Dementia affects over 750,000 people in the UK (Alzheimer’s society, 2003). Clinicians and healthcare managers report dissatisfaction with current healthcare options available for people with dementia (Stubbings & Sharp, 1999). Multisensory Environments (MSEs) utilising advanced sensory stimulating equipment targeting the senses, have been successfully used in dementia care, severe learning disabilities and palliative care (Baker et al, 1997). Despite this, no controlled studies have been conducted to explore the efficacy of this intervention on functional performance. This study explores to what extent, if any, MSEs influence function, mood and behaviour of people with moderate / severe dementia compared with a control activity (gardening). In addition, sensory needs were identified using the Adult Sensory Profile to explore whether sensory preferences are associated with improved performance. Participants were selected from people with a diagnosis of moderate / severe dementia. They were randomly allocated to one of two groups (MSE or gardening). Following baseline assessment, each participant attended their allocated intervention 3 times a week for 4 weeks. Assessment was carried out before and after each session using the Assessment of Motor and Process Skills (function) and the Neurobehavioural Rating Scale (mood and behaviour). Results revealed a significant main effect of intervention in both function and mood and behaviour. Sessional analysis revealed significant improvement in motor performance for the MSE group. Overall, both activities were found to improve function and mood and behaviour. Participants who attended the MSE group and improved significantly in function fell within the low registration quadrant of the sensory profile. This suggests that the MSE is more suitable for those who require increased sensory stimulation. This study supports the use of sensory activity for people with moderate / severe dementia and recommends the use of the PAL and Adult Sensory Profile to plan and facilitate activity.

Learning can be explicit or implicit. Explicit learning takes place intentionally, in the presence of factual task-relevant knowledge; whereas implicit learning takes place unintentionally, without concurrent acquisition of knowledge about task performance. The relative benefits of implicit learning have been well investigated within healthy populations. Research consistently demonstrates that skills learnt implicitly are more likely to be retained, and are more robust under secondary task load. However, study protocols tend to involve laboratory based activities, which do not take into account the complexities of motor learning in natural settings. Direct transferability of the findings to stroke rehabilitation is therefore questionable. Two factors in explicit and implicit learning are the concepts of attentional capacity and attentional focus. Attentional capacity refers to the ability to attend to and process incoming information, whereas attentional focus refers to the location of attention in relation to specific aspects of the task being performed. Theories propose that focussing on specific movements (internal focus) may actually constrain or interfere with automatic control processes that would normally regulate movement, whereas if attention is focussed towards the movement effect (external focus) the motor system is able to more naturally self-organize, resulting in more effective performance, and learning. An internal focus of attention is therefore allied to explicit learning; whilst an external focus of attention is allied to implicit learning. This research aimed to improve understanding of explicit and implicit learning within early gait rehabilitation post stroke; primarily through the development and testing of explicit and implicit models of learning interventions. It has comprised three phases; a review of the literature; an observational study to gain insight into current practice; and a feasibility study to test the ability of therapists to deliver interventions with a bias towards either an explicit or implicit approach. Therapists were found to favour the use of explicit techniques; internally focussed instructions and feedback statements were used in high quantities. Practice therefore appeared to be at odds with current evidence; albeit primarily from healthy populations. Guidance for the delivery of explicit and implicit learning models in clinical practice was developed, and then tested in a feasibility study. Therapists demonstrated the ability to change their practice to bias either explicit or implicit learning; both approaches were found to be acceptable to patients and therapists. Recommendations are made on the content and evaluation of explicit and implicit learning models in future research, and specifically, in a Phase II pilot study.

Background: Schizophrenia has long been considered to be remarkably heterogeneous, and there have been a number of attempts to identify sub-groups of this disorder which are more homogeneous. Nevertheless, most of these have not been used in either research or clinical practice to any great extent, because diagnoses by way of these strategies would be unstable over time and impractical. In such circumstances, the vulnerabilitystress model has led to the development of a new concept of sub-grouping schizophrenia into 4 sub-types – drug related, traumatic, anxiety, and stress sensitivity. This conceptualisation is quite promising, not only because it may provide stable and practical diagnoses, but also because the terminology used therein is useful when it comes to destigmatising those who are currently diagnosed with schizophrenia. Methodology: In order to adapt this concept for practical use, this project set out to develop a semi-structured interview for making diagnoses according to it. Thereafter, psychometric properties of the interview were examined. This assessment tool was then used to confirm the longitudinal stability of the diagnosis. In order to establish the construct validity of this classification system, it was examined if the anxiety and stress sensitivity sub-groups in this system were different in terms of their external validators. Three psychopathological variables – evaluative belief, fear of negative evaluation from others, and depression – were assessed in a cross-sectional study during this process of validation. Three other clinical variables – two for the duration of hospitalization and one for the risk of self harming – were also used in a retrospective cohort study for the evaluation of the predictive value of the differentiation. Results and conclusion: Both the English and Japanese versions of the semi-structured clinical interview for psychosis sub-groups (SCIPS) were developed to sub-group patients into 4 categories, and their reliability and concurrent validity were established. The 6 month stability of SCIPS diagnoses of the drug related, anxiety and stress sensitivity sub-types was also indicated through a longitudinal study. A preliminary analysis provided little evidence of construct validity. The risk of self harming was, however, suggested as being associated with a distinction between the anxiety and stress sensitivity categories when the SCIPS was applied to a broader range of psychosis, including schizophrenia and schizoaffective disorder.

