Huntington’s Disease (HD) is a devastating hereditary neurodegenerative disease for which there are currently only symptomatic treatments. Several potentially curative pharmaceutical and genetic therapies are however in varying stages of development and therefore an increasing number of large-scale clinical trials of disease-modifying therapies are imminent. There is consequently a need for biomarkers which are sensitive to beneficial attenuation of disease-related changes. Functional, neuroimaging and biochemical biomarkers have been developed in HD (Andre et al. 2014;Weir et al. 2011). Neuroimaging biomarkers are strong candidates based on their clear relevance to the neuropathology of disease, proven precision and superior sensitivity compared with some standard functional measures (Tabrizi et al. 2011;Tabrizi et al. 2012). Their use in early-stage clinical trials, as surrogate end-points providing initial evidence of biological effect, is becoming increasingly common. Comparison of biomarkers in HD will help to clarify which measures, over varying time intervals, are most sensitive to disease progression. Additionally, the identification of robust fully-automated methods, comparable to manual and semi-automated gold-standards, would facilitate large-scale volumetric analysis. These methods however require validation in observational studies of neurodegenerative disease before they can be applied to sensitive clinical trial data. This thesis will develop and evaluate biomarkers for use in HD; both furthering our understanding of the disease and in preparation for use as end-points in clinical trials. A direct comparison of the sensitivity of diffusion and volumetric imaging biomarkers to HD-related change will be reported for the first time. Several exploratory imaging investigations are also described which enhance current knowledge of the relationship between neuroimaging metrics, brain functioning and behaviour, additionally strengthening the argument for the clinical relevance of neuroimaging measures as surrogate end-points in HD. The thesis will conclude with a comprehensive biomarker evaluation in early-stage HD, along with suggested strategies for selection of primary and secondary trial end-points based on effect sizes and corresponding sample size requirements.

Tourette syndrome (TS) is a neurodevelopmental disability characterised by a cognitive profile of executive function deficits, particularly relating to inhibitory control. There is much evidence that TS is likely to occur comorbidly with other disorders and that this may exacerbate the presence of cognitive disruptions. Attention Deficit Hyperactivity Disorder (ADHD) is one of the neurodevelopmental disorders that TS often occurs comorbidly with. This review provides an examination of TS including its clinical presentation, aetiology, comorbidities and cognitive profiles. A similar discussion is followed for ADHD. This leads to an examination of the key processes and measures of attention and inhibition with reference to these disorders. It is hoped that by examining these shared profiles, it might lead to a greater understanding of the overlap between these two neurodevelopmental disorders.

Background: In the brains of both demented and non-demented subjects the most common pathologies are Alzheimer’s disease (AD) related pathologies and white matter lesions (WML). It is widely assumed that small vessel disease (SVD) is the main cause of WML, although evidence suggests neurodegenerative pathologies may also be involved in the pathogenesis of WML. However, investigation of these pathologies is hindered due lack of standardized histological criteria for WML assessment and the current use of semi-quantitative assessment is incapable of detecting subtle variations in pathologic burden across cases. The main aim of this study was to improve the post mortem assessment of WML/WMH and AD-related pathology in the ageing human brain by the use of post mortem MRI and quantitative neuropathological assessment, and to investigate possible associations between AD pathology and white matter integrity.! Methods: Formalin fixed brains underwent post mortem MRI and white matter hyperintensitites (WMH) were assessed according to the Age-Related White Matter Change (ARWMC) scale. ARWMC scores were compared with corresponding semi-quantitative neuropathological scores obtained by an extensive assessment of the white matter. In a cohort of AD and control brains semi-quantitative and quantitative assessment of hyperphosphorylated tau (HPT), amyloid-beta (Aβ) pathology and SVD were compared. The influence of AD-related pathology and SVD on white matter integrity was then investigated using a combination of post mortem MRI-based WMH assessment, quantitative neuropathological assessment using Tissue Micro Array (TMA) methodology and Sclerotic Index. Key findings: MRI-based assessment of fixed post mortem brains was found to be a practical method that reliably reflects WML in the frontal, parietal and occipital WM comparable with an extensive histological assessment at 7 mm intervals. Digital quantification of cortical HPT, Aβ and SVD pathology revealed widespread variations in pathological burden. HPT, Aβ pathology and SVD had a significant influence on WMH severity in both non-demented normal aged and AD brains, however, HPT, but not SVD, was the most significant predictor of WMH score. Conclusion: This study showed that MRI-based assessment of fixed post mortem brains is a practical method for the assessment of white matter integrity and TMA is a practical method for quantitative neuropathological assessment of degenerative neocortical pathologies. HPT was found to be the strongest predictor of WMH. However, further studies are required to elucidate the different patho-physiological mechanisms that may underlie WM damage in the ageing brain.

