Turning around to interact with the environment is a common activity of daily living. The location of a target for interaction may be known or unknown prior to turning and the angle of a turn may vary depending on the task to be carried out. Stroke and Parkinson’s disease could compromise coordination of body movement during turning which may pose a risk for instability and subsequent falls. The sequence of onset latency, peak velocity and timing of peak velocity of body segments (eye, head, shoulder, pelvis and foot) while turning on-the-spot were investigated in people with stroke and age-matched healthy controls (study 1) and in people with Parkinson’s disease and age-matched healthy controls (study 2). The effect of target predictability, turn angle and turn direction on the sequence of the movement of the body segments were also investigated. Participants were asked to stand in front of a light and either turn to a specific light (predictable condition) or locate and turn to a random light (unpredictable condition) placed at 45°, 90° or 135° to the right or left when the light in front extinguished. The results showed that the people with stroke and Parkinson’s disease (PD) initiated the movement of the segments later, had lower peak velocities and attained the peak velocities later than their control counterparts. People with PD showed more simultaneous onset of rotation of body segments as compared to their age-matched control when turning to 135°. The sequence of onset of rotation of the body segments was similar between the people with PD and their age-matched controls for all the other turning tasks. People with stroke also had comparable sequence of onset of rotation of body segments with their age-matched controls for all the turning tasks. While people with stroke presented with consistent pattern of peak velocity of the body segments for all the turning tasks, their control counterparts showed differences in the pattern of the peak velocities when turning to dominant and non-dominant sides. People with PD showed similar peak velocities of pelvis and foot when turning 45° to initially affected side as compared to separate peak velocities of the pelvis and foot in the stroke and control groups. The peak velocities of the segments (head, shoulder, pelvis and foot) occurred at more or less the same time for most of the turning tasks. Impairment of the relative movement of body segments during functional tasks could challenge the balance of an individual. The sequence of movement of body segments in the different tasks could therefore be related to balance during turning to identify which of the strategies of turning could present with risk of falls. Predictability of a target, turn angle and turn direction should be considered when developing interventions to avoid falls during turning and strategies for improving speed of reacting to perturbations should be developed for people with stroke and Parkinson’s disease.

In ammation is recognised as an important contributor to Alzheimer's disease (AD) pathogenesis alongside extracellular deposits of amyloid β protein (Aβ) and intraneuronal deposits of hyper-phosphorylated tau protein. Microglia are the key component of innate immunity within the central nervous system, and the source of in ammation in the brain. The amyloid cascade hypothesis places Aβ at a key point in the pathogenesis of AD. Consequently, immunisation against Aβ is a promising experimental treatment for AD. The current study presents a neuropathological follow-up of a unique cohort of AD patients who took part in the active Aβ42 immunisation clinical trial (AN1792, Elan) and in whom reduction in Aβ load had been observed. The hypothesis of the study is that Aβ42 immunisation affects the microglial activation level and profile associated with the reduction in Aβ. Levels of the microglial markers indicative of specific microglial functions, the microglial receptors involved in antigen recognition and uptake, complement component C1q, IgG, Aβ42 and phospho-tau in the brain tissue (frontal, temporal and parietal lobes) of immunised (n=11) and non-immunised (n=28) AD patients were analysed using immunohistochemistry. In immunised brain, a two-fold reduction in Fc receptor I (P=0.001) and Fc receptor II (P=0.002), a ten-fold reduction in macrophage scavenger receptor A (P <0.001), and a 40% reduction in lysosomal glycoprotein CD68 (P=0.018) compared to non-immunised brain were observed. Similarly, Aβ42 and phospho-tau levels were also decreased by 80% and 40% respectively. No changes in the microglial activation and antigen-presentation receptor HLA-DR, calcium-adapter channel Iba-1, or the levels of IgG and C1q were detected. The load of all microglial markers, IgG and C1q correlated with the phospho-tau load in non-immunised cases. In addition, Iba-1 and Fc RII load inversely correlated with Aβ42 load in the non-immunised group. These correlations no longer held in the immunised group. Instead, a positive correlation between the number of MSR-A positive microglial clusters and Aβ42, and an inverse correlation between C1q and Aβ42 were noted in immunised AD cases. The current study is the first of its kind in presenting a detailed immunohistochemical profile of microglia in human AD and following active Aβ42 immunisation treatment. In addition, a consistent and reproducible method for automated microscopy image analysis was developed as part of this project contributing to research methodologies. The results support the changes in the level and profile of microglial activation implied by the hypothesis. The data also suggest a link between immune system activation and the tau pathology in AD. The ability of microglia to change their profile and switch targets following stimulation by active immunisation is demonstrated in human brain.

