Advances in diagnostic tools and disease slowing treatments have led to an increased focus on diagnosing Alzheimer's disease (AD) during the early stages of the disease. Early diagnosis of AD improves quality of life for patients and caregivers by allowing for participation in disease slowing interventions. However, early diagnosis of AD may have unintentional psychological and social consequences for patients and caregivers. To combat these potential consequences, it is important that psychosocial interventions, such as support groups, are available at the time of diagnosis. A review of literature demonstrated that early stage AD patients and their informal caregivers benefited from support groups attended by both patients and caregivers, referred to as early stage AD patient-caregiver dyad (PCD) support groups. However, there is a gap in knowledge regarding the need for early stage AD PCD support groups in rural areas. The purpose of this study was to evaluate the need for early stage AD PCD support groups in rural WA.A needs assessment survey was developed and distributed for a period of one month to four clinics and one senior center in five rural WA towns. Twelve informal caregivers and five community members who did not have AD or care for someone with early stage AD were included in data analysis. Results demonstrated that participants lacked information about early stage AD PCD support groups and barriers to accessing these groups. Even with a lack of information about early stage AD PCD support groups, a majority of participants indicated that these groups would address their many unmet needs, and 52.9% of participants were likely to participate in early stage AD PCD support groups. Further studies should be performed to capture the need for early stage AD PCD support groups in rural WA.

Protein misfolding diseases (PMDs) are a broad group of disorders including Alzheimer’s, Parkinson’s and prion diseases. They are characterised by the presence of aggregated, misfolded host proteins which are thought to cause cell death. Prion diseases are associated with misfolded prion protein (PrPSc), which has a tendency to form fibrillar aggregates. By contrast, Alzheimer’s disease (AD) is associated with misfolded amyloid beta (Aβ), which aggregates to form characteristic Aβ plaques. A feature which is common across PMDs is that small assemblies (oligomers) of the misfolded proteins are thought to be the important neurotoxic species, and it has been proposed that there may be a shared mechanism leading to cell death across PMDs caused by oligomers. In this study, the toxicity of different misfolded forms of recombinant PrP (recPrP) and recombinant Aβ (recAβ) and the mechanisms leading to cell death were investigated using a primary cell culture model. In addition, the importance of the disulphide bond in recPrP in relation to oligomer formation was explored using size exclusion chromatography and mass spectrometry, the toxicity of the different resulting oligomer populations were also investigated. Both recPrP oligomers and fibrils were shown to cause toxicity to mouse primary cortical neurons. Interestingly, oligomers were shown to cause apoptotic cell death, while the fibrils did not, suggesting the activation of different pathways. By contrast, recAβ fibrils were shown to be non-toxic to cortical neurons, Aβ oligomers, however, were shown to cause toxicity. Similar to recPrP, my data showed that it is likely that recAβ 1-42 oligomers also cause apoptosis. However, by contrast this seemed to be caused by excitotoxicity, which was not found to be the case for recPrP. Additionally, I have shown that the presence or absence of the disulphide bond in PrP has a profound effect on the size of oligomers which form. RecPrP lacking a disulphide bond leads to the formation of larger oligomers which are highly toxic to primary neurons. Findings from this study suggest that structural properties such as the disulphide bond in PrP can affect the size and toxicity of oligomers, furthermore, whilst oligomers have been shown to be important in both AD and prion diseases, they may not trigger the same pathways leading to cell death.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in alterations in memory, language, executive function and emotional behaviour. Although it can be characterised by symptoms, by the time they arise significant pathological alterations have already emerged in the central nervous system, namely increased amyloid plaques, neurofibrillary tangles and neuronal loss. Despite known pathological hallmarks the exact aetiology of AD is poorly understood and no current treatments are available. However, there is growing interest in the role of neuroinflammation in AD, with increases observed in the early stages of disease and with disease progression. Moreover, it has been suggested that peripheral inflammation can influence neuroinflammation and worsen neurodegeneration. Using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRS) we can non-invasively measure biomarkers of neuroinflammation and degeneration allowing multi-modal