Background: Cerebral autoregulation (CA) refers to the ability of the brain to maintain a relatively constant cerebral blood flow (CBF) in response to significant changes in cerebral perfusion pressure. CA is governed by several key mechanisms, which can be described as neurogenic, myogenic and metabolic. Idiopathic Parkinson’s disease (PD) is a common neurodegenerative disease with a significant autonomic component, and it has been hypothesised that CA in PD may therefore be impaired. However, to date, the literature on this subject has been limited in its scope, of uneven quality and has yielded conflicted findings. Objective: This Thesis aimed to determine if dynamic CA is impaired in patients with idiopathic PD, compared to healthy control subjects, and if dynamic CA varies between the ‘on’ and ‘off’ states of PD. Methods: CA was assessed by means of continuous non-invasive monitoring of arterial blood pressure (BP) and velocities in the middle cerebral arteries bilaterally using transcranial Doppler ultrasound. A cohort of patients with idiopathic Parkinson’s disease were studied in both their clinically ‘on’ and ‘off’ states, and their data were compared to that obtained from age- and sex-matched healthy controls. In addition to assessing the CA response to spontaneous fluctuations in BP, a variety of paradigms were used to induce changes in mean cerebral blood flow velocity and BP, including passive arm movement and hyperventilation. Results: This study has demonstrated that CA responses to spontaneous fluctuations in BP do not differ significantly between the on and off states of PD, but do differ significantly between PD patients and healthy controls, ultimately suggesting that CA is altered, but not necessarily impaired, in idiopathic PD. CBF velocity responses to passive arm movement and hyperventilation did not differ significantly between the on and off states of PD, or between PD patients and healthy controls.

This thesis is comprised of four parts: A literature review, a research paper, a reflective critique of the research process and a service evaluation. A systematic literature review was undertaken concerning longer term stroke survivors accounts of social and emotional challenges after stroke. This resulted in 12 studies which were then explored. All 12 studies used qualitative approaches and sought to gain direct accounts from stroke survivors concerning these issues. The studies collated accounts from stroke survivors about their social and emotional experiences through particular study lenses of social support, social participation, quality of life, quality of friendship, quality of spousal relationship and personal perspectives. The studies were then examined in order to understand their contribution to the literature. Across the studies it was clear that from the stroke survivors viewpoint, rehabilitation service models tended to be focussed on early intervention and lacked a longer term strategy which supported emotional and social adjustment. Five main themes across the studies were identified. These were: Loss & Maintenance of friendships; Losses in Social world and role leading to isolation; Social participation & community integration changes; Pre and post stroke self, continuous/discontinuous self; and Emotional responses. These themes were examined more closely in order to appreciate their thematic meaning for stroke survivors and the contribution the various studies had made to this. Recommendations for future research from these results are discussed. A research study interviewed six stroke survivors (ranging from 1-9 years post stroke) in order to gain their views and experiences about any social cognition changes since their stroke. Open ended qualitative interviews were recorded verbatim and then analysed using Interpretative Phenomenological Analysis. Three superordinate themes emerged from this analysis: My changed sense of self in relation to others; Managing my social behaviour; and My altered states of feeling. Each of these superordinate themes contained a number of sub themes. Stroke survivors’ self-understanding of these issues and their views about the impact this has had on relationships is discussed and recommendations are made. A reflective critique records the personal experiences of the author during the research and thesis process. This describes the challenges and lessons of engaging in the academic and research process for this thesis. A service evaluation describes the establishment and provision of a six month pilot offering an in house psychological service for staff within an acute medical hospital alongside a physiotherapy service. Psychological services were offered as a brief treatment model and also provided consultancy and training to staff at all levels. Over the six months, 53 members of staff were seen for direct psychological consultation/treatment. Data were collected regarding professional group, and frequency of sessions and the 10 effectiveness of the service on staff well-being was measured using the HADS as a measure of individual change. Organisational sickness absence data was gathered as a measure of the pilots cost effectiveness within the organisation. Data were also collected on the types of issues that staff presented with and the category of staff that attended. Results showed that staff anxiety decreased at a highly significant level, and depression at a significant level, but the level of returns of the questionnaires was very low. Staff sickness absence due to stress was compared to the same six months of the previous year and had decreased by 40% resulting in substantial cost savings. Staff sickness across the division dropped from 5.29% to 3.87% over the 6 months. Staff reported sleep problems, low mood and emotional events as the most frequent issues that made them stressed, but loss of confidence in work role and being affected by events at work were also frequently reported; indicating the importance of a service that links in to the organisation. The treating psychologists reported bereavement issues as the most common treatment issue arising from users of the pilot. The evaluation is critically discussed, comparisons are made to published information about the national picture and recommendations are made for future evaluation and research.