Artificial synaptic plasticity is a programming approach used in artificial neural simulations to replicate the change in efficacy between two synapses observed in biological neurons. This biological synaptic plasticity is thought to enable neurons to control the connections between them. This control is then thought to lead to complex behaviour such as path integration. This stochastic process of activity dependent biological synaptic plasticity forces groups of neurons to operate together. The operation of large subsets of neurons underlies the cognition and memory formation in animals, without which life could not flourish. The most well studied region in the brain for synaptic plasticity is the hippocampus.This region was the first to display both long term potentiation, as well as long term depression. It has also been implicated in memory retention and has been shown to display spatial tuning. Furthermore, the discovery of place cells, and the more recent discovery of grid cells has created a surge of interest in the region. Entirely plausible models for grid field, place field, and memory formation have been suggested. The hippocampus could very well be the first brain region to be understood which does not represent purely sensory input. This thesis applies the rules of activity dependent synaptic plasticity to the hippocampus by modelling the region in silicon. This model focuses on the head direction cells, grid cells, and place cells. The head direction cells are generated using rotational inputs. The grid cells are then generated using both head direction input and forward motion inputs. Finally, the place cells are created using grid cell inputs. To facilitate the construction of this model, a simulator has also been created.

Spinal cord injury (SCI) leads to severe functional deficits and currently there are no effective treatments. In addition to the initial mechanical damage to axons, neurons and glia, traumatic injury also triggers a complex array of cellular and molecular events. Some of these processes are thought to contribute to mechanisms of progressive damage (secondary mechanisms) whilst others concurrently promote limited repair. Functional outcome depends on the interaction of these two processes. However, the interacting dynamics and time course with which they impact the functional outcome is not fully understood. Secondary processes are studied with molecular and anatomical approaches and loss of axons or neurons are used to infer reduced function. Similarly, recovery of functional outcome is mostly assessed using behavioural approaches. However, these are unable to differentiate recovery due to compensatory plastic changes in the brain which might contribute to recovery. Therefore, the first aim of the thesis was to develop an electrophysiological approach to directly assess functional changes in spinal cord circuits following a contusion SCI. The second aim was to use this protocol combined with behavioural testing in order to investigate the use of human embryonic stem cell derived mesenchymal stem cells (hESC-MSCs) as a potential therapy for spinal cord injury. An electrophysiological approach was used to assess spinal cord function after contusion injuries at the cervical (C6) level of the rat spinal cord. Contusion injuries due to high velocity impact were made using an Infinite Horizon Impactor device. Cord dorsum potentials (CDPs) evoked by supramaximal electrical stimulation of a radial nerve (to activate sensory fibres) or within the pyramids (to activate corticospinal fibres) were used to measure changes in the function of these fibre systems in the vicinity of the injury. Animals were investigated at different time points from acute up to 6 months post injury to characterise the temporal progression of changes in spinal cord function. Contusion injury produced an immediate substantial reduction in sensory circuit function which was highly localized to the site of the impact. However, CDPs continued to be evoked both above and below the injury site. This suggests that the main sensory axons in the dorsal column which carry impulses past the level of the injury are not substantially affected and deterioration of function at the injury centre is a result of damage to the neurons and axon collaterals located at the site of impact. Further worsening occurred over the following 3 days but was more marked above the level of the injury possibly because it is due to demyelination of the main sensory axons. However, CDP mapping at 2 