UK.

Despite major advances in stroke research only a limited number of stroke patients can benefit from current treatments. Cerebral ischaemia result from sudden loss of blood supply to the brain, which causes brain dysfunction and death. Pre-existing inflammation is an important contributing factor in the no-reflow phenomenon, preventing the brain from restoring perfusion and worsen stroke outcomes. This thesis investigates the effect of systemic inflammation on cerebral blood flow (CBF) using Laser speckle contrast imaging (LSCI). We aim to explore potential mechanisms that may contribute to inflammation-induced impairments in brain reperfusion and tested a novel therapeutic intervention to improve CBF perfusion and ischemic outcomes. First, we sought to establish a suitable in vivo model to investigate the role of interleukin-1β (IL-1β) as a systemic inflammatory agent using LSCI. CBF was measured at 20 min and 4h after reperfusion in C57BL6 mice, given systemic (intraperitoneal) IL-1β or vehicle before 20 minute and 30 min MCAO. Systemic interleukin-1 caused a severe reduction in CBF followed by significant reperfusion defect and increased blood brain barrier (BBB) breakdown compared with vehicle as early as 4h after stroke in the 30 min but not the 20 min MCAO occlusion duration. Restriction in CBF was observed alongside hyper-coagulation of the platelet in the vasculature of mice receiving interleukin-1. In this thesis, we used a novel ADAMTS13 variant Ala1144Val 7 (hereafter referred to as constitutively active (ca) ADAMTS13) in order to evaluate it is effect as a potential treatment of ischemic stroke. ADAMTS13 function is to cleave von Willebrand factor (VWF) therefore preventing and dissolving microvascular platelet aggregation. We tested it is activity on transient MCAO with systemic inflammation and ischaemia/reperfusion injury at a delayed time point of 4h reperfusion. The primary measure of efficacy was the restoration of CBF to the MCA region which was evaluated using LSCI. We demonstrated a significant restoration of CBF and reduced lesion volume and BBB breakdown in animals treated with caADAMTS13 at 6 h reperfusion. Moreover, caADAMTS13 induced a significant dissolution of platelet aggregates and a reduction within the stroked hemisphere of MCAO mice. Our results support evidence that systemic inflammation contribute to the no-reflow phenomenon as well as excessive ischaemic damage. Furthermore, we identified the presence of platelets aggregates at acute time of 4 h following MCAO reperfusion, suggesting their contribution to the early CBF deficit. Our results also introduce a novel caADAMTS13 variant as a potential viable therapeutic option for the treatment of ischaemic stroke.

Objective: This study aimed to explore families' experiences of loss following acquired brain injury (ABI). The study also aimed to contribute to our understanding of grieving processes in the context of ABI and of the factors that promote coping and adjustment. Design and Methodology: The study utilised an interpretative phenomenological approach to explore the lived experiences of families affected by brain injury. Eleven family members and survivors of ABI from four family units took part in two or three semi-structured interviews. Data was analysed using a step-by-step interpretative phenomenological analysis (IPA) procedure developed specifically for group data. Results: Several themes emerged from the analysis which were clustered into three group experiential statements: "grief and loss through a relational lens"; "the family as a 'jigsaw puzzle'" and "new insights and opportunities". Conclusions: Due to the joint nature of the interviews, there was an opportunity to view loss through a systemic, relational lens, which is a unique contribution of this study. Losses were frequently experienced as shared between both survivors and family members. A lack of social recognition of the losses that families experience following brain injury was identified. Families reflected on what had contributed to adjustment following brain injury, including how the individual strengths of family members contribute to a cohesive and unified family system.

Cerebral small vessel disease (SVD) is highly prevalent in the general population, increases with advancing age, and is a common cause of stroke and dementia. SVD affects multiple clinical domains and manifests on neuroimaging primarily as white matter hyperintensities (WMH), subcortical infarcts, lacunes, perivascular spaces, and microbleeds. Apart from stroke and dementia, SVD was previously thought to be clinically 'silent' but it is becoming apparent from cross-sectional studies that SVD is accompanied by neuropsychiatric, cognitive, and gait symptoms that do not meet the current clinical lexicon for stroke or dementia. Identifying earlier clinical markers of brain damage is essential for identifying patients for SVD treatment trials. We aimed to track and characterise whether subtle nonfocal symptoms are longitudinally associated with SVD lesion progression on brain MRI. We conducted a literature review of all SVD clinical features and a systematic review and meta-analysis of SVD-associated neuropsychiatric and cognitive features. We recruited patients with recent non-disabling ischaemic stroke, performed diagnostic MRI, and questioned participants and informants about neuropsychiatric, cognitive and gait symptoms. We repeated MRI and subjective symptom assessments at 3-6 monthly intervals for 12 months, longitudinally assessing WMH volume change and incident infarcts. We also analysed combined functional and cognitive associations with SVD progression in a separate stroke population. Finally, we assessed neuropsychiatric symptom-lesion associations in cognitively impaired and older adult populations. In our systematic review and meta-analysis, we found small but important associations between SVD severity and apathy, fatigue, and delirium, but not with subjective memory complaints, while anxiety and other neuropsychiatric symptoms were inconclusive. In 203 patients followed up for one year after a stroke (55% lacunar/45% cortical), we found that incident infarcts occur in 20% of patients, are mostly subcortical, co-associate with depression and brain fog, and there were trends towards associations with fatigue, falls, unsteadiness, episodes of confusion, and informant-reported cognitive and functional decline. We identified that that worse baseline WMH are associated with falls, apathy and brain fog, worse six-month WMH with falls and unsteadiness, and worse 12-month WMH with a trend towards falls. We found that longitudinal WMH progression is associated with falls and brain fog, with trends towards associations with worsening informant-reported neuropsychiatric symptoms and subjective memory complaints. In 264 separate stroke patients, we identified that one-year, but not baseline, WMH volumes associate strongly with contemporaneous cognitive scores, and co-varying longitudinal worsening of cognition and function post-stroke is associated with increasing WMH volumes. We found that worsening neuropsychiatric symptoms are associated with WMH progression in a cognitively impaired population. We established that in an older population, apathy independently associates with longitudinal WMH progression, while depression, anxiety, and subjective memory complaints do not. Overall, these findings highlight the existence of a potential clinical syndrome for identifying future SVD progression in high-risk patients. SVD progression is dynamic and can progress rapidly. These results support a need to clarify the prevalence of the SVD syndrome in the general population and to develop clinical prediction models to guide whether treatments could be trialled in individuals who are at high risk for SVD progression.

Aphasia is a prevalent and debilitating consequence of stroke that often persists chronically. The overarching purpose of this thesis was to better understand the neural compensatory mechanisms that take place to minimise language dysfunction, and promote language recovery, in post-stroke aphasia. This thesis proposes that existing theories of aphasia recovery can be conceptualised as specific examples of two more fundamental principles, degeneracy and variable neurodisplacement (Chapter 2). 'Degeneracy' predicts that upregulated compensatory regions should not be engaged during language in health, while 'variable neurodisplacement' predicts that such regions might be downregulated during health to save resources but upregulated when task difficulty is increased in controls. The thesis then investigates the neural regions that are functionally involved in language recovery post-stroke. Chapter 3 reports an Activation Likelihood Estimation meta-analysis of coordinate-based language functional neuroimaging studies. The language network is bilateral in aphasia and controls. Regions of the right anterior insula and inferior frontal gyrus were more likely to be activated during language in aphasia than controls, overlap with the Multiple Demand network and were more likely to be activated during higher than lower demand language tasks, consistent with enhanced utilisation of spare capacity within right hemisphere executive regions via variable neurodisplacement. Unexpectedly, Chapter 3 found that multiple undamaged midline and right hemisphere regions were less likely to be activated during language in aphasia than controls, consistent with functional diaschisis. Chapter 4 reports one of the first language multivariate pattern analysis functional imaging experiments in post-stroke aphasia and controls. Chapter 4 suggests the existence of a novel form of 'information diaschisis' in which having a stroke is associated with lower language information processing in a bilateral set of undamaged, predominantly domain-general regions which in turn is associated with, and might contribute to, language impairment post-stroke. Chapter 5 analysed longitudinal functional imaging and neuropsychological data from participants with aphasia poststroke. Language profiles were multidimensional at 2 weeks post-stroke and could be represented by three orthogonal components representing fluency, semantic/executive function and phonology. Different language components had uncorrelated recovery trajectories that were associated with changing activation in different neural regions during aphasia recovery. This provides insights into the multidimensional nature of aphasia recovery and suggests that future clinical rehabilitation trials should take a 'personalised medicine' approach that accounts for each patient's specific language profile when deciding targets for non-invasive brain stimulation.

Implementation and uptake of novel and cost-effective medicines can improve patient health outcomes and healthcare efficiency. However, the relative uptake of new medicines recommended by the National Institute for Health and Care Excellence often lags behind other comparative countries' health systems. One example is the uptake of direct oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation, which was slow and had a high level of unexplained variation across different health economies in England. This research aimed to explore barriers and enablers to the uptake of DOACs from the perspectives of patients, healthcare professionals, and key stakeholders by conducting systematic and narrative reviews and semi-structured interviews. Data collected from 21 patients, 23 healthcare professionals, and 23 key stakeholders recruited from three different health economies was analysed using the Framework method. The findings identified a range of intersecting factors acting as barriers and/or enablers to the uptake DOACs. While there were a wide range of experiences and views, an agreement between patients and healthcare professionals/key stakeholders on several identified factors was observed. Attributes of the innovation, characteristics of patients and prescribers, local health economy readiness for change, implementation process, and external health system context were suggested as influences. Mapping of the findings to the Diffusion of Innovations in Service Organisations model identified 11 components for a future toolkit development to facilitate uptake of nationally recommended new medicines. This thesis highlighted the role of patients, consideration of all costs associated with new medicines, and compatibility with the health economy's care model impact on the uptake.

Background: Psychological distress such as depression is common following ABI and is often more debilitating than changes experienced in thinking and physical abilities. Distress can impact negatively on long-term outcomes including social and occupational functioning, quality of life and adjustment to the injury and its consequences. It is suggested that interventions focusing on an individual's values (what is truly important to them) can improve mood and adjustment, and lead to increased meaningful behaviours despite their injury. However, depression can reduce motivation for engaging in valued activities. In individuals without an ABI, imagery has been shown to increase engagement and motivation for planned activities. The current study therefore explored the use of a values-based intervention for individuals with an ABI and symptoms of depression. Mental imagery was optional and added to the intervention for instances where participants experienced reduced motivation to engage in the values-based activities discussed during therapy sessions. Method: The study aimed to recruit six individuals with an ABI who were undergoing inpatient neurorehabilitation at one of two London hospitals. All participants were over the age of 18 and experiencing symptoms of depression, and were not of high risk (i.e., they did not present with suicidal intent or substance misuse). Participants took part in a values-based intervention, which aimed to increase their engagement in activities that were personally meaningful to them. Measures of psychological distress and values-based behaviour were completed as close to daily as possible during the baseline period of two, three or four weeks, the intervention stage (consisting of five to seven sessions) and the two-week follow-up. Throughout the study participants were also assessed using standardised questionnaires of mood, quality of life, adjustment, future thinking, and behaviour. Data was analysed by comparing participant's scores on each measure to their scores at earlier time points. Results: Four individuals completed the intervention, with three completing follow-ups. The following was found: o All individuals demonstrated an increase in values-consistent behaviour when tracking specific values that were identified in early sessions (i.e., they engaged with more things that mattered to them). o Most participants reported engaging in additional values-based behaviours in addition to those discussed with the therapist. o Three out of four participants improved on at least one questionnaire postintervention, with the most improvement made in depression. However, findings were not always maintained at follow-up and were inconsistent across measures (e.g., participants often demonstrated a reduction in depression on standardised questionnaires but not on daily ratings of low mood). o The intervention was feasible and deemed acceptable by all participants. Conclusions: This was the first study to explore the use of a values-based intervention for neurorehabilitation inpatients with an ABI and symptoms of depression. The flexible nature of the research therapy meant that participants physical and thinking abilities could be considered when establishing value-based activities within sessions, encouraging them to engage in meaningful behaviours despite their injury. Most participants reported increased values-consistent behaviours and reduced symptoms of depression over the course of therapy. However, results were inconsistent across participants and measures. Additionally, study limitations including not reaching the desired number of participants, the sole use of self-report and the uncontrollability of the rehabilitation environment during COVID-19, are likely to have impacted on findings.

