The dissertation examined family caregivers’ perceptions of wandering behavior after their loved one has been diagnosed with ADRD (Alzheimer’s disease and related dementias). Semi-structured in-depth face-to-face interviews of a convenience sample of 22 caregivers in the Dallas metropolitan area were conducted. Responses were analyzed using a grounded theory approach. The use of qualitative methods facilitated the study of how caregivers of a loved one with ADRD understood and explained in their own voice the wandering behavior associated with the disease and how their views of the behavior informed the caregiving process. In particular, this research examined why some caregivers tend to recognize wandering behavior as significant early on while the ADRD patient is still living in the home (and community) and modifications can be made to keep him or her there despite the behavior, and why some caregivers do not. Findings indicated that caregivers were concerned about the general safety of their loved one. Precautions were taken within the home for conditions related to frailty, but were much less likely to be taken to address wandering behavior and its negative consequences. Three groups of caregivers emerged: (a) those who primarily reacted to their loved one’s problem behaviors including wandering, and intervened minimally; (b) those who were proactive, making modifications in their routines and environment to protect their loved one after a trigger event; and (c) those who had a mixed response, who did the best that they could with what they had. This last group of caregivers took on additional roles, modified their homes for safety, but environmental stressors and inadequate supports limited their interventions. Implications of the findings for aging in place and community, further research, policy-making, and practitioners are discussed.

Alzheimer’s Dementia (AD) is among the most common diseases in the Geriatric population, and its prevalence is expected to quadruple by 2047.Vascular Dementia (VaD) is the second most frequent cause of dementia, with studies indicating VaD accounts for 10-20% of dementia cases across the globe. A diagnostic model differentiating AD and VaD would be clinically and scientifically valuable, considering the treatment approaches for these conditions are different. Although there are differences between AD and VaD on their neuropsychological profiles, a diagnostic model that successfully differentiates AD and VaD on neuropsychological testing has not been developed, despite previous attempts. Our study addresses this gap in the literature by examining two diagnostic models used to predict the conversion of AD from mild cognitive impairment, and a third model was proposed to differentiate AD from VaD. We conducted ROC Analyses using the variables LM II Standard Score, Animals Total, and CDRS Sum based on a previous diagnostic model. The sensitivity and specificity for the diagnosis of mild VaD were calculated for all possible scores of each test measure. The Animals Total cutoff score of 7 achieved excellent sensitivity and specificity, receiving 96% and 92%, respectively. In this sample, patients who could name at least seven animals under 60 seconds were highly likely to be diagnosed with VaD. LM II Scaled Score also achieved statistical significance (p <0.001) and a cutoff score of 4 received 96% sensitivity and 77% specificity. Patients who achieved an LM II Scaled Score of 4 or higher were highly likely to be diagnosed with VaD.

