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This thesis describes the extensive evaluation of a population-based cohort of children following arterial ischaemic stroke (AIS). AIS is an important cause of acquired brain injury in children. Children with new onset AIS over a one year period living in the southern part of England were prospectively identified using mUltiple sources of ascertainment and then followed-up at 12 months post-AIS to assess outcome using a comprehensive range of assessment tools. The study identified 96 incident cases of AIS giving an incidence rate of 1.60 per 100,000 per year. Infants had the highest rate of AIS. Black and Asian children were at increased risk compared with White children. Capture-recapture analysis was used to estimate that the study ascertained 88% of cases. In most cases (83%) at least one underlying risk factor for AIS was identified. Risk factors varied by age and ethnicity. The case fatality rate was 9%. Children with underlying chronic systemic conditions had the the highest risk of death. The recurrence rate of 1 % was the lowest ever reported for a large study of childhood AIS. Using assessment tools validated for use in childhood AIS, parents judged 34% of children to have fully recovered and 44% of physician assessed children made a good outcome. The sensorimotor domain was the most affected but increasing age was associated with better sensorimotor outcome which disagrees with the commonly held view of increased plasticity in younger children but may be in-keeping with the phenomenon of early vulnerability. A range of other domains including cognitive and language domains, adaptive behaviour, participation, behaviour, and quality of life were assessed.

The aim of this doctoral thesis was to investigate the genetic variation underlying ischaemic stroke and its subtypes, and to determine how this genetic variation is related to other diseases such as Alzheimer's Disease. First, a genome wide meta-analysis was performed as part of the METASTROKE collaboration (12,389 cases, 62,004 controls) to validate existing associations with ischaemic stroke, and to attempt to identify novel associations. Four existing associations were validated, however no novel associations could be identified. Secondly, a number of approaches were taken to evaluate the hypothesis that early onset cases of ischaemic stroke subtypes have a stronger genetic predisposition. All known associations with ischaemic stroke subtypes were found to have stronger effects in younger onset cases, evidence was found genomewide of stronger effects in younger onset cases, and younger onset cases were found to have higher heritability. Thirdly, a covariate-informed approach to genetic association analysis was investigated to determine if such an approach has more power than conventional approaches to detect associations with ischaemic stroke and its subtypes. An age-at-onset informed approach was found to have more power than standard analysis. The approach was used to identify a novel association of an MMP12 locus with large vessel disease stroke, which was found to be overexpressed in carotid plaques compared to controls. Finally, a genetic risk score approach was used to evaluate the shared genetic contribution to ischaemic stroke and Alzheimer's Disease. A significant genetic correlation between the two diseases was identified and the association was considerably stronger for the small vessel subtype of ischaemic stroke.

Community genetic studies provide an important opportunity to discover the genetic basis of new inherited diseases, while at the same time providing impacting medical benefits for the communities involved. Discovering a disease gene provides important insights into the molecular genetic basis of an inherited disease. Once the genetic cause of a disorder is established, diagnostic testing may be performed to provide affected families the chance of early diagnosis and treatment intervention, support may be provided via premarital or prenatal counselling, and educational benefits may be provided regarding the causes and nature of inherited disease. This thesis involves the molecular genetic investigation of three novel neurological conditions. The first of these, a complex form of hereditary spastic paraplegia (HSP) associated with developmental delay (GM2 synthase deficiency), was found to be caused by mutations in the 84GALNTl gene. The disorder was discovered in families from Kuwait, · , : Canada and the Amish. The biochemical outcome of altered ganglioside biosynthesis, leading to GM2 synthase deficiency, was confirmed using HPLC and mass spectrometry. The second condition, neurodevelopmental delay associated with speech disorder in a large Amish kinship, was found to be caused by a missense mutation in the HERC2 gene. Encoded mutant HERC2 protein was found to have a reduced half-life compared with its wild-type counterpart, leading to a significant reduction in HERC2 levels in affected individuals. e The third genetic condition was found to be caused due to missense mutations at a mutation hotspot in the TFG gene leading to both pure and complex forms of HSP in a British-Pakistani consanguineous family, and an Indian family in which parents were not known to be related. Two different missense mutations resulting into two different amino acid outcomes at the same highly conserved amino acid residue in the TFG gene caused this condition. Thus, the molecular genetic investigations defined here identify new molecular causes of neurological disease and define genes which are essential for normal neuronal development. More in-depth investigation of the disease mechanisms underlying these conditions may in turn translate into providing treatment therapies for affected families in near future.