investigation of its role in normal aging and AD. Considering this the objectives of this study were to (i) Use PET and MRS to investigate neuroinflammatory and metabolite alterations in transgenic (TG) models of AD and their wildtype (WT) animals. (ii) Assess rates of cognitive decline in these models using memory based tests. (iii) Investigate relatively new TgF344AD rat as an AD model by characterising younger time-points than previously reported. (iv) Investigate the contribution of peripheral inflammation on AD progression. PET and MRS imaging was carried out longitudinally in the APPswe×PS1de9 mouse. Neuroinflammation was confirmed ex vivo and cognitive ability was assessed by behavioural tests. Results revealed significantly increase hippocampal and thalamic neuoinflammation in old TG mice as assessed by [18F]DPA-714 PET and supported by immunohistochemistry. Reduced neuronal marker N-acetlyaspartate was seen with age and was exacerbated in the TG mice. Accelerated cognitive decline was also seen in TG mice. PET and MRS imaging was carried out at 6 and 12 months in the TgF344AD model, which expresses amyloid and tau pathology as well as neuronal loss. No cognitive decline was observed in TG rats; however increased anxiety behaviour was seen. Increased [18F]DPA-714 PET was observed as an effect of gene in the thalamus at 6 months and the hypothalamus at 12 months. Increases in glutamate were seen with age in the TG rats but not the WTs. Increased inflammation and metabolite alterations were seen with aging. The effect of peripheral urinary tract infection (UTI) on cognition and imaging out was assessed. Imaging was carried out prior to and after re-current UTI. Infection induced cognitive decline in infected TG but not WT rats. Infection had an increasing effect on hypothalamic neuroinflammation in WT rats but a decreasing effect on TG rats, which masked the original gene differences. This thesis is set out in the alternative format with each experimental study represented as a chapter. Results in this thesis implicate neuroinflammation in AD development and progression. In addition, we report systemic infection-CNS interactions accelerating cognitive decline in AD and highlight the importance of understanding the effects of comorbidities in disease.

Made available in DSpace on 2014-06-11T19:22:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-10-07Bitstream added on 2014-06-13T18:49:46Z : No. of bitstreams: 1 solemanhernandez_ss_me_rcla.pdf: 1264234 bytes, checksum: dce378514ee92f0c8e3932ce876cf8a6 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Os objetivos deste estudo compreenderam: a) caracterizar a presença de apatia em pacientes com DA residentes na comunidade; b) analisar os efeitos do treinamento com pesos na apatia, funções cognitivas frontais, funcionalidade motora e variáveis metabólicas destes pacientes; c) verificar as possíveis relações antes e após quatro meses de treinamento com pesos, na apatia, funções cognitivas frontais, funcionalidade motora; e d) verificar se há diferenças em funções cognitivas e funcionalidade motora segundo o nível de apatia dos pacientes. Para tanto, participaram do estudo 28 pacientes com DA, com idade média de 78,8 ± 6,6 anos, escolaridade de 4,8 ± 3,5 anos que foram alocados em grupo treinamento (GT) e grupo de convívio social (GCS). Todos os pacientes foram avaliados de acordo com os seguintes testes: Escore de Avaliação Clínica de demência; Questionário Baeck Modificado para Idosos; Mini Exame do Estado Mental; Montreal Cognitive Assessment; Teste de Fluência Verbal semântica; Teste do desenho do Relógio; Bateria de Avaliação Frontal; Escala Cornell para Depressão em demência; Inventário Neuropsiquiátrico (domínio Apatia); Bateria de Testes Motores de Andreotti & Okuma; protocolo do Banco de Wells; Teste de Resistência de Membros Superior da Bateria de Testes da AAHPERD; Teste de Sentar-se e Levantar-se da cadeira em 30 segundos. Além disso, os pacientes realizaram exames laboratoriais para mensurar níveis séricos de Colesterol Total e frações, Homocisteína e Glicemia. O GT realizou um protocolo de treinamento com pesos (TP) durante quatro meses, três vezes na semana, em dias não consecutivos com duração de 60 minutos cada sessão. Este treinamento consistiu em realizar três séries de 20 repetições com intervalo de dois minutos entre séries e exercícios para os... / The objectives of this study were: a) characterize the presence of apathy in community dwelling patients with AD; b) analyze the effects of resistance training on apathy, frontal cognitive functions, motor function and metabolic variables of these patients; c) verify possible relations before and after four months of resistance training in apathy, frontal cognitive functions, motor function; and d) verify if there are differences in cognitive and motor function according to the level of apathy of the patients. To do so, participated in the study 28 patients with AD, mean age 78.8 ± 6.6 years, education 4.8 ± 3.5 years who were divided into training group (TG) and group of social interaction (GSI ). All patients were