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD is characterized by two hallmark pathologies: β-amyloid plaque deposition and neurofibrillary tangles (NFT) of hyperphosphorylated tau. For several decades, the amyloid cascade hypothesis has been prevalent. Inflammation was believed to be another factor associated with AD pathogenesis. On the other hand, according to the cholinergic hypothesis of AD, the loss of the cholinergic neurons results in a decrease in acetylcholine level, and in turn induces cognitive and memory deficits. Acetylcholinesterase inhibitors (AChEI) have been the most common prescriptions for AD since 1993. Donepezil is the most commonly used AChEI in the treatment of mild, moderate and severe AD cases and has less adverse effects. According to another hypothesis, the myelin hypothesis, the deposits of Aβ and tau could be by-products of age-related myelin repair processes. Reduced myelin stability may relate to changes in levels of diverse myelin extra components, like lipids and their oxidized products, as well as expression levels of Myelin Basic Protein-MBP. We have successfully established chronic inflammation mouse model in adult, wild-type C57BL/6J mice through subcutaneous, continuous infusion of lipopolysaccharides (LPS) in our lab. We found LPS from the oral bacterium Porphyromonas gingivalis (P. gingivalis) appears to trigger more pronounced neuroinflammation and cognitive impairment than the gut bacterium Escherichia coli (E. coli). Our study aims at a) confirming the contribution of chronic inflammation induced by P.g to the development of AD and the neuropathological changes in mice, b) at exploring the effect of Donepezil on the neuropathological changes in this chronic inflammation mouse model and c) at exploring if there is a difference regarding the presence/expression of MBP among the four groups. Forty-eight male 24-week-old C57BL/6J wild type (C57) mice were divided into 4 treatment groups with 12 mice per group; Group 1: Normal saline injection + normal saline infusion; Group 2: Normal saline injection + P.g.-LPS infusion; Group 3: Donepezil injection + normal saline infusion; Group 4: Donepezil injection + P.g.-LPS infusion. P.g-LPS or normal saline infusion was administered through subcutaneously implanted ALZET® osmotic pumps for 28 days. Donepezil or normal saline injection was administered through the intraperitoneal injection (ip) for 29 days. The Donepezil (1mg/kg/d) or normal saline ip injection was administered one day before the P.g-LPS or normal saline - filled pump implantation. Following 21 days of either P.g.-LPS or normal saline infusion and 22 days of injections, Morris Water Maze (MWM) test was conducted for the assessment of spatial learning and memory of the mice. The experiment lasted until day 26. On day 29 of the experiment, the mice were euthanized by Isoflurane overdose. Serum was isolated after centrifugation of the blood collected by intracardiac puncture. The right hemisphere was snap-frozen for the inflammatory cytokine ELISA assay and the left hemisphere was fixed in 10% formalin overnight, then switched to 70% EtOH for histology and immunohistochemistry (IHC). The sections were immunostained with MBP as a primary antibody. One-way ANOVA showed that there was no statistically significant difference in Day 0 Body Weight after treatment group assignments were made. No adverse effects were observed on the general health of the mice throughout the study. Although there was a statistically significant difference in body weight among groups on Day 7, these body weight differences were transient and did not maintain. The ELISA revealed that there were no significant differences in the IL-1β levels in the brain among all the groups. Regarding MWM, two-way ANOVA revealed no statistically significant differences in the latency to platform between the 4 groups. Nevertheless, a significant difference was noted between the different days. Taken collectively, the results of the spatial learning and reference memory suggest that P. gingivalis-LPS did not induce cognitive dysfunction in these mice. Last but not least, one-way ANOVA revealed no significant differences between the 4 groups in the MBP positive area. In the present study, no statistically significant differences were observed between the 4 groups in the brain IL-1β levels determined by ELISA, spatial learning and reference memory assessed by the MWM, and the MBP protein expression in hippocampus by IHC, respectively. Our previous finding that P.g-LPS induces neuroinflammation and cognitive deficit was not replicated in the current study. We do not know the exact reasons. There is a possibility that the daily injections might affect the neurobehavior performance of mice. This is confirmed by the observation that the mice in the current study had an overall elevated IL-1β in brain, even in the Sal+Sal group. To demonstrate the proposal that the stress from the daily injection might affect the immune responses to chronic LPS, a study with and without daily injection under the same setting will be needed.

This qualitative study used semi-structured interviews to explore how 6 people talked about their difficulties before and after a dementia diagnosis. The Assimilation of Problematic Experiences Scale (APES) was used to analyse the data and describe participants’ internal processes as they became increasingly aware of their problems. Assimilation analysis views successful therapeutic change as accepting and integrating an aspect of the self that had previously been denied, due to it being too painful. The findings of the study build on the research evidence that suggests that despite the enormity of its psychological implications individuals find ways of integrating a dementia diagnosis into their sense of self. This occurred within an oscillating progress; stepping in and out of awareness, illustrating the paradox of acceptance and denial. Social support was crucial in enabling participants to sustain a positive sense of self in the face of this adjustment.

