Introduction: Elevated blood levels of Cardiac Troponin (cTnT) are the gold standard for diagnosis of acute coronary syndrome (ACS). However cTnT is not detectable for 3-4 hours after symptom onset; an early marker of myocardial ischaemia is therefore desirable. The peptide Calcitonin Gene-Related Peptide (CGRP) is released from nerve endings during myocardial ischaemia and has cardioprotective effects. Intermedin (IMD), from the same family, is elevated in myocardial infarction and oxidative stress in animal studies. Methods: I enrolled 81 patients with chest pain, suspected to have acute coronary syndrome to a chest pain study (1). Samples were taken on admission, at 12hours after pain, the next day and the following day. Samples were analysed for intermedin, & CGRP (radioimmunoassay) and High-Sensitivity troponin (HsTnT). Study 2 assessed 30 patients undergoing Percutaneous Coronary intervention (PCI) with 6 controls. Samples taken, pre, 1,5, 10,30, 120 or 240 minutes post balloon inflation and next day. Results: Study 1- Intermedin showed a non-significant trend towards elevation in ACS patients. In those patients who were (cTnT) negative «0.03ng/ml) on presentation, IMD & CGRP were significantly elevated. CGRP was significantly elevated at 12 hours after ACS onset and appeared to remain elevated for 48 hours. HsTnT identified more ACS on an admission sample than cTnT. Study 2 - IMD showed a small but significant rise at ten minutes after balloon inflation. HsTnT was significantly elevated the next day following PC!. Neither marker was related to number of stents/inflations, balloon pressure or length of inflation. Conclusions: The novel peptide IMD is elevated in ischaemia and infarction, but the rise is too small to be clinically useful. CGRP had a significant rise in ACS patients, but again of a small magnitude. The time course of their elevation is incompletely defined. HsTnT is more sensitive in ACS than cTnT on a presenting blood sample.

Electrophysiological stimulation has been proffered as having the potential to improve rehabilitation in stroke survivors suffering residual motor deficits. Interindividual variation exists in the response to these interventions, undoubtedly mediated at least in part by genetic factors. The thesis identified 3 candidate genes in neural plasticity, and determined their impact on the efficacy of paired associative stimulation (PAS) and transcranial direct current stimulation tDeS in forearm muscles, which are often the target of rehabilitation therapies . Three candidate genes in neural plasticity were examined- BDNF, COMT and ApoE. Genotype-mediated baseline differences in cortical excitability were found. Females who were homozygous for the BDNF val allele had significantly larger VO curves than those who carried a met allele. COMT val homozygotes showed a trend towards smaller VO curve area at baseline, which approached significance (p=O.0504). Baseline I/O curve area was undifferentiated across ApoE genotype groups.

White matter injury often results in clinical neurodevelopmental deficits; however, molecular mechanisms remain partially understood and there is currently no clinically effective treatment. The purpose of this study was to elucidate the molecular and cellular mechanisms underlying developmental white matter ischaemia to aid the search for therapeutic interventions. In this thesis, a particular priority was to develop an ischaemia paradigm enabling study of the extended effects of ischaemia in a controlled environment. To achieve this, I sought to use organotypic slice cultures (OSC), whereby cerebellar slices could be generated from animals where the white matter is developing and maintain it whilst exposing it to a short oxygen-glucose deprivation (OGD) insult at some defined point in the culture cycle. Using this approach, I show that culture treatment at 7 days in vitro (DIV) with OGD for twenty-minutes triggered significant injury as judged by a 58.6% reduction in cell viability 3 days post-injury. TUNEL labelling showed about 60% of cell death was apoptotic in nature. Gene expression studies using Q-RT -PCR confirmed caspase-dependent cell death. OGD also produced marked oligodendrocyte loss and myelination disturbances as seen by immunocytochemistry. Post-OGD, astrocytes and microglia became activated, and cytokine and iNOS mRNA expression was upregulated. After a transient demyelinating insult with OGD, GluR-antagonists were effective against cellular damage and myelination disturbances. Myelin gene, oligodendroglial transcription factor, and BCL-2 mRNA expression were also maintained following administration of GluR-antagonists. In addition, there seemed to be some NG2+ OPCs differentiated into MBP+ oligodendrocytes during the recovery phase as seen by proliferation- marker BrdU. Western blotting showed that a mechanism by which GluR-antagonists confer protection was independent of the CREB transcriptional activity. The results also suggest ischaemia-induced NF-kB and p38MAPK signalling pathway activation may be attributable to ionotropic GluR stimulation. The cellular damage and myelination disturbances in this ex vivo model of white matter ischaemia provides a system to study remyelination following CNS injury- induced demyelination, and may serve as a valid pre-animal test-bed for examining potential pharmacotherapies.

