Increasing evidence suggests that free radical-mediated oxidative damage to various biologically important macromolecules correlates with the normal aging process. Alzheimer's disease is a devastating disease of elderly people. Epidemiological and clinical studies have shown that Alzheimer's disease is the most common cause of dementia in the elderly. Postmortem histological studies of the brains of former patients with Alzheimer's disease have shown that cerebral neurodegeneration is the primary cause of this condition. The working hypothesis for the present study is that $\beta$-amyloid, a protein associated with neural damage in the brains of Alzheimer's disease patients, produces free radicals which, by leading to a disruption of calcium homeostasis and neuron degeneration, play an important role in the progressive pathologic process of Alzheimer's disease. Consequently, antioxidant intervention should, by scavenging free radicals, prevent or terminate the oxidative cascade and offer protection to neurons from $\beta$-amyloid induced toxicity. In this project, we investigated: (1) the free radical formation in autopsy samples of Alzheimer and control cortex by using the electron paramagnetic resonance spin-trapping method; (2) the mechanism of calcium increase induced by $\beta$-amyloid and the protective effects of antioxidants on $\beta$-amyloid induced calcium disruption and cytotoxicity in cultured neurons; and (3) the effect of hypoxia induced oxidative stress on $\beta$-amyloid induced calcium disruption and cytotoxicity in cultured neurons. In this study, we found that the formation of free radicals in homogenates of frontal cortex from brains taken at autopsy and verified histologically to be from patients with Alzheimer's disease, was 22% higher $\rm (p < 0.05)$ than age matched controls as determined by electron paramagnetic resonance spectroscopy. Following incubation in the presence of ferrous sulfate (200 $\rm\mu M),$ samples of Alzheimer's frontal cortex produced nearly 50% more free radicals than did controls $\rm (p < 0.01).$ We also found that the fragment of $\beta$-amyloid comprised of amino acids 25-35, induces a rapid, concentration-dependent increase in cytosolic free calcium in PC12 neuronal cells. This action of $\beta$-amyloid 25-35 is not altered by pretreatment with the calcium channel blockers nifedipine or cobalt, with the depletor of intracellular calcium stores cyclopiazonic acid, or with the phospholipase C inhibitor neomycin. However, the effects of $\beta$-amyloid 25-35 on cytosolic free calcium are absent in calcium-free buffer, and are blocked by the antioxidant lazaroid U-83836E, by vitamin E and by cholesterol. $\beta$-amyloid 25-35 is also neurotoxic and produces a concentration dependent reduction in the viability of PC12 cells in culture. The neurotoxic action of $\beta$-amyloid is blocked by U-83836E, by vitamin E, and by cholesterol, but not by nifedipine or cobalt. When SH-SY5Y neuronal cells were preincubated in anoxic conditions for one hour, $\beta$-amyloid induced calcium disruption and cytotoxicity were amplified by this hypoxia induced oxidative stress. The interaction of anoxia and $\beta$-amyloid is blocked in a dose dependent manner by U-83836E and vitamin E. These data indicate that both the disruption of calcium homeostasis and the neurotoxicity of $\beta$-amyloid in neurons are mediated by free radical based processes.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on Sep. 2, 2009). Includes bibliographical references.

Memoria para optar al título de Periodista / Chile se encuentra en una etapa de cambios socioculturales, económicos y demográficos, y es justamente en este último punto donde se entrelazan dos situaciones de gran relevancia para el presente y para el futuro del país. Por un lado, la esperanza de vida ha aumentado considerablemente en las últimas décadas, llegando así a los 79 años en promedio. Y, por otra parte, pero en base a la misma idea, el país tiene 2.6 millones de personas en la etapa adulto mayor, lo que equivale al 15% de la población chilena. Si bien existen varias problemáticas a abordar en torno a la tercera edad, existe un tema en específico que requiere de gran atención y urgencia: la enfermedad de Alzheimer. Este diagnóstico, ligado al olvido, a la pérdida de memoria de la persona, se ha convertido en la quinta causa de muerte en Chile y se estima que será la tercera en Estados Unidos. Sin embargo, a pesar de esto, nuestro país todavía no cuenta con las herramientas suficientes para diagnosticar, tratar, cuidar y hacerse cargo de los más de 90 mil enfermos de Alzheimer que hay en Chile. Ni de ellos, ni de sus familias. A través de esta investigación hemos querido dilucidar cuáles son las verdaderas opciones que tiene una persona con Alzheimer en Chile, incluyendo su acceso a costosos medicamentos para retrasar el progreso de la enfermedad, como la posibilidad de un diagnóstico temprano o la opción de ayuda monetaria y psicológica por parte del Estado. En síntesis, distinguir las políticas públicas vigentes –y relacionadas con esta demencia– que existen hoy en Chile.

