Thesis (M.S.)--University of Michigan, 1992.

Thesis (M.S.)--Oregon State University, 2006. / Printout. Includes bibliographical references (leaves 55-60). Also available on the World Wide Web.

Le diagnostic de maladie d'Alzheimer (MA) chez les patients de moins de 65 ans ou early-onset Alzheimer's disease (EOAD) est souvent difficile car la présentation clinique est fréquemment atypique, dominée par des signes non amnésiques. Les études antérieures sur les marqueurs de diagnostic précoce en imagerie se sont intéressées à l'imagerie structurelle et fonctionnelle dans l'EOAD mais aucune à la perfusion en IRM par la technique de marquage de spin ou arterial spin labeling (ASL). En effet, l'analyse de l'ASL demeure complexe, en particulier à l'échelle individuelle, du fait du faible rapport signal sur bruit des cartographies de perfusion et de l'hétérogénéité des zones atteintes à la phase initiale de la maladie. Notre premier objectif était technique et a consisté à optimiser l'interprétation des cartographies d'ASL grâce à la projection des anomalies de perfusion sur la surface du cortex extraite de l'acquisition morphologique T1 réalisée au cours du même examen, permettant d'accéder à une représentation tridimensionnelle interactive des données perfusionnelles. Le traitement des cartographies intégrait plusieurs étapes successives dont une correction des effets de volume partiel, une normalisation d'intensité spécifique et un lissage surfacique. Ce procédé a été appliqué sur les cartographies de 18 patients atteints d'EOAD avec une qualité de segmentation et de représentation des cartographies surfaciques obtenues jugées respectivement optimale et bonne dans 72 % des cas par deux lecteurs. Notre deuxième objectif était clinique et avait pour but de caractériser les altérations perfusionnelles et métaboliques par ASL et 18fluorodésoxuglucose-TEP (18F-FDG-TEP) sur un groupe de 37 patients atteints d'EOAD. Cette étude préliminaire à montré : (i) un pattern anatomique pathologique commun au niveau des lobules pariétaux inférieurs et des lobes temporaux ; (ii) des discordances entre les 2 techniques avec des lésions plus étendues en 18F-FDG-TEP et la détection en ASL de zones hypoperfusées additionnelles au niveau des lobes frontaux non visibles en 18F-FDGTEP. Ces deux travaux suggèrent que l'ASL pourrait donc devenir une séquence complémentaire clef dans l'arsenal des techniques d'imagerie utiles à un diagnostic précoce de l'EOAD et de la MA. Son utilisation en pratique clinique nécessite cependant une optimisation de sa représentation visuelle, et l'application corticale surfacique utilisée dans ce travail en représente une des voies potentielles. / The diagnosis of Alzheimer's disease (AD) in patients under the age of 65 years, called early-onset Alzheimer's disease (EOAD), remains a challenging issue due to the high incidence of atypical clinical presentations with non-memory symptoms. Although EAOD has been widely explored by structural and functional imaging, no previous study has examined the contribution of ASL in the assessment of cortical perfusion in this disease. Indeed, the analysis of ASL remains complex, especially at the individual level, due to the weak signal-to-noise ratio of the perfusion maps and the heterogeneity of pathological areas in the initial phase of the disease. Our first objective was technical and has consisted in optimizing the visual interpretation of ASL maps by the cortical surface-based projection of the perfusion alterations on the structural T1 sequence acquired during the same imaging protocol, providing a 3D interactive display of the perfusion data. Data processing included several successive steps, such as a partial volume effect correction, a specific intensity normalization and a surface-based smoothing process. It was applied on the perfusion maps of eighteen EOAD patients and the quality of segmentation and of cortical surface-based perfusion maps were scored as optimal in 72% in both cases by two readers. Our second objective was clinical and aimed to characterize the cerebral hypoperfusion and hypometabolism by ASL and 18F-FDG-PET in a group of 37 EOAD patients. Our preliminary study showed: (i) a similar pathological pattern located in the inferior parietal lobules and in the temporal cortex, (ii) discrepancies between the two modalities with the presence of more widespread hypometabolic regions detected by 18F-FDGPET and additionnai areas of alterations in the frontal lobes detected by ASL without apparent hypometabolism. Our studies suggest that ASL may become a useful complementary tool which, in combination with the existing structural and functional techniques, could offer improved efficiency in the difficult early detection of EOAD and AD. Its use in clinical practice, however, requires an optimization of its visual representation, and the cortical surface-based projection applied in this work represents one of the potential ways to this image quality improvement.