evaluated according to the following tests: Clinical Dementia Rating; Modified Baecke Questionnaire for Elderly; Mini Mental State Examination; Montreal Cognitive Assessment; Semantic Verbal FluencyTest; Clock Drawing Test; Battery Frontal Assessment; Cornell Scale for Depression in dementia; Neuropsychiatric Inventory (domain Apathy); Motor Battery Test of Andreotti &Okuma; Wells protocol; upper limb strength from AAHPERD battery; Sit and Stand up from a chair in 30 seconds. Besides that, the patients undertook laboratory tests to measure serum levels of total cholesterol and fractions, homocysteine and glucose. The TG participated in a resistance training protocol (RT) for four months, three times a week on nonconsecutive days lasting 60 minutes each session. The training consisted in performing three sets of 20 repetitions, with two minutes between sets and, exercises for major muscle groups. GSI participated in reading, clippings, group dynamics activities and non-systematized mild walking during the same period, frequency and duration of the RT. It was used as statistical analysis... (Complete abstract click electronic access below)

Alzheimer’s disease (AD) is the most prevalent form of dementia affecting the elderly, and as the aging population increases the social and economic burden of AD grows substantially. Pathological hallmarks of AD include the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), as well as significant neuron loss. Amyloid plaques consist of aggregated amyloid beta (Aβ) peptide, which is generated from the proteolytic processing of amyloid precursor protein (APP) in addition to several other peptides. While the processing of APP has been characterized, its primary physiological function and its involvement in AD pathology are poorly understood. Developing a greater understanding of the function of APP, and the molecular and cellular functions it is involved in or other proteins it is associated with, could provide insight into its role in AD pathology. To investigate the function of APP695, the neuronal isoform of APP, we used mass spectrometry to compare changes in protein expression and phosphorylation between APP-null B103 and APP695-expressing B103-695 rat neuroblastoma cells. Mass spectrometry-based proteomics has become a powerful technique for the unbiased identification of proteins from complex mixtures. Quantitative proteomics using labeling techniques, such as stable isotope labeling by amino acids in cell culture (SILAC), allow relative quantitation of multiple samples at once. More recently, with advances in mass spectrometer technology, label-free quantitation has become a reliable quantitative proteomics approach. Additionally, mass spectrometry can be used for the analysis of post-translational modifications, such as phosphorylation, a dynamic modification involved in the regulation of many cellular processes. Phosphoproteomics identifies site-specific phosphorylation and surrounding sequence information, which can be used for consensus motif analysis to provide further information about potential changes in kinase activity. Identifying changes in phosphorylation and kinase activity also provides information about signaling pathways and functions that may be affected by APP695 expression. Comprehensive proteomic and phosphoproteomic datasets can be used to gain insight into the molecular mechanisms that may be regulated by APP695 expression, or involved in AD progression and pathology, leading to the development of novel therapeutic and preventative strategies for AD. Proteomic and phosphoproteomic analysis of B103 and B103-695 cells identified several significant protein expression and phosphorylation changes that may be mediated by APP695-expression. Global-scale proteomic analysis identified increased expression of Ras and ƴ-synuclein in B103-695 cells, which was further validated in human AD brain tissue. Phosphoproteomic analysis showed increased phosphorylation of Histone H4 at Ser47, and led to the investigation of PCTAIRE-2 (Cdk17), and PCTAIRE-3 (Cdk18) expression, which were all shown to be increased in AD transgenic mouse tissue, culture primary rat neurons treated with Aβ, as well as mild cognitive impairment (MCI) and AD human brain tissue. Label-free quantitative proteomics was used for the analysis of human brain tissue from the cortex of individuals affected by AD, MCI, Parkinson’s disease (PD), and progressive supranuclear palsy (PSP) compared to cognitively normal, control samples. A number of differentially expressed proteins were identified in AD, MCI, PD, and PSP tissue. Bioinformatic analysis of the comprehensive proteomic datasets from AD, MCI, PD, and PSP human brain tissue identified several proteins consistent with corresponding disease pathology and neurodegeneration, such as inflammatory proteins. While some of the molecular and cellular functions were unique among neurodegenerative diseases, there also appears to be overlap of affected functions, suggesting there may be a more common mechanism of neurodegeneration.