In neurons, brain derived neurotrophic factor (BDNF) facilitates cell survival, differentiation and long term potentiation (LTP) by binding predominantly to its receptor tyrosine kinase B (TrkB). In contrast, precursor BDNF (proBDNF) facilitates synaptic withdrawal, long term depression (LTD) and cell death via pan neurotrophin receptor (p75NTR) and sortilin. Additionally, a polymorphism in the pro region of proBDNF referred to as Val66Met, has been of interest in both healthy and diseased brain. The healthy Met66 carriers have been associated with reduced hippocampal volumes, episodic memory and protective for late-onset Alzheimer's disease (AD). AD is a progressive neurodegenerative disease characterised by synaptic withdrawal at early stages and with profound neuronal death at later stages. It was therefore hypothesised that proBDNF:mature BDNF ratio would be increased in AD brain, which may contribute to the detrimental effects seen in AD. It was also expected that the Val66Met polymorphic variants would bind differentially to their receptors and influence AD pathogenesis. Highly pure recombinant human (rh) proBDNF variants were successfully produced in this study. The rhproBDNF bound with three-fold less affinity to TrkB and p75NTR as shown by surface plasmon resonance and in rat phaeochromocytoma cells expressing TrkB (PC 12-TrkB) mediated three-fold less prosurvival signalling than rhBDNF. In cotiical neurons, rhproBDNF mediated dose dependent reduction in cotiical cell viability. Interestingly, Val66 variant facilitated hippocampal L TD whereas the Met66 variant blocked LTD. Apart from LTD, all binding and signalling profiles via TrkB, p75NTR and sortilin were independent of Val66Met polymorphism. This was indicative of a possible involvement of an additional coreceptor for p75NTR other than sortilin in LTD. Importantly in AD, even though BDNF and proBDNF levels were significantly reduced, the proBDNF:BDNF ratio was increased; independent of Val66Met polymorphism. Collectively, the increased proBDNF:BDNF ratio in AD patients would favour proBDNF-dependent neurotoxic signalling. However, compared to non-demented Val66 elderly, Met66 carriers had less proBDNF, suggesting a possible protective role for this polymorphism. Future studies using larger samples would further validate this finding

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by Amyloid-B CAP) and tau deposition in the brain. The number of patients suffering AD is estimated at 36 million worldwide, making AD the most common fonn of dementia. There is no efficient therapy for AD, thus efforts to develop new pharmacological strategies to treat AD need to be intensified. Increasing evidence establishes a central role of soluble and oligomeric form of AP peptide in the pathogenesis of AD. AP accumulates in the synaptic compartment and disrupts the synaptic functionality, leading at least to synaptic loss and neurodegeneration. These events strongly correlate with cognitive deficits characteristic of the pathology. The mechanisms promoting AP production as well as the intracellular pathways responsible for synaptic degeneration are not well known. Objective of this study was thus to decipher the signaling pathways involved in A~ oligorners toxicity, focusing on cj Jun N-terminal kinase (JNK). JNK has been extensively studied for its role in stress stimuli and AD. Here we found that JNK participates to the production of AP oiigomers, promoting phosphorylation of APP at Thr668 residue. Moreover we reported a strong activation of the JNK pathway in the synaptic compartment in both in vitro and in vivo models of synaptopathy. This correlates with the reduction of dendritic spines density and a decrease of postsynaptic markers (AMP AR and NMDAR subunits, PSD-95 and drebrin). To confirm the involvement of JNK in synaptic degeneration induced by AP oligomers we phannacologically inhibited JNK action, using the specific cell permeable peptide, D-JNKll. Treatment with D-JNKII reduces the amyloidogenic cleavage of APP, and thus the production of AP oiigomers. Moreover, D-JNKll reverts synaptic degeneration preventing loss of dendritic spines and proteins from the postsynaptic membrane. Finally, the peptide prevents long term potentiation and long term depression alterations and completely reverts cognitive deficits. These results provide essential new infotmation about the molecular changes that ultimately lead to the disruption of synaptic functionality and validate JNK inhibition as a new pharmacological strategy for the treatment of AD.

This thesis comprises three main sections. The first is a literature review on the influence of marital relationship on the experience of spouse carers of people with dementia. Due to methodological weaknesses findings need to be interpreted with caution, however, the research suggests that positive premorbid and concurrent relationships are indicative of greater wellbeing in spouse carers, and also that dementia impacts negatively on marital relationship. Implications for clinical practice and ideas for future research are explored. Section Two is a report on a study exploring spouse carers' experience of their marital relationship whilst caring for a husband or wife with severe dementia. Ten spouse carers (six wives and four husbands) of people suffering from severe dementia participated in a semi-structured interview which was transcribed and analysed in accordance with Interpretative Phenomenological Analysis (IPA) methodology. Five interrelated processes with 19 sub-themes were identified; Establishing connections and forming a lasting relationship, Experiencing dementia as a threat to the relationship, Attempting to maintain the existence of a relationship, Desire to care and Experiencing the impact of caring on wellbeing. Implications for clinical practice and further research are discussed. The third section provides a critical appraisal of the research process and includes an exposition of key lessons learnt, future Continuing Professional Development needs and personal reflections on future functioning as a researcher within the role of a Clinical Psychologist.