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, with an incidence of up to 50% in western populations over the age of 85 and a high heritability (up to 80%). The identification of risk factors for the development of LOAD is imperative for improving our understanding of this disease and for identifying therapeutic targets for treatment or prevention. Currently, the major known risk factors for the development of LOAD are age and the ApoE ε4 genotype. Previous studies have implicated plasma levels of the amyloid beta (Aß) peptide as a LOAD-associated quantitative trait and identification of loci influencing this trait could provide new insights into LOAD. In this thesis, plasma levels of the Aß peptides Aß40 and Aß42 have been measured in two isolated populations and genome-wide linkage and association analyses were performed. The genome-wide association analyses identified a number of promising quantitative trait loci; highlighting both novel and previously reported LOAD genes for further study, whilst also providing an excellent resource for genetic convergence studies with other LOAD related traits. Several studies have reported an association between levels of oxidative stress and levels of Aß such that increasing levels of Aß appear to increase markers for oxidative stress and vice versa. The role of oxidative stress in LOAD and aging was therefore also investigated through analysis of mitochondrial mutational burden and DNA damage respectively, using DNA isolated from both blood and the brain and by carrying out a candidate gene association study of loci involved in mitochondrial function in LOAD cases and controls. Approaches to the investigation of mitochondrial genetics for the study of LOAD are comprehensively reviewed, adapted and tested and the results indicate a need for additional research in this aspect of the disease. This thesis therefore presents a focus on two aspects of genetic research into LOAD, a complex disease with multiple environmental and genetic influences which aims to advance our understanding of the disease and bring us closer to treatment and prevention strategies.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder associated with aging. AD is by far the best understood and most studied neurodegenerative disease. Substantial advances have been made over the last decade, however it is debatable how much closer we are to a clinically useful therapy. A long standing goal in the AD field has been to improve the accuracy of early detection, with the assumption that the ability to intervene earlier in the disease process will lead to a better clinical outcome. Major facets of this effort have been the continued development and improvement of AD biomarkers, with a strong focus on developing imaging modalities. AD is accompanied by two pathological hallmarks in the brain: extracellular neuritic plaques composed of the beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. Evidence of Aβ as the driving force behind the progression of AD (the amyloid cascade hypothesis) was first published by Hardy & Higgins in 1992, and this peptide has been the focus of therapeutic and diagnostic testing for decades. Significant technological advances in recent years now allow imaging of amyloid pathology in vivo. These methods evaluate Aβ burden in a living person, and could potentially serve as both a biomarker, and as a diagnostic tool to detect disease. Pittsburgh Compound B (PiB) is currently the best studied of these imaging agents, however, our current knowledge of the quantitative relationship between PiB binding and amyloid pathology in the brain is limited. A better understanding of how these variables relate to one another is essential for the continued development of reliable diagnostic biomarkers for AD. We analyzed increasingly insoluble pools of Aβ to quantify their relative contributions to the overall Aβ burden, and to determine if any of these measures could be used to predict disease status. We found that the amount of PiB binding in a cortical region of the brain could distinguish cases of mild cognitive impairment (MCI) when corrected to the amount of PiB binding in the cerebellum. As the Aβ peptide ages, the amino acid aspartate may spontaneously convert to an isoaspartate residue through a succinimide intermediary. The presence of iso-Asp Aβ has been used to indicate the presence of aged plaques in AD and Down syndrome cases. We sought to investigate the potential relationship between levels of ‘aged’ Aβ in the plasma as indicated by iso-Asp Aβ and disease state, as a potential biomarker for the presence of AD pathology. We found that AD cases had lower levels of all forms of Aβ in plasma when standardized to the group average, and that plasma levels of Aβ and iso-Asp Aβ were reversed between disease groups. A follow up study is required, however, these initial data are a promising step towards utilizing aged iso-Asp Aβ plasma levels as a potential biomarker to indicate disease state.

Alzheimer’s disease (AD) is a very complex disorder and the most common form of dementia. The two pathological hallmarks of AD are extracellular amyloid-β (Aβ) plaques in cerebral cortex, and intraneuronal neurofibrillary tangles. In the early stages of the disease it can be difficult to accurately diagnose AD, as it is difficult to distinguish from normal signs of aging. There is thus a need for sensitive non-invasive tools, able to detect pathophysiological biomarker changes. One such approach is molecular imaging of Aβ plaque load in brain, using PET (positron emission tomography) ligands. We have developed and characterized two novel Aβ plaque neuroimaging PET ligands, AZD2184 and AZD4694. The 2-pyridylbenzothiazole derivate AZD2184, is a 11C-labeled PET ligand with a higher signal-to-background ratio compared to the widely used PET ligand PIB, a 11C-labeled phenylbenzothiazole based tool. This makes it possible to detect smaller changes in Aβ plaque deposition load, and therefore theoretically, also earlier diagnosis. A drawback with 11C-labeled PET ligands is the relatively short half-life. To meet the need for PET ligands with a longer half-life, we developed the pyridylbenzofuran derivate [18F]AZD4694. Although development of fluorinated radioligands is challenging due to the lipophilic nature of aromatic fluorine, we successfully developed a 18F-labeled PET ligand with a signal-to-background ratio matching PIB, the most widely used 11C-labeled PET ligand in clinical use. 3H-labeled derivates of AZD2184, AZD4694, and PIB, showed lower binding specificity towards Aβ plaques containing ApoE. The ApoE genotype per se did not significantly affect ligand binding, instead, the amount of ApoE incorporated to the Aβ plaques appears to be of importance for the binding characteristics of these amyloid PET ligands. Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid precursor protein (APP) to Aβ peptides, making BACE1 inhibition an attractive therapeutic target in AD. We developed and characterized three novel BACE1 inhibitors, AZD3839, AZ-4217, and AZD3293. AZD3839 and AZ-4217 contains an amidine group which interacts with the catalytic aspartases Asp-32 and Asp-228 of BACE1, effectively inhibiting the enzyme. All three compounds are potent and selective inhibitors of human BACE1, with in vitro potency demonstrated in several cellular models, including primary cortical neurons. All three compound exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in several species, and two of the compounds (AZD3839 and AZD3293) were progressed into clinical trials. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Submitted.</p>