Spatial neglect is a syndrome that is most frequently associated with damage to the right hemisphere, although damage to the left hemisphere can also result in signs of spatial neglect. It is characterised by absent or deficient awareness of the contralesional side of space. The screening and diagnosis of spatial neglect lacks a universal gold standard, but is usually achieved by using various modes of assessment. Spatial neglect is also difficult to treat, although prism adaptation training (PAT) has in the past showed some promise. Study one aimed to first identify the spatial neglect assessments used the most by clinicians as a first step to reaching a universal consensus. This online survey attracted 454 responses from clinicians in 33 countries. In identifying and quantifying the selection of spatial neglect assessments (and reasons for their use), the survey found tentative signs of emerging consensus - in line with previous research. This survey also found that professionals worldwide express a desire for harmonisation, citing the varied range of assessments available to them. Study two was designed to ascertain whether PAT could enhance engagement in occupational therapy for stroke - an established intervention for stroke survivors. This study video-recorded patients (n=43) and therapists taking part in a visual search activity. These videos were later rated by an expert occupational therapist, finding that PAT did not significantly enhance engagement in occupational therapy by our operationalisation. This work highlights the need for a universal definition of engagement in therapy, and the potential need for interventions to enhance engagement and, by extension, outcomes after discharge. Study three aimed to uncover whether PAT has any efficacy (i.e. in the short term) in treating spatial neglect, specifically on cognitive and open-loop pointing outcomes. This aim was formulated following previous reviews of PAT effectiveness which were inconclusive (at best). This systematic-review and meta-analysis of eight eligible studies (N=216) found no evidence to suggest that PAT is efficacious in resolving the signs of spatial neglect within one month post-intervention. The use of PAT to treat spatial neglect lacks a clear evidence base, and more work is required to identify its mechanism(s) of action and how well it can resolve signs of spatial neglect. These studies highlight that the care of stroke and brain injury survivors with spatial neglect could be better-informed; the current literature provides a varied account of the assessment of, and interventions for, spatial neglect. There are promising signs of an appetite for harmonisation of assessment. For PAT, this thesis highlights that further work may be required to fully appreciate the limits of its usefulness in the clinical setting.

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, contributing to multiple neurological disorders ranging from stroke, to mild cognitive impairment and dementia. However, despite a huge number of studies on the subject, we have a limited understanding of how SVD affects cognitive ability. This thesis aims to address this knowledge gap, by examining domain-specific cognitive abilities in a range of clinical and non-clinical presentations of SVD. In the introductory chapters of this thesis I will discuss what is meant by the term cerebral small vessel disease (SVD), describing key radiological features of SVD and its varied clinical and non-clinical presentations. However, before considering the current consensus on how SVD impacts different domains of cognitive ability, I will first consider what happens to these abilities in the context healthy cognitive ageing. Finally, I will consider the current consensus on the pattern of cognitive changes that occur in SVD and will examine the vast and often conflicting evidence that underpins this. To gain a comprehensive overview of the published literature examining cognitive abilities in SVD, Chapter 4 presents a systematic review and meta-analysis of 69 studies presenting cognitive data for at least one cohort with SVD (n=3679) and one comparison control group without SVD (n=3229). Results indicated that relative to controls, cohorts with SVD performed more poorly on cognitive tests in all of the cognitive domains examined. Meta-regression analyses suggested that fewer years of education in the SVD vs. control groups accounted for a proportion of the differences in their test scores in some cognitive domains. Further meta-regression analyses suggested that cohorts with SVD-related cognitive impairment or dementia performed more poorly on tests in certain cognitive domains than cohorts with stroke or non-clinical presentations of SVD. Overall, however, SVD cohorts performed more poorly than controls on cognitive tests in all domains, regardless of their SVD presentation. Chapters 5 and 6 focus more closely on the key radiological markers of SVD and their associations with cognitive test scores using data from the Lothian Birth Cohort 1936 (LBC1936): a cohort of relatively healthy, community-dwelling, older individuals. To increase the fidelity with which SVD is typically measured, I combined computational volumes and visually-rated MRI markers of SVD to construct a variable representing the total MRI-visible burden of SVD. The study in Chapter 5 presents the results of cross-sectional associations between this latent SVD variable and latent variables of processing speed, verbal memory and visuospatial ability, within a structural equation modelling framework (SEM; n=540; mean age 72.6±0.7 years). Age, sex, vascular risk, depression status, and age-11 IQ were included as covariates. The latent SVD variable was negatively associated with all cognitive factors, in line with the results of the systematic review and meta-analysis. However, after accounting for the shared variance between the different cognitive domains (a construct described as general cognitive ability, which previous studies have not accounted for), only the association between the latent SVD variable and processing speed remained significant. This suggests that SVD's association with slowed processing speed is not driven by, but is independent of its association with poorer general cognitive ability. In Chapter 6 this work is developed further by exploring associations between the latent SVD variable and decline in the same latent cognitive factors over a period of 9 years, from the age of around 73 to 82, again in the LBC1936. This was carried out using latent growth curve modelling within a SEM framework. Age, sex, vascular risk, and age-11 IQ were included as covariates. Results indicated that the latent SVD variable was associated with greater decline in general cognitive ability and processing speed. However, after accounting for the covariance between tests of processing speed and general cognitive ability, only the association between greater SVD burden and decline in general cognitive ability remained significant. Whereas the results of Chapter 5 suggested that SVD burden at age 73 may have specific and independent effects on processing speed measured at the same age, the results of our longitudinal analyses suggest that SVD burden at age 73 associates with declining processing speed due to SVD's overarching association with general cognitive decline. In the final chapter of this thesis, I summarise the findings of these three studies, discuss their limitations, and make recommendations for future research.

Dysphagia can occur if damage is done to the muscles and soft tissues which carry out swallowing or any of the neuronal centres or pathways which control it. Neurogenic dysphagia occurs secondary to neurological pathology such as strokes or Parkinson's disease (PD). Functional imaging studies performed during swallowing have shown areas of the motor cortex and cerebellum display increased activity, although the cerebellum has not been extensively studied. These brain regions or 'swallowing centres' act to control the process of swallowing. Most of what is known about swallowing in health and disease pertains to cerebral cortical swallowing centres and post stroke dysphagia. Over the cerebral cortex, swallowing centres are known to be asymmetrically active with a 'dominant' or more active hemisphere and a 'non-dominant' or less active hemisphere. Hemispheric strokes are more likely to cause dysphagia if the patient's dominant swallowing hemisphere is affected. Recovery of dysphagia is associated with neuroplastic changes over the undamaged hemispheric swallowing centre. Failure to recover is associated with a lack of compensatory neuroplasticity. Studies have shown neuro-stimulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) and pharyngeal electrical stimulation (PES) can modulate neuronal activity within the brain and act to encourage plastic changes. Cerebellar rTMS is a new rTMS approach which could be as efficacious as traditional cortical targeted rTMS while being safer and easier to administer. More work needs to be done to refine neuro-stimulatory techniques such as cerebellar rTMS before investigating their effects in patients with neurogenic dysphagia. Addressing these needs, for refinement and more dysphagic patient studies, were the overarching aims of this thesis. The first study was a two-part cerebellar rTMS healthy participant (n = 15) 'virtual lesion' reversal study. Cortical virtual lesions were administered to the dominant pharyngeal motor area following which each participant had uni-hemispheric ipsi-lesional, contra-lesional cerebellar pharyngeal area rTMS or sham in a crossover manner. Measurements of pharyngeal motor evoked potential (PMEP) amplitudes and swallowing behaviour (measured using a behaviour timing task) were taken at baseline and at 15-minute intervals for 1 hour. Cerebellar rTMS fully reversed suppressed PMEP amplitudes and disrupted swallowing behaviour following the cortical virtual lesion. In the second study (n = 13), the PMEP and swallowing behavioural effects of uni-hemispheric were compared to bi-hemispheric cerebellar rTMS. This three-part study involved first comparing the abilities of these techniques to excite cerebral motor cortical pharyngeal areas before assessing their effects on a virtual lesion. Bi-hemispheric cerebellar rTMS was found to be significantly more effective than uni-hemispheric cerebellar rTMS in causing cortical excitation and reversing the disrupted PMEP and behavioural virtual lesion after-effects. The third study involved the exploration of the PMEP and swallowing behavioural effects of vermis cerebellar rTMS. In this two-part crossover study, healthy participants (n = 13) were first randomly allocated to either vermis cerebellar rTMS, uni-hemispheric cerebral rTMS or sham cerebellar rTMS. The PMEP amplitude effects of these interventions were then compared against each other. In the second part of the study the swallowing effects of vermis cerebellar RTMS were compared against sham. Surprisingly, cerebellar vermis rTMS was found to suppress cortical PMEP amplitudes and disrupt swallowing behaviour in a similar manner to the often-used cortical virtual lesion protocol. The fourth study comprises a protocol paper of an ongoing cerebellar rTMS in post stroke dysphagia (PSD) study. The study is designed as a two-part crossover study. The first part aims to investigate the cortical PMEP and swallowing effects of uni-hemispheric cerebellar rTMS. Swallowing is being assessed using videofluoroscopy (VFS) and the penetration aspiration scale (PAS). The second part is a dose response study involving high dose cerebellar rTMS (Administered twice daily for 5 days) being compared to low intensity (once daily for 3 days) and sham. The final study is a comparison of the effects of three different types of neurostimulation, 5 Hz (excitatory) cortical rTMS, 1 Hz (inhibitory) cortical rTMS and pharyngeal electrical stimulation (PES) in patients with Parkinson's disease (PD) and dysphagia (n = 12). Each intervention was compared against sham. PMEP amplitudes and VFS PAS measurements were recorded. Challenges with recruitment resulted in the study being underpowered. No significant differences from sham were seen for all three interventions. However, following post-hoc analysis wherein data from the two excitatory interventions (5 Hz rTMS and PES) were combined, a significant improvement in PAS scores for thin fluids (IDDSI 0) was observed. In my thesis I have illustrated how human cerebellar rTMS stimulation can reverse a virtual lesion; refined the technique of cerebellar rTMS thereby making it more effective and shown, for the first time, site specificity of neurological response with regards to vermis and hemispheric cerebellar rTMS. Furthermore, the patient studies I have designed and performed aim to provide translational data regarding the effectiveness of neurostimulation in patients with PSD and PD dysphagia. Despite sub-optimal recruitment, post-hoc analysis of combined excitatory data (5 Hz rTMS and PES) showed that neurostimulation can lead to swallowing improvements in patients with PD dysphagia. My findings are in keeping with my overarching aims and support the translation of promising neuro-stimulatory techniques from the bench to the ward.

Carotid atherosclerosis is a major risk factor for ischaemic stroke which is a leading cause of death worldwide. For stroke survivors, 1 in 4 will have another stroke within five years. Carotid CT angiography (CTA) is commonly performed following an ischaemic stroke or transient ischemic attack to help guide patient management in the secondary prevention of stroke. For example, carotid endarterectomy surgery plus medical therapy or medical therapy alone. The degree of carotid stenosis is the mainstay in making this decision and uses only one aspect of anatomical information that can be obtained from a carotid CTA scan. Radiomics, sometimes called 'texture analysis', is the extraction of quantitative data from medical images that may not be apparent to the naked eye and has already demonstrated clinical utility in oncology for applications ranging from lesion characterisation to tumour grading and prognostication. Machine learning refers to the process of learning from experience (in this case data), rather than following pre-programmed rules. This thesis presents the findings of a proof-of-principle study to assess the value of radiomics in identifying the 'vulnerable plaque' and the 'vulnerable patient' within the context of cerebrovascular events. To evaluate the potential of radiomic features as imaging biomarkers, their reproducibility and robustness to morphological perturbations were assessed, as well as their biological associations with both PET and immunohistochemistry data. The ability of radiomic features to classify different carotid artery types, namely, culprit, non-culprit and asymptomatic carotid arteries was assessed using several machine learning classifiers. This was subsequently compared with a deep learning approach, which has greater capacity for data mining than feature-based machine learning approaches. Overall, radiomics could extract further useful information from carotid CTA scans. Culprit versus non-culprit carotid arteries in symptomatic patients and asymptomatic carotid arteries from asymptomatic patients had different radiomic profiles that could be leveraged using machine learning for better classification performance than carotid calcification or carotid PET imaging alone. Reliable and robust CT-based carotid radiomic features were identified that were associated with the degree of inflammation underlying the carotid artery. If validated with future prospective studies, this has the potential to improve personalised patient care in stroke management and advance clinical decision-making.