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Alzheimer’s disease (AD) is a devastating brain disease that leads to a gradual loss of mental functions. The level of mental activity decline in AD is best correlated with the degree of synaptic loss. The latter is secondary to aggregations of two harmful proteins: neurofibrillary tangles (NFT) and beta-amyloid (Aβ) peptide. Such factors impair inter-neuronal communication thereby weakening the electrical activity of the brain. Non-invasive recording of the electrical activity along the brain scalp, known as Electroencephalography (EEG), reveals an overall power content shift towards the lower bands of the frequency domain in AD. Computational modelling studies have investigated biomarkers of EEG abnormalities in AD with the aim of a better understanding of altered neural processes in AD. The findings of these studies suggested that connectivity loss in the thalamocortical system, impaired production of the acetylcholine (ACh) neurotransmitter and deregulation of neuronal ionic channels are possible biomarkers of abnormal EEG activity in AD. This thesis presents a detailed investigation into the neural causes underpinning abnormal oscillatory activity in AD. The effects of excitatory neuronal death on beta band power (13-30 Hz) are assessed using a conductance-based network model of 200 neurons. Neurobiological studies have shown that cortical neuronal death is mediated by dysfunctional ionic behaviour. This work investigates the influence of deregulated negative feedback to the membrane potential of cortical neurons on the oscillatory activity of a cortical network model of 1000 neurons. Furthermore, a large-scale neuronal model with important characteristics is developed for the purpose of studying the interplay between various synaptic degeneration and compensation mechanisms. and abnormal oscillatory activity in AD. Finally, the influence of compensation mechanisms on the lesioned thalamocortical network is investigated with an improved neuronal model. The ultimate goal of the thesis is to provide insights for drug design in AD therapy and to contribute to the prevention measures of AD.

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This thesis explores the requirements of technology to support people with dementia in the home. More specifically, it aims to establish design requirements for systems that prompt people with mild to moderate dementia through multi-step tasks. Chapter 1 presents existing literature that is relevant to the development of cognitive prostheses for people with dementia. The review describes patterns of cognitive decline in dementia, the impact of these deficits on everyday tasks, and technological and non-technological methods of support. Chapter 2 presents the problems of dementia in the home from a professional carer perspective. Nine interviews and one focus group were conducted with 22 occupational therapists and professional carers. The transcripts were analysed using Grounded Theory Analysis (GTA), in accordance with Strauss and Corbin (1990). The analysis revealed three main themes: 'Problems in the home' (daily activities, risks, and interpersonal interaction), 'underlying deficits' (sequencing, memory/orientations, and learning), and 'consequences' for the person with dementia (physical wellbeing and control) and the informal caregiver (relationship and care demands). The implications of these themes for the design of assistive technology are discussed. Chapter 3 presents the problems of dementia from a patient-caregiver perspective. Eight home visits and two individual interviews were conducted with people with mild to moderate dementia and informal caregivers. GT A revealed four main themes: 'Problems in the home' (daily activities, domestic tasks, leisure, and interpersonal interaction), 'underlying deficits' (sequencing and memory/orientation), 'consequences' for the person with dementia (Physical wellbeing and control), and the informal caregiver (relationship and care demands), and 'situated factors' (verbal cues, visual cues, and familiarity). The perspective is compared to the professional carer perspective, and the design implications are discussed. Chapter 4 describes the types of problems people with dementia experience when performing kitchen tasks. Six people with mild to moderate dementia were video recorded performing activities in their own kitchen. These included making a cup of tea/coffee, a bowl of soup, beans on toast, and tea/coffee with toast. Twenty-two video recordings were transcribed and analysed. Errors that prevented task accomplishment were recorded and grouped to form error classifications. Eight error types were identified with four main themes: 'Sequencing' (intrusion, omission, and repetition), 'orientation' (locating and identifying), 'operation' of appliances, and 'incoherence' (toying and inactivity). The error types are discussed in relation to cognitive theory and the implications for designing prompting systems. Chapter 5 describes an experiment embedded in a real activity, designed to evaluate the effect of a novel cueing method. Eight participants with moderate dementia carried out real cooking activities (making porridge with syrup and chocolate comflake cakes) with a care worker. At certain points, the participants were required to tum on/off the cooker. Correct control selection was scored under three different cueing conditions that represented the association between hotplates and controls. Condition 1 used the original design (symbols), condition 2 used verbal (written) cues, and condition 3 used a lighting effect (hotplate and corresponding control would light up). The implications of the experiment for the design and evaluation of technological prompts are discussed. Chapter 6 describes future steps that should be taken to develop prompting systems for people with dementia. This includes a review of recent developments in pervasive computing that match the design requirements for prompting systems, and an interactive design framework that should be used to guide the design of prompting systems for domestic settings. Chapter 7 provides a summary of the thesis. This includes an overview of requirements for technology to support people with dementia at home. The methodological contributions of the thesis are also discussed.