Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the inter-membrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in several neurodegenerative disorders. One disorder HtrA2 is implicated in is Alzheimer's disease (AD). AD is characterized by the presence of oligomers and fibrils of the amyloid 13 (AI3) peptide that is generated from cleavage of the amyloid precursor protein (APP) by 13- and y-secretases. HtrA2 degrades APP at the mitochondria, and binds the neurotoxic Al3 (1-42) peptide. In this report, the ability of HtrA2 to prevent the aggregation of a model suqstrate CS and the toxic Al3 (1-42) peptide were investigated. Using CS aggregation assays, HtrA2 was seen to have a moderate ability to delay and prevent the aggregation of CS, and this activity was significantly increased following removal of the PDZ domain. Additionally, using EM and lD-WG NMR analyses HtrA2 was seen to significantly delay the aggregation of the Al3 (1-42) peptide via a dual proteolytic and chaperone-like function. These results show a novel chaperone-like activity for HtrA2 and a model emerges from this work in which HtrA2 monitors the inter-membrane space of the mitochondria using a dual proteolytic and chaperone-like function to turnover stress-damaged proteins. Furthermore HtrA2, along with other quality control factors, may be involved in the metabolism of regular as well as aberrant levels of intramitochondrial Al3 (1-42) peptide, which is known to lead to oxidative stress and mitochondrial dysfunction. / Thesis / Master of Science (MSc)

Alzheimer's disease is a progressive neurodegenerative disorder of the central nervous system. One pathological characteristic is excessive neuronal loss in specific regions of the brain. Among the areas most severely affected are the basal forebrain cholinergic neurons and their projection regions, the hippocampus and cortex. Neurotrophic factors, particularly the neurotrophins nerve growth factor and brain-derived neurotrophic factor, play an important role in the development, regulation and survival of basal forebrain cholinergic neurons. Furthermore, brain-derived neurotrophic factor regulates the function of hippocampal and cortical neurons. Neurotrophins are synthesized in hippocampus and cortex and retrogradely transported to the basal forebrain. Decreased levels of neurotrophic factors are suspected to be involved in the neurodegenerative changes observed in Alzheimer's disease. We examined autopsied parietal cortex, hippocampus and nucleus basalis of Meynert samples from age- and gender-matched Alzheimer's diseased and neurologically non-impaired individuals using the quantitative technique of competitive RT-PCR. We also examined parietal cortex samples by Western blotting. We demonstrate a 3.4-fold decrease in brain-derived neurotrophic factor mRNA levels in the parietal cortex of patients with Alzheimer's disease compared to controls (p < 0.004) but fail to observe changes in BDNF protein levels in that brain region. We also demonstrate, for the first time, BDNF mRNA in the nucleus basalis of Meynert and report an age-related decline in the levels of BDNF mRNA in both control and AD samples. Using the competitive RT-PCR technique we fail to observe differences in BDNF mRNA levels in the hippocampus between AD and control subjects, conflicting with previous in situ hybridization studies and RNase protection assays. A decrease in brain-derived neurotrophic factor synthesis could have detrimental effects on hippocampal, cortical and basal forebrain cholinergic neurons and may account for their selective vulnerability in Alzheimer's disease. / Thesis / Master of Science (MS)

Research in the last decade has focused on the impact of the caregiver role (Cantor, 1983), the nature of caregivers (Brody, 1981, 1983), and the stress and burden associated with caregiver (Zarit, Todd and Zarit, 1986). Health professionals working with caregivers have attempted to focus on interventions to reduce feelings of burden and to increase effective coping. Evaluation of educational interventions to reduce caregiver stress and burden has been a recent research focus. Unfortunately, research has shown that it is altruistic to believe that caregiver stress and burden can be alleviated by educational interventions. Family caregivers are faced with the task of learning about the nature and complexity of dementia and the unusual behaviours which accompany Alzheimer's disease. A resource booklet, written to assist caregivers to learn about the disease, about management strategies and about their own feelings may be more effective than interventions to reduce stress. The evaluation focused on whether the resource booklet would provide information which family caregivers would perceive to be relevant and useful. The evaluation was conducted using a convenience sample of ten caregivers. Two time intervals were used to collect information on caregivers' reactions to the resource booklet; one week following the initial reading of the booklet and 4-6 weeks post-reading. A written questionnaire at time one, and follow-up telephone interviews at time two, were used to measure caregivers' reactions to the booklet. Results indicated that the information in the booklet was useful in assisting caregivers to manage care, and that the caregivers found the booklet easy to read and the format acceptable. / Thesis / Master of Science (Teaching)