White matter damage can occur in a variety of neurological diseases where it contributes significantly to impairment of brain function. Dysregulation of ion gradients across membranes is a common phenomenon across many diseases and can be damaging due to increased metabolic demand, oedema and activation of destructive enzyme cascades. Breakdown of ionic gradients can occur under many circumstances. For example, loss of energy supply to ion pumps causes disruption early in stroke progression. Activation of ion channels through voltage or ligand gating contributes greatly to complications such as intracellular calcium overload in many diseases. This thesis investigated the contribution of different mechanisms of ionic alterations to white matter damage in ischaemic stroke and multiple sclerosis as well as to establish potential treatment options. Particular attention was paid to consequences of glutamate receptor activity. Using the oxygen glucose deprivation model of ischaemia, in the mouse brain slice, it was found that ischaemia-induced potassium release is greater in cortical grey than in corpus callosum white matter. This distinction is dependent on release of vesicular glutamate, as demonstrated by abolition by calcium free media and glutamate receptor antagonists. Variation of ischaemia-induced acidification of grey and white matter was also investigated but no difference between the two tissues was found. A new acute model of demyelination was established, using direct application of cuprizone to the isolated mouse optic nerve, and protection afforded by glutamate receptor antagonists was determined. Antagonism of AMPA and NMDA receptors acted in synergy to provide greater protection than block of each alone. This effect may allow treatment at lower concentrations to limit adverse side effects. When applied separately, NMDA receptor antagonists provided more protection than AMPA receptor antagonists, suggesting this channel contributed more to the injury progression. The same combination of glutamate antagonists was then investigated in the OGD model of ischaemic stroke but provided no more protection than AMPA receptor antagonist alone.

Objectives: This research aimed to explore the prevalence of health anxiety in stroke survivors and its relative impact on quality of life. Design: A cross-sectional design was used including between group comparisons of high and low health anxious stroke survivors. Methods: One hundred and five stroke survivors took part in the study. Measures of interest were health anxiety, general anxiety, depression, disability and quality of life. Information on participant's demographics and medical histories were also assessed. Results: Thirty percent of the sample scored above the clinical cut off for health anxiety. Stroke survivors with high health anxiety were found to have significantly lower levels of quality of life and higher rates of depression. Regression analysis found health anxiety to be a significant predictor of quality of life in addition to levels of depression and disability. Conclusions: The prevalence of health anxiety in stroke survivors was significantly higher than the general population. Those with high health anxiety were found to have both poorer quality of life and higher levels of depression. Given the high prevalence and potential impact on quality of life clinicians may benefit from routinely screening for health anxiety in stroke survivors. Future research should explore the use of existing evidence based psychological interventions for health anxiety in this population.

Stroke remains a devastating health issue worldwide with limited treatment available. Interleukin-1 (IL-1) is a major cytokine implicated in the pathogenesis of stroke, and the blood-brain barrier (BBB) is a major target of IL-1-induced neuroinflammation. The extracellular matrix (ECM) plays a dynamic role in the brain and recent evidence has identified laminin (LM)-10 as a mediator of BBB repair. The aim of this thesis was to determine the role of LM-10 as a modulator of endothelial inflammation and angiogenesis, as well as the role of cerebrovasculature IL-1R1 signalling on laminin expression after stroke. First, I sought to establish a suitable in vitro model to investigate the role of LM-10 as a modulator of IL-1 beta-induced endothelial activation and the angiogenic response of cerebral endothelial cells. I determined a novel role of LM-10 as a modulator of IL-1 beta-induced intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in hCMEC/D3 cells and demonstrated that LM-10 increases endothelial proliferation and migration. I elucidated a novel relationship between IL-1 beta and Hippo signalling, and demonstrated altered Hippo signalling on LM-10. In order to investigate the role of cerebrovasculature IL-1R1 signalling on laminin expression after cerebral ischaemia, I induced conditional deletion of IL-1R1 in brain endothelial cells and performed experimental stroke by occlusion of the middle cerebral artery (MCA). I found that laminin alpha 4 (expressed in LM-8) is more dynamically regulated than laminin alpha 5 (expressed in LM-10) across several time points post-stroke and that laminin alpha 4 expression is regulated by endothelial IL-1R1 signalling. To assess the role of laminin alpha 5 after stroke in vivo, I generated a conditional deletion brain endothelial cell-specific laminin alpha 5 mouse strain and successfully confirmed laminin alpha 5 deletion. I induced experimental stroke by occlusion of the MCA but did not observe an effect of laminin alpha 5 on infarct volume, neurological outcome or cerebral blood flow recovery after stroke. Our results support evidence that the ECM plays a dynamic role in inflammatory conditions in the brain and I have identified a novel crosstalk between IL-1 beta and the Hippo pathway. Although I did not observe an effect of laminin alpha 5 in ischaemic stroke, I believe that further investigation of the isoform specific roles of laminins in cerebrovascular diseases will provide new insights in the role of the ECM during the pathophysiology of stroke that could lead to new therapeutic treatments.

Introduction: Over the past four decades, China has experienced increasing gap between the rich and poor, along with rapid economic development, and increased the numbers of heart disease and stroke. The population in Chins is ageing. It is unclear whether socioeconomic inequalities are associated with increased risk of heart disease and stroke in older people and their surviving in China. This PhD study aimed to investigate the associations of multiple measurements of socioeconomic status (SES) with incidence of heart disease and stroke in older Chinese people and all-cause mortality in those patients. Methods: Two prospective community-based cohort studies were conducted in Anhui province and in four other provinces in China. The Anhui cohort consisted of a random sample of 3,336 older adults, of whom 1,736 aged ≥65 years recruited from urban areas in 2001 and 1,600 aged ≥60 years from rural areas in 2003. In a standard questionnaire interview, they were recorded for sociodemographic, behaviours/lifestyles, social networks and supports, cardiovascular diseases and other related risk factors. SES was measured by urban-rural living, educational level, occupational class, satisfactory income, and any serious financial problems occurred in the past two years. Heart disease and stroke were documented based on self-reported doctor-diagnosis. The cohort members were followed up until 2011 to monitor vital status and causes of mortality, during which three waves of re-interviews were taken for survivors to further document incident heart disease and stroke. Following the same protocol as that in the last two surveys in the Anhui cohort study, the Four-province cohort study completed a baseline survey in 2008-2009 for 4,314 participants who were aged ≥60 years, who were randomly recruited from Guangdong, Shanghai, Heilongjiang, and Shanxi. The Four-province cohort study was followed up until 2012 to monitor the vital status and with re-interviewing survivors. The data of the Anhui cohort and the Four-province cohort studies were analysed in multivariate Cox regression models to examine the associations of SES with incidence and mortality of heart disease and stroke, respectively. Results: The data from the two cohort studies showed that low SES was generally associated with increased incidence of heart disease and stroke and all-cause mortality in older adults with these diseases, although the association varied with SES indicators. Pooled data demonstrated that while rural versus urban living was associated with reduced incidence of heart disease (multivariate adjusted hazard ratio 0.56, 95% CI 0.44-0.71), it increased mortality in participants with heart disease (3.57, 2.01-6.34). Rural living was associated with increased incidence of stroke (1.66, 1.08-2.57) and non-significantly all-cause mortality in participants with stroke (1.98, 0.70-5.59). While high occupational class was associated with increased incidence of stroke (1.56, 1.01-2.38), low level of education was significantly associated with mortality in participants with heart disease (1.59, 1.05-2.39). Low income or having financial problems was associated with increased incidence of heart disease (1.42, 1.00-2.00 in low family income) and all-cause mortality in people with heart disease (2.68, 1.08-6.65 in low personal income). Conclusions: In China older people with low SES had increased risks of heart disease (except for rural living) and stroke (except for occupational class). Impact of low SES on increased mortality in older people with heart disease and stroke appeared stronger. Strategies targeting different SES groups involving comprehensive approaches are needed to reduce incidence of heart disease and stroke and improve surviving in older people with heart disease and stroke.

This authoethnographic study draws together the experiences of the researcher and bereaved family members of patients who died in hospital following an acute stroke. It takes the form of a Sonata Framework that mirrors the author's narrative around the duration and onset of his mother's stroke, hospital care and ultimate discharge home to die. Although symptoms experienced by individuals with malignant and non-malignant disease are similar, evidence suggests the transition from acute to palliative care remains problematic for patients following an acute stroke, not least when seeking to identify when someone is nearing end of life. A qualitative interview study aimed to explore the personal experiences of family members whose relative had died following admission to an acute stroke ward. In order to do this, six adult relatives of patients who died in hospital following an acute stroke were interviewed using a semi-structured interview schedule. Data were inductively analysed to produce basic, organising and global themes, and presented in the form of thematic networks: The Family Experience and Dying & Death. Further findings were deductively derived through the lens of the Sonata Framework. Findings suggested shortfalls in the provision of palliative and end of life care following acute stroke, although areas of good practice were identified. Overall, participants were complimentary of the care provided to their family member although the transition from acute to palliative was variable. The quality of communication between patients, relatives and staff was patchy, with no evidence of engagement with the hospital palliative care team, nor any discussions instigated by staff relating to preferred place of death. This study provided evidence of some improvement in local palliative and end of life care provision when compared with previous research, although gaps in such provision still exist. Staff should receive palliative and end of life care training, including communication skills training to identify individuals who may be nearing the end of life and to instigate timely conversations with their family members. Further research relating to the provision of palliative and end of life care for individuals following an acute stroke is recommended.

Background: Stroke patients are at high risk of dementia. While cardiovascular comorbidities, such as hyperlipidaemia and atherosclerosis, have been linked to dementia in the general population, it is unclear whether the associations persist in stroke patients, who usually suffer more cardiovascular comorbidities. Statins have been recommended for secondary prevention in stroke patients, but it is unclear whether they have any cognitive effects separate from reducing risk of vascular events. Aim: To triangulate the potential roles of major blood lipids, atherosclerosis and statins in the development of dementia after stroke. Methods: First, I conducted a systematic review to identify the gaps in previous studies on the association of the three factors with post-stroke dementia. In response to the limitations of the previous studies, I conducted three cohort studies using the Clinical Practice Research Datalink (CPRD) for blood lipids, atherosclerosis and statin use, respectively. Given the limitations in the CPRD data, I further used UK Biobank to explore whether the CPRD results could be replicated using similar analytic strategies. Results: My systematic review suggested that hyperlipidaemia was not associated with post-stroke dementia, atherosclerosis was associated with increased risk of post-stroke dementia and post-stroke statin use may reduce the risk. Only one small-scale trial was available, and all other studies were observational with key methodological limitations. My CPRD study on major blood lipids showed that low-density lipoprotein (LDL) cholesterol was associated with increased risk of post-stroke dementia (adjusted hazard ratio [aHR] 1.29, 95% confidence interval [CI] 1.14-1.47, per one log-mmol/L increase), with a linear increasing trend in the risk across quintiles and different guideline targets of LDL cholesterol (all P-trend <0.001). Conversely, triglycerides were associated with decreased risk of dementia (aHR 0.79, 95% CI 0.70-0.90, per one log-mmol/L increase), with a linear decreasing trend in the risk across quintiles of triglycerides (P-trend <0.001). No significant association was found for high-density lipoprotein (HDL) cholesterol. My CPRD study on atherosclerosis suggested that stroke patients with prior atherosclerotic cardiovascular disease (ASCVD) were more likely to develop subsequent dementia (aHR 1.18, 95% CI 1.12-1.25). After full adjustment for potential baseline confounding, however, the risk of post-stroke dementia is attenuated (aHR 1.07, 95% CI 1.00-1.13), with no linear relationship between the age of ASCVD onset or duration of pre-stroke ASCVD and post-stroke dementia (all P-trend >0.05). My CPRD study on statin use found that statin initiation within the first three months after stroke was associated with lower risk of dementia (aHR 0.70, 95% CI 0.64-0.75). After accounting for non-persistence, the risk was further decreased (aHR 0.55, 95% CI 0.50-0.62). My UK Biobank study supported the CPRD findings. The observed associations tended to be stronger than from the CPRD, while mostly not statistically significant due to low incidence of post-stroke dementia in the younger volunteer population in UK Biobank. Conclusions: Blood lipids may affect the risk of post-stroke dementia in different ways, with higher risk associated with LDL cholesterol, lower risk associated with triglycerides, and no association with HDL cholesterol. Stroke patients with prior ASCVD were more likely to develop subsequent dementia but the direct impact of pre-stroke atherosclerosis on the occurrence of post-stroke dementia may not be substantial. Statins have the potential to reduce the risk of dementia over and above future vascular events. Further trials and more real-world studies are needed to confirm the potential benefits of statins, to determine the optimal target of LDL cholesterol and to clarify the roles of triglycerides in the prevention of dementia.

Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, accounting for 49% of 6.5 million annual stroke deaths worldwide, and over half of all disability adjusted life years lost to stroke. Current understanding of pathophysiology is incomplete, partly due to limitations of the existing pre-clinical models of spontaneous disease. Here we show that zebrafish larvae can be used to model spontaneous ICH and exhibit comparable pathological outcomes to human condition, therefore offering an alternative model for pre-clinical study for ICH. Zebrafish larvae are associated with several practical advantages including high fecundity, optical translucency and non-protected status prior to 5 days post fertilisation. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we can quantify pathological outcomes and neuroinflammation following ICH. Using these assessable outcomes we can quantify improvement after ICH with targeted drug treatment, to ameliorate primary injury and secondary neuroinflammatory responses. Due to the spontaneous nature of blood vessel rupture in this model we can investigate the relationship between clinically relevant risk factors and ICH in zebrafish. In this study we show that the zebrafish larvae represent a novel model for pre-clinical ICH investigation that is appropriate for use in medium throughput drug screening. The zebrafish larval model has potential to reduce the number of protected animals used in pre-clinical ICH investigation and to support the advancement of the stroke field with practical translatable outcomes to directly benefit patients in the clinic.

Post-Stroke Fatigue is a common and debilitating condition affecting stroke survivors’ quality of life, rehabilitation outcomes, mood and life expectancy. There is no widely accepted evidence-based method of assessment, measurement or management of fatigue. Improved knowledge of both stroke survivor and health care practitioner perspectives on post-stroke fatigue could inform care pathways. This thesis addresses four research questions 1) How is post-stroke fatigue perceived? 2) What are the psychometric properties of current fatigue measurement scales? 3) How do healthcare practitioners assess post-stroke fatigue? 4) How is post-stroke fatigue managed? These four questions were answered through five studies. Study 1. A systematic search and literature review of validity, reliability, and acceptability of fatigue specific scales. Study 2. Thematic analysis of archived posts on the Stroke Association hosted forum TalkStroke. Study 3. Thematic analysis of semi-structured interviews with 25 stroke survivors and supporters investigating the lived experience of post-stroke fatigue. Study 4. An online survey of 137 stroke rehabilitation therapists. Study 5. Framework analysis of 2 focus groups with healthcare practitioners exploring post-stroke fatigue care pathways. Study 1. Many outcome measures have been developed for fatigue in chronic conditions, however there is still no gold standard outcome measure for post-stroke fatigue when considering psychometric properties. Study 2. Six themes were generated, encapsulating forum users perception that fatigue is a legitimate symptom of stroke which can be coped with and conceptualised in a variety of ways. Study 3. The unpredictable and variable nature of fatigue is distressing and acts as a barrier to routine, roles and personal aspirations. Study 4. Therapists use a variety of assessment and management strategies in clinical practice, predominantly focused on self-management. Notable variation was found between respondents’ definitions and characterisations of post-stroke fatigue. Study 5. Approaches to assessment and management varied by profession and setting, often led by one perceived specialist within the clinical team. The resulting lack of standardised approach may affect continuity of care. Stroke survivors, their supporters and healthcare practitioners find understanding and explaining post-stroke fatigue challenging due to its variable and multi-faceted presentation. Perhaps as a result of its subjective nature, no measurement scales used in a stroke population have been found to have optimal psychometric properties. In the clinical setting, measurement tools are often used as an addition to extensive subjective assessment to enable the healthcare practitioner to assess the impact of fatigue. Management strategies vary dependent on profession and setting, leading to unstandardised care pathways and information provision.

This thesis comprises a systematic literature review investigating the effect of animal-assisted therapy for anxiety and pain in hospitalised children and a research paper comparing the effects of endovascular thrombectomy versus intravenous thrombolysis for acute ischemic stroke. Findings from the systematic review suggest that animal-assisted therapy significantly reduced the hospitalised children’s self-report anxiety although increased their heart-rate compared to controls. The original research paper found that those in the thrombectomy group were performed significantly better in terms of delayed memory compared to the thrombolysis group with a large effect size.

The aim of this thesis was to assess the feasibility of the outcome measures included in a pilot randomised controlled trial of mirror therapy in upper limb rehabilitation and to explore the acceptability of mirror therapy within three months of stroke onset. A systematic literature review investigated the contextual application and psychometric properties of the graded Wolf Motor Function Test, an upper limb assessment tool and indicated psychometric evaluation was essential. Assessment of the reliability (n=30) and responsiveness (n=40) of the graded Wolf Motor Function Test was completed, followed by assessment of the responsiveness of the Functional Independence Measure (n=40) and patient-reported outcome measures (n=39) included in the pilot trial. Finally, a focus group study was conducted to explore perceptions of mirror therapy by stroke survivors (n=3). The graded Wolf Motor Function Test was reliable and responsive, and findings indicated the use of video for scoring may not be required. The Functional Independence Measure and patient-reported outcome measures demonstrated adequate responsiveness. However, in light of the level of attrition found by six-month follow-up, continuing assessments at this time point was not recommended. Themes identified from the focus group indicated the importance of therapist actions to facilitate stroke survivors to self-manage their recovery within and beyond the hospital setting. This PhD thesis has contributed to the development of a main trial examining the effectiveness of mirror therapy, which is currently underway. Although considered important to stroke survivors, patient-reported outcome measures are not often reported in clinical trials and this is the first study to assess the responsiveness of those included, in the early stages of stroke. The focus group study provided a novel exploration of stroke survivors perceptions of mirror therapy treatment. This thesis contributes to the choice of outcome measure and treatment by occupational therapists in upper limb stroke rehabilitation.

Aphasia can arise due to stroke (post-stroke aphasia, PSA) or neurodegeneration (primary progressive aphasia, PPA). Two clinical and theoretical issues of relevance to PSA and PPA are addressed in this thesis. First, there have been few detailed direct comparisons across the full phenotypic ranges of PSA and PPA. Second, graded differences between aphasic subtypes and within-subtype heterogeneity suggest that phenotype differences observed across patients might reflect graded variations across multidimensional aphasic spectra rather than mutually exclusive diagnostic categories. Thus, the aim of this thesis was to compare directly the full ranges of PSA and PPA using a graded multidimensional framework to map out graded intragroup and intergroup differences. Chapter 2 uncovered graded variation in PSA and PPA along phonological, semantic, and fluency-related dimensions. Plotting all cases in the transdiagnostic shared multidimensional space revealed that 'fluent' PSA were often less fluent than 'non-fluent' PPA. Classification analysis showed that semantic dementia occupied a unique region of this multidimensional space due to the selectivity of the semantic deficit. Chapter 2 highlighted the importance of a shared test battery for this transdiagnostic approach. The Mini-Linguistic State Examination (MLSE) is a novel clinical assessment tool which is in development to address the lack of a standardised linguistic assessment tool valid for aphasia across aetiologies. Chapter 3 conducted the first formal validation of the MLSE and compared it to established aphasia tests, finding that the MLSE is highly sensitive to the presence of language impairments in PSA. Chapter 4 compared linguistic impairments across PSA and PPA on the MLSE, extending the multidimensional framework from Chapter 2 by extracting brain-behaviour relationships that underly variance in aphasia across aetiologies. Language impairments across PSA and PPA varied along three key dimensions: phonology, semantics and syntax, which were related to unique neural correlates in: left hemisphere superior and posterior temporal lobe, bilateral anterior temporal lobes, and left hemisphere subcortical regions and periventricular white matter, respectively. Chapter 5 extended the multidimensional framework to typical amnestic Alzheimer's disease (AD) and atypical visual variant AD. These groups varied gradedly along a spectrum of visual processing impairments; typical AD with mild visual impairments and mild visual variant AD overlapped in the middle of this spectrum. Overall, the transdiagnostic, multidimensional approach applied in this thesis highlights that considering patient variance along continuous dimensions instead of categorical systems has benefits for comparing directly the full phenotypic space of different disorders and relating principal behavioural dimensions to unique neural correlates of structural brain abnormalities.

Introduction: Cerebral small vessel disease (SVD) is responsible for a third of strokes and is the most common cause of vascular dementia. It is characterised by white matter lesions and more diffuse damage outside of the lesions. Despite its importance, the mechanisms causing white matter damage are incompletely understood. Both increased blood-brain barrier (BBB) permeability and inflammation have been suggested to play a role. We hypothesised that BBB permeability and microglia activation would be increased in SVD and explored the relationship between these processes and other imaging, cognitive and blood markers. Methods: A PET/MR system was used to acquire simultaneous dynamic contrast enhanced MRI with Patlak modelling to measure BBB leakage, and [C11]PK-11195 PET to assess microglia activation. We recruited 20 sporadic SVD patients, 20 monogenic SVD patients (CADASIL) and 20 healthy controls to this study. Results: BBB permeability in the white matter of the sporadic SVD group was significantly higher than control (p=0.001), with a significantly higher volume of focal hotspots (p=0.010). The focal hotspots of activated microglia also had a significantly higher mean in the white matter (p<0.001). The role of BBB permeability and PK binding in CADASIL was less clear, with no difference in permeability but a significantly higher mean of focal hotspot of activated microglia in the CADASIL white matter, compared to control (p=0.015). In the sporadic SVD and CADASIL groups, the number of voxels containing both significant permeability and microglia activation was significantly lower than expected (p < 0.001). Conclusion: Areas of focal increase in both BBB permeability and microglia activation occur in SVD and therefore may have a role in the pathophysiology of white matter damage. In this cross-sectional dataset, the two processes were spatially independent of one-another. However, we cannot exclude a temporal relationship, where one process may precede another, without follow-up data. Further research is needed to see if these markers predict white matter damage in longitudinal studies, and whether they can be altered therapeutically.

Platelet activation, thrombus growth and subsequent thromboembolism underpins the pathophysiology of ischaemic stroke. At sites of atherothrombotic plaque rupture, it is established that platelet surface receptor glycoprotein (GP) VI-dimer binds to exposed sub-endothelial collagen, initiating the signalling required to cause platelet activation. Then, separate platelet-fibrin interactions cause the thrombus to grow, culminating in distal tissue ischaemia; crucial in thrombotic diseases such as ischaemic stroke. The work in this thesis demonstrates that GPVI-dimer binds to fibrin also, causing platelet activation through a mechanism independent of collagen. In ischaemic stroke this is important as it not only implicates GPVI-dimer in the large-artery atherosclerotic stroke subtype, it suggests a key role in cardioembolic stroke, where fibrin, rather than collagen, is the key platelet ligand. We compared the platelet surface expression of GPVI-dimer in a control, pre-stroke atrial fibrillation (AF), and a stroke population admitted to hospital using flow cytometry. We also measured platelet activation by platelet P-selectin exposure in all the cohorts. The results demonstrate that both AF and stroke patients have more ‘active’ circulating platelets compared to the controls. Furthermore, both AF and stroke patients – irrespective of AF type or stroke aetiology, express more GPVI-dimer on their platelets compared to controls. In the stroke cohort, GPVI-dimer expression was significantly higher at day-90 post-stroke than at admission. The ability of GPVI to interact with the two main ligands that drive thrombosis, collagen and fibrin, cements its role as a key platelet receptor in human thromboembolic disease. These results intimate an important role for GPVI-dimer in driving thrombotic risk pre-stroke, as well as after having a stroke, suggesting that the direct inhibition of GPVI-dimer could be a promising future antithrombotic target.

