Cytoplasmic dynein is a multisubunit complex responsible for the transport of cellular components from the cell periphery towards the nucleus. The role of the dynein complex in vesicle trafficking, organelle positioning and chromosome segregation during mitosis has been extensively studied but still little is known of specific roles of distinct subunits of the complex. Cytoplasmic dynein is a dimeric complex consisting of heavy chains, intermediate chains, light intermediate chains and three light chains. In order to investigate the roles of the cytoplasmic dynein subunits, two mouse lines with chemically generated single point mutations in the intermediate chain 1 and 2 genes (Dync1i1, Dync1i2) were subjected to a behavioural analysis. The mouse line carrying a mutation in the intermediate chain 2 showed working memory deficits which suggested impairment in hippocampal functions. In order to examine the effects of mutation at the cellular level primary mouse embryonic fibroblasts (MEFs) lines were derived from embryos carrying mutations in the intermediate chains and used as a model system. Cell functions, such as trafficking of epidermal growth factor (EGF) positive endosomes, Golgi assembly were examined. Furthermore, biochemical analyses were performed focused on the expression of dynein subunits and their assembly in the functional complex. Alternative splicing is known to produce multiple isoforms of the intermediate chains. The analysis of various splice variants of these genes in a panel of mouse tissues resulted in detecting new isoforms which were compared with bioinformatics data available for human and rat thus establishing the splicing pattern of the mouse intermediate chains. Legs at odd angles (Dync1h1Loa) is another mutant mouse line carrying a point mutation in the dynein heavy chain which results in neurological defects. Here the effects of the Loa mutation in the trafficking of membranous organelles were investigated by an infection of cultured MEFs with Salmonella enterica serovar Typhimurium. Furthermore, upon the induction of a cellular stress the wildtype and the Loa homozygous cells showed significant differences in stress granule assembly suggesting the impairment in the stress signaling.

This thesis investigates the neuroimaging and neuropsychological characteristics of Posterior Cortical Atrophy (PCA) which is most often caused by Alzheimer’s disease (AD) pathology. Posterior cortical atrophy describes a predominantly posterior pattern of atrophy and cognitive deficits. PCA has been poorly characterized and is likely to have been under-recognized. Using magnetic resonance imaging (MRI), patterns of cortical thickness were assessed in patients with pathologically-confirmed AD and different clinical presentations during life (including amnestic, visual and behavioural phenotypes). In addition to atrophy in the medial temporal lobe, tissue loss in posterior regions is indicative of AD pathology. Since medial temporal lobe atrophy is not specific to AD, posterior atrophy may aid distinction between AD and other dementias. Using easily-applied visual rating scales for medial temporal and posterior atrophy in patients with pathologically-confirmed AD and frontotemporal lobar degeneration (FTLD), it was shown that posterior atrophy ratings improve classification accuracy of AD from FTLD and controls. Cross-sectional and longitudinal image analysis techniques were used to characterize atrophy patterns in PCA compared with controls and typical amnestic AD. Whilst the cross-sectional analysis revealed differential patterns of tissue loss in these two groups, with PCA showing greatest atrophy in posterior parietal regions, and typical AD predominantly in medial temporal lobe regions, longitudinal results showed that at five years disease duration, both PCA and typical AD had global grey matter loss and cortical thinning compared with controls. The nature of visual deficits in PCA was assessed by administering detailed neuropsychological tests. The behavioural data showed that visual deficits were not uniformly affected in PCA, with considerable heterogeneity of visual impairments shown. Cortical thickness measures were used to assess atrophy patterns in PCA patients with predominant space versus object perception impairments, revealing overlap in cortical thinning patterns between these two PCA subgroups. In summary this thesis investigates the common and differential atrophy patterns of atypical AD presentations as well as the degree of heterogeneity of deficits which exist within the PCA presentation.