No / The use of electroencephalograms (EEGs) to diagnose and analyses Alzheimer's disease (AD) has received much attention in recent years. The sample entropy (SE) has been widely applied to the diagnosis of AD. In our study, nine EEGs from 21 scalp electrodes in 3 AD patients and 9 EEGs from 3 age-matched controls are recorded. The calculations show that the kurtoses of the AD patients' EEG are positive and much higher than that of the controls. This finding encourages us to introduce a kurtosis-based de-noising method. The 21-electrode EEG is first decomposed using independent component analysis (ICA), and second sort them using their kurtoses in ascending order. Finally, the subspace of EEG signal using back projection of only the last five components is reconstructed. SE will be calculated after the above de-noising preprocess. The classifications show that this method can significantly improve the accuracy of SE-based diagnosis. The kurtosis analysis of EEG may contribute to increasing the understanding of brain dysfunction in AD in a statistical way.

Coupled with normal age-related regression in muscle mass, adults with cognitive impairment are at high risk for exacerbated declines in muscle strength, associated psychological well-being, and overall independence. Working from the environmental press model, a 12-week strength training intervention was designed to both support participants' continuing abilities and meet varied needs. Tailoring the environment helps optimize participation, which is essential if participants are to experience the greatest possible gains from a group-based exercise program. The intervention was a group-based, progressive strength training program designed specifically for adults with dementia at two dementia care centers. The exercises were performed three times each week and the sessions were led by the centers' activities leaders. Participants used hand-held barbells when performing the upper-body exercises. Findings indicated that individuals retain the capability to enhance their own quality of life through active participation in a therapeutic intervention. This is illustrated by the consistent effort of exercising participants to perform appropriately during the exercise intervention. Not only were adults able to demonstrate effort to appropriately participate, but the intervention supported high levels of correct performance of the exercise repetitions which is important for achieving physical gains. Exercisers did not experience improvement in physical abilities nor did they significantly differ at posttest from non-exercising participants in measures of physical ability and function or quality of life. The program was deemed to be a feasible intervention for adults with dementia as indicated by both regular participant attendance at the program sessions and high levels of effort to engage appropriately in the exercises. Due to the lack of opportunities for adults with dementia to participate in stimulating or meaningful activities, and the individuals' susceptibility to excess disability, the strength training program is a viable intervention to incorporate into the regular activities programming at dementia care centers. Future research should utilize the progress made by this study to continue exploring the environmental variables that most greatly affect the participation of adults with dementia, as well as outcome measurements that best capture important effects of participation in exercise for these individuals. / Ph. D.

Alzheimer's disease~(AD) is the most frequent neurodegenerative dementia and a growing health problem. Early and accurate diagnosis and prediction of AD is crucial because treatment may be most efficacious if introduced as early as possible. Neuropsychological testing, which is clinically used, sometimes fails to recognize probable dementia, especially to recognize the disease at an early time point such as the mild cognitive impairment~(MCI), which is the prodromal stage of AD. Recently, there has been a realization that magnetic resonance imaging~(MRI) may help diagnoses of AD and MCI. In this dissertation, we introduce an MRI-analysis based algorithm to help diagnose the illness before irreversible neuronal loss has set in, and to help detect brain changes between MCI patients who may convert and may not convert to AD. Given a set of brain MR images, the algorithm first calculates the distance between each pair of images via a registration process. Then images are projected from a high dimensional Euclidean space to a low dimensional Euclidean subspace based on the calculated distances, with a dimension reduction method. Finally classical supervised classification approaches are employed to assign images to appropriate groups in the low dimensional space. The classification accuracy rates we obtained in our experiments are higher than, or at least comparable to, those reported in recently published papers. Moreover, this algorithm can be extended to explore the pathology distribution of AD. Exploring the distribution of AD pathology is of great importance to reveal AD related regional atrophy at specific stages of the disease and provide insight into longitudinal sequence of disease progression. Calculating distances between different brain structures produces different classification accuracy. Those structures yielding higher classification accuracy are considered as pathological regions. Our experimental results on pathology localization are also compared with the reproduced results using other existing popular algorithms; the observations are consistent. / Ph. D.