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2016-06-06T12:10:03Z No. of bitstreams: 2 Dissertação - Stephanie Toledo Piza Maurano - 2014.pdf: 609176 bytes, checksum: f12745cac385e6d01adbcfcb69724fc0 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-06-06T15:26:33Z (GMT) No. of bitstreams: 2 Dissertação - Stephanie Toledo Piza Maurano - 2014.pdf: 609176 bytes, checksum: f12745cac385e6d01adbcfcb69724fc0 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-06-06T15:26:33Z (GMT). No. of bitstreams: 2 Dissertação - Stephanie Toledo Piza Maurano - 2014.pdf: 609176 bytes, checksum: f12745cac385e6d01adbcfcb69724fc0 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-11-11 / This study aimed to evaluate the cognitive performance of patients with glaucoma and compare it to people with Alzheimer's disease (AD). Glaucoma patients, AD and control group (healthy elderly) were assessed using the MMSE (Mini Mental State Examination) and the subtests verbal fluency, word list memory, delayed recall of the word list, word list recognition test Boston naming test and construction praxis from CERAD (Consortium to Establish a Registry for Alzheimer's Disease). The results of each test were compared between the groups. One hundred and twelve patients were evaluated, 50 healthy elderly with a mean age of 71.2 ± 5.2 years; 41 patients with glaucoma (72.2 ± 4.4 years) and 21 patients with AD (79.0 ± 7.6 years). AD patients had, on average, advanced disease. Noted a reduction in the cognitive assessment tests in all evaluated, both for patients with glaucoma, and for those with AD compared with controls (p <0.001 for all). When the results from patients with glaucoma and AD were paired, it was noted that the AD patients had lower cognitive function (p <0.001), except for the tests CERAD Boston (p = 0.1) and praxis (p = 0.6). Glaucoma patients, however, presented results of cognitive tests similar to those described for patients with mild AD, including lower values for MMSE (21.9 ± 3.7), Boston (10.6 ± 2.6) and praxis (5.9 ± 2.3). / Este estudo teve como objetivo avaliar o desempenho cognitivo de pacientes com glaucoma e compará-lo a uma população diagnosticada com demência de Alzheimer (DA) e seus controles. Pacientes com glaucoma, DA e grupo controle (idosos saudáveis) foram avaliados através do MEEM (Mini Exame do Estado Mental) e os subtestes fluência verbal, memória de lista de palavras, evocação tardia da lista de palavras, reconhecimento da lista de palavras, teste de nomeação de Boston e praxia construtiva do CERAD (Consortium to Establish a Registry for Alzheimer’s Disease). Os resultados de cada teste foram comparados entre os grupos. Foram avaliados 112 pacientes, sendo 50 idosos saudáveis com idade média de 71,2 ±5,2 anos; 41 pacientes com glaucoma (72,2 ± 4,4 anos) e 21 pacientes com DA (79,0 ±7,6 anos). Os pacientes com DA apresentaram, em média, doença avançada. Notou-se redução da avaliação cognitiva em todos os testes avaliados tanto para os pacientes com glaucoma quanto para aqueles com DA quando comparados com os controles (p<0,001 para todos). Ao se parear os pacientes com glaucoma e DA, notou-se que os últimos apresentaram função cognitiva inferior (p<0,001), exceto para os subtestes do CERAD Boston (p=0,1) e Praxia (p=0,6). Os pacientes com glaucoma, entretanto, apresentaram resultados dos testes cognitivos semelhantes àqueles descritos para pacientes com DA leve, inclusive com valores inferiores para MEEM (21,9 ± 3,7), Boston (10,6 ± 2,6) e Praxia (5,9 ± 2,3).

It is widely accepted that A-beta (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in the Alzheimer’s disease (AD) brain, yet little is known about the contribution of APP preceding AD pathogenesis. Our data presented here suggest that APP has a functional role in cell cycle regulation and proliferation. First, we demonstrat that APP is pathologically phosphorylated at Thr668 and that P-APP localizes to the centrosomes. Furthermore, P-APP is proteolytically processed in a cell cycle -dependent manner to generate its pathogenic metabolites. Using Stable Isotope Labeling by Amino Acids in Culture (SILAC) and mass spectrometry analyses, we also show that expression of APP results in the expression of proliferation-associated proteins and the phosphorylation of proteins associated with cell cycle regulation and transcription. Here, we demonstrate that APP expression and oligomeric Aβ42 elicit Ras/ERK signaling cascade and glycogen synthase kinase3 (GSK3) activation. Both ERK and GSK3 are known to induce hyperphosphorylation of tau and of APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human brain samples show increased expression of Ras, activation of GSK3 and phosphorylation of APP and tau, which correlate with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulate these events and show enhanced Ras-ERK signaling, GSK3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which we show enhances APP proteolysis and Aβ generation, denotes a vicious feed-forward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and an inhibition of this would impede the mitotic catastrophe and neurodegeneration observed in AD.