GNB1L is a novel gene located in the 22ql1.2 DS critical region. It has been genetically implicated in the psychiatric subtypes of 22qll.2 DS including schizophrenia and autism. Previous research suggests that GNB1L is important in the brain, but has shed no light on a potential function. The aim of this current investigation was to begin characterising Gnbll and its role in the brain. This was in order to elucidate a function of GNB1L, and therefore identify a possible pathogenic mechanism in which it may contribute to psychiatric subtypes of22ql1.2 DS. Gnbll+/ - lacZ gene-trap mice demonstrate deficits in pre pulse inhibition of the startle response, a characteristic of psychosis in humans. In these mice, strong, region-specific, Gnbl1 expression was observed in embryonic and postnatal brain stages of development. Prominent regions of expression included the cerebral cortex, hippocampus, and cerebellum. There was consistent expression in these regions, indicating that Gnbll may play a role in their development and function. A brain specific yeast two-hybrid assay linked Gnbll to proteins with known brain specific functions. From this assay, and a previous yeast two-hybrid, a review of Gnbll protein interactions revealed many links to the canonical Wnt signalling pathway. This pathway is essential for regulation of key events in neurodevelopment, and plays a significant role in the adult brain. A GST pull-down assay confirmed Gnbll interaction with Hipkl, a regulator of the Wnt signalling pathway, which has importance in the developing cerebral cortex. Investigations in vitro revealed that both HIPKl and GNB1L negatively regulate Wnt target gene expression through inhibition of ~ catenin activity. Further assays found potential inhibitory mechanisms of GNB1L and HIPKl in the pathway. Disrupted Wnt signalling has been previously implicated in pathophysiology of psychiatric disorders, and components of the pathway are commonly used as drug targets for treatment of psychosis. This thesis provides a novel functional role for GNB1L, and further implicates deficits in Wnt signalling as a potential pathological mechanism of psychosis in 22ql1.2 DS patients. This may lead to better diagnosis and treatment of these patients in the future.

Background: Defence Medical Rehabilitation Centre (DMRC) Headley Court is the UK Defence Medical Services' premier rehabilitation facility and since 2008 it has provided the DMS Centre of Excellence for mild traumatic brain injury (MTBI). In response to concern over the potential incidence and significance of MTBI in the UK armed forces, as well as much media and parliamentary interest in this so-termed 'signature injury', DMRC established a four phase treatment programme for UK service members with suspected MTBI. The focus of this thesis is Phase 2 of this treatment programme: a psycho educational intervention for military personnel who report persistent symptoms following an MTBI event. Aims: This thesis aimed to provide empirical evidence regarding the effectiveness of the Phase 2 intervention, and to explore patients' experiences of both MTBI and their treatment at DMRC Headley Court. Methods: The thesis consists offive studies using quantitative and qualitative methodologies. Results: First, a cohort study compared those who had completed the Phase 2 intervention (n =55) to a control group (n =73) and found that treatment was associated with a lower impact of symptoms relating to memory and emotions. However, it was also associated with a greater impact of executive functions symptoms. Further, the results also showed that a longer delay between MTBI events and clinical assessment was related to poorer outcomes following the intervention. Second, a qualitative study using semi-structured interviews (N=16) revealed that MTBI is experienced as a highly disruptive event, initially characterised by a sense of chaos and confusion. Third, a further qualitative analysis (N=16) indicated that the Phase 2 intervention is experienced as flexible and tailored, and that it helps to reestablish order and continuity. Fourth, an experimental design was used to explore the effect of the intervention on positive psychological change following MTBI using the emotional Stroop task (N=22). The results showed no differences in attentional bias between Phase 2 patients and MTBI controls. However, all participants reported greater benefit finding over time. Finally, in a second experimental study, Phase 2 patients were compared to controls in terms of their ability to manage a stress inducing task (N=23). No group differences in cardiovascular reactivity were observed, but the Phase 2 patients reported feeling more stressed generally. Conclusion: The results suggest that MTBI can generate a sense of chaos and confusion. The Phase 2 intervention at DMRC Headley Court helps to reduce symptoms relating to memory and emotions and is experienced by service members as bringing order and stability into their lives. To conclude, early intervention following MTBI shows promise for improving related symptom experience. Treatment may need to be longer than 12 weeks to bring about changes in benefit finding and stress management.