The diagnosis of Alzheimer's disease (AD) is stressful for both patients and their family caregivers (FCG). As the disease progresses, the patient's memory, functioning status, and behavioral problems get worse, and the needs of the patient that must be addressed by family caregivers increase dramatically. This research examines the impact of the subjective burden with the objective stressors on FCG's depression and to determines which psychosocial resources can be used to either mediate or moderate this relationship. I examine the baseline data that was collected from 670 family caregivers of Alzheimer's patients in the Resources for Enhancing Alzheimer's Caregiver Health (REACH) II clinical trial (REACH II), 2001-2004. The measurements used in the current study are caregivers' background and context factors, objective stressors, subjective burden, psychosocial resources, and symptoms of depression. Three research questions will be investigated in this study: (1) How do the caregivers' background and context factors affect FCGs experiences of objective stressors and subjective burden during the caregiving process? (2) What is the relationship between the objective stressors and subjective burdens, and what impact, if any, do they have on FCGs'depressive symptoms? (3) How do psychosocial resources mediate and or moderate the relationship between the primary stressors and FCGs'depression experiences? / Master of Science / The diagnosis of Alzheimer’s disease (AD) is stressful for both patients and their family caregivers (FCG). In 2018, an estimated 5.7 million Americans have been diagnosed with Alzheimer’s disease (Alzheimer’s Association 2018). As the disease progresses, the patient’s memory, functioning status, and behavioral problems get worse, and the needs of the patient that must be addressed by family caregivers increase dramatically. As Aneshensel, Carol S., Leonard I. Pearlin, Joseph T. Mullan, Steven H. Zarit, and Carol J. Whitlatch (1995) noted in their book Profiles in Caregiving: The Unexpected Career, the role of caregiving is generally an ‘unexpected job’ for FCGs (Aneshensel et al. 1995). Based on Pearlin’s stress process model (SPM), the primary goal of my thesis is to compare the impact of the subjective burden of caregiving with that of objective stressors on FCG’s depression, and to determine whether psychosocial resources can either mediate or moderate this relationship. Objective stressors refer to the AD patient’s memory and behavior problems, his or her cognitive impairment, self-care activities, and functional status. Subjective burden is the FCG’s emotional response to objective stressors. Objective stressors and subjective burden are associated with each other, and they are primary stressors in the SPM. Psychosocial resources include FCG’s religious coping, their positive experiences of caregiving, their social networks and whether they were satisfied with social support that they received from others. The present study is important for two reasons. First, rather than focusing on subjective burden alone, the model examined how objective stressors (i.e. burden) influence mental health through their impact on subjective burden. Second, previous influential studies of the stressors of caregiving either did not include the moderating effects of psychosocial resources (Pearlin et al., 1999), or included a limited number of resources and found that they did not play a significant role in how caregiving stress influences caregivers mental health (Aneshensel et al. 1995). In my thesis, I will explore both of the mediating and moderating effects of four types of psychosocial resources. I examine the baseline data that was collected from 670 family caregivers of Alzheimer’s patients from the Resources for Enhancing Alzheimer’s Caregiver Health (REACH) II clinical trial (REACH II), 2001–2004 (Schulz, Burgio, and Stevens 2006). The study participants target on FCGs who are vulnerable to the caregiving stressors. The purpose of the baseline data was to describe the AD patients’ cognitive impairment and behavior problems at the initial stage of the REACH II study, the demands caused by the impairments imposed upon FCGs, the psychosocial resources adopted by FCGs to relieve the caregiving stress, and the consequences of the primary stressors on FCGs’ daily lives. I will explore three research questions in the current study: (1) How do the caregivers’ background and context factors affect FCGs experiences of objective stressors and subjective burden during the caregiving process? (2) What is the relationship between the objective stressors and subjective burdens, and what impact, if any, do they have on FCGs’ depressive symptoms? (3) How do psychosocial resources mediate or moderate the relationship between the primary stressors and FCGs’ depression experiences? The measurements used in the current study are caregivers’ background and context factors, objective stressors, subjective burden, psychosocial resources, and symptoms of depression. Data analysis is primarily based on multiple linear regression. I will also use the post-hoc probing methods to specifically test the significance of the moderating test. There are four key findings in the present study. First, caregivers’ background and context factors have some significant associations with objective stressors and subjective burden, but overall, their impact is minimal. Second, subjective burden has a stronger impact on depressive symptoms than all of the objective stressors do. Third, subjective burden undermines all four psychosocial resources tested in the current study. Fourth, the mediating and moderating effects of psychosocial resources have a negligible impact in the caregiving stress process. Surprisingly, the effect of subjective burden on depressive symptoms among FCGs remained largely unchanged after all psychosocial resources were included in the model as mediators and moderators. In the mediational test, the effects of subjective burden on depression decreased by only 14 percent after all psychosocial resources were taken into account. Likewise, each of these psychosocial resources had only a negligible effect on moderating the impacts of stressors. The study suggests that unless there is a full understanding of the effects of these stressors on caregivers’ well-being, any interventions or preventive actions will be of limited utility. Future research should pay more attention to exploring the relationships between the subjective burden and objective stressors, and examining their different impacts on FCGs’ depression experience. Additionally, the fact that none of the psychosocial resources have a buffering effect in the caregiving process suggests that there is little in the lives of caregivers that mitigates the deleterious effects of caregiving stress on Alzheimer’s caregivers. Policymakers and mental health providers should consider the stress of caregiving, as reflected in both its objective and subjective aspects, as a major risk factor in the lives of those who care for family members with Alzheimer’s disease. Those factors may play a causal role in caregivers’ mental disorders and suicidal ideation.