weeks showed almost complete recovery of the potentials above this compared to 3 days reflecting a repair mechanism which is possibly remyelination. The fact that CDP amplitudes at 2 weeks are very close to those recorded immediately after injury suggests that most of the loss of function produced by the contusion is due to primary mechanical trauma and that secondary mechanisms contribute relatively little to the loss of function. CDP amplitudes recorded 4 weeks, 7 weeks and 3 months after injury remained closely similar to 2 weeks suggesting a prolonged period of stability in the sensory system. However, a later phase of deterioration is observed at 6 months below the injury possibly due to extension of the injury cavity causing further neuronal loss. Histology also revealed significantly larger cavities in 6 month survival animals. CDPs evoked by stimulation of the corticospinal tract below the injury level were profoundly depressed immediately following a contusion reflecting extensive damage to the main component of the CST in the dorsal columns while potentials above the injury were not acutely affected. There was a further reduction in CDP amplitudes rostral to the injury at 3 days due to demyelination or die back of CST fibres in the dorsal columns. Substantially this improved at 2 weeks and then remained stable up to 6 months. Below the injury there was a gradual increase in the strength of corticospinal connections evident by an increase in CDP amplitudes at 7 weeks which was maximal by 3 months. This reflects plasticity in the spared corticospinal projection probably those in the lateral component. Mesenchymal stem cells (MSCs) from bone marrow (BM) have been reported to promote repair and some functional improvement in animal models. However, autologous transplantation of BM-MSCs has several disadvantages such as the need for invasive harvesting, variable cell quality and slow proliferation. We have successfully derived MSC-like cells from human embryonic stem cells (hESCs) and have found that these cells show anatomical evidence of repair after transplantation in an animal model of SCI (Mohamad, 2014). Delayed transplants of hESC derived MSCs (hESC-MSCs) were performed in a cervical (C6) contusion (175 kdyn) injury model. These cells were transplanted 3 weeks after injury and immunosuppression was begun two days prior to this and continued for the remainder of the study. Functional outcomes were evaluated behaviourally using grip strength and horizontal ladder walking to assess improvement in forelimb function. In electrophysiology experiments cord dorsum potentials (CDPs) evoked by supra-maximal electrical stimulation of a radial nerve or within the pyramids were used to measure changes in the function of these fibre systems in the vicinity of a spinal cord injury at 7 weeks post-transplant. There was a substantial reduction in the gripping ability immediately after the contusion injury followed by a modest spontaneous recovery. Weekly assessment of the grip strength score before and after transplantation revealed no differences in hESC-MSC transplanted and control groups of animals. Similarly, ladder walk analysis revealed loss of co-ordinated forelimb-hindlimb stepping and increased errors of forepaw placement on the ladder rungs after injury. There was no difference in the recovery of co-ordination or improvement of forelimb function after hESC-MSC transplants compared to control animals. Similarly, terminal electrophysiological experiments showed that the amplitudes of CDPs evoked by radial nerve stimulation were closely similar at all recording locations in both groups of animals. However, corticospinal evoked CDPs showed deterioration of function in the transplanted animals compared to the control group of animals. Histology indicated that hESC-MSCs survived in considerable numbers and were present in all transplanted animals at 7 weeks leading to solid infilling of the injury site and a reduction in injury site extent compared to the medium injected control group of animals. In conclusion, the results in the first part of the thesis suggest that maximum damage after contusion injury occurs at the time of injury and spontaneous recovery of function largely mitigates the small amount of the secondary damage. Therefore, injury due to high velocity impact might not be amenable to neuroprotective therapies. Furthermore, evidence of modest spontaneous plasticity in the spared corticospinal system suggests some compensatory plasticity after the injuries.

