The thesis was designed to gain insight into how Alzheimer’s disease influences selfhood from first-personal accounts of illness. The focus of the study was narrowed further by concentrating on the autobiographies of individuals diagnosed with Early-Onset Alzheimer’s disease (EOAD). The purpose of this thesis was to analyze the autobiographies of individuals with EOAD with the aim of understanding their selfhood. In this thesis I argue that, Alzheimer’s disease may influence a change in self, however, the self is not lost entirely. This thesis draws on the philosophical conception of narrated self as it allows for one perpetually constructed self, whereby a change in self does not necessarily mean the self is lost entirely. Through an interpretive analysis of six autobiographical accounts of Alzheimer’s, this thesis demonstrates that Alzheimer’s disease influences a loss of sense of self but that autobiography enables individuals with Alzheimer’s to (re)construct self.

Little is known about the specific cognitive impairments that may be the cause of the reported increased crash rate in individuals with early dementia. Though, it is widely accepted that attention, visuospatial and perceptual abilities are central in being able to operate a vehicle safely. This study had three objectives. The first was to clarify the neuropsychological profile, with an emphasis on attention, visuospatial and perceptual abilities, of individuals with early dementia with Lewy bodies (DLB), the next was to examine the driving performances of two groups of individuals with early dementia (i.e., early Alzheimer’s disease, AD, and early DLB) and the last was to examine the degree of association between neuropsychological impairments and driving impairments in hopes of predicting poor driving outcomes. Fifty-six participants were recruited from three groups; 20 individuals diagnosed with early AD, 15 individuals diagnosed with early DLB and 21 healthy age-matched controls. All participants were administered the following neuropsychological tests: the Mini-Mental Status Exam (MMSE), the Dementia Rating Scale (DRS-2), the Boston Naming Test (BNT), the Test of Everyday Attention (TEA), the Visual Object and Space Perception Test (VOSP) and the Useful Field of View (UFOV). Additionally, a simulated driving task was completed, with data being collected through primary measures recorded by the simulator as well as an experimenter based driving assessment using a demerit-point test. Results indicated that individuals with early DLB were found to be most impaired in their visuospatial abilities, selective and divided attention abilities, and were found to have significant cognitive fluctuations. Driving performances confirmed that drivers with early dementia were at greater risk for motor vehicle collisions (MVC) and they were found to commit a significant number of driving errors during the driving simulation. Finally, this study was able to demonstrate that in drivers with early AD, attentional impairments were the strongest predictors of driving impairment, whereas in drivers with early DLB, visuospatial impairments were indicative of driving impairment.

Background: Given that brain pathology precedes clinical symptoms in Alzheimer’s disease (AD), identifying pre-symptomatic biomarkers is critical in order to implement symptom-delaying strategies as early as possible. Magnetic resonance imaging (MRI) is an ideal method for detecting early brain changes in Alzheimer's disease, as it is non-invasive, easily repeatable, and widely available. To date, MRI biomarker research has largely focused on neuronal loss in grey matter, but there is a lack of research on white matter and its relationship with cognitive performance. Diffusion tensor imaging (DTI) is a MRI-based technique that is particularly sensitive to microstructural white matter characteristics, making it an ideal method to study white matter changes. Methods: Longitudinal DTI and clinical data from the Alzheimer’s Disease Neuroimaging Initiative 2 database were used to examine the 1) within-group microstructural white matter changes in individuals with AD and healthy aging controls at baseline and year one; 2) the between-group microstructural differences in individuals with AD and controls at both time points; and 3) the relationship between white matter and cognitive performance at both time points. Results: 1) Within-group: Tract-based Spatial Statistics reveal that individuals with AD have reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in the corpus callosum; internal and external capsule; corona radiata; posterior thalamic radiations; superior and inferior longitudinal fasciculus; fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; tapetum; medial lemniscus; cerebellar and cerebral peduncle; and hippocampal cingulum at year one compared to baseline. Controls also had reduced FA and increased MD at year one compared to baseline, but such changes were less extensive and did not include the hippocampal cingulum. 2) Between-group: Relative to controls, individuals with AD had lower FA and higher MD in the corpus callosum, internal and external capsule; corona radiata; posterior thalamic radiation; superior and inferior longitudinal fasciculus and fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; tapetum and hippocampal cingulum. 3) There was a positive relationship between FA and an ADNI- derived memory composite score in individuals with AD. Conclusion: The results revealed that DTI holds potential as an AD biomarker given its sensitivity to detect microstructural white matter characteristics. Longitudinal tracking of brain imaging and AD clinical signs in large cohorts are necessary to further evaluate potential clinical utility. / Graduate