The negative behavioural and emotional symptoms of Post-Traumatic Stress Disorder (PTSD) have been extensively reported in the literature. However, much less is known about the neuropsychological and neurobiological characteristics of the disorder. This thesis consists of two papers, the first being a review which highlights the emerging picture of literature in the field of neuropsychology in PTSD, with particular reference to findings in those cognitive domains of general intellectual functioning, memory, attention and executive function. Given that the findings associated within these domains are mixed, the second paper reports the outcome from a neuropsychological study of cognitive differences that was conducted to contribute to current knowledge in the area of neurocognition and visual memory in PTSD in particular. Trauma exposure, current PTSD, depressive and anxiety symptoms and performance on a range of neuropsychological tests were examined in tertiary care outpatients with PTSD (n=26), individuals who had been exposed to severe trauma but without current PTSD (n=26), and healthy controls (n=26). In addition to previously reported deficits in verbal learning and fluency in PTSD, deficits in visual spatial memory were also found. These observable deficits in visual memory may reflect characteristic features of PTSD, such as reported difficulties in remembering certain aspects of traumatic events and the presence of visual flashbacks. It is uncertain whether these deficits represent a risk factor for PTSD, or a consequence of trauma, as suggested by research in animal models.

The ergochromes possess useful anti-tumour properties whilst chromones are useful drugs for the treatment of allergic asthma. The aim of the project was to synthesise ergoflavin or an analogue for the first time, and to this end novel synthetic methods for a, 6-unsaturated ketones and oxygenated dienes were developed. Two major routes are described: The first uses aliphatic starting materials and allows the construction of highly substituted chromones by an intramolecular Diels-Alder reaction. To achieve this a synthetic method to novel phenylthio substituted 3-unsaturated ketone equivalents ( a'-phenylthio-3-amidoketones) was developed. It consisted of nitrile oxide additions to l-phenylthioprop-2-ene, whilst additions to 1-phenylsulphinyl-l,2-propadiene were also investigated, The second route involved the use of a preformed aromatic ring and; (a) an intramolecular Diels-Alder reaction to form a pyrone ring or - (b) an intermolecular Diels-Alder reaction and subsequent Friedel-Crafts cyclisation to give a pyrone ring. For this, a selenium dlene protection, alkylatlon and deprotection methodology was developed. Depending upon the substrate and oxidative conditions a, 3-unsaturated ketones, allylic alcohols, dienes and lactones were obtained, A second route to 4-oxygenated-l,3-butadienes provided the impetus to develop a titanium reagent for the oleflnation of 4-substltuted-3-buten-2-ones, Finally, an investigation into radical cyclisatlons of allylically substituted phenylseleno substrates was made.

This thesis represents an attempt to further our knowledge of the ophthalmic complications of spina bifida and hydrocephalus by means of literature review and a long term clinical study, and to determine whether regular ophthalmic supervision can assist in the general management of affected children. The ophthalmic complications of spina bifida have often been reported in the literature and thought to merit regular supervision of affected children, yet few centres currently offer this service. In this study 322 children attending one regional centre were examined repeatedly over a six year period by one ophthalmologist. Ophthalmic complications were found to be very common. They frequently provided evidence of raised intracranial pressure due to shunt dysfunction even when other objective evidence was lacking. Every spina bifida and hydrocephalus clinic should have an ophthalmalogist in its medical team. Preservation of visual function and early diagnosis of raised intracranial pressure in these children should result from this arrangement.