Diss. (sammanfattning) Stockholm : Stockholms universitet, 2009. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Heidelberg, Univ., Diss., 2007.

Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Master of Science in the School of Informatics, Indiana University May 2003 / Alzheimer's disease is a progressive, age-related, degenerative brain disorder, which is one of the most serious diseases in old people. The patients' memory is lost and their personality and behavior are changed gradually; furthermore, this process is irreversible until the patients die [1]. Alzheimer's disease first attacks the entorhinal cortex; then to the hippocampus, which help to control short-term memory; then to other regions, especially the cerebral cortex, which is very important in using language and reasoning [1 , 2]. After its attack, the neurons degenerate and lose synapses and eventually die [1 , 2]. According to the age of having this disease, Alzheimer's disease can be divided to early-onset (usually at age 30 to 60) and late-onset (at age of 65 or older) [1]. About 5% to 10% of Alzheimer's disease cases are early onset [1 ]. Another way to describe Alzheimer's disease is according to the inheritance pattern. In this way, Alzheimer's disease also can be divided to: sporadic Alzheimer's disease, which has no certain inheritance pattern; and familial Alzheimer's disease (FAD), which has certain inheritance pattern [1]. All FAD are early onset [1 ]. Alzheimer's disease is a progressive disease and the progression of symptoms can be divided into mild, moderate and severe phases [2, 3]. The symptoms of mild Alzheimer's disease include loss of memory, disorientation, and difficulty of performing routine tasks. [2]. Patients in this phase can live independently [3]. The moderate symptoms include having great difficulty in daily living, wandering, personality changes, agitation and anxiety [2]. Patients in this phase should be cared by other people. People in severe phase lose all communication functions, almost cannot think, and need total care [2].

Individuals with Alzheimer Disease (AD) exhibit deficits across multiple cognitive domains years before clinical diagnosis, when they are in the preclinical stages of the disease. Four studies were conducted to (a) examine the preclinical neuropsychological characteristics of English- and French-speaking Alzheimer Disease (AD) participants from the Canadian Study of Health and Aging (CSHA) and (b) determine the utility of select CSHA neuropsychological and demographic measures in predicting AD over a five-year period. Both English- and French-speaking AD participants demonstrated cognitive changes on episodic memory, verbal fluency, and speeded visuomotor processing tasks five years prior to diagnosis, however declines in performance between initial- and re-assessment were not uniform across these domains for either language group. Advanced age and declines in delayed episodic memory were the most significant indicators of progression to AD over a five-year period for both language groups. A validation study was conducted to investigate how well the predictors of AD prognosticate diagnostic outcome for an independent group of at-risk English-speaking participants. The best predictors of AD for the English-speaking group (age, episodic memory, and speeded visuomotor processing) accurately classified close to 70% of individuals from the at-risk sample. The present findings will contribute to diagnostic decisions regarding AD in older English- and French-speaking Canadian adults.

Individuals with Alzheimer Disease (AD) exhibit deficits across multiple cognitive domains years before clinical diagnosis, when they are in the preclinical stages of the disease. Four studies were conducted to (a) examine the preclinical neuropsychological characteristics of English- and French-speaking Alzheimer Disease (AD) participants from the Canadian Study of Health and Aging (CSHA) and (b) determine the utility of select CSHA neuropsychological and demographic measures in predicting AD over a five-year period. Both English- and French-speaking AD participants demonstrated cognitive changes on episodic memory, verbal fluency, and speeded visuomotor processing tasks five years prior to diagnosis, however declines in performance between initial- and re-assessment were not uniform across these domains for either language group. Advanced age and declines in delayed episodic memory were the most significant indicators of progression to AD over a five-year period for both language groups. A validation study was conducted to investigate how well the predictors of AD prognosticate diagnostic outcome for an independent group of at-risk English-speaking participants. The best predictors of AD for the English-speaking group (age, episodic memory, and speeded visuomotor processing) accurately classified close to 70% of individuals from the at-risk sample. The present findings will contribute to diagnostic decisions regarding AD in older English- and French-speaking Canadian adults.