In 2015, an estimated 46.8 million people were living with dementia, a number predicted to increase to 74.7 million by 2030 and 131.5 million by 2050. Whilst there are numerous causes for the development of dementia, Alzheimer's disease is by far the most common, accounting for approximately 50-70% of all cases. Current therapeutic agents against Alzheimer's disease are palliative in nature, managing symptoms without addressing the underlying cause and thus disease progression and patient death remain a certainty. Whilst the main underlying cause for the development of Alzheimer's disease was originally thought to be an abnormal deposition of insoluble amyloid-β peptide derived plaques within the brain, the failure of several high-profile therapeutic agents, which were shown to reduce the plaque burden without improving cognition, has recently prompted a shift in focus to soluble oligomeric forms of amyloid-β peptide. Such soluble oligomers have been shown to be toxic in their own right and to precede plaque deposition. Soluble amyloid-β oligomers have been identified in various subcellular compartments, including the mitochondria, where they form a complex with the 17β-HSD10 enzyme resulting in cytotoxicity. Interestingly, hallmarks of this toxicity have been shown to be dependent on the catalytic activity of the 17β-HSD10 enzyme, suggesting two therapeutic approaches may hold merit in treating Alzheimer's disease: disrupting the interaction between the 17β-HSD10 enzyme and amyloid-β peptide, or directly inhibiting the catalytic activity of the 17β-HSD10 enzyme. In 2006, Frentizole was identified as a small molecule capable of disrupting the 17β-HSD10/amyloid interaction. The work described herein details the generation of a robust screening assay allowing the catalytic activity of the 17β-HSD10 enzyme to be measured in vitro. This assay was subsequently employed for small molecule screening using two methodologies; first in a targeted approach using compounds derived from the Frentizole core scaffold, and second in an explorative manner using a diverse library of compounds supplied by the National Cancer Institute. As a result, a range of novel small molecule inhibitors of the 17β-HSD10 enzyme have been identified and the most promising characterised in terms of potency and mechanism of action. De-selection assays were developed to allow the efficient triage of hit compounds and work was begun on a cellular based assay which would allow the ability of compounds of interest to reverse a disease relevant phenotype to be assessed in a cellular environment. As such, we now have a number of hit compounds which will form the basis for the generation of subsequent series of derivatives with improved potency and specificity, as well as the robust assays required to measure such criteria, potentially leading to the generation of novel therapeutic agents against Alzheimer's disease.

This study explores the possibility that attentional deficits are an early clinical symptom of Alzheimer's disease. The three goals are to demonstrate that individuals with Alzheimer's disease are impaired on tasks of attentional processing, to compare the sensitivity of currently used measures of attention to attentional dysfunction, and to compare the behavioral response styles (errors of commission) of Alzheimer's disease subjects and non-impaired subjects. The subjects were 22 males and 46 females with a mean age of 70.76 years. Thirty-six had the presumptive diagnosis of Alzheimer's disease; 18 were identified as mildly impaired and 18 as moderately impaired on the Cognitive Capacity Screening Examination. The remaining 32 subjects comprised the non-impaired control group. Five measures of attention were administered to all participants: the Digit Span Subtest of the WAIS-R, the Seashore Rhythm Test of the Halstead-Reitan Neuropsychological Battery, the Vigilance and Distractibility tasks of the Gordon Diagnostic System, and the Concentration/Interference task. The results show a significant difference in attentional processing between normal (non-impaired) subjects and subjects diagnosed with Alzheimer's disease. All measures of attention used in this study, except the Concentration/Interference task, differentiated normal subjects from moderately impaired Alzheimer's disease subjects. The Digit Span Subtest and the Seashore Rhythm Test were unable to differentiate between normals and mildly impaired Alzheimer's disease subjects or between mildly and moderately impaired Alzheimer's disease subjects. The Gordon Diagnostic System was able to distinguish normals form mildly impaired Alzheimer's disease subjects and mildly from moderately impaired Alzheimer's disease subjects. On the Gordon Diagnostic System the Alzheimer's disease subjects made significantly more errors of commission than did the normal subjects. This investigation concludes that attentional processing dysfunction occurs in the dementing process associated with Alzheimer's disease. The findings suggest that the Gordon Diagnostic System is a more sensitive technique for assessing attentional dysfunction than the other measures of attention used in the study.

The results of neuropsychological tests are often used by clinicians to make important decisions regarding a demented patient's ability to competently and/or independently perform activities of daily living. However, the ecological validity of most neuropsychological instruments has yet to be adequately established. The current study examined the relationship between neuropsychological test performance and functional status in 42 individuals diagnosed with Alzheimer's Disease. A comprehensive battery of cognitive tests was employed in order to assess a wide range of neuropsychological abilities. Functional status was measured through the use of both a performance-based scale of activities of daily living (The Direct Assessment of Functional Status; Loewenstein et al., 1989) as well as by a caregiver/informant-based rating scale (Instrumental Activities of Daily Living; Lawton & Brody, 1969). Findings suggest that neuropsychological functioning is moderately predictive of functional status. Memory performance was the best predictor of functional status in most ADL domains, followed by executive functioning and visuospatial abilities.

