Dissertation (Ph. D.)--University of Akron, Dept. of Psychology, 2006. / "May, 2006." Title from electronic dissertation title page (viewed 09/16/2006) Advisor, Philip A. Allen; Committee members, Kevin P. Kaut, Martin D. Murphy, Raymond E. Sanders, Daniel L. Ely; Department Chair, Paul E. Levy; Dean of the College, Ronald F. Levant; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

This study was designed with the aim of exploring from a qualitative point of view the communicative abilities of people affected by dementia. From among the different discourse genres, narratives were selected as these appear frequently in conversation and at the same time are a complex activity in which different cognitive and social skills interact. In spite of their apparent simplicity, they require an extended effort by the teller, who needs to choose an appropriate point in the conversation when the narrative can be introduced, recall all the necessary details and organize them in a comprehensible order, possibly employing a series of devices to hold the audience's attention. The focus on the investigation of communicative disorders was chosen with the aim of gaining a better understanding of what is normal or neurotypical in narrative discourse production. As a possible cause for impairment in communication I opted for dementia because it is a major health issue of which we have only a partial understanding. In particular, inconsistencies in the diagnostic practices have been pointed out, revealing an urgent need for a more accurate description of the behavioural symptoms. The data under examination have been collected in informal conversations with sixteen people affected by dementia. Further information on the communicative behaviour of the person affected by dementia was elicited from a family member by means of a semi-structured interview. The application of a simplified version of Labov and Waletzky's (1967) framework of narrative analysis, integrated with insights from Conversation Analysis, and contributions from anthropology, social sciences, narratology, as well as cognitive psychology, yield a number of results. Although a certain amount of variation was observed in the behaviour of the participants, the overall results seem to reflect findings from previous research and show how the progressive deterioration of the ability to retrieve and encode autobiographical memory is reflected in the diminishing ability to structure narrative discourse. Complex or canonical narratives seem to become frequent as dementia progresses, narratives become more fragmented, and contain more pauses and fillers, confusion in the chronological organization and confabulation, which is often fitted into previously established storylines; stories and story chunks are frequently repeated, then are reduced to brief comments that are scattered throughout discourse, so that they are no longer recognizable as narratives, but only as traces. The findings also add information on this process, such as that the ability to provide all the necessary details of orientation seems to be compromised since the early stages of the condition, as well as the ability to plan the narration, due to impairment of the executive function. Speakers in the moderate to severe stages displayed either a tendency to withdraw from the conversation or the opposite tendency to rely on a number of repetitions of small stories, story chunks and formulaic expressions, and on confabulation, in order to provide their contribution to the interaction. Some instances of potentially disordered behaviour displayed by mildly impaired participants have highlighted that both the interactional outcome and the frequency with which they appear in discourse can help make decisions on the level of acceptability of apparently deviant linguistic expressions. This may contribute to the description of the early symptoms of dementia. More research is urgently needed on the discourse abilities of neurotypical elderly speakers, as well as more collaboration between the clinical and linguistic field.

Alzheimer's disease (AD) is a neurodegenerative condition affecting millions of individuals worldwide and is a major source of mortality in elderly populations. While it is well established that there is a strong genetic basis for the disease, the epigenetic mechanism underlying the disease is largely unknown. The main purpose of this thesis is to understand the alteration of epigenetic modifications associated with the disease and its progression. In particular, we examine how alterations in the cytosine methylation and cytosine hydroxymethylation, two epigenetic modifications that are critically important for the development and function of the brain, are associated with advancing stages of Alzheimer's disease. Eight progressive AD brain samples were examined for changes in DNA methylation and hydroxymethylation by both dot blot analysis and a new oxidative bisulfite (OXBS) deep sequencing technology. The initial results of dot blot analysis reveal a statistically significant decrease in 5hmC associated with intermediate stage AD among the samples. This data suggests that the alterations in epigenetic modifications is likely associated with the pathophysiology of Alzheimer's disease, not only shedding new light on our understanding of the epigenetics of the disease, but also providing the basis for our future investigation on the exact cause and effect relationships of these epigenetic changes and their respective stages in Alzheimer's.

Patients with dementia due to Alzheimer's disease (AD) tend to exhibit impairments in in their episodic memory. In yes-no tests of recognition memory, patients with AD often display liberal response bias, a stronger tendency to recognize unstudied items as already-studied "old" items. Such tendency is believed to be related to false memory, which can decrease the quality of life in many AD patients. In this study, we analyzed the effect of different instructional manipulations within yes-no recognition memory task on response bias. Younger healthy adults, older healthy adults and one AD patient were evaluated for recognition memory performance and response bias in three different conditions of instructional manipulation. In each session separated by a week-long interval, participants were shown 120 words to study and 240 words, half of which were studied items, to be tested for recognition memory. Instructional manipulation was added in the testing phase of each condition. In one session, the participants were asked if the words were old, studied items; in another session, they were asked if the words were new, unstudied items; finally in the third session, participants were asked to identify if the words were either old or new. Our findings corroborated previous studies by observing liberal response bias in AD and moderately conservative response bias in health adults. We found that the instructional manipulations did not have a significant effect on response bias in either control group while the effect in the AD patient was inconclusive.