: Carotid stenosis causes 15-20% of all ischaemic strokes, which can be preceded by TIA or minor stroke but usually occur without warning. Risk of stroke is 10-15% in symptomatic disease and optimal medical treatment is unknown in the acute period prior to carotid endarterectomy (CEA) or where there are contraindications to surgery. In contrast, risk is now <2% per annum in asymptomatic disease; due to improved medical treatment however optimal treatments are unknown. Methods are required to identify asymptomatic patients at high risk of stroke to improve treatment by targeting CEA and intensive therapies to those who may benefit. The mechanism of these strokes in carotid atherosclerosis is predominantly thought to be due to thrombo-embolism. Transcranial Doppler (TCD) embolic signal (ES) detection may therefore be a useful technique in investigating the prevention of ischemic stroke. Data in symptomatic and occlusive disease suggest a haemodynamic mechanism may also contribute to stroke risk; however there are limited data in asymptomatic disease. Methods: In symptomatic carotid stenosis a randomised controlled trial was used to compare two anti- platelet regimens. A novel ambulatory TCD ES detection protocol and concurrent platelet aggregometry were used as surrogate markers. In asymptomatic carotid stenosis secondary analysis of a large multicentre international trial (ACES) was performed, analysing optimal protocols for TCD ES detection. In a sub study, TCD cerebrovascular reactivity (CVR) was also investigated. The influence of improvements in treatments on ES over time and changes in treatments over a two year follow-up period were also analysed to investigate prevention of ischemic stroke in asymptomatic carotid stenosis. Results: In symptomatic stenosis, aspirin in combination with either dipyridamole or clopidogrel reduced embolism to a similar extent. ES had temporal variation in ambulatory recordings. In asymptomatic carotid stenosis, ES detection on 2 baseline recordings is an independent risk prediction tool for ipsilateral stroke which was better than shorter recordings or one recording only. CVR did not predict risk but this lack of association may reflect a low number of endpoints. A trend, but non-significant decrease, in ES over time was observed despite changes in treatments. Higher blood pressure and absence of anti-platelet therapy were associated with risk of ipsilateral strokelTlA and any stroke/cardiovascular death. Conclusion: ES are surrogate markers in both symptomatic and asymptomatic carotid stenosis. In acute symptomatic atherosclerosis, clopidogrel or dipyridamole in addition to aspirin reduce embolism to a similar extent and may be useful for prevention of embolic ischemic stroke. In asymptomatics, ES on either of 2 baseline recordings predict 2 year risk of ipsilateral stroke, however there is insufficient data for the use of CVR. Improvements in treatments at baseline did not prevent ES and the technique may be useful to identify patients at high risk who may benefit from carotid endarterectomy to prevent future ischaemic stroke. ES detection may also be important to identify those at low risk to target treatments appropriately. Consistent use of anti-platelet therapy and control of blood pressure are important in the prevention of ischemic stroke and cardiovascular death in asymptomatic carotid stenosis.

Posterior circulation ischemic stroke accounts for a quarter of ischemic strokes. Recent studies have shown that these patients have a high early risk of further ischaemic events especially if they have 2:50% vertebrobasilar (VB) stenosis; there is paucity of data on the diagnosis and management of these patients. The gold standard technique to diagnose VB stenosis is intra-arterial angiography (IAA) which carries a risk of stroke; this can be avoided by using non-invasive imaging techniques. I systematically reviewed the literature on studies which compared the accuracy of three commonly used non-invasive imaging techniques (contrast-enhanced magnetic resonance angiography (CE-MRA), computed tomographic angiography (CTA) and duplex ultrasonography) to IAA, the gold standard, in order to diagnose VB stenosis. There were 13 studies for vertebral stenosis, these showed CE-MRA and possibly CTA to be better than duplex. I then performed the first prospective study (40 patients) comparing CE-MRA, CTA and duplex to IAA in the same patient group demonstrating that CE-MRA had the highest sensitivity followed by CTA and then duplex. The two main studies which have shown that 2:50% symptomatic VB stenosis carries a high risk of further ischaemic events followed-up patients for 90 days. I examined my patient group with longer term follow-up (mean 14 months). This study showed a higher risk of recurrent ischaemic events (odds ratio (OR) 2.56(95%CI 1.11-5.9),p=0.023) and VB stroke or TIA (OR 2.8(95%CI 1.24-6.32),p=0.01 ). I reviewed data from patients who had endovascular vertebral intervention at St George's and systematically reviewed the literature. This study showed that vertebral artery stenting is a technically successful procedure (99.4%) with a periprocedural stroke risk of 0.5%; one year TIA, stroke and mortality rate was 3.9%, 5.0%, and 3.6% respectively. However, the included studies were retrospective studies of varying quality; large-scale prospective trials are needed to determine the benefits of stenting.