No / The medial temporal lobe (MTL) memory system is damaged early in Alzheimer's disease. Cognitive tests designed to help diagnose the disease must detect dysfunction in this system, but must also be insensitive to the cognitive slowing that characterizes normal ageing. On the assumption that the MTL system forms new memories by binding together the many informational aspects of events into units, The Placing Test was designed to index this function by measuring the ability to remember associations between faces and their locations. The influence of normal ageing was minimized by using procedures that compensate for the difficulties in learning and retrieval caused by the cognitive slowing of normal ageing. In two experiments The Placing Test was administered as part of a battery of neuropsychological tests to a group of healthy older people. In both studies, performance in The Placing Test correlated significantly with other measures of memory, but had weaker associations than standard memory measures with other types of cognitive function. The Placing Test appeared not to be biased by age, education or gender, although a larger sample is needed to verify this. A final study examined the performance of 16 patients with suspected Alzheimer's disease. These patients showed clear impairment in The Placing Test, with 81% scoring below the 5th percentile, despite the majority having normal MMSE scores. It is concluded that The Placing Test provides a quick, simple and sensitive measure of memory that has potential to be useful in routine diagnostic investigations for Alzheimer's disease.

Yes / Family relationships are important for wellbeing across the life course and are known to be important for people living with dementia, bringing benefits to self-esteem and identity, as well as providing support for people living at home. Recent research has explored the impact of dementia upon relationships. Much of this research is qualitative in nature and rarely included in systematic reviews, however, it has the potential to provide significant contributions to understanding the interplay between family relationships and dementia and to inform interventions. A systematic synthesis of qualitative research concerning the impact of dementia upon family relationships was undertaken, using thematic synthesis. Eleven articles were reviewed, which address the perspectives of people living with dementia and their spouse and/or adult children. The aims of this review are to illuminate what is currently known about the reciprocal influences between family relationships and dementia from the perspectives of the family (including the person with dementia); and to consider the implications of these findings for research and practice. Four super-ordinate themes were identified: A shared history, negotiating the impact of dementia upon the relationship, openness and awareness, and shifting sands. This synthesis contributes to an emerging field but also highlights gaps in current understanding of the impact of dementia upon relationships and in providing appropriate interventions. Implications for research and practice are considered.

Yes / A participatory film-making study carried out in long-term social care with 10 people with Alzheimer-type dementia found that places the participants had known early in life were spontaneously foregrounded. Participants’ memories of such places were well-preserved, particularly when photo-elicitation techniques, using visual images as prompts, were employed. Consistent with previous work on the ‘reminiscence bump’ in dementia, the foregrounded memories belonged in all cases to the period of life between approximately 5 and 30 years. Frequently the remembered places were connected with major life events which continued to have a strong emotional component. The continuing significance of place in the context of long-term dementia care is considered from a psychogeographical perspective.