Transcranial direct current stimulation (tDCS) is a popular non-invasive brain stimulation technique, which has the potential to modulate cortical excitability. The effects of tDCS are known to outlast the stimulation period, and in some cases, repeated applications have been found to produce long lasting clinically relevant effects. The primary aim of this thesis was to explore the reliability and therapeutic potential of this technique. In Chapters 3 and 4 transcranial magnetic stimulation (TMS) was used to measure tDCS effects. These experiments revealed substantial variability regarding the way in which healthy adults responded to stimulation. Notably, there were differences between participants regarding the direction and magnitude of change in cortical excitability. Furthermore, even when group level effects were found reliably, there was substantial intra-subject variability across repeated testing sessions. Subsequent experiments in Chapters 5 and 6, explored the biological and behavioural effects of tDCS in individuals with Gille de la Tourette’s syndrome (GTS). GTS is a neurodevelopmental disorder characterised by motor and phonic tics which have been linked to hyper excitability within motor-cortical regions. Therefore, these experiments aimed to reduce cortical excitability of targeted regions in the hope that this would impact on tics. Disappointingly, no such effects were found immediately after a single session of tDCS (Chapter 5). Consequently, it was hypothesised that repeated applications may be necessary for significant reductions in tics to occur. This was investigated in Chapter 6 using an in-depth case study. The results were encouraging, in particular there was a substantial drop in tics following 10 days of tDCS at 1.5mA intensity. The stimulation was well tolerated and the treatment regimens were closely adhered to, despite tDCS being delivered in the participants own home with remote supervision. A weaker stimulation intensity was not as effective. The findings of Chapters 3-6 highlight that the optimal stimulation parameters may vary from person to person, and that exploration of individual data is critical in therapeutic contexts. The results also suggest that tDCS may be helpful as a treatment for GTS and furthermore highlight the feasibility of home use stimulation.

This thesis compared the effect on weight loss of either replacing diet beverages (DBs) with water or continuing to consume DBs (study 1 in healthy overweight and obese, n=89 and study 2 in patients with type 2 diabetes, n=81) adults during a 24-wk weight-loss program (for study1 and 2) and 18 month weight loss and weight maintenance plan (for study3, n=89). In study 1, compared with the DB group, the water group had a greater decrease in weight (1.2kg more weight loss in the water group compared with the DBs Group ,P=0.015), BMI (0.5 kg/m² more BMI reduction in the water compared with the DBs Group ,P=0.002), fasting insulin (1 mU/l more Fasting insulin reduction in the water compared with the DBs Group,P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR)(0.2 more HOMA-IR reduction in the water compared with the DBs Group, P < 0.001) and 2-h postprandial glucose(0.305 mmol/l more 2hpp reduction in the water compared with the DBs Group,P < 0.001). In study 2, weight (2.5 kg more weight loss in the water compared with the DBs Group, P=0.005) and BMI (0.9 kg/m² more BMI reduction in the water group compared with the DBs Group, P=0.005) decrease after 18 months in the water group compared with the DBs group was significant. There was also a greater reduction in fasting insulin levels (1.8 mU/l more Fasting insulin reduction in the water group compared with the DBs Group,P < 0.001), better improvement in HOMA-IR (0.5 more HOMA-IR reduction in the water group compared with the DBs Group, P < 0.001), a greater decrease in 2-h postprandial plasma glucose (0.5 mmol/l more 2hpp reduction in the water group compared with the DBs Group, P < 0.001) and glycated hemoglobin (0.2 more HbA1c reduction in the water group compared with the DBs Group, P=0.030) in the water group compared with the DBs over 18 months. In study 3, obese participants with Type 2 diabetes in the water group of study 2 had more weight loss (1.16 kg more weight loss in the water group compared with the DBs Group, P=0.006) and BMI (0.5 kg/m² more BMI reduction in the water group compared with the DBs Group, P=0.006). Also reduction of fasting insulin (1.6 mU/l more Fasting insulin reduction in water group compared with DBs Group,P < 0.001), fasting plasma glucose (0.3mmol/l more Fasting plasma glucose reduction in the water group compared with the DBs Group, P=0.003), HOMA-IR (0.7 more HOMA-IR reduction in the water group compared with the DBs Group, P=0.003) and 2 hour postprandial glucose (0.3 mmol/l more 2hpp reduction in the water group compared with the DBs Group, P=0.027) was greater in the water group. By contrast, changes in waist circumference and lipid profiles were not significantly different between the two groups in these three studies. Replacement of DBs with water after the main meal in obese and overweight healthy and type 2 diabetic women who were regular users of DBs may cause greater weight reduction during 24 weeks and also in the longer period of an 18 month weight management program. In addition, replacement of DBs with water offers clinical benefits to improve insulin resistance. Generally, better improvements in energy and carbohydrate metabolism may occur when water rather than DBs is consumed over a weight loss program.