Unhealthy diets and physical inactivity are important modifiable risk factors for premature mortality and major chronic diseases, such as cardiovascular disease (CVD) and type 2 diabetes (diabetes). However, few large-scale studies have examined the combined influence of overall diet quality and physical activity on longevity and the risk of clinically-diagnosed CVD and diabetes in adults recruited from the general population. Of popular opinion, is the notion that the health risks from poor diets can be compensated by physical activity; i.e. that one can “outrun a bad diet”. The food industry has often sought to sway public opinion towards the belief that dietary indulgences can be enjoyed as long as one engages in sufficient physical activity. However, it is unclear if the risk of premature mortality and cardiometabolic disease from unhealthy diets can be offset by physical activity, and vice versa. Therefore, the overall theme of this dissertation is to examine the epidemiological associations of diet quality and physical activity on the risk of mortality, CVD and diabetes. Specific objectives are to: 1) Study the independent associations of overall diet quality and physical activity on the primary outcomes of all-cause mortality, cardiovascular disease, and diabetes. 2) Examine the dose-response associations between physical activity and the risk of mortality and cardiovascular disease, including more of the evidence base by employing comprehensive exposure dose-harmonisation methods. 3) Examine the interactions between diet and physical activity on the health outcomes: a. If the risk of mortality and cardiometabolic disease from unhealthy diets can be offset by physical activity, and vice versa. (i.e. compensation) b. If diet and physical activity can work synergistically to further lower the risk of mortality and cardiometabolic disease, beyond the independent effect from each exposure alone (i.e. synergism) 4) Quantify the population health impacts of diet and physical activity, in terms of preventable events (deaths and disease cases) associated with both exposures, as well as the population attributable fractions (PAFs) of poor diet and inactivity contextualised with other major lifestyle risk factors. 5) Examine the long-term trajectories of physical activity (increases, decreases, and maintenance) on the risk of mortality. These investigations can bring further clarity to the public health messaging around diet and physical activity for improving longevity and the prevention of cardiovascular disease and diabetes.

In most cases, spontaneous intracerebral haemorrhage (ICH) is thought to result from cerebral small vessel diseases (SVDs). Cerebral amyloid angiopathy (CAA) and arteriolosclerosis (non-CAA SVD) are the two main types of SVD associated with ICH. The risk of recurrent ICH and post-stroke dementia may be higher with CAA-associated ICH compared with non-CAA SVD-associated ICH. It is, therefore, important to identify the type of SVD associated with ICH. Commonly, ICH in the cerebral lobes (lobar ICH) is thought to be associated with CAA, whereas non-lobar ICH is associated with non-CAA SVD. However, this generalisation is not accurate. The aims of my thesis were to (a) histopathologically assess the types and severity of SVDs associated with lobar and non-lobar ICH using brain autopsy tissue, (b) explore whether brain imaging (magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT)) biomarkers can be used in living patients to identify the type of SVDs associated with ICH and (c) determine whether CT biomarkers can predict outcome after ICH. Throughout my thesis, I use data from two overlapping studies of ICH. The Lothian Audit of the Treatment of Cerebral Haemorrhage (LATCH) is a prospective community-based audit of all residents in the Lothian Health board region of Scotland who were aged 16 years or above and had an incident ICH between 1st June 2010 and 31st May 2013 inclusive. During LATCH and until 31st May 2016, consecutive adults with SVD-associated ICH were able to consent to have apolipoprotein E genotyping, brain MRI and brain autopsy as part of the prospective Lothian INtraCerebral Haemorrhage Pathology, Imaging and Neurological outcome (LINCHPIN) study. In an autopsy study of 126 LINCHPIN participants with first-ever SVDassociated ICH, I found that 98% of participants with a non-lobar ICH had moderate or severe non-CAA SVD. In contrast, 60% of participants with a lobar ICH had moderate or severe CAA, while many had moderate or severe non-CAA SVD, either with or without CAA. The most common approach used in clinical practice to identify CAAassociated ICH is the MRI-based modified Boston criteria for CAA. However, I found that only about one-third of ICH patients during LATCH were able to undergo MRI. Also, in 16 LINCHPIN participants with research MRI, the modified Boston criteria showed limited accuracy against the histopathological assessment of CAA on subsequent research autopsy. Molecular imaging using tracers designed to detect parenchymal β-amyloid in Alzheimer’s disease, such as flutemetamol, may also identify the perivascular β-amyloid found in CAA. I found that in LINCHPIN brain tissue samples, the amyloid tracer flutemetamol labelled both parenchymal and perivascular β amyloid. Among 20 participants with first-ever ICH, flutemetamol PET scans were 86% sensitive and 77% specific for CAA-associated ICH based on the modified Boston criteria. Brain CT is the test that usually diagnoses ICH. I found in 62 LINCHPIN participants with first-ever lobar ICH that subarachnoid haemorrhage and finger-like projections on CT, and APOE ε4 allele possession were independently associated with CAA-associated lobar ICH defined on subsequent autopsy. I developed diagnostic models and criteria (“Edinburgh criteria”) based on these predictors that could accurately rule in or exclude CAA-associated lobar ICH. I performed a multicentre external validation study of the Edinburgh criteria. In a preliminary analysis, the CT-only diagnostic criteria (subarachnoid haemorrhage and finger-like projections) had high sensitivity (88%) and good specificity (84%) for CAA-associated lobar ICH. The risk of recurrent ICH is a key outcome for ICH survivors. I found that the risk of recurrent ICH was significantly higher in participants with first-ever lobar compared with non-lobar ICH. Among lobar ICH participants, the risk of recurrent ICH was significantly higher in those classified as high risk on the CT-only Edinburgh criteria for CAA-associated lobar ICH compared with those classified as low risk. Predicting death or disability is also important in ICH. I found that the severity of SVD on the diagnostic brain CT was an independent predictor of death or disability at one year after the ICH, after adjusting for known prognostic factors. Brain imaging biomarkers, particularly on brain CT, are potentially useful for identifying the type of SVD associated with ICH. Having developed the CTbased Edinburgh criteria for CAA-associated lobar ICH, I performed preliminary multicentre studies assessing their diagnostic accuracy and prognostic value. In the future, I aim to perform the full analyses of these diagnostic test accuracy and prognostic studies to determine the clinical utility of the Edinburgh criteria. Other research should assess the clinical and economic effect of the Edinburgh criteria on the prognosis of ICH. More work is needed to investigate the prognostic relevance of coexistence of CAA and non-CAA SVDs in lobar ICH, and whether these groups can be differentiated using imaging biomarkers.

Stroke is the leading cause of disability for adults and the second leading cause of death worldwide. It is characterised by a sudden weakness or numbness of the face, arm or leg, most often on one side of the body. The most common type of stroke is an ischaemic stroke, the blockage of a cerebral vessel and is causing dementia. Nuclear Factor Erythroid 2 (NFE2)- Related Factor 2 (Nrf2) is a transcription factor and master regulator of a battery of antioxidant and anti-inflammatory genes such as Heme oxygenase-1 (hmox1), NAD(P)H dehydrogenase quinone 1 (nqo1), glutamate-cystine antiporter (xCT; gene slc7a11), sulfiredoxin 1 (srxn1). As astrocytes play a central role in the neuroprotective effects of boosting Nrf2, the overarching hypothesis of the present work is that boosting the Nrf2 pathway in astrocytes will prevent oxidative stress and pro-inflammatory damage caused by ischaemia/reperfusion and thereby protect neurons from damage and diminish cognitive deficits and neurodegeneration that may lead to dementia. A mouse model of transient focal cerebral ischaemia was chosen to reproduce ischaemia in controlled conditions, by occluding the middle cerebral artery. Modest duration of ischaemia (15 minutes) was sufficient to cause ischaemic neuronal damage in the striatum and to significantly increase oxidative stress, inflammatory markers and to activate Nrf2-signalling. Furthermore, oxidative stress and inflammation were found despite reperfusion and in areas spared of neuronal death, suggesting they may still be at risk of cellular damage. Despite persistent elevations in oxidative stress, inflammatory glial cells and cytokines 4 weeks after ischaemia, there were no alterations to Nrf2-signalling suggesting that boosting Nrf2- signalling may confer protective effects. Nrf2 overexpression in GFAP-expressing astrocytes in a mouse model (GFAP-Nrf2 mice) has been shown to confer protection against inflammation and oxidative stress in neurodegenerative models. Following ischaemia, GFAP-Nrf2 mice presented a significant reduction of neuronal damage, oxidative stress was markedly reduced, and levels of reactive astrocytes were increased in the peri-infarct of the cortex. This was paralleled with a significant increase of cxcl10 and anti-inflammatory il-4rα cytokine gene expression. These promising results led to next study the potential protective effects of boosting Nrf2 in astrocytes on cognitive and neurological deficits 4 weeks after ischaemic stroke. In this experiment, ischaemia impaired cognitive functions at 4 weeks and this was paralleled with oxidative stress and inflammation. Neuronal damage caused by ischaemia was not significantly altered between wild-type and GFAP-Nrf2 animals despite upregulated Nrf2- signalling in GFAP-Nrf2 mice compared to wild-types. Nrf2 overexpression in astrocytes increased microglial response and reduced inflammatory c3, but their cognitive functions were further impaired compared to wild-types. Altogether these studies suggest that Nrf2 exerts different effects after ischaemia depending on the severity of stroke and the timepoint analysed. Furthermore, these results suggest that there is ongoing signalling between microglia and astrocytes. This work provides an original contribution to understanding the potential protective effects of Nrf2 overexpression in astrocytes and its limitations.

Stroke is a major global health burden with limited therapeutic options. Two major subtypes of stroke exist, ischaemic stroke (IS) and intracerebral haemorrhage (ICH). IS occurs following cerebrovascular occlusion, whereas ICH occurs when a vessel bursts and blood enters parenchymal brain tissue. The acute inflammatory response to both of these subtypes is thought to exacerbate neuronal injury and contribute to poor patient outcomes. The prototypical cytokine interleukin-1 (IL-1) sits at the apex of many inflammatory processes and a substantial amount of preclinical evidence strongly implicates IL-1 in IS pathogenesis. However, despite this, it is currently unclear whether IL-1 contributes to ICH pathophysiology. Thus, the primary aim of this doctoral thesis was to determine the contribution of IL-1 to ICH. Further, the canonical IL-1 family is composed of two distinct proteins, IL-1a and IL-1b, which require proteolytic processing to activate the IL-1 receptor. Therefore, the secondary aim of this doctoral thesis was to further our understanding of the active IL-1 proteolytic processing pathways in IS and ICH. Initial work carried out for this thesis refined the collagenase-induced mouse model of ICH to reduce animal usage and suffering. This refined model was subsequently used to uncover novel dichotomous actions of IL-1 in ICH. Using RNA sequencing, IL-1 was revealed as the major upstream regulator of cerebral inflammation that controlled harmful monocyte trafficking to the haemorrhaged brain. However, inhibition of IL-1 actually worsened neuromotor injury following ICH by preventing an IL-1-dependent increase in cerebral blood flow to the affected hemisphere. IL-1b was the predominant IL-1 molecule produced in ICH, but inhibition of the IL-1b processing enzyme, caspase-1, showed this pathway was not necessary for immune recruitment. Similarly, pharmacological and genetic targeting of the NLRP3 inflammasome, which sits upstream of caspase-1 activation, did not affect inflammation or lesion size in a clot-induced mouse model of IS. Overall this thesis exposes novel actions of IL-1 in ICH. Whilst IL-1 appears to be a major upstream regulator of harmful immune recruitment in both IS and ICH, it may also positively regulate cerebral blood flow in ICH. Therefore, future work should build upon the findings in this thesis and segregate the downstream molecular mechanisms governing IL-1s beneficial and harmful effects, in order to provide novel therapeutic targets for both stroke subtypes.

Background: An estimated 1.2 million stroke survivors living in the United Kingdom (UK), currently rely on family caregivers for daily support. The needs of stroke family caregivers are not routinely assessed by most stroke services. An early identification of their needs and support is crucial to maintain their well-being and caregiver role. At present, stroke-specific caregiver screening tools are lacking. Aim: To adapt the Carers’ Alert Thermometer (CAT), a short screening tool developed in the context of end-of-life care and develop the CAT-S for use with stroke family caregivers. Methods: This was a multi-phase study, underpinned by principles of action research. Between February 2016 to December 2017 qualitative and quantitative data were collected sequentially from purposive samples of stroke family caregivers (n=76) and staff working within stroke services (n=238) in the UK. Semi-structured interviews were conducted to inform the contents of the CAT-S. Key items for inclusion were identified through a modified Delphi survey and consultation with an expert panel. The CAT-S was then piloted in North West England to test its usability and usefulness in practice to identify the needs of family caregivers of stroke survivors. Thematic analysis and content analysis were used to analyse qualitative data. Quantitative data were analysed using descriptive statistics. Findings: The CAT-S comprises the key challenges that are experienced by stroke family caregivers. Additional items that were not present on the original CAT were identified and included. These were the training needs of family caregivers to provide care and support for their emotional needs. The CAT-S was found to be useful and acceptable by both staff and stroke family caregivers and resulted in action plans and support being provided. The CAT-S is a potentially valuable tool in prioritising family caregivers requiring comprehensive assessments.