Alzheimer’s disease (AD) is the leading cause of dementia accounting for between 60-80% of all dementia related cases. It is the 6th leading cause of death in the US and is the only one in the top 10 leading causes of death without a prevention or cure. As the life-expectancy across the world continues to increase, the number of AD cases are expected to likewise increase dramatically. AD is a multifaceted disease. There is no one pathway or genetic predisposition that researches can pinpoint as causing disease in all cases. Approximately 5-10% of cases are caused by an inherited genetic mutation, while 90-95% of cases are sporadic with determined underlying mechanism. This makes treatment for disease extremely difficult. In recent years focus has been given to modifiable risk factors to lower risk for AD, including exercise, diet, cardiovascular health, education, and smoking. This study reviews the possible protective effects of exercise on the development of AD. Randomized control trials (RCTs), longitudinal studies, and meta-analyses and studies in AD mouse models are scrutinized to determine whether there is an association between exercise and lower risk of AD, and to potentially pinpoint the molecular mechanisms behind this protective effect. The majority of studies concur that exercise does lower risk of AD, but the mechanisms still need to be elucidated. Although more research is needed, the results so far have been promising.

Alzheimer's disease (AD) is the neurodegenerative disease responsible for the majority of dementia cases across the United States. Its pathology involves the accumulation of protein plaques in areas of the brain directly involved with learning and memory formation, causing cognitive impairments and loss of independence in everyday life. Deep brain stimulation (DBS) is a relatively young field in medicine that has gained a great deal of traction with its efficacious clinical outcomes in neurological diseases including Parkinson's disease, epilepsy, depression and obsessive-compulsive disorder. More recently, researchers have sought to discover the proper application of DBS to improve the formation of episodic memory to provide a comparable or superior therapy for AD. Many experiments have been performed using different electrical parameters, hardware, or locations stimulated in the brain, which produced mixed results for benefits in memory reinforcement. Of the various brain structures available to target, the Entorhinal Cortex (EC) has been shown to lead to numerous positive outcomes. Additionally, one study used a novel approach, applying DBS in response to the neural activity of the individual brain during memory encoding tasks, which produced improvements in memory performance. This proposal aims to use these modalities in concert - a closed-loop stimulation approach that monitors neural activity and targeting the EC - in AD dementia patients to act as an adjuvant therapy to current acetylcholinesterase inhibitor medications that provide weak efficacy when used alone. This will be conducted in a 2 year, multicenter, double-blind, randomized controlled clinical trial comparing treatment with dual therapy consisting of DBS and an acetylcholinesterase inhibitor, to those with acetylcholinesterase inhibitor monotherapy. Participants will have mild or moderate AD at baseline, evaluated using the Mini-Mental State Examination and their progress in both experimental arms will be recorded using the 13 item Alzheimer's Disease Assessment Subscale-Cognitive over a 2-year period. Investigators will study the primary outcome of delaying cognitive decline, with secondary effects involving the differences between age groups, stages of AD and how frequently stimulation was received in those within the DBS and standard therapy group. The results from this study have the potential to further improve future approaches involving DBS in the treatment of AD dementia, as the projected number of those affected by the disease continues to grow with advances in modern medicine.

Alzheimer’s disease (AD) is a widespread neurodegenerative disorder that affects tens of millions of patients worldwide. Throughout the last two decades an incredible amount of time and resources have been funneled into hopefully finding medications that would provide a cure. Unfortunately, no such compound has been identified and instead the only FDA approved medications for AD to date target symptomatic management and may not even be effective for longer than a couple of years. To this end, this paper sets out to identify modifiable risk factors for AD as well as provide recommendations for clinicians on how best to utilize the tools currently available to them to treat AD. Additionally this paper addresses common flaws in AD clinical trial study designs and provides future research directions to expand outside of the popular amyloid hypothesis and instead potentially focus on a multi-pathway mechanism of the disease. The following thesis will outline several potential mechanisms that can lead to the hallmark pathologies seen in AD, primarily amyloid deposition and neurofibrillary tangles as well as neuronal death. The majority of commercial and research interest into AD has been focused on the amyloid hypothesis and the notion that stopping the formation of amyloid plaques would stop the disease course. However, in recent years other mechanisms and neurotoxic pathways such as inhibition of tricarboxylic acid (TCA) cycle enzymes, neuroinflammation, and tauopathy have been shown to contribute both to the formation of amyloid plaques as well as contributing to AD pathology in their own right. The modifiable risk factors explored in this paper include the effects of triglycerides as well as intake of antioxidant vitamins and omega-3-fatty acids, both of which are beneficial for brain health. This paper will also highlight some of the extensive research on the Apolipoprotein E gene and the effects the various alleles have on AD risk. These being the putative protective effect of the APOE2 allele, “neutral” effect of the most commonly found APOE3 allele, and finally the deleterious effects of the APOE4 allele, believed to be the strongest genetic risk factor for late-onset AD.