Behavioural and psychological symptoms of dementia (BPSD) are common features of dementia, affecting up to 98% of patients with dementia. BPSD is a term expressing a heterogeneous group of non-cognitive symptoms that include psychosis, depression, agitation, and aggression. These symptoms are very distressing for all concerned and can also result in considerable social and economic costs. Antipsychotics are sometimes used to manage BPSD and their use has been linked to serious side-effects particularly stroke and an increased risk of death and this topic has been the subject of great controversy in recent times certainly since the publication of the government-commissioned Banerjee report into the use of antipsychotics for people with dementia was published in 2009 which revealed the problem of antipsychotic prescribing in dementia. This prompted the UK government to take a number of measures, such as introducing the National Dementia Strategy in 2009 and auditing of antipsychotics prescribed for patients with dementia. Yet despite warnings from agencies and the recommendations by the National Institute for Health and Care Excellence, inappropriate antipsychotic prescribing has not completely stopped. The reasons for this are multifactorial and health professionals' views about it are not extensively documented through research. In fact, dementia is still considered one of the biggest challenges facing society, the Dementia Challenge was launched in 2012 by the Prime Minister to deliver faster improvements in dementia care and research by 2015. I sought to explore, understand and explain the views of a range of healthcare professionals and personnel involved in the formal care of patients with dementia in relation to the prescribing of antipsychotic drugs in this patient group in formal settings. My aim was to generate a Grounded Theory about the complexities that exist in real practice that impede appropriate prescribing of antipsychotics for patients with dementia. I conducted twenty-eight qualitative semi-structured face-to-face interviews in 2012 and 2013 with health professionals from a variety of settings in one county in the UK. My research proposal was approved by the University of Reading Research Ethics Committee, and the participating NHS organisations. I developed a detailed theory, grounded in the data, outlining the complex nature of the problem which explains why anti psychotics might continue to be prescribed in dementia. I developed three thematic categories from the data and integrated these into one core category named 'Caught in a cleft stick? Difficult decisions in challenging circumstances' that accounts for instances where the prescribing of antipsychotics in dementia by GPs still takes place. BPSD is problematic, affecting patients and carers in different ways.

The CLU gene is associated with Alzheimer's disease (AD). With its protein, clusterin, having the ability to bind to various ligands, such as amyloid beta, thus it has become a worthy target in AD research Therefore, the focus of this thesis was to investigate the implications of clusterin within mild cognitive impairment (MCI) and AD. Aims and Objectives This thesis encompassed four main studies. The first investigated if SNP rs11136000 influenced plasma clusterin in MCI and AD, compared to an age-matched cognitively healthy control group. The second study assessed if plasma soluble receptors (sLRP1 and sLRP2) were related to clusterin in MCI and AD. The third was a method development study to isolate high-density lipoproteins (HDL) from smaller volumes of plasma than previously used. The fourth study investigated if the function of HDL was altered by MCI and AD. Results In the first study, plasma clusterin levels were higher in the MCI and AD groups, compared to the control group, with the MCI group having the highest levels. In the second study, although sLRP1 were similar, sLRP2 decreased in the AD group, compared to the control and MCI groups. The third study showed that HDL could be isolated from a smaller volume of plasma without loss of detection ability. The final study identified increased SAA and decreased clusterin and LCAT inAD. Discussion and Conclusion Overall, this thesis has demonstrated various clusterin and soluble receptor-related changes in those with cognitive decline and that the presence of AD influenced the proatherogenic phenotype of HDL. In conclusion, observing such changes in cognitive decline may be useful biomarkers, as well as targets for therapies towards delaying the onset of such an irreversible disorder.

Alzheimer's disease and Parkinson's disease dementia syndrome are progressive brain disorders which lead to dementia. Attempts to develop disease-modifying therapies have been frustrated by an incomplete understanding of the pathogenesis of these debilitating disorders. In Alzheimer's disease cognitive deficits may be explained by oligomeric amyloid-β that initiate a cascade of events that culminates in dementia. In Parkinson's disease dementia syndrome the aggregation of α-synuclein into oligomers is considered the disease-causative toxic mechanism in the disorder. The work reported in this thesis employed animal models of learning and memory to evaluate the therapeutic efficacy of putative small therapeutic molecule compounds in the alleviation of behavioural symptoms related to Alzheimer's disease and Parkinson's disease dementia syndrome. The emphasis on small molecule compounds was deliberate, as these are the most likely to be orally bioavailable and blood-brain barrier penetrable. The experimental results showed that oligomeric amyloid-β is associated with the cognitive deficits found in Alzheimer's disease. Similarly, the formation of α-synuclein into oligomers appears to be the disease-causative toxic mechanism in Parkinson's disease dementia syndrome. The major finding in this thesis is that pharmacological targeting of these toxic oligomeric mechanisms may protect against the onset or slow the progression of Alzheimer's disease and Parkinson's disease dementia syndrome.

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