Functional communication relies heavily on connected speech production, which depends mostly on word retrieval. A common consequence of brain damage or neurodegenerative disorders is acquired language impairments (i.e., aphasia), which affects a complex array of cognitive domains, including connected speech production and more specific features of language processing. However, the precise nature of some of these deficits remains unclear. Specifically, there is no converging evidence on how these deficits are affected at different levels of language production (i.e., single-word versus connected speech), or how word properties (i.e., noun/verb differences and psycholinguistic features) impact language processing. In this thesis, I addressed these issues through six empirical studies based on 48 chronic left hemisphere post-stroke aphasia patients. The patients' performance was compared directly to an age/education matched neuro-typical group, to validate novel tests and analysis protocols. Initially, a verb semantic battery was developed, which showed that the psycholinguistic features of the word, rather than word class per se, influenced single-word processing. This battery serves as a useful addition to existing clinical tests, and can inform sensitive assessments and intervention planning. Neuroimaging analyses showed that single-word processing is mainly supported by left anterior and posterior temporal regions, whereas additional left frontal regions are engaged by increased semantic complexity. Post-stroke aphasia was also explored in terms of a graded disorder along multiple fundamental dimensions. This approach showed that performance across noun-verb processing tests was not dichotomous but reflected graded differences in behavioural performance and within the cortex. Conversely, connected speech production was associated with additional cognitive demands and extra brain regions, which can be split into three components: verbal fluency supported by left frontal regions; verbal quality related to attention, self-monitoring, and executive control processes underpinned by left frontal and parietal regions; and speech rate, which relied on the left motor cortex and sensory auditory regions presumably for online feedback. Generally, seven fundamental components of aphasia were identified in a unified model: phonological production, semantic processing, phonological recognition, executive functions, as well as the three connected speech components. In a systematic fashion, a lack of direct map between the effect of psycholinguistic properties and these components was observed. The evidence further revealed weak/moderate correlations between word retrieval at single-word level and connected speech, suggesting that single-word tasks may not provide a sufficient reflection of connected speech output. In contrast, a strong correlation was observed between metrics from different connected speech tasks, and strong discourse genre effects were found on quantity and diversity metrics for neuro-typical adults and people with aphasia. Storytelling narrative outperformed the other discourse genres across many contrasts, albeit at a cost of time. Therefore, a novel index was proposed and validated that allows for a quick yet efficient measure of content word production during connected speech. Further evidence indicated that expressive deficits in aphasia mainly reflect quantitative (fewer words) rather than qualitative (complex words) degradation. Overall, the current thesis provides converging neuropsychological, psycholinguistic and neuroimaging insights into the nature of language deficits post-stroke, as well as evidence on the organisation of language functions, and proposes that language is modulated by independent but interactive components supported by a wide range of left brain regions.

Cerebral small vessel disease (SVD) is a cerebrovascular pathology that affects the small vessels of the brain, resulting in heterogeneous brain tissue changes. These can lead to neuropsychiatric symptoms such as apathy, a loss of motivation, and depression, which is characterised by low mood and a loss of pleasure. Apathy and depression are both prevalent symptoms in SVD, but an understanding of the relationship between underlying disease processes and the expression of these neuropsychiatric symptoms remains poor. This thesis uses magnetic resonance imaging techniques to examine the neurobiological basis of apathy and depression in SVD. We show that apathy is related to focal grey matter damage and distributed white matter microstructural change. These microstructural changes underlie large-scale white matter network disruption, which is related to apathy, but not depression. We then show that depression, as a construct, can be dissociated into distinct symptoms which are associated with overlapping and distinct areas of cortical atrophy over time. This suggests that depression as a general syndrome may be characterised by atrophy in core structures, while different symptoms are associated with atrophy in more specialised areas. Consistent with these patterns of overarching tissue damage, we find that apathy, but not depression, predicts conversion to dementia in patients with SVD. Our findings suggest that different types of SVD-related pathology lead to apathy and depression. Diffuse white matter damage may lead to widespread network disruption, resulting in apathy and cognitive impairment. In contrast, depressive symptoms are associated with focal patterns of grey matter atrophy over time. This highlights the importance of differentiating neuropsychiatric symptoms, and paves the way for targeted treatment approaches.

Non-invasive measures of central blood pressure through pulse wave analysis may be key to future management of cardiovascular disease risk in currently healthy and clinical populations. One device that can non-invasively estimate central blood pressure is the SphygmoCor XCEL. The validity of this device has been demonstrated compared to invasive measures, but the reliability has previously only been demonstrated in younger, non-clinical populations. In day-to-day life, blood pressure measures are taken in a variety of postures and fasting states depending on user preference, clinician preference, time of day and environment. The acute effects of posture and fasting state on these central measures have not been widely investigated. Therefore the purpose of the first and second studies in this thesis was to focus on a) reporting the between-day reliability of the SphygmoCor XCEL in an older, non-clinical sample (age >50y) and a hyper-acute stroke sample, and b) report the individual and combined effects of posture and fasting state on a variety of peripheral and central blood pressure measures in these populations. The SphygmoCor XCEL was demonstrated to have generally excellent between-day reliability (using an intra-class correlation coefficient > 0.75 as the criterion excellence value) in fasted and non-fasted, and seated and supine states in both populations. Posture had a significant effect on diastolic pressures in both populations (p < .05), whereas fasting state had a significant effect on the majority of peripheral and central systolic and diastolic pressures, as well as measures of arterial stiffness (Augmentation Index, Augmentation Index at a heart rate of 75 b·min-1; p < .05). These studies demonstrate that the SphygmoCor XCEL is a reliable tool for use in population demographics where its findings are particularly pertinent (those over the age of 50 or those suffering from stroke), and that posture and fasting state should both be taken into consideration when interpreting peripheral and central blood pressure measures. Increased levels of sedentary time and reduced physical activity are common after stroke, potentially due to the perception that sedentary time is a normal and an important way of relaxing after stroke. The third study in this thesis investigated the effects of sedentary time on peripheral and central blood pressure measures and measures of arterial stiffness, thereby investigating whether low level physical activity (intermittent heel raises) could prevent this damaging process. Three hours of sedentary time was sufficient to cause significant increases in peripheral and central blood pressure (p < .05). Intermittent heel raises significantly mitigated this damage but did not prevent it (increases of 10.7 mmHg peripheral systolic blood pressure and 9.6 mmHg central blood pressure in the three-hour sedentary condition compared with increases of 5.2 mmHg and 5.6 mmHg respectively in the three-hour heel raise condition). Due to the significant effects observed in study 3, a pilot ‘heel raise intervention’ trial was undertaken (the fourth study of this thesis). Participants completed a heel raise protocol on six days per week for ten weeks to determine whether the acute effects demonstrated in the third study could be replicated chronically. This study found no significant improvements in any body composition, central and peripheral haemodynamic, arterial stiffness or cognitive variables (p > .05). This thesis has demonstrated the reliability of the SphygmoCor XCEL in new populations and demonstrated the effect of posture and fasting state on peripheral and central measures. It has also reported that three hours of sedentary time is sufficient to cause significant increases in BP but this can be mitigated through lower limb physical activity. Although this lower limb physical activity causes acute improvements in blood pressure, this does not translate into chronic improvements over the course of a ten-week exercise programme, although these findings must be interpreted with caution due to the small sample size.

Stroke is one of the leading causes of disability with over three-quarters of patients experiencing an upper limb impairment varying in severity. Early, intense, and frequent physical rehabilitation is important for quicker recovery of the upper limbs and the prevention of further deterioration of their upper limb impairment. Rehabilitation begins almost immediately at the hospital. Once released from the hospital it is intended that patients continue their rehabilitation program at home supported by a community stroke team. However, there are two main barriers to rehabilitation continuing effectively at this stage. The first is limited contact with a physiotherapist or occupational therapist to guide and support an intensive rehabilitation programme. The second is that conventional rehabilitation is tough to maintain immediately after stroke due to fatigue, lack of concentration, depression and other effects. Stroke patients can find exercises monotonous and tiring, and a lack of motivation can result in patients failing to engage fully with their treatment. Lack of participation in prescribed rehabilitation exercises may affect recovery or cause deterioration of mobility. This thesis examines the hypothesis that upper limb stroke rehabilitation can be made more accessible and enjoyable through the use of modern commercial virtual reality (VR) hardware, with personalised models of user hand motion adapted to user capability over time, and VR games with tasks that utilise natural hand gestures as input controls to execute personalised physical rehabilitation exercises. To support the investigation of this hypothesis a novel adaptive, gamebased, virtual reality (VR) rehabilitation system has been designed and developed for self-managed rehabilitation. Hands are tracked using a Leap Motion Controller, with hand movements and gestures used as in input controller for VR tasks. A user-centred design methodology was adopted, and the final version of the system was evolved through several versions and iterative testing and feedback through trials with able-bodied testers, stroke survivor volunteers, and practising clinicians. A key finding of the research was that an adapted form of Fitts's law, that models difficulty of reaching and touching objects in 3D interaction spaces, could be used to profile movement capability for able-bodied people and stroke patients vii in upper arm VR stroke rehabilitation. It was also found that even when Fitts's law was less effective, that the statistics of the regression quality were still informative in profiling users. Fitts law regression statistics along with information on task performance (such as percentage of hits) could be used to adapt task difficulty or advising rest. Further, it was found that multiple regression could provide better movement capability profiles with a modified form of Fitts law to account for varying degrees of difficulty due to the angles of motion in 3D space. In addition, a novel approach was developed which profiled sectors of the 3D VR interaction space separately, rather than treat movement through the whole space as being equally difficult. This approach accounts for some stroke patients having more difficulty moving in some directions than others, e.g. up and left. Results demonstrate that this has potential but may need to be investigated further with stroke patients and with larger numbers of people. The VR system that utilised the movement capability model was evolved over time with a user-centred design methodology, with input from able-bodied people, stroke patients, and clinicians. A final longitudinal study investigated the suitability of three bespoke games, the usability of the system over a longer time, and the effectiveness of the movement profiler and adaptive system. Throughout this experiment, the system provided informative user movement profile variations that could identify unique movement behaviour traits in individuals. Results showed that user performance varied over time and the adaptive system proved effective in changing the difficulty of the tasks for individuals over multiple sessions. The VR rehabilitation games incorporated enhanced gameplay and feedback, and users expressed enjoyment with the interactive experience. Throughout all of the experiments, users enjoyed wearing a VR headset, preferring it over a standard PC monitor. Most users subjectively felt that they were more effective in completing tasks within VR, and results from experiments provided empirical evidence to support this view. Results within this thesis support the proposal that an appropriately designed, adaptive gamebased VR system can provide an accessible, personalised and enjoyable rehabilitation system that can motivate more regular rehabilitation participation and promote improved motor function.

There is a great need to improve the rehabilitation and assessment of arm and hand function of stroke survivors in the home due to cost, time and availability of healthcare professionals. Robotics and haptic technologies can be used to improve and facilitate rehabilitation and assessment in the home. The primary goal of this thesis was to explore the feasibility of using lightweight, low-cost haptic devices for remote home-based rehabilitation. The strategy that this thesis followed was to develop tools, perform unit testing, and finally assess feasibility with target users in a series of case studies. The thesis started by developing an assessment tool, specifically the Nine Hole Peg Test (NHPT), and investigated how haptic devices can be used to enhance the data collection for this task to garner more information regarding the level of manual dexterity a stroke survivor has in their impaired limb. The next study investigated collaboration in haptic environments and how the findings from a collaborative haptic experiment could be used to influence task design for future experiments with haptic environments. The final study assessed the feasibility of a home-based assessment and rehabilitation system with elements of telerehabilitation and remote collaboration and interaction providing four complete case studies from stroke survivors. In summary, our findings showed that by combining physical apparatus with a virtual world, less variable results are observed than in purely virtual haptic tasks. We also showed that interaction techniques in collaborative haptic environments change depending on the shape of the objects in the virtual task - this information can be used to influence task design to target specific motor deficits when using the device for exercise. Finally, the home-based study showed the feasibility of using the experimental rig at home and provided improvement measures that matched the perceived benefits to arm function that the participants described on completing the trial.