A series of abstract thinking and reasoning tasks was administered to patients with Alzheimer's disease (AD) and a sample of nondemented older adults matched on age, education, and gender variables. The performance of the AD patients was inferior to control subjects on all verbal and nonverbal reasoning tests, including a newly developed test of analogical reasoning, the Goranson Analogy Test (GAT). Preliminary psychometric analyses of the GAT revealed very high internal consistency, good convergent and divergent validity, and adequate predictive validity. Further analyses revealed that reasoning with pictures was just as easy as reasoning with words for AD patients, indicating that modality of presentation has little effect on reasoning performance. Error analyses revealed no qualitative differences in performance between AD patients and nondemented controls. Taken together, the findings suggest that abstract thinking and reasoning abilities decline with the onset of Alzheimer's dementia. A neurocognitive model of analogical reasoning is proposed to account for the study findings. / Graduate

The Apolipoprotein E (APOE) ε4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease (AD) while the ε2 allele confers a reduced risk compared with the most common ε3 allele. Neuroimaging studies using magnetic resonance imaging (MRI) have shown that APOE genotype affects brain structure and function. The aims of the research presented in this DPhil thesis were twofold: 1) to investigate the effect of APOE genotype on brain function in healthy adults using magnetoencephalography (MEG), which is a direct measure of neuronal activity and 2) to explore interactions between the AD risk factors APOE ε4 allele, age and female gender and their effects on brain structure and function using resting-state functional MRI and diffusion tensor imaging. MEG revealed similar neuronal activity at rest for APOE ε2 and ε4 carriers, i.e. those with opposite AD risk, indicating a more general effect on the functional architecture of the brain that is not directly linked to AD risk. However, differences between APOE ε2 and ε4 carriers became apparent when reactivity to stimuli was explored using the excellent temporal resolution of MEG. APOE ε4 carriers showed faster sensory pro- cessing and APOE genotype effects were found for functional networks associated with attention. In the second part of this project, female APOE ε4 carriers showed overall significantly reduced functional connectivity between the hippocampus and precuneus and a significant age-related decrease in connectivity of these regions. Increased vulnerability of this connection might be one reason for increased AD risk and interventions targeting hippocampal connectivity might be especially effective in at-risk populations. The research presented in this DPhil thesis showed a complex pattern of APOE genotype effects on brain structure and function. While global APOE genotype effects on functional and structural connectivity do not follow patterns of AD risk, more specific measures of connectivity and task-related brain function could be of use in the development of preclinical markers for AD development.

Currently, the world population is aging. People over 75 is one of the fastest growing age groups. This is the group most affected by Alzheimer's disease. Reliable early diagnosis and tracking methods are essential to assist therapy and prevention. This research aims to study anisotropy texture in tomographic brain scans to diagnose and quantify the severity of Alzheimer's disease. A full methodology to study computer tomography, magnetic resonance imaging and multispectral magnetic resonance imaging is presented in this thesis. Before applying any texture method to the tomographic brain images, a segmentation technique has to be used to extract the different regions of interest. We propose the use of connected filters and iterative region merging to perform the segmentation. Gradient vector histogram is applied to study the texture anisotropy of computer tomography scans. Computer tomography scans present evidence of texture changes in demented subjects compare to normal subjects. The overlap between these groups is considerable, so anisotropy texture using computer tomography does not seem to add more useful information to the diagnosis of Alzheimer's disease than other clinical criteria. Another method to study texture anisotropy is grey-level dependance histogram, which is based in a 3D generalisation for arbitrary orientation of the 2D co-occurrence matrices. This texture technique is applied to magnetic resonance imaging scans, where features extracted from the grey matter component have a strong correlation with the mini mental state examination1 scores. Finally, Multispectral Grey-Level Dependence Histogram (MGLDH), Absolute Difference Histogram (ADH) and spatial correlations are texture techniques designed to study multispectral images. These techniques are applied to multispectral magnetic resonance images. We evaluate the performance of the different multispectral texture methods, and compare them with single channel texture methods.