Class of 2016 Abstract / Objectives: To promote Alzheimer’s disease (AD) awareness in older adults and caregivers by creating and implementing an interactive educational program in several Southern Arizona senior centers, evaluate the helpfulness of the intervention, the confidence and the motivation of the participants. Methods: A 30-minute educational program consisting of a PowerPoint presentation with various interactive learning methods and a 10-minute question and answer session was delivered to those 55 years of age and older at senior centers across Southern Arizona. An anonymous questionnaire was conducted after each educational program to assess the helpfulness of the program, the subject’s familiarity with AD and their motivation to create a personal action plan after participation, and demographic information. Responses from the participants were compared with a priori alpha at 0.05. Results: A majority of participants in the study were female (69.9%) the median age was 75. One hundred (98%) of the participants strongly agreed or agreed that the interactive educational program was helpful in understanding AD, and 95 (96.9%) stated they were more motivated to create a personal care plan. There was no difference between the males or females’ self-reported familiarity with dementia (p = 0.25) or AD (p = 0.75) after program participation, but >50% of overall participants who were not already very familiar with Alzheimer’s disease increased in familiarity. Conclusions: An interactive approach to educating community-dwelling older adults and their caregivers on AD was helpful to the participants, and they were more motivated to create personal care plans.

>Magister Scientiae - MSc / Alzheimer’s Disease (AD) is a neurodegenerative disease which results from the irreversible loss of neurons in the brain. The disease is characterized by progressive cognitive impairment with recurrent short-term memory loss. AD is the leading cause of dementia and 4th leading cause of death in the elderly. Success in the treatment of AD has been limited, with drugs only treating it at a symptomatic level due to its pathology being complex and poorly understood. However, it is known that the cholinesterase and MAO-B enzymes play an important role in the disease through their association with production of amyloid plaques and oxidative stress respectively, two mechanisms associated with cell death and the symptoms seen in AD.

Background: Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by impairments in language. The presence of Alzheimer disease (AD) neuropathology has been observed in approximately 40% of PPA cases. Cross-sectional and longitudinal features of cortical atrophy in PPA are emerging but less is known about the integrity of subcortical structures, particularly the thalamus. As a major relay station in the brain, the thalamus is implicated in language functioning given its reciprocal connections with perisylvian regions in the cortex. High-dimensional brain mapping was used to characterize thalamic morphology in individuals with and without non-semantic PPA. Further, shape differences were compared between PPA participants with suspected AD pathology (PPAAβ +) and those without suspected AD pathology (PPAAβ -) as determined by amyloid PET scans. The relationship between shape and specific language deficits were also investigated. Method: Thalamic integrity was examined in 57 PPA participants relative to cognitively healthy controls (N=44) with similar demographics. MR scans were acquired using high-resolution T1-weighted MPRAGE volumes following the ADNI protocol. Thalamic shape features were estimated using Large Deformation Diffeomorphic Metric Mapping. Thalamic nuclei of interest included mediodorsal, pulvinar, and anterior regions. General linear models compared differences in thalamic shape between groups. Pearson models characterized relationships between thalamic nuclei and language function. Results: After controlling for whole brain volume, thalamic volume did not differ between groups [F(1, 99)=0.80, p=0.80]. However, PPA participants exhibited significant bilateral inward shape deformation in dorsal and ventral regions that extended in an anterior to posterior fashion, and unilateral outward deformation in medial and lateral regions only in the left thalamus relative to controls [F(9, 91)=5.75, p<0.001, Wilk's Λ=0.64]. There were no shape differences between PPAAβ + and PPAAβ – groups. Pearson models revealed significant correlations between confrontation naming and shape deformation in the left pulvinar (r=0.59, p<0.01) and left anterior (r=0.55, p<0.01) thalamic nuclei for the PPAAβ + group only, such that lower language scores reflected greater localized volume loss. Conclusions: In the absence of volumetric differences, shape measures were able to capture unique aspects of localized morphologic differences in PPA that corresponded to worse naming performance only in those with suspected AD pathology. Thalamic changes appear to be a contributing and unrecognized component to the presentation and language characterization of PPA.