Despite its generally low annual global incidence rate, Creutzfeldt-Jakob disease (CJD) has become a subject of considerable interest in recent years. This is due to concerns that there may be a possible causitive link with Bovine Spongiform Encephalopathy and that this may forewarn of a future epidemic of CJD in Humans. Despite recent discoveries of CJD related abnormalites in lymph-node tissues, in-vivo diagnosis of CJD is difficult and relies on a series of clinical tests and observations to provide a probabilistic diagnosis of the disease. The confirmed diagnosis is currently only obtainable via biopsy or post-mortem histology. Medical imaging, specifically Magnetic Resonance Imaging (MRI), may offer a potential in-vivo diagnostic aid due to the reported presence of observable abnormalities in the MRI of CJD patients. To date research in this field has been hampered by a general lack of clinical data and the published work has been forced to consider exclusively the results of in-vivo MRI measurements. The National Creutzfeldt-Jakob disease Surveillance Unit in Edinburgh, U.K. has compiled a large and unique MRI dataset of post-mortem images of the Human brain from all deceased patients whose clinical presentation suggested CJD. Post-mortem confirmation of diagnosis is also held. This thesis describes the findings of an investigation to evaluate the potential of this post-mortem MRI dataset to provide diagnostically useful information in the task of assessing the CJD status of a patient. It uses image intensity analysis based tests to provide results whose performance may be compared to the accepted radiological methods of visual inspection of hard-copy data. By plotting distributions of statistical intensity metrics for specific regions of interest, known to have shown abnormalities in in-vivo MRI cases, the relationship between the MR image intensity for these regions and the ultimate patient diagnosis was determined. Additional work investigating methods for determining shape and intensity symmetry, which can help differentiate between disorders, is also described. Through the analysis of specific brain regions, it is shown that the MRI tests described display sensitivity to the condition of CJD. Future work is needed to investigate whether equivalent results can be produced by similar tests on in-vivo MRI data, when this becomes available. This could potentially offer a useful non-invasive pre-mortem test for CJD that would aid the task of clinical patient assessment.

The cytokines, a family of poly-peptides that are central to the coordination of the inflammatory response, exert significant influence on the progression of acute cerebral ischaemic injury, or 'stroke'. Evidence has accumulated for a similarly significant role for cytokines in physical repair and neurological recovery after stroke, via actions within the injured central nervous system and through mediation of peripheral inflammation. This thesis addresses the spatio-temporal expression profile of cytokines in response to cerebral ischaemia in the rat, and the influence of elevated peripheral cytokine concentration on physical repair of the CNS.

No description available.

Psychological models of motor control, although often developed by work with people who have specific pathologies, have been contained very much within the academic sphere of psychology. Physiotherapy and methods of movement rehabilitation have also been developed within the bounds of one profession. With the increasing trend towards working in multidisciplinary settings the opportunity now exists more readily to cross professional boundaries and integrate these two separate knowledge bases in order that better rehabilitation programmes can be developed and in recent years this has begun to happen. With this in mind the research reported here set out to investigate the motor function of stroke patients who have reached a plateau of motor recovery, using dual task methodology. Two experiments were conducted, one involving the "automatic" movement of walking and the other more controlled hand and finger movements. In addition to information about movement it was hoped to investigate whether there was evidence for more than one central information processing system. The results of the walking experiment were inconclusive because of a number of methodological issues which are discussed. The results of the second experiment indicate that there may be evidence for more than one central information processing system. They also showed that in a dual task situation stroke patients differentially allocate their cognitive resources in favour of the movement task. These results are interpreted in terms of stroke patients monitoring their movement more closely. The, results are discussed in terms of a psychological framework of movement control, and issues are raised about whether physiotherapists could make use of this type of approach in developing movement rehabilitation programmes for stroke patients.

The aim of the study was to evaluate the effectiveness of a night hospital nursing service for elderly people suffering from dementia; in particular, to establish the appropriateness of night support for this group and their carers. The study developed as a result of previous work that demonstrated that some carers requested "inpatient" admission for their relative/friend because of the stress of providing support and supervision at night. The research methods involved an evaluative structure - process - outcome, quality assurance and case study approach. An operational policy for the service was drawn up, as were nursing standards (process) . The service was evaluated over a two year period. Patient outcomes were measured using a visual analogue scale at intervals over six months to identify behavioural changes. Similarly, carers' feelings of anxiety and coping ability relating to their caring role were measured. Changes in patient behaviour and carer anxiety and felt ability to cope were analysed using the Wilcoxon matched-pairs signed ranks test. Carers were interviewed to elicit the effects their relatives' attendance at CREST had on their day to day lives. Changes in the use of community care services as a result of CREST were also identified. The sample consisted of 38 patients and their informal carers. Nursing activity was observed using non-participant observation to establish both the type of activity and peak work load periods. The results demonstrate that CREST had a positive outcome in terms of supporting patients' carers and that patients' behaviour did not change significantly while attending the night hospital. This latter result has been interpreted as a positive outcome in that people suffering from dementia can be expected to deteriorate over time. In conclusion it is anticipated that the results of this study have significance for planning nursing services for the care group involved and should assist in identifying the number and grade of staff needed to deliver optimum care at night to elderly people with dementia. Recommendations for changes in the operational policy have been made which will assist managers in planning new services. The research suggests that new nursing services for this group in the health authority will be more closely related to the individual needs of patients and their carers than has been achieved hitherto. This strategy should lead to fewer patients needing long term in-patient care.