Stroke is the leading cause of death and permanent neurological disability in the developed world and a significant burden on the NHS and wider economy. A third of all strokes are caused by thrombo-embolism from unstable carotid atherosclerotic plaques. The exact pathogenesis of plaque progression and instability is unknown. The aim of this thesis was to investigate carotid plaque instability from a clinical perspective and on a molecular level. Patients with spontaneous embolisation detected during Transcranial Doppler (TCD) monitoring were significantly more likely to have recent symptoms and recurrent events than those patients without evidence of spontaneous embolisation. Features of unstable plaque histology including large lipid core, intra-plaque haemorrhage, plaque inflammation, neovascularisation and cap rupture all decreased with time since event from 0-28 days but then increased in prevalence thereafter. Ultrasound features found to be related to unstable plaques included Grayscale Median (GSM) <25 and plaque area >80mm[superscript 2]. Finally a predictive model was created to identify patients with a histologically unstable plaque using clinical and ultrasound parameters. Using whole-genome wide microarray and results validated using qRT-PCR in an independent cohort, expression of the CCL19 and CTSG genes were significantly upregulated in plaques from patients with unstable plaques graded according to 1. Clinical; 2. Ultrasound; 3. TCD microemboli and 4. Histological criteria. Using ELISA, serum concentration of CCL19 was significantly higher in patients with clinically and histologically unstable plaques (p=0.02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (P=0.03) with co-localisation to CD3 positive T-cell lymphocytes. In conclusion there is further evidence that plaque instability is greatest in the hyper and acute period after symptom onset. CCL19 is significantly over-expressed in patients with clinically unstable carotid atherosclerotic plaques and warrants further investigation. Clinical and non-invasive ultrasound imaging criteria can be used to predict the patient with the unstable plaque.

Stroke is a global healthcare problem with very high rates of morbidity and mortality; therefore, early diagnosis and prevention are of paramount importance. Many strokes are caused by atherosclerotic plaques in the carotid arteries, and these are often assessed using ultrasound examinations that include the measurement of the degree of stenosis. However, despite the degree of stenosis being an important clinical marker of disease severity, there is an urgent need for additional parameters that can identify high-risk, vulnerable plaques, which may be more likely to cause stroke regardless of the degree of stenosis. This thesis describes the development of techniques for measuring plaque characteristics from ultrasound image sequences, testing the hypothesis that parameters obtained from these measurements can help identify vulnerable carotid plaques. Novel methods to track plaque boundaries in ultrasound image sequences were developed (Chapters 2 and 3). This allowed the dynamic assessment of plaque echogenicity (Chapter 3), a novel method of quantifying plaque surface irregularities (Chapter 4), and the investigation of arterial wall (Chapter 5) and plaque (Chapter 6) mechanics. In the penultimate chapter (Chapter 7), these parameters were integrated in the form of a carotid plaque risk index (CPRI) and its efficacy in predicting the presence of patient symptoms was assessed. The dynamic measures of plaque echogenicity and the novel plaque surface irregularity index correlated significantly with the presence of patient symptoms. The CPRI, which combines these parameters with the degree of stenosis, improved diagnostic accuracy compared to the degree of stenosis on its own, and led to a better separation of the symptomatic and asymptomatic patient groups. The methods for characterising plaque characteristics developed in this thesis could be valuable for identifying vulnerable carotid plaques. The risk index, if its efficacy is confirmed in subsequent clinical trials, may help reduce the incidence and burden of stroke.

Parkinson’s disease (PD) is estimated to affect one person in every 800, it is a condition that affects physical appearance and individuals can experience a wide range of psychological symptoms. No previous research has directly explored visible difference or associated psychological difficulties within PD, despite research existing for other chronic health conditions. Literature Review: Using a meta-ethnographic approach, the literature review examined twelve qualitative studies exploring individuals’ experiences of PD. Seven third order constructs, grouped under four overarching main themes were identified. Individuals experienced uncertainty in adjustment and coping, and associated emotional challenges of living with PD. A sense of being trapped was reported and living with the disease undermined spontaneity, as life was constrained by routines in drug regimens and relentlessly planned activities. The review demonstrated an understanding of the lived experience of PD and highlighted the psychological demands of living with the disease. The review also indicated that specific experiences of PD were under-reported and highlighted the need for further research. Empirical study: The empirical study explored shame (general, external and body), psychological morbidity (anxiety, depression, social anxiety and fear of negative evaluation), quality of life and body image disturbance in individuals with PD. The findings demonstrated that participants experienced higher levels of general shame and body image disturbances compared to non-clinical populations and significant associations between shame and psychological morbidity were found. It was found that participants quantitatively reported low levels of shame (external and body), fear of negative evaluation and social anxiety but qualitatively expressed embarrassment, self-consciousness and associated concealment and avoidance behaviours in relation to PD symptoms. It was suggested that open-ended questions may have facilitated participants to share their experiences in comparison to responding to quantitative self-report measures alone. Interpretations of the findings, clinical implications and suggestions for future research were discussed.