When family members no longer have the capacity to meet Alzheimer's Disease (AD) caregiving demands at home, a move to a nursing home or other formal care facility becomes the only solution. Recognizing this as a time of transition, three research questions were identified: (1) What do family caregivers to AD individuals experience as they shift their caregiving from home to formal care settings? (2) How does caregiving in formal care differ from caregiving at home? and (3) How do family caregivers perceive the relationships that develop between families and formal care staff? Specific attention was paid to the experiences of spouses and adult children. Using a qualitative approach, two specific bodies of data were investigated. First, transcripts of a series of 30 focus groups with 179 caregivers, and second, ten follow-up interviews were analyzed. Both spouses and adult children overwhelmingly identified physical exhaustion and often emotional exhaustion as the pervasive common experience. After reaching this state, caregivers identified the pivotal nature of events in contributing to placement. These kinds of events turn out to be more like turning points than crises. Caregivers in this study identified five themes that were influential in their decision-making process. In order of their importance to the caregivers, they were: events, the health care system, caregiver-care receiver relationship, support, and options and availability. A male spouse caregiver was likely to cite a turning point event centered on an incontinence problem, while for a female spouse caregiver, it was an AD safety issue. The health care system was usually a negative influence and served to delay the placement decision. Immediately, after placement, family caregivers noted shifts in control, involvement and personal reorganization. Family caregivers frequently noted the development of a caregiving relationship with staff. The individuals whom the family caregivers mentioned most often were the aides. Their bottom line was that staff deliver quality care, which they equated with caring about the resident rather than only taking care of them. The findings from this study have implications for theory development, family caregivers, formal care staff, and health care policy.

Alzheimer's disease (AD) is significantly more prevalent among African Americans than within the general population, but rates of early detection are lower in the African American community. Researchers have demonstrated that both pessimistic Alzheimer's-directed health beliefs, and negative perceptions of the effectiveness and the accessibility of medical care act as barriers to care seeking by African American family members of individuals with the disease. Recent research into causal judgments made by potential caregivers about individuals with undiagnosed AD suggests that gender bias and errors in attribution may constitute covert barriers to both lay and professional interpretations regarding the need for cognitive assessment. This study used grounded theory to investigate whether African American family caregivers hold integrated, gender-distinct beliefs about causal attributions of their family member's cognitive decline which may contribute to a delay in care-seeking behaviors. The health belief model was used in conjunction with the attribution theory as the conceptual framework for understanding the data. Purposive sampling of geriatric and memory clinics, and a church was used to recruit eight family caregivers who participated in in-depth interviews. The results indicated that there is a significant lack of caregivers' knowledge and understanding of AD regardless of gender, and that this lack is linked to delays in diagnosis. These results may be used to support the development of a new theory of family caregivers' knowledge and understanding of AD. The social change implications include decreasing delayed diagnosis through increased educational awareness, community outreach programs, and universal mandatory cognitive testing of AD for at-risk individuals.

There are few, yet contradictory, reports in the literature regarding whether persons with Alzheimer's disease demonstrate a disturbance of nonverbal communication or pantomime. While some researchers ascribe all disturbances of gestural behavior to apraxic phenomena, others have viewed a disturbance of pantomime as the consequence of language disorder or general intellectual deterioration. This investigation was conducted (1) to determine whether persons with Alzheimer's disease demonstrate a disturbance of pantomime recognition, pantomime expression, or both, compared to healthy, aged controls; (2) to determine the relation of performance on measures of pantomime recognition and pantomime expression to performance on measures of cognition/intelligence, language, and praxis in Alzheimer subjects; (3) to determine whether Alzheimer subjects improve pantomimic expressive performance on imitation of the examiner; and (4) to determine whether a statistically significant difference in pantomimic expressive performance between Alzheimer and control subjects is also a clinically obvious difference. Forty-five subjects (30 subjects with Alzheimer's disease and 15 healthy, aged controls) were administered measures of pantomime recognition, pantomime expression, cognition/intelligence, language, and praxis. In addition, 13 graduate students in speech-language pathology viewed and judged as being "normal" or "abnormal" 15 expressive pantomimes performed by 10 Alzheimer and 5 control subjects. Results indicated that there was a significant difference between groups in performance on both pantomime measures; the Alzheimer subjects performed less well than controls. The performance of Alzheimer subjects on both pantomime measures was also more closely related to performance on measures of language and cognition/intelligence than to praxis. Alzheimer subjects improved pantomimic expressive performance on imitation of the examiner, to the extent that between groups performance no longer differed significantly. Finally, graduate student judges rated the pantomimic expressive performance of Alzheimer subjects as being "abnormal" significantly more often than the pantomimic expressive performance of controls. Because the pantomime variables were related to both the language and cognition/intelligence variables, and the language and cognition/intelligence variables were related to one another, it was concluded that these variables were functionally interdependent, and therefore, these results for this sample conformed with central mechanism explanations for a disturbance of pantomime.

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