Factors associated with the development of post traumatic stress symptomatology have frequently been reported in the literature over the last decade. However, of the empirical studies examining these factors, few have used appropriate methodological designs and most have examined one factor in isolation. This pilot study used a cross-lagged panel analysis design to investigate 11 factors previously identified in the literature as being causally related to the development of post traumatic stress symptomatology. The 11 factors investigated were: perceived controllability, perceived predictability, perceived threat, shattering and confirmation of core assumptions, causal attributions, supportive and unsupportive behaviour, peritraumatic dissociation and the personality factors of neuroticism and introversion. 13 participants were recruited through Cheltenham General Hospital's accident and emergency department after being involved in a road traffic accident (RTA). They were interviewed on three occasions; ten days post RTA, ten weeks post RTA and six months post RTA and were required to complete four questionnaires. It was found that participants who had high levels of post traumatic stress symptomatology at ten days received low levels of supportive behaviour at six months. Participants who perceived the accident to be unpredictable at ten days had low levels of symptomatology at six months. Two other factors were also found to be causally related to the development of post traumatic stress symptomatology; confirmation and neuroticism, but these factors must be treated with caution due to the possibility of an unspecified third variable. The remaining seven factors were not found to be causally related to the development of symptomatology. Overall these findings support the interactive field theories which propose that post traumatic stress symptomatology develops through a complex interaction of numerous factors from the emotional, social and cognitive domains and cannot be related to specific linear factors.

The purpose of this study is to extend the literature on recognition and identification of non-verbal communicative signals of emotion in those suffering from Alzheimer's disease. To date, there have been few studies in this area, yet emotion processing deficits may have an important effect on the quality of life of Alzheimer's patients and their families. The experimental condition consisted of a set of tasks involving face and prosody discrimination problems in which participants were asked to choose between a number of stimuli presented on cards (facial cues) or on audio-tape (prosody cues). In addition, a measure of general cognitive ability was taken. Firstly, it was found that, relative to a group of healthy older adults, performance on cognitive tasks was depressed, while performance on emotion processing tasks was not depressed to the same extent. Thus, the ability to recognise and identity non-verbal affect cues in emotional facial expression and emotional prosody was relatively preserved in patients with Alzheimer's disease. Secondly, no relationship was found in the Alzheimer disease group between performance on face recognition and prosody tasks. This evidence is consistent with the notion that the mechanisms responsible for discriminating emotional facial expression are dissociated from those involved in discriminating emotional prosody. However, these findings need to be interpreted with caution in view of the small sample size and low statistical power. Lastly, a number of post-study hypotheses were generated in relation to the Alzheimer disease group. These related to the number and type of errors made on tasks of face and prosody discrimination and suggestions were made regarding further investigation in this area. Finally, limitations of the study, implications for clinical practice, such as assessment and intervention focussing on preserved emotion processing ability and suggestions for future research are considered.

Introduction Epilepsy is especially prevalent in low- and middle-income countries, including those in sub-Saharan Africa (SSA). There are few case-controlled data on epilepsy from SSA, where epilepsy remains largely untreated and highly stigmatized. Aims To determine the prevalence of active epilepsy among adults in a rural population in northern Tanzania. To describe the pattern of disease and quantify the epilepsy treatment gap (ETG) in this population. Methods People with epilepsy (PWE) were identified through door-to-door screening of the adult study population (n=103,026) using a previously validated screening questionnaire. Controls were recruited from the background population. Odds ratios for risk factors and impacts of epilepsy were calculated using logistic regression. The burden of neurocysticercosis (NCC) was assessed using neuro-imaging in cases and serology. The ETG was estimated according to self-reported antiepileptic drug use. Results We identified 291 PWE along with 182 controls. The age-standardised prevalence of active epilepsy was 2.91/1,000. All PWE had convulsive epilepsy, 71.5% being of focal onset. Risk factors for epilepsy were a positive family history (OR 29.0), febrile convulsions in childhood (OR 20.4) and obstetric complications (OR 3.4). Eight cases had NCC; six cases and no controls had antibodies to Taenia solium (p=0.036). PWE were less likely to have completed primary education (OR 0.3) and were more likely to be divorced or separated (OR 7.7). The ETG was 68.4%. Conclusions This is one of the largest community-based studies of epilepsy from SSA to date. The large proportion of focal-onset epilepsy suggests a considerable burden of acquired epilepsy. The high ETG may reflect the stigma experienced by PWE in this population.