Ischaemic stroke initiates pathological mechanisms that contribute to injury. Despite significant research into this area available clinical treatments are limited, highlighting the need for continued research to identify novel therapeutic targets. Previously, pre-clinical NMDA receptor antagonists have demonstrated neuroprotection, yet they have failed to translate at clinical trial. Both Glutamate and ATP release are key contributors to excitotoxic injury following stroke, therefore it is rational to consider the possibility of multi-pathway targeting as a potential neuroprotective strategy. The aim of this project was to investigate the use of the current clinically available NMDA receptor antagonist, Memantine Hydrochloride, alone and in combination with a ubiquitous P2 receptor antagonist, PPADS, within an in vitro and in vivo model of ischaemia. An in vitro neural-glial co-culture was exposed to oxygen-glucose deprivation. Memantine exacerbated cell death at high concentrations, and significantly reduced cell death at low concentrations. P2 receptor inhibition also significantly reduced in vitro cell death. Furthermore, combined low concentration treatment further enhanced the protective effect of both antagonists in vitro. However, this was not shown following treatment in vivo. Sustained mini pump Memantine administration at a therapeutic dose significantly increased infarct volume following middle cerebral artery occlusion in vivo. These results may have important implications for the selection of Memantine doses in Alzheimer’s disease patients that may also experience an ischaemic episode. This study provides evidence that low dose combined targeting of glutamatergic and purinergic excitotoxicity produces neuroprotection following in vitro ischaemia, providing a novel therapeutic target for ischaemia research. This supports the concept of combined NMDA and P2 receptor targeting as a potential therapeutic target for stroke. This study also provides evidence that Memantine exhibits a toxic action in vitro and in vivo, questioning the current use of the drug and its potential to exacerbate stroke injury.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Nigrostriatal dopamine (DA) neurons are particularly susceptible to degeneration in PD, and the concomitant loss of DA signalling in the striatum is believed to underlie the motor symptoms of PD. Transgenic rodent models expressing PD-related genes have previously revealed changes to DA synapse function as one of the earliest stages of PD progression, often preceding protein aggregation and cell death. However, such models often rely on foreign gene promoter elements that do not accurately replicate the genetic expression pattern and protein levels found in PD. This thesis explores the electrically evoked release of two monoamines, DA and 5- HT (serotonin), in mice that express wild-type human (-synuclein at a range of levels, through a bacterial artificial chromosome vector (BAC), on a mouse synuclein-null background. Potential mechanisms underlying monoamine neurotransmission deficits were also investigated. Furthermore, this thesis explored the evoked release of DA in BAC transgenic rats that express the G2019S and R1441C mutant forms of the human Leucine-rich repeat kinase 2 (LRRK2) gene. All of the models covered express PD-related genes under regulation of endogenous promoter elements, which increases the physiological relevance of gene expression pattern and levels of gene expression in comparison to transgenes with foreign promoters. Fast-scan cyclic voltammetry, using carbon fibre microelectrodes, was used to sample electrically evoked DA and 5-HT in acute brain slices. High performance liquid chromatography was used to determine DA content. Mice that express relatively high levels of human (-synuclein (SNCA-C mice), at approximately double the level ofWT mice, have a -30% deficit in evoked DA release from the dorsal striatum, but not the ventral striatum, when compared to control mice (Snca -j-). Investigations performed here showed that the DA release deficit depends on the level of human (-synuclein expression. It was also identified that SNCA-C mice do not have detectable changes to the responsiveness ofDA D2 autoreceptors that regulate DA release. However, DA release in SNCA-C mice was more responsive than Snca -j- controls to the vesicle mobilising properties of cocaine, which suggests altered vesicle mobilisation as a possible mode of action for (-synuclein overexpression. No changes to 5-HT release, explored in substantia , nigra, were observed in SNCA-C mice suggesting that the deficit in neurotransmission does not apply to all monoamines. Rats that express the G2019S or R1441C mutant forms ofLRRK2 revealed an agedependent deficit of evoked DA release in the dorsal striatum, but not the ventral striatum. This deficit in DA release was not accompanied by changes to striatal DA content or the rate of DA uptake, which suggests a change in DA releasability. Taken together, these data suggest that PD related forms of SNCA and LRRK2 cause changes to DA function by affecting DA releasability from axons. Findings presented here are in agreement with other literature to suggest changes in DA synapse function as one of the earliest stages of PD pathophysiology, and may contribute to a deeper understanding of the molecular mechanisms involved in PD.