Patients with Alzheimer’s Disease (AD) demonstrate a sensitive and specific short-term memory impairment for visual bindings (e.g. the combination of shapes and colours) that is absent in healthy ageing (Parra et al., 2009) and other dementias (Della Sala et al., 2012). This impairment is also seen in cases of asymptomatic, familial AD (Parra et al., 2010). The visual short term memory binding (VSTMB) impairment in AD has clear clinical and neuropsychological implications which are investigated in this thesis. Firstly, the utility of the VSTMB paradigm was contrasted with the Free and Cued Selective Reminding Task with Immediate Recall (FCSRT-IR) – which has recently been posited as a useful diagnostic marker of AD pathology (Dubois et al., 2014). The results indicated that the former is not affected by age, where the latter is, suggesting that the VSTMB paradigm provides a suitable baseline to measure cognitive decline associated with AD. The development of a parallel version of the FCSRT-IR is also reported. Secondly, a 24-week longitudinal study of patients receiving treatment for AD (donepezil hydrochloride) revealed that patients who respond to this treatment on cognitive scales also experience change in VSTMB performance. These responders, however, did not significantly improve on the FCSRT-IR during the study. This suggests that anticholinergic treatment may have an effect on VSTMB performance. Additionally, a meta-analysis that investigates the effect of a study’s funding on donepezil RCT outcome showed that industry-funded studies report larger changes in cognition than independent studies. Lastly, an auditory binding experimental paradigm was developed, with a view to reveal a non-visual binding impairment in AD, investigating whether the binding impairment reflects a general or modality-specific memory impairment. The overall conclusions of this thesis confirm that the VSTMB impairment has significant promise as an index of AD. The auditory binding paradigm, by contrast, shares conceptual similarity with the VSTMB paradigm, but may have restricted clinical use within the AD patient population.

Introduction The present study explored the nature of the semantic deterioration normally displayed in the course of Alzheimer’s disease (AD). The aim was to disentangle the extent to which semantic memory problems in patients with AD are best characterized as loss of semantic knowledge rather than difficulties in accessing semantic knowledge. Method A longitudinal approach was applied. The same semantic tests as well as same items were used across three test occasions a year apart. Twelve Alzheimer patients and 20 matched control subjects, out of a total of 25 cases in each group, remained at the final test occasion. Results and Conclusions Alzheimer patients were impaired in all the semantic tasks as compared to the matched comparison group. A progressing deterioration was evident during the study period. Our findings suggest that semantic impairment is mainly due to loss of information rather than problems in accessing semantic information.

Alzheimer’s is a widespread neurodegenerative disease, growing larger and larger in the world. Once developed, the disease has no cure. To this day, there is only mitigating drugs. To be able to start this treatment rapidly, a method to distinguish healthy individuals from prospective Alzheimer’s diseased needs to be developed. Cerebrospinal fluid is thought to contribute to the development of such method, through its close substitution of fluids, molecules and proteins from the brain. It may provide a progressive marker of the disease, a substance differently expressed in the healthy and diseased; a biomarker. The aim of the present study was to develop and evaluate a stable method for degradation and analysis of peptides and proteins in the cerebrospinal fluid using mass spectrometry techniques, such as selective reaction monitoring. Mass spectrometry is often used after a first dimension separation with liquid chromatography. Three degradation methods were evaluated, resulting in a protocol with the detergent DOC being the most beneficial. Tryptic peptides occurred in a concentration of 10 % w/v due to the SDS-PAGE gels and database searches concomitantly. The elution pattern from the liquid chromatography enables a narrow selection in the sensitivity for each peptide. Chromatographic preferences such as column, hydrophobicity and time span was determined, and unwanted peptides filtered away. A specific protein, the amyloid precursor protein APP, is thought to play a significant part in the development of Alzheimer’s disease. The protein is located in the neurons, cleaved and processed to produce the neurodegenerating plaques found in the brain at the diseased. Three isoforms are found in the neurons, APP695, APP751 and APP770. When cleaved, a shorter soluble tryptic peptide is generated from all APP isoforms. This was the target for the current study, as a potential progressive biomarker. The method developed was able to separate and distinguish the soluble APP751 isoform, but not the APP695 or APP 770 isoforms, most probably due to glycosylations of the two resembling isoforms.