Stroke is a public health concern throughout the world due to its association with high levels of mortality and long-term morbidity. Stroke is a chronic condition. There is evidence that the use of self-management strategies can be associated with positive outcomes for people with chronic conditions. The evidence relating to stroke and self-management informs stroke policies in the UK. However, there is minimal understanding of self-management in the context of stroke. Rehabilitation interventions which can adequately address the longer term needs require an understanding of key factors which may influence self-management in stroke survivors. The overall aim of the research presented in this thesis was to explore the concept of self-management in the context of stroke. This thesis presents a mixed methods study that was designed to address three specific and connected research questions. This thesis described three studies. Firstly, through a systematic review of qualitative studies with thematic synthesis it systematically examined the current literature to determine stroke survivors' experiences of living with stroke and the biopsychosocial factors that may influence these experiences of post-stroke life as well as the components of these factors that might be relevant to self-management. Secondly, through a prospective quantitative cohort study, it investigated the biopsychosocial individual characteristics associated with self-management and self-efficacy in adults with stroke. Finally, through a qualitative interview study, it explored the meaning(s) ascribed to "self-management" by stroke survivors and healthcare professionals. The key findings taken together reveal new insights into the psychosocial phenomena that shape coping and adjustment after stroke; the biopsychosocial factors that influence selfmanagement and self-efficacy; and the conceptualisations of self-management. This thesis therefore develops new understandings of self-management in the context of stroke. Findings have implications for formulation, organization and delivery of better aftercare and the rehabilitation that follows.

Cerebral small vessel disease (SVD) is a chronic disease of the small cerebral blood vessels and a common cause of dementia. Surrogate markers for cognitive impairment are required for future treatment trials. Patients with SVD have similar risk factors and MRI features as Alzheimer's disease. Blood biomarkers would be useful for diagnostic and prognostic purposes. St George's Cognition and Neuroimaging Study (SCANS) is a longitudinal study investigating the potential of MRI as a surrogate marker for cognitive impairment. This report examines the baseline data from SCANS. 121 patients with lacunar stroke and white matter hyperintensities had multi modal MRI, neuropsychological testing and had blood sampling for biomarkers of endothelial activation . Patient group performed worse in executive function and information processing speed compared to normative data. Patients had more white matter lesions, smaller whole brain volumes and lower fractional anisotropy and higher mean diffusivity on diffusion tensor imaging. Multiple regression, suggested brain volume was the best predictor of impaired information speed processing (P=0.001) and median white matter FA for executive dysfunction (p=0.004). High numbers (>9) of cerebral microbleeds were associated with impaired executive dysfunction. Blood biomarkers were tested in 106 patients. Patients had lower tissue factor (TF), tissue plasminogen activator (tPA) antigen and plasmin activation inhibitor-1 than controls. TF was associated with lesion volume and tPA was associated with the number of clinical strokes.

No description available.

Dementia presents a significant health care burden. Older post-stroke patients suffer high rates of dementia. Subcortical ischaemia may be an important mechanism of cognitive decline, particularly in older patients with cerebrovascular disease. It is hypothesised that abnormal heart rate and blood pressure variability will increase white matter lesion volume through hypoperfusion. This may lead to a subcortical pattern of cognitive decline characterised for example by deficits in attention and concentration. Stroke patients aged > 75 years and free of dementia had a series of cardiovascular autonomic, brain imaging and neuropsychometric investigations performed more than three months following incident stroke. Annual neuropsychometric assessment included CAMCOG score and measures of reaction time and concentration using a series of visual and numerical tasks presented on computer (Cognitive Drug Research Assessment System). Autonomic function is impaired in older stroke patients in the long term after stroke. These deficits are weakly associated with cross-sectional measures of sub-cortical performance but do not predict subsequent decline in cognitive function. Twenty-four hour blood pressure variability is associated with white matter disease and excessive nocturnal dipping is associated with impaired cognitive function. Again blood pressure variability does not help predict subsequent change in white matter lesion burden or cognitive function. This study provides limited support for the hypoperfusion theory of post-stroke cognitive impairment. However it does not indicate a role for heart rate and blood pressure variability in the mechanism of increasing white matter disease or decline in cognition in the two years following stroke.

Stroke affects more than 150,000 people every year and is the third major cause of adult disability in the UK. Stroke rehabilitation plays an important part in the motor skills recovery of the stroke patients. This thesis forms part of the development of an upper arm rehabilitation system which involves the use of Functional Electrical Stimulation (FES). Motivation for this use of stimulation to augment remaining voluntary effort in strokepatients is explained and the necessary components comprising the system are described. The task considered in this thesis is reaching, which involves elbow extension and shoulder elevation. FES is applied to two muscles, triceps and anterior deltoid respectively, to assist in these movements. A review of the literature has revealed possible control schemes which could be implemented with FES. Relatively few, however, have actually been implemented in clinical trials. This work, aims to apply selected controllers in clinical applications. A series of controllers are examined, starting from the simplest feedback controller going to more advanced model-based Iterative Learning Control (ILC) controllers. These include phase-lead ILC, input-output linearisation, and Newton-method based ILC. ILC algorithms are commonly used in industrial robots for precise control. The aim of this work is to transfer these algorithms to clinical settings. ILC algorithms are used to provide finely-controlled levels of FES assistance to patients during repetitive training tasks. To use a model-based controller, kinematic and dynamic models of the Armeo and human arm have been developed. The muscle model of the human arm has been derived using a Hill-type model while the Hammerstein model is used to model the stimulated muscle. The complete system has then been used in a clinical study involving five stroke patients. Improvements in clinical measured Fugl-Meyer Assessment (FMA) scores were seen in the stroke patients after the trials.