La maladie d’Alzheimer (MA) est la pathologie neurodégénérative entraînant une démence la plus fréquente. Elle touche plus de 3% des plus de 65 ans. Les lésions cérébrales qui la constituent sont les dépôts de substance β amyloïde (Aβ) et les dégénérescences neurofibrillaires responsables de la mort neuronale, en particulier dans le cortex et l’hippocampe. Ces lésions s’accompagnent d’une réaction inflammatoire centrale qui participe au processus de neurodégénérescence. Les modèles murins d’endotoxémie reproduisent une réaction inflammatoire du système nerveux central comme observé chez l’homme. Nous avons utilisé un modèle murin d’endotoxémie par injections périphériques de LPS et mis en évidence une activation microgliale, une augmentation de la production d’Aβ et de l’expression de BACE1 ainsi qu’une altération du métabolisme dans l’hippocampe des animaux en réponse au LPS. Ces réactions sont contrôlées par la kinase de stress PKR (double-stranded RNA-dependant protein kinase) dont l’invalidation exerce in vivo un effet neuroprotecteur. La production d’Aβ serait régulée dans ce modèle par l’activation PKR-dépendante du facteur de transcription STAT3, responsable du contrôle transcriptionnel de BACE1. L’activation de PKR a été retrouvée à plusieurs niveaux du processus dégénératif associé à la MA et a été identifiée comme un potentiel biomarqueur diagnostique et pronostique de la maladie. Nos résultats confirment le rôle de PKR dans la pathogénèse de la MA et l’intérêt de l’inhibition de PKR pour la recherche thérapeutique. / Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia. More than 3% of those over 65 years are affected. Pathological features of AD are β amyloid (Aβ) deposition and neurofibrillary tangles resulting in neuronal death, specifically in cortex and hippocampus. Brain inflammation is associated and involved in the neurodegeneration process. Murine models of endotoxemia show inflammation in the central nervous system as observed in humans. Using a model of endotoxemia by peripheral LPS injections in mice, we observed an activation of microglia, an increase of Aβ production and BACE1 expression and a decreased metabolism in the hippampus of LPS treated animals. These reactions are controlled by the stress kinase PKR (double stranded RNA-dependent protein kinase) whose invalidation exerts a neuroprotective effect in vivo. Aβ production in this model would be regulated by the PKR-dependent activation of the transcription factor STAT3, responsible for transcriptional control of BACE1. Activation of PKR is involved at several levels of the degenerative process associated with AD and has been identified as a potential diagnostic and prognostic biomarker of AD. These results confirm the role of PKR in the pathogenesis of AD and the interest of PKR down-regulation for therapeutic research.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterised by deficits in language, behaviour and memory. Increasing evidence suggests that mid-life obesity and a diet high in fat are risk factors for AD. In contrast, life-threatening weight loss occurs and worsens as the disease progresses, despite adequate or increased food intake. A greater understanding of energy balance in AD may therefore uncover novel targets for therapy. The aim of this thesis was to test the hypothesis that 3xTgAD mice display altered energy balance and that experimental changes to this balance will alter cognition. To address this hypothesis, three key objectives were set up; to characterise the energy balance profile, characterise behaviour and memory, and evaluate the response to an high fat (HF) diet in a triple transgenic (3xTgAD) model, an experimental mouse model of AD. Energy balance was characterised in non-transgenic (Non-Tg) control and 3xTgAD mice, demonstrating altered body weight, food intake and metabolic rate in the 3xTgAD mouse model of AD. At 2-month of age male 3xTgAD mice displayed greater food intake and body weight, but no difference in metabolic rate, whereas from 12 months of age 3xTgAD mice weighed less, despite eating more, and had a higher metabolic rate than Non-Tg control mice. This provides evidence that there is a shift towards a hypermetabolic state from 12 months of age in 3xTgAD mice, which may represent a key stage in advancement of the disease process. Behaviour and memory were characterised in Non-Tg control and 3xTgAD mice in a battery of tests at different ages. 3xTgAD mice showed changes in open-field activity/anxiety from 3 months of age. Memory impairments were first detected in 3xTgAD mice at 3 months of age as deficits in odour recognition memory, mirroring early impairments seen in AD patients. Deficits in spatial memory were then observed in both the Y-maze spontaneous alternation and Morris water maze tests from 5 months of age. Finally, deficits in non-spatial visual object memory were observed in 3xTgAD mice in the novel object recognition test at 8 months of age. Energy balance, behaviour and memory were assessed in Non-Tg control and 3xTgAD mice in response to an HF diet. Non-Tg control and 3xTgAD mice displayed similar energy balance profiles in response to an HF diet. The HF diet was found to worsen memory in Non-Tg mice in odour recognition at 3-4 and 7-8 months of age, in the Morris water maze at 7-8 months of age and in novel object recognition and spontaneous alternation at 11-12 and 15-16 months of age. Similarly, the HF diet worsened memory in 3xTgAD mice in odour discrimination at 3-4 and 7-8 months of age, the Morris water maze at 7-8 and 11-12 months of age, and in spontaneous alternation at 15-16 months of age. As an HF diet induced memory impairments, in both Non-Tg control and 3xTgAD mice, it suggests that diet-induced deficits may therefore, not be specific to AD, but rather to cognition in general. Overall, these data demonstrate that 3xTgAD mice show AD-like age-dependent changes in energy balance, behaviour and memory. Furthermore, an HF diet produced impairments in memory in 3xTgAD mice, but these effects were not specific to AD, as an HF diet also led to deficits in control animals. These data support a role for energy balance in the progression of AD, although the underlying mechanisms remain poorly understood. 3xTgAD mice may therefore represent a good model to examine energy balance during AD and to evaluate targets for future therapies.