Background: The iron-heart hypothesis, put forward in 1981, proposes that higher iron levels are responsible for an increased risk of cardiovascular disease in men and post-menopausal women compared to pre-menopausal women. However, despite 30 years of research into this suggested association, there is still no consensus regarding the causal effect of iron on CVD. Objectives: To establish the likelihood of a causal effect of iron metabolism on risk of coronary heart disease (CHD) and stroke using five markers of iron metabolism, and a combination of observational epidemiology, genetic epidemiology and causal inference methods. Results: The observational association of serum iron, ferritin, transferrin and transferrin saturation (TS) with risk of CHD and stroke was assessed in 16,906 male and 17,110 female participants of the EPIC-CVD prospective cohort. Results of this study, which is the largest prospective study to investigate the association of iron markers with CHD and stroke, indicated an inverse association of iron levels with CHD risk in men but not in women. Further, there was no evidence of a difference in risk of CHD in women by menopause status. Serum iron showed a positive association with risk of composite stroke in men and women, but there was no evidence of an association of other iron markers with stroke. Results of a Mendelian randomization (MR) analysis using established genetic variants associated with serum iron, ferritin, transferrin and TS in published genetic association studies, suggested a non-significant inverse association of iron status with risk of CHD, and no association with ischemic stroke. A genome wide association analysis in 39,000 participants of the INTERVAL blood donor trial, led to discovery of associations with genetic variants at 26 novel loci for serum iron, ferritin, transferrin, TS and soluble transferrin receptor (sTfR), providing new instruments for MR analysis. A new MR analysis of serum iron, ferritin, transferrin, TS and sTfR was performed, including up to 10 new genetic variants and an additional iron marker (sTfR). Results of this new analysis indicated a significant inverse effect of iron levels on CHD. However after exclusion of genetic variants associated with CVD risk factors, there was no longer evidence of an association of markers of iron status with risk of CHD. There was also no evidence of an association of iron markers with ischemic stroke before or after exclusion of variants associated with CVD risk factors. Conclusion: Findings from this PhD do not support a causal effect of increased iron levels on CHD. Further, the inverse association of iron markers with CHD in MR analysis appears to be the result of confounding by CVD risk factors. Results for stroke remain inconclusive due to the small numbers of cases available and should be investigated in further studies.

Introduction: Anxiety is common and potentially debilitating after stroke. There is no reliable evidence to guide treatment. Barriers exist in accessing psychological care after stroke. Little is known about anxiety subtypes and what provokes anxiety in people after stroke. Treatment approaches effective in non-stroke populations may not be feasible or generalisable to stroke patients. Aims: The first aim is to develop an intervention for treating anxiety after stroke and evaluate its feasibility in patients. The second aim is to test the feasibility of a randomised controlled trial (RCT) to evaluate the intervention's effectiveness. Methods: I used a range of clinical research methodologies: i) a systematic review to summarise the design of anxiety interventions in stroke and acquired brain injury and their efficacy; ii) a prospective cohort study to investigate the frequency of anxiety subtypes, anxiety-provoking stimuli, factors associated with anxiety, and clinical outcomes associated with anxiety after stroke; iii) a study of diagnostic validity and reliability of two anxiety measures, iv) complex intervention development using a systematic approach; v) a feasibility RCT-Treating Anxiety after StroKe (TASK RCT) Results: My anxiety intervention was practical to deliver and acceptable to patients. The TASK RCT procedures were feasible at a small scale. This thesis will inform further refinements of the intervention and trial procedures in preparation for the large scale definitive TASK RCT.

Asymptomatic carotid artery disease (CAD) confers a less than two per cent annual stroke risk for patients on best medical therapy, however a group of patients remain high risk for cerebral ischaemia. There is no current way of identifying such patients. This study evaluated whether carotid plaque volume (CPV) is related to cerebral ischaemia and plaque instability. Given the prominent role of antiplatelet therapy in primary and secondary prevention, antiplatelet resistance amongst patients admitted for a carotid endarterectomy (CEA) was also evaluated. Patients admitted for a primary CEA in Greater Manchester were invited to participate. Following endarterectomy, CPV was calculated using a validated water immersion technique and note made of the stenosis severity, symptom type and time from symptom. A proportion of these patients underwent transcranial Doppler (TCD) insonation of the middle cerebral artery to detect microemboli, 3D tomographic ultrasound (t-US) to measure CPV, histological analysis of the plaque along with blood sampling for antiplatelet resistance and measurement of lipoprotein-associated phospholipase A2 (Lp-PLA2), P-Selectin and high sensitive C-reactive protein (Hs-CRP). Data from a carotid surveillance clinic was explored to evaluate the effectiveness of 2D arterial duplex in carotid surveillance. Mean CPV was significantly increased in symptomatic patients and the rate at which it decreased was similar to the rate at which the benefit from CEA decreases. CPV was not related to the degree of stenosis and could be measured accurately by 3D t-US. Mean CPV was significantly increased in those patients with a histologically unstable plaque and mean Lp-PLA2 was significantly increased in those with a marked inflammatory plaque. Mean platelet aggregation was significantly increased in symptomatic patients and correlated significantly with the number of cerebral emboli. The use of 2D duplex surveillance alone is not sufficient in identifying those patients who will benefit most from CEA. CPV is a potential marker of high risk plaques with provisional results indicating it can be measured accurately using 3D t-US. Routine antiplatelet resistance testing should be considered in patients with CAD, especially those who have suffered previous CV events.

Stroke is a major global health problem with limited treatment options. Mesenchymal stem cells (MSCs) hold great potential as a novel regenerative therapy for stroke having previously been shown to promote repair and functional recovery in rodent models of cerebral ischaemia. This is increasing evidence that much the beneficial effects observed are mediated by the MSC secretome, collective term for the vast array of chemokines, cytokines and growth factors secreted by the cells. The aim of this doctoral thesis therefore was to further investigate the role of the MSC secretome in promoting repair after ischaemic stroke. The potential of in vitro preconditioning strategies to increase the efficacy of an MSC therapy was explored. It was found that priming human bone marrow-derived MSCs with interleukin-1α (IL-1α), a pro-inflammatory cytokine, increased secretion of granulocyte-colony stimulating factor (G-CSF). Conditioned medium derived from IL-1α primed cells led to decreased secretion of tumour necrosis factor-alpha (TNF-α) and IL-6 from lipopolysaccharide (LPS)-stimulated microglia. Building upon this work, the efficacy of conditioned medium was assessed in ischaemic stroke using the intraluminal filament model of middle cerebral artery occlusion (MCAO). In the initial study, conditioned medium was administered to mice at the time of stroke. This had a neuroprotective effect leading to reduction (30%) in lesion volume and modest improvements in 28-point neurological score and nest building performance at days 2 and 4 respectively compared with the vehicle treated group. Delaying administration to 24 h post-stroke led to increased nest building scores at day 9 and significantly improved neurological scores from day 7 onwards independently of neuroprotection. In conclusion while future work is required to determine the mechanisms of action and define which mediators are responsible for promoting repair, the MSC secretome has great potential as therapy for ischaemic stroke.

There is little research exploring the psychological experience of acquiring a CI(communication impairment) in adulthood, possibly due to a perception that people with a CI are unable to participate in an interview (Bronken, Kirkecold, Martinsen, Wyller and Kvigne 2012). This study seeks to challenge this perception and explore the experiences of adults who have had to adjust to a change in their communication due to a stroke or head injury. Five participants were interviewed (3 face to face and 2 by email) about their experience from the moment they realised their communication had changed until the current day. All of the participants were 2 years or more post acquiring their CI. The data was analysed using Interpretative Phenomenological Analysis. Results indicate the levels of fear, anxiety and confusion triggered at the time of acquiring the CI and a need for more awareness of CIs within hospital environments. The importance of compassionate communication and psychological support within healthcare services was noted. Aninstinctual drive or motivation to find an alternative way to communicate and adetermination to keep communicating were also highlighted, as well the challenges of living with a CI; including a lack of awareness within society. The study also highlights the significance of expressive writing, singing, humour, laughter and finding the positive to support recovery, adjustment to living with the CI and psychological well-being in the longer term. Considerations for what could be offered therapeutically by counselling psychologists are discussed throughout. Gaps in the literature and further areas for research are identified, such as attachment history and acquiring a CI and the impact of a CI on the family homeostasis.

After stroke, changes to body perception are common. However, little is known about what these disturbed perceptions feel like to the stroke survivor. This programme of work used embodiment theory to explore stroke survivors' experiences of altered body perception and whether these perceptions were uncomfortable from a biopsychosocial perspective. It explored whether participants indicated a need for clinical interventions and the feasibility of using assessment tools to collate information about the body. A range of methodologies were used. A scoping review of the literature identified 28 studies exploring first-person accounts of altered body perception. Stroke survivors described the body across conditions as strange and unfamiliar; reflecting a changed awareness and means of relating to the body. Concurrently, a phenomenological study was conducted. A purposive sample of 16 stroke survivors able to communicate verbally, at least six-months post-stroke and experiencing motor and sensory impairments, were selected. Semi-structured interviews were conducted and analysed using interpretative phenomenological analysis. Participants described uncomfortable altered perceptions. The body did not exist, was hindered by strange perceptions and uncontrollable. The body was isolated, but participants were hopeful for improvement. Altered perceptions were difficult to comprehend and describe. From this, a feasibility and acceptability study explored the use of three assessment tools to communicate the altered body. Ten participants experiencing including a proportion with communication problems, were purposively selected. Participants wanted to communicate the experience of altered body perception and discomfort to health professionals and their preferred visual tools to achieve this. Stroke causes a complex sense of physical and psychosocial disembodiment, which is uncomfortable and of concern to survivors. Embodiment research suggests these domains may interact with one another. Clinical recognition and support to communicate altered body perception and discomfort from a holistic perspective may elucidate the multimodal experience of altered perceptions and foster new approaches for rehabilitation.

Background: Stress is a known risk factor for stroke, but there is a lack of understanding of the role stress plays in transient ischaemic attack (TIA). TIA is a warning sign of stroke, but effective management of risk factors can reduce the threat for the individual. Research Aim and Questions: The aim was to explore the perceptions of stress for people who have experienced a TIA and address the following questions: 1. What is the patients' understanding of the relationship between perceived stress and TIA? 2. How has perceived stress affected the patients' physical and mental health and well-being? 3. What actions has the patient taken to influence perceived stress and have these actions made a difference? Methodology and Methods: The study was conducted following a classic grounded theory tradition. Thirteen semi-structured interviews were undertaken with people who had experienced a TIA. Participants were recruited from outpatient clinics located in three Scottish Health Boards. Findings: Perceived stress was commonly experienced by participants and it was a significant feature throughout their TIA journey. Although not universally acknowledged as a contributing cause of TIA, stress formed part of their lived experiences. The presence or absence of perceived stress was an influencing force in relation to their mental and physical health and well-being. Factors that influenced stress could stabilise or destabilise a sense of equilibrium. Equilibrium was the achievement of a balance between interdependent elements and formed the core category: the equilibrium of health and well-being for the individual. Conclusions: The study led to the discovery of the substantive theory: if perceived stress can be effectively self-managed after a TIA, a state of equilibrium can be achieved which supports health and well-being. This new knowledge raises the opportunity to improve health and well-being after TIA and potentially reduce the risk of stroke.

A carotid atherosclerotic plaque represents a nidus of inflammation mere centimetres below the blood-brain barrier. This inflammation, along with associated regions of microcalcification, are histopathological features of atheroma at risk of rupture (so-called “vulnerable plaques”) that trigger thromboembolic stroke. While conventional clinical imaging simply measures the degree of vessel stenosis, it is a crude measure that reveals little of the metabolic processes affecting plaque vulnerability. Our research demonstrates the utility of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF), measuring inflammation and microcalcification respectively, to identify culprit carotid atheroma in vivo, and establish how these processes influence plaque vulnerability. Furthermore, for stroke care it is the downstream thromboembolic effects upon the brain that are key. While proinflammatory conditions may increase the risk of stroke, the relationship between atheroma inflammation and the peri-infarct inflammatory response following a stroke remains poorly defined. Our work demonstrates how inflammatory activity in symptomatic carotid atheroma, measured using PET, influences both chronic small vessel disease and the evolution of lesion volume in the post-stroke period. Using metabolic imaging we can both identify vulnerable atheroma in vivo and demonstrate how these processes affect infarct evolution. We show that whilst inflammation is a generalised process, microcalcification is a focal process that may represent a point of maximum vulnerability. These results also reveal the complexity of the atheroma-brain interaction that may simultaneously trigger events while also influencing stroke evolution in the early recovery period. This has important implications for understanding pathophysiology of both atherosclerosis and stroke evolution, advancing drug-discovery, and potential clinical applications to minimise the impact from this devastating disease.