In this thesis I explored cognition, psychopathology and the role of Catechol-O-Methyltransferase (COMT) in children at increased risk of schizophrenia with the aim of making a contribution to our understanding of the processes that take place early in the development of psychosis. Two samples were studied. The first sample came from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) where I examined the relationships between a priori selected cognitive domains and psychotic experiences (PEs). The results indicated that impaired processing speed and attention were related to greater risk of PEs in children, with processing speed being a key cognitive feature. Moreover, the relationships between cognition and later occurrence of PEs were similar to those that have previously been reported between cognition and schizophrenia. I also examined whether genetic variation in COMT was associated with PEs indirectly through cognition and anxiety disorders. The findings showed that COMT was indirectly associated with PEs through processing speed, IQ and attention. The second sample comprised children with 22q11.2 Deletion Syndrome (22q11.2DS). I examined the nature and prevalence of psychopathology and cognitive dysfunction in the sample and their siblings and to what extent the children’s intellectual impairment indirectly influences the risk of psychopathology associated with the deletion. There were high rates of psychopathology and cognitive impairments in children with 22q11.2DS. However, I found no evidence for an indirect association between the deletion and the risk of psychopathology through cognition. Finally, there was no evidence that COMT is related to the susceptibility of children with 22q11.2DS to cognitive and psychiatric problems. These findings have potentially important implications for our understanding of the development of psychosis during childhood and they also show that using different research designs to investigate specific aims in samples at increased risk enables the researcher to widen their scope of interpretation.

Introduction Acute viral encephalitis is a severe form of brain inflammation due to sporadic infection, typically with herpes simplex virus, or epidemic/pandemic infections. Epidemiological data are particularly important for pandemic viruses. Although new reporting approaches are often considered, no real-time clinical data collection tool has been developed. These data are dependent on diagnosis of individual cases. However, the aspects of management that result in delays and missed diagnoses are not clear and it is not known if interventions can improve sample collection and diagnosis. Whilst the importance of cytokines and associated mediators is increasingly recognised, signatures associated with specific aetiologies have not been established. Also, it is not known whether these mediators correlate with clinical severity and outcome, or their impact on blood-brain barrier permeability. Methods I undertook a national surveillance study through neurology networks, and investigated alternative notification approaches. I undertook a multicentre cross-sectional study of clinical investigation, studied viral load and assessed the impact of a lumbar puncture pack. I used bead array to assess mediator profiles and assessed the albumin ratio and viral load, in samples from a Health Protection Agency study. I examined profiles with respect to aetiology, disease severity and outcome and compared this with histopathology tissue and a blood-brain barrier model. Results In the context of a pandemic influenza virus, existing mechanisms identified limited cases, and a smartphone application was developed to collect real-time data. Delays in lumbar puncture and sub-optimal sample collection were identified, in association with a lower viral load. A lumbar puncture pack improved sample collection. Mediator profiles differed between those with an infectious versus immune-mediated aetiology, and those of unknown aetiology best reflected infectious; particularly myeloperoxidase, in part relating to neutrophils in cerebrospinal fluid and parenchyma. The interleukin1 antagonists, IL1RA and IL10, were associated with coma and outcome; and IL10 with reduced blood-brain barrier permeability. Adhesion molecules may counteract this, in both clinical samples and the model. Conclusions Current limitations of detection may be augmented with novel real-time technologies. Diagnosis is limited by delayed and sub-optimal sample collection, which can be improved with a simple pack. Mediators profiles may assist in the distinction of infectious from immune-mediated encephalitis, and cytokines that act against IL1 correlated with clinical severity and outcome. This may be more closely associated with outcome than viral load, although this may reflect sample timing. These findings should direct future research to develop approaches for improved diagnostics and adjunctive therapies.