Accumulation and aggregation of the 42-residue amyloid-[beta] (A[beta]) protein fragment, which originates from the cleavage of amyloid precursor protein by beta and gamma secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the A[beta] sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of A[beta] and prevent its toxic effects on neuronal cells in culture. Here, we use molecular dynamics simulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) [beta]-sheet breaker peptide with an A[beta] fibril structure from solid state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand-fibril contacts, including a possible difference in the effect of histidine on ligand-fibril [pi]-stacking interactions, and the role of the proline residue establishing contacts that compete with those essential for maintenance of the inter-monomer [beta]-sheet structure of the fibril. Our results show that molecular dynamics simulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic A[beta] will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation. We have also performed long explicit solvent MD simulations of unliganded amyloid fibril in three putative protonation states, in order to better understand the energetic and mechanical features of the fibril receptor. Over 100 ns MD simulations, the trajectories where fibril has Glu11 and Glu22 side-chains protonated exhibit the least deviation from the initial solid state NMR structures. Free energy calculations on these rajectories suggest that the weakest fibril interface lies in the lateral rather than transverse direction and that there is little dependence on whether the lateral interface is situated at the edge or middle of the fibril. This agrees with recent reported steered molecular dynamics calculations. Secondly, in an effort to improve the ability of atomistic simulation techniques to directly resolve protein tertiary structure from primary amino acid sequence, we explore the use of a molecular dynamics technique based on swarm intelligence, called SWARM-MD, to identify the native states of two peptides, polyalanine and AEK17, as well as Trp-cage miniprotein. We find that the presence of cooperative swarm interactions significantly enhanced the efficiency of molecular dynamics simulations in predicting native conformation. However, it also is evident that the presence of outlying simulation replicas can adversely impact correctly folded replica structures. By slowly removing the swarm potential after folding simulations, the negative effect of the swarm potential can be alleviated and better agreement with experiment obtained.

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterised by severe memory loss and the accumulation of amyloid-beta (Aβ) and tau pathology within neocortex and medial temporal lobe (MTL) structures. Episodic memory impairment is a defining feature of early AD. The hippocampal formation (HF), a major network involved in both memory formation and retrieval is one of the first areas affected by AD pathology. However, the aetiology of AD is unknown; specifically how Aβ and tau pathologies cause memory impairment and how the physiological function of HF is affected. In this thesis, the 3xTgAD mouse was used as a high fidelity model of human AD pathological progression to study the function of HF during early (intracellular Aβ) and more progressive (extracellular plaque and hyperphosphorylated tau pathology) AD stages, referred to as ‘young’ and ‘old’ respectively. Specifically we: i) applied the hippocampal-dependent What-Where-Which (WWWhich) task to study the onset and progression of episodic-like memory decline (previously uncharacterised in the 3xTgAD mouse); ii) examined allocentric spatial memory in radial arm water maze (RAWM) and spontaneous alternation (SA) behaviour in T-Maze to discern whether cognitive differences exist between spontaneous and negatively reinforced tasks (the latter could be influenced by an exaggerated stress response); and iii) performed electrophysiological recordings in vivo from the HF of urethane-anaesthetised 3xTgAD and control mice to study basic synaptic connectivity, short-term synaptic plasticity and neuronal reverberation across the CA1-DG axis using a multi-site electrode. Our results showed an early and specific deficit for WWWhich episodic-like memory in the 3xTgAD model, with a decline in performance witnessed in mice as young as 3 months. In contrast, 3xTgAD component memory comprising single or dual associations of ‘What’, ‘Where’, ‘Which’ and ‘When’ remained intact suggesting the episodic impairment was due to dysfunction during the association of three component information streams within hippocampus (Chapters 3 and 4). 3xTgAD mice were equally impaired for allocentric spatial memory in RAWM and in their SA behaviour, suggesting no inherent advantage of examining cognition in paradigms which elicit behavioural distress (Chapter 5). We witnessed the development of subtle synaptic abnormalities in young 3xTgAD mice in the form of enhanced short-term paired pulse facilitation in CA1 and DG, however, a paucity of response facilitation in CA1 in response to train stimulation. In contrast, we saw intact basic synaptic function (fibre integrity and synaptic connectivity) in 3xTgAD mice of both young and old ages, suggesting gross hippocampal circuitry remained in place (Chapter 6). Finally, we saw an effect of normal ageing on cognition in the WWWhich and spatial tasks (Chapters 4 and 5), and a decline in neuronal reverberation with age in control and 3xTgAD mice. Dysfunction in these two parameters (behavioural and electrophysiological) coincided with the onset of intracellular Aβ accumulation within HF in 3xTgAD mice. This suggests a role of intracellular Aβ in impairing the physiological function of HF in AD which translates as cognitive decline in hippocampal-dependent forms of memory. Episodic memory was found to be especially sensitive to AD-related pathology and impairment, thus the WWWhich task may be applied to faithfully study the onset of cognitive decline in other AD mouse models. Further examination of the relative contribution of Aβ to hippocampal dysfunction in the 3xTgAD model is required.