Stroke is a significant contributor to the global burden of disease in adults. With the risk of recurrent stroke high, preventative medicines aimed at risk factor reduction are the method of choice for addressing the challenge of increased morbidity and mortality and improving patient outcomes. Research in stroke has shown that adherence to medication is problematic and survivors face considerable practical and physical barriers to taking prescribed medicines. Understanding these challenges can inform the development of strategies to improve medication taking behaviour through delivery of interventions in the primary care setting. This thesis aims to identify potential strategies to inform interventions to improve medication taking in stroke. The research: identified key barriers and facilitators of medication adherence for the secondary prevention of stroke - firstly from within the primary care setting and then from the perspective of an online stroke forum; explored the appropriateness of the online forum as a method of data collection for conducting qualitative research compared with a traditional qualitative interview approach; investigated medication taking among community stroke survivors to characterise patients who receive help with medicines and estimate the proportion who have unmet needs and miss medicines; and examined attitudes from across the stroke spectrum towards a novel approach to medication taking for secondary prevention (i.e. fixed-dose combination polypill). Findings showed that survivors face considerable barriers to medicine taking, but that facilitators, particularly the caregiver role, can encourage good medication taking practice. The online forum has potential as a source of data to understand stroke survivors' behaviour, and a novel strategy to taking stroke medicines has promise. These findings enhance current thinking around medicine taking behaviour in stroke and can inform the development of effective interventions to improve medication taking practices and address nonadherence among stroke survivors. Implications for clinical practice are discussed, and recommendations are provided for future research.

Cerebral small vessel disease (SVD) is a leading cause of stroke and vascular dementia. The majority of cases are sporadic, occurring in the elderly hypertensive population. However, there also exist patients with familial disease. The most common form is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene. In recent years, other genes have also been found to cause familial SVD, such as COL4A1/A2, HTRA1, FOXC1 and TREX1. Genome wide association studies (GWAS) have also revealed loci associated with sporadic SVD strokes and its related features. This thesis explores the genetic basis of SVD primarily from the angle of the 'one gene, one disease' hypothesis. We explore the phenotype of familial SVD using CADASIL as a prototype. We next adopt a candidate gene approach to rare variant discovery using high throughput sequencing (HTS) techniques in two forms: 1) a multi-gene sequencing panel to examine the presence of rare variants in a cohort of 993 presumed-sporadic, early-onset SVD stroke patients, and 2) whole genome sequencing in 118 pedigrees with suspected familial SVD. We also evaluate the prevalence of known disease-causing mutations in the general population using a cohort of whole genome sequenced non-SVD patients, and other control databases. We demonstrate that a few presumed-sporadic SVD stroke patients may in fact have familial disease that was not previously diagnosed. We show that known and novel rare variants in candidate genes are found in our cohort of familial SVD patients, and suggest a possible role for rare variants in genes associated with related phenotypes and sporadic disease in this cohort. Finally, we identify known disease-causing variants in relatively high frequencies in the population, and show that conclusions on the pathogenicity of variants based on allele frequency and functional analyses may sometimes be misguided, thus highlighting the current limitations we face in the clinical interpretation of variants identified on HTS. In recent years genetic studies have revealed that pathways in different familial diseases are likely to converge in the pathogenesis of sporadic disease. Further uncovering the genetic basis of undiagnosed cases of familial SVD may shed light on the mechanisms underlying the sporadic form of disease, and may in turn drive the identification of potential therapeutic targets.

Delirium is a severe neuropsychiatric syndrome, characterised by the acute onset of inattention, altered level of arousal, and other mental status abnormalities. Delirium is extremely common in acute stroke, affecting at least 1 in 5 such patients admitted to hospital. It is a serious complication of stroke, being associated with higher mortality, longer length of hospital stay and higher dependency at discharge. The pathophysiology of delirium is not completely understood, and there are no specific treatments. This thesis investigated the role of cortisol in the development of delirium after stroke and also investigated the role of delirium and of cortisol in the development of cognitive impairment in the 12 months after stroke. The thesis specifically investigated whether levels of cortisol in saliva are elevated in delirium and also whether there is a loss of the normal diurnal rhythm in delirium, evidenced by elevated afternoon salivary cortisol levels and reduced morning level to afternoon level ratio. The thesis also investigated whether cortisol levels are persistently elevated in the year after stroke in those who developed delirium and whether cortisol levels are associated with cognitive decline. Finally it investigated whether acute and/or chronic changes seen on Computed Tomography (CT) brain scans taken around the time of stroke onset are associated with the development of delirium after stroke A longitudinal cohort study was conducted in 95 participants aged 60 years or over, who were admitted to hospital with a clinically confirmed stroke. Participants gave informed consent, or proxy consent was obtained if they lacked capacity to consent. At baseline participants underwent brief cognitive testing and were then assessed for the presence of delirium, using DSM IV criteria, at regular intervals during the first two weeks after stroke. At each assessment a saliva sample was collected in the morning and in the afternoon, to measure cortisol. Participants were then visited at 1 month, 4 months and 12 months after stroke onset, at which point they were assessed for the presence of delirium, further saliva samples were taken and a cognitive test battery was completed. 26 (27%) participants developed delirium during the course of the study period. The study found elevated salivary cortisol levels in those with delirium at up to 4 months after stroke, but at 12 months there was no difference between the delirium and no delirium group. A loss of the diurnal rhythm was seen in those who developed delirium at 5 days after stroke, but the diurnal variation had returned to a normal pattern at follow-up. However, in a multivariate analysis, controlling for age, sex, stroke severity (NIHSS), current illness burden (APACHE II), chronic illness burden (CCI) and prior cognitive impairment (IQCODE), neither median salivary cortisol levels in the first two weeks after stroke, nor the ratio of morning to afternoon cortisol levels were independent predictors of delirium diagnosis, although median 9am cortisol approached significance (OR=0.95, 95% confidence interval (CI) 0.89-1.01, p=0.08). In a random effects logistic regression analysis, the probability of developing delirium decreased over time from stroke onset and increased per unit increase in salivary cortisol (nmol/L), however this effect was not statistically significant (OR 1.02, CI 0.84-1.19 P=0.70 for morning cortisol and OR 1.05, CI 0.82-1.25 p=0.46 for afternoon cortisol). Global cognition, measured by the MoCA, was significantly poorer in the delirium group at each time point throughout the 12 months after stroke. However, there was a trend towards improvement in MoCA scores in the whole cohort throughout the 12 month follow-up, with the exception of those who developed the most severe delirium. The presence of delirium at any point during the 12 month follow-up did not affect the rate of change of the MoCA scores over the 12 months after stroke. The presence of brain atrophy identified on admission CT brain scans was independently associated with delirium (OR 3.7, CI 1.15-11.88, p=0.02), however the presence of a visible acute or chronic stroke lesion and the presence of white matter lesions were not. Finally, those who developed delirium had a worse functional outcome, longer length of hospital stay and were more likely to require institutional care or a package of care at home, compared with those who did not develop delirium. This thesis has contributed to our understanding of the mechanisms and phenomenology of delirium after stroke, and has also highlighted areas for further research which will be required to unpick the complex pathophysiology of delirium.

Introduction Globally stroke remains the leading cause of adult disability. An aging population and a reduction in stroke case fatality has led to an increasing number of people living with stroke i.e. stroke survivors. The ability to perform important day-to-day activities, such as walking and housework, is frequently impaired in stroke survivors. Therefore, it has become essential to address the long-term needs of stroke survivors, prompting focussed research on life after stroke. A reduction in physical fitness after stroke may contribute to stroke related disability. It is possible to improve physical fitness by regular, structured physical activity. Improving physical fitness after stroke and increasing physical activity are aspects of life after stroke that are increasingly being researched. Although the evidence base for the benefits of physical fitness training is growing, research has indicated that benefits gained are not always maintained at follow-up. To facilitate the uptake and maintenance of physical activity after stroke, it is essential to understand why many stroke survivors do not undertake regular physical activity. Understanding this difficult concept will enable the tailoring of behaviour change interventions to promote and maintain physical activity after stroke. However, there has been limited work in developing theory driven behaviour change interventions to increase physical activity in stroke survivors. Therefore, the aim of this thesis was to develop and test a behaviour change intervention to increase physical activity after stroke. Methods In order to address the above aim, six interlinking studies were conducted within the development and feasibility stages of the MRC framework for the development of complex interventions. A systematic review (study one) examined barriers and facilitators to physical activity perceived by stroke survivors. This study showed a lack of literature in this area, and that the already published studies had limited generalisability to the UK stroke population. Therefore, it was deemed appropriate to conduct a qualitative study (study two) to examine the perceived barriers and facilitators to physical activity in the local stroke population. Both studies one and two highlighted the influence of self-efficacy towards increasing physical activity. As part of earlier work conducted prior to this PhD, there was previously unanalysed data on perceived barriers and facilitators to physical activity after stroke. These quantitative data encompassed specific questions exploring self-efficacy and intention to physical activity post stroke. In light of the evidence it was deemed necessary to analyse these data (study three). It was envisaged that the behaviour change intervention would incorporate a feedback device, so participants could clearly see how much daily physical activity they were undertaking. An opportunity arose to collaborate with a team at Newcastle University who had developed an accelerometer that incorporated an immediate feedback screen. Therefore, a device validation study was conducted as study four. Results from studies one to four were combined, with the use of the Theoretical Domains Framework, and the behaviour change intervention was developed. Two uncontrolled pilot studies (studies five and six) were conducted to determine the feasibility and acceptability of the behaviour change intervention to the stroke population. Results The systematic review included six articles, providing data on 174 stroke survivors. Commonly reported barriers were environmental factors, health concerns and stroke impairments. Commonly reported facilitators were social support and the need to be able to perform daily tasks. Qualitative interviews were conducted with 13 stroke survivors, at which point data saturation was reached. The most commonly reported TDF domains were ‘beliefs about capabilities’, ‘environmental context and resources’ and ‘social influence’. The quantitative study provided data from 50 stroke survivors. Intention and self-efficacy were high, with self-efficacy graded as either 4 or 5 (highly confident) on a five-point scale by [34 (68%)] participants, whilst 42 (84%) participants “strongly agreed” or “agreed” that they intended to increase their walking after their stroke. Ten participants were recruited to validate the new accelerometer. Mean time since stroke was 29 days (SD =27.9 days). The 10 participants walked a mean distance of 245 meters (SD=129m) and their mean walking speed was 0.79ms-1 (SD=0.34ms-1). The Culture Lab were unable to develop the accelerometer in the necessary time frame and therefore no accelerometer was available for trialling the behaviour change intervention. Therefore, pedometers were used to record step count during the behaviour change intervention. A total of four participants took part in the 12 week behaviour change intervention, over two study periods. All participants managed to increase their step counts during this time. The studies had problems both with recruitment and retention of participants. These issues have been discussed. Conclusions This work has enhanced the understanding of the barriers and facilitators perceived by stroke survivors to increase physical activity. This work has allowed the development of a theoretically driven, complex behaviour change intervention that was successfully trialled with a small group of stroke survivors. Areas of further research have been discussed.

Morbidity due to noncommunicable diseases (NCDs) has become a worldwide epidemic. As a result, the United Nations (2015) Sustainable Developmental Goals (SDGs) included goal (3.4) that aims to reduce the premature mortality from NCDs by one third. All countries, regardless of income, are required to develop strategies and achieve a reduction in the burden of NCDs. This study, conducted in the Sultanate of Oman, aimed to explore individuals' knowledge, perceptions, actions and intentions to modify their lifestyle to reduce their risk of stroke. The Health Belief Model (HBM) was used as the underpinning theoretical framework to provide a broader conceptual understanding of the Omani sociocultural and structural influences on individuals' lifestyles. A convergent mixed methods design within a realist social constructionism methodology was used. Both quantitative (344 questionnaires) and qualitative (10 interviews) data were integrated using a narrative weaving approach. The study results confirm that both agency and structure influenced the adoption of healthy behaviours in Oman. The study indicates that the study participants are likely to engage in health-related behaviours when they perceived the benefit of such a course of actions in term of it reducing their risk of stroke. The study found that in the Omani setting, individual factors such as fear, family experience and physical sickness, the psychological status of chronic conditions and a cost-benefit analysis of the behaviour influence the individuals' decisions to practise a healthy lifestyle. The major finding in the study showed that perceptions of risk vary among individuals who share the same culture and religion, particularly individual perception of religious belief was found to influence their susceptibility to stroke risk. In addition, the study identified some sociocultural and structural factors that influenced the individuals' decisions to engage in a healthy lifestyle. This study presents an extended HBM to incorporate the role of individual religious beliefs as an individual factor. The study suggests that health improvement plans are needed in Oman to develop both individual- and community- level interventions to achieve the target of SDGs for NCDs.