Intrinsic protein folding pathways are modulated by molecular chaperones, such as the diverse group of heat shock proteins (Hsps). Among these is the small heat shock protein (sHsp) family which in the mammalian genome consists of 10 low molecular weight (15-30kDa) members. The sHsps have classical chaperone functions but additionally contribute to pathways that protect against cellular stresses, maintain the cytoskeleton, prevent protein aggregation and regulate apoptosis. They contain a characteristic C-terminal α-crystallin domain, which is exclusive to the sHsp family. In addition to their constitutive expression under physiological (non-disease) conditions, they are also induced under conditions of stress/heat shock which is thought to play a role in response to protein misfolding that underpins disease. There are a wide range of diseases in which the sHsps function or are dysfunctional by mutations, such as neurodegenerative disorders, cataract, and desmin related myopathy. Each of the 10 sHsps is believed to have a unique expression profile. Seven of the sHsps are expressed in heart and muscle, but little is known about their precise expression and/or physiological role in the CNS. In the present study the expression of the mammalian sHsps in various mouse tissues including the brain was investigated. This provided evidence for the constitutive expression of 4 sHsps in the brain. In situ hybridization using naïve adult mice revealed a distinct white matter (oligodendrocyte) specific expression pattern for HspB5 (αBcrystallin). HspB1 (Hsp25) and HspB8 (Hsp22) demonstrated overlapping expression in the lateral and dorsal ventricles of the brain, as well as expression in a distinct set of motor neurons in the ventral horn of the spinal cord. Further, cellular immunostaining and subfractionation of brain tissue supports a distinct cellular and subcellular protein expression of HspB1, HspB5, HspB6 (Hsp20) and HspB8 in the brain. Both HspB5 and HspB6 were enriched in the myelin fraction. In view of the potential for induction of these sHsps by stress and modulation in chronic brain diseases we systematically investigated the sHsp signature in two distinct models of intracellular (R6/2) and extracellular (ME7) proteinopathies. These models recapitulate key features of Huntington’s and prion disease, respectively. Analysis of the sHsps in the R6/2 Huntington’s disease (HD) mouse model showed a specific down-regulation of HspB5 in the white matter at all time points analyzed. All other sHsps investigated did not change in this model of HD. Analysis of the sHsps in ME7 prion disease showed up-regulation of HspB1, HspB5 and HspB8 in the hippocampus. For HspB1, this was selective to an anatomically defined sub-population of astrocytes distributed in the stratum radiatum. In contrast, all GFAP positive astrocytes throughout the hippocampus exhibited induced expression of HspB5 and HspB8. Based on QT-PCR data, the changes in expression of the sHsps in either model was not under transcriptional control, suggesting translation/posttranslational regulation. The differing results in the two models suggest that the presence of intracellular (R6/2) or extracellular (ME7) aggregates may dictate the sHsp response associated with non-neuronal cells. In view of the emerging significance of non-neuronal cells in chronic diseases the data supports adaptive and differential responses that might contribute to and/or provide a route to therapy of distinct aspects of neurodegeneration.

Huntington's Disease (HD) is one of many neurodegenerative diseases that are associated with protein misfolding, aggregation and oxidative stress. While several changes in the redox homeostasis have been shown to occur in HD animal models and HD brains, the formal relationships between intracellular protein misfolding that occurs in HD, redox dysregulation and cellular toxicity are unknown. Therefore, several cellular models of intracellular polyglutamine (polyQ) protein misfolding were established for mechanistic studies. Various in vitro transient and stable cell expression systems expressing an N-terminal fragment of huntingtin (htt) (httExon 1, httEx1) with/or without a polyQ expansion and fused to fluorescent proteins were characterized. Mutant httEx1 (mhttEx1) constructs expressed in both neuronal and non-neuronal cell lines produced early polyQ aggregates and intracellular inclusion bodies (IBs) followed by cell toxicity that increased over time in time-course experiments. Using oxidation-sensitive probes, reactive oxygen species (ROS) were measured in polyQ-expressing cells using single, live-cell imaging analysis by confocal microscopy or population assays in order to explore the relationship between polyQ aggregation, ROS production and cellular toxicity. This study highlighted an early increase in ROS due to the expression of aggregation-prone mhttEx1 in both transient and stable cellular systems that coincided with polyQ aggregation, but preceded cell death. Suppression of ROS and toxicity was achieved by two antioxidant compounds (L-NAC and Trolox). Moreover, the use of MitoQ (Coenzyme Q10 covalently attached to triphenylphosphonium cation (TPP+)) at nanomolar concentrations abrogated the increased ROS due to mhttEx1 suggesting a mitochondrial origin of ROS. Given that molecular chaperones regulate the folding/misfolding of proteins and are involved in the regulation of the cellular redox homeostasis, the role of the redoxactivatable chaperone DJ-1 in HD was investigated. Protein expression analysis in HD cell models, a rodent model of HD and human HD brain samples showed an up-regulation of DJ-1 protein expression compared to control samples. Oxidation of DJ-1 was also elevated in the human HD cortex. To test for a functional role of DJ-1 elevation and oxidation in HD, DJ-1 was overexpressed with wild-type or mhttEx1 in cell lines and mouse primary astrocytes. Overexpression of DJ-1 accelerated mhttEx1 aggregation and toxicity both of which could be suppressed by exposure of cells to mild oxidants suggesting that DJ-1, when redox-activated to a chaperone, modulates polyQ aggregation and toxicity. This hypothesis was tested by overexpression of mhttEx1 with a DJ-1 mutant lacking a critical redox activatable cysteine (Cys106). The C106S-DJ-1 mutant lost its ability to reduce polyQ aggregation and toxicity under oxidising conditions upon co-expression with mhttEx1 suggesting that DJ-1 indeed functions as a modulator of polyQ misfolding and toxicity. Together this work suggests that ROS may be produced during polyQ aggregation and is involved in cellular toxicity. This study also shows that DJ-1 regulates both, polyQ aggregation and toxicity in cell models and given the increased DJ-1 expression in vitro and in vivo (human HD), this protein could be a potential target for HD therapy.

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