No description available.

Since identification that mutations in NOTCH3 are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the early 1990s, there has been extensive characterisation of the clinical and radiological features of the disease. However therapeutic interventions remain elusive, partly due to a limited understanding of the vascular pathophysiology and how it leads to the development of strokes, cognitive decline and disability. The apparent rarity and heterogenous natural history of CADASIL potentially make conducting any longitudinal or therapeutic trials difficult. The role of disease biomarkers is therefore of some interest. This thesis focuses on vascular function in CADASIL and how it may relate to clinical and radiological markers of disease. Establishing the prevalence of CADASIL in the West of Scotland was important to assess the impact of the disease, and how feasible a trial would be. A mutation prevalence of 10.7 per 100,000 was demonstrated, suggesting significant under diagnosis of the disease across much of Scotland. Cerebral hypoperfusion is thought to be important in CADASIL, and it has been shown that vascular abnormalities precede the development of brain pathology in mouse models. Investigation of vascular function in patients, both in the brain and systemically, requires less invasive measures. Arterial spin labelling magnetic resonance imaging (MRI) and transcranial Doppler ultrasound (TCD) can both be used to obtain non-invasive and quantifiable indices of vascular function. Monitoring patients with MRI whilst they receive different concentrations of inspired oxygen and carbon dioxide can provide information on brain function, and I reviewed the practicalities of this technique in order to guide the design of the studies in this thesis. 22 CADASIL patients were recruited to a longitudinal study. Testing included peripheral vascular assessment, assessment of disability, neurological dysfunction, mood and cognition. A CO2 reactivity challenge during both TCD and arterial spin labelling MRI, and detailed MRI sequences were obtained. I was able to demonstrate that vasoreactivity was associated with the number of lacunes and brain atrophy, as were carotid intima-media thickness, vessel stiffness, and age. Patients with greater disability, higher depressive symptoms and poorer processing speed showed a tendency to worse cerebral vasoreactivity but numbers were small. This observation suggests vasoreactivity may have potential as a therapeutic target, or a biomarker. I then wished to establish if arterial spin labelling MRI was useful for assessing change in cerebral blood flow in CADASIL patients. Cortical grey matter showed the highest blood flow, mean (SD), 55 (10) ml/100g/min and blood flow was significantly lower within hyperintensities (19 (4) ml/100g/min; p &lt;0.001). Over one year, blood flow in both grey matter (mean -7 (10) %; p = 0.028) and deep white matter (-8 (13) %; p = 0.036) declined significantly. Cerebrovascular reactivity did not change over one year. I then investigated whether baseline vascular markers were able to predict change in radiological or neuropsychological measures of disease. Changes in brain volume, lacunes, microbleeds and normalised subcortical hyperintensity volume (increase of 0.8%) were shown over one year. Baseline vascular parameters were not able to predict these changes, or those in neuropsychological testing. NOTCH3 is found throughout the body and a systemic vasculopathy has been seen particularly affecting resistance vessels. Gluteal biopsies were obtained from 20 CADASIL patients, and ex vivo myography investigated the response to vasoactive agents. Evidence of impairment in both vasodilation and vasoconstriction was shown. The addition of antioxidants improved endothelium-dependent relaxation, indicating a role for oxidative stress in CADASIL pathology. Myography measures were not related to in vivo measures in the sub-group of patients who had taken part in both studies. The small vessels affected in CADASIL are unable to be imaged by conventional MR imaging so I aimed to establish which vessels might be responsible for lacunes with use of a microangiographic template overlaid onto brain images registered to a standard brain template. This showed most lacunes are small and associated with tertiary arterioles. On the basis of this thesis, it is concluded that vascular dysfunction plays an important role in the pathophysiology of CADASIL, and further assessment of vascular measures in longitudinal studies is needed. Arterial spin labelling MRI should be used as it is a reliable, non-invasive modality that can measure change over one year. Furthermore conventional cardiovascular risk factor prevention should be undertaken in CADASIL patients to delay the deleterious effects of the disease.