The prevalence of obesity is growing worldwide partly due to an increase in consumption of diets high in fat. Obesity is known as a risk factor for developing Alzheimer’s disease (AD) later in life. Both obesity and AD are associated with cognitive deficits and experimental high-fat diets can impair memory in cognitively normal rodents but also worsen memory deficits in AD mouse models. What is still unclear is the molecular mechanisms behind the detrimental effects of a high-fat diet on memory and if sex can influence its effect. Data in this thesis demonstrated that compared to females, male control non-transgenic (Non-Tg) mice had earlier deficits in memory after a high-fat diet that were associated with hyperinsulinemia. However, female Non-Tg mice were more vulnerable to ultrastructural changes in mitochondria morphology and loss of synapses after 6 months of a high-fat diet, changes that were similar to those observed in control-fed female triple-transgenic mice (3xTgAD). Finally, the memory deficits observed after a high-fat diet in cognitively normal mice were not associated with obesity and adiposity, as treatment with resveratrol (RSV) an anti-obesogenic compound, attenuated body weight gain and adipose tissue but failed to reverse memory impairment. In control fed 3xTgAD mice, RSV rescued memory deficits. In all experiments a high-fat diet had no detectable effect on cognitive impairment in 3xTgAD mice. In conclusion, the present thesis demonstrates that the sex-dependent differences in the effect a high-fat diet on memory are likely due to hyperinsulinemia and mitochondrial impairment and do not depend on obesity phenotype. These results demonstrate the importance of gender when studying both obesity and AD and are relevant for future clinical trials.

This thesis deals with a business project to establish a rest home for people, who are due to Alzheimer's disease fully dependent on the assistance of others. The aim is to map the current situation in the market of social services in Czech Budejovice and it's surrounding area and find out if it is possible to establish a profitable business. In the theoretical part there is a description of the conditions of the business plan and the possibility of getting a grant from EU.

The purpose of the current study was to explore the relationship between cognitive status and depression in a sample of geriatric patients. Participants included 282 geriatric patients ranging in age from 65 to 96 years who were classified according to diagnosis as: DAT, VaD, MCI, and Norm. All were referred for neurocognitive testing from the Geriatric Assessment Program (GAP) at the University of North Texas Health Science Center (UNTHSC) in Fort Worth, Texas. This study sought to identify factor structures for two versions of the GDS using a geriatric sample of cognitively impaired and intact patients. It then compared these factors to each other to determine whether the GDS-15 is truly a shorter version of the GDS-30. These were then compared to a previously determined factor structure. This study explored whether the four-factors of the GDS-30 are able to differentiate cognitive diagnostic groups. Further, this study sought to identify whether the severity of cognitive decline impacted GDS factor score for each of the cognitively impaired groups. Results revealed a two-factor model of the GDS - 15 and a four-factor model with the GDS - 30. The GDS-15 factors did not differ from the first two factors of the GDS-30. Comparison between the GDS-30 factor structure and that reported by Hall and Davis (in press) revealed no significant differences despite the inclusion of a normal, non-demented group in the current study. Comparisons of subscale scores revealed that DAT patients tended to score lower than the other groups on all but the cognitive impairment subscale. Severity level analyses indicated that as severity of deficits increases, awareness of deficits decreases. This study found that although the GDS-30 is a good screening tool for depression in geriatric patients, it is not particularly useful in differentiating cognitive status group. Also, the GDS-15 was not found to be a good substitute for the GDS-30.