abstract: The purpose of this study is to identify the needs of older adults with Alzheimer's disease (AD) and related dementias (ADRD) admitted to a rehabilitation setting where they are expected to physically and mentally function to their optimal level of health. To date, no studies have identified the needs and concerns of ADRD patients in rehabilitation settings. The Needs-Driven Dementia-Compromised Behavior (NDB) Model, the researcher's clinical experience, and the state of the current scientific literature will help guide the study. An exploratory qualitative research approach was employed to gather data and discover new information about the ADRD patient's needs and related behavioral outcomes. The qualitative findings on the discrepancies and similarities in perceptions of ADRD patient needs were obtained by examining formal and informal caregivers' perceptions. The researcher recruited registered nurses and certified nurse assistants (RNs and CNAs, formal) and family/friends (informal) who have provided care to patients in inpatient rehabilitation facilities to participate in focus groups and individualized focused interviews. The data were collated and analyzed using a thematic analysis approach. The overarching theme that developed as a result of this approach revealed discordant perceptions and expectations of ADRD patients' needs between the formal and informal caregivers with six subthemes: communication and information, family involvement, rehabilitation nurse philosophy, nursing care, belonging, and patient outcomes. The researcher provided recommendations to help support these needs. These findings will help guide the development of nurse-lead interventions for ADRD patients in a rehabilitation setting. / Dissertation/Thesis / Doctoral Dissertation Nursing and Healthcare Innovation 2014

abstract: The apolipoprotein E (APOE) e4 genotype is the most prevalent known genetic risk factor for Alzheimer's disease (AD). In this paper, we examined the longitudinal effect of APOE e4 on hippocampal morphometry in Alzheimer's Disease Neuroimaging Initiative (ADNI). Generally, atrophy of hippocampus has more chance occurs in AD patients who carrying the APOE e4 allele than those who are APOE e4 noncarriers. Also, brain structure and function depend on APOE genotype not just for Alzheimer's disease patients but also in health elderly individuals, so APOE genotyping is considered critical in clinical trials of Alzheimer's disease. We used a large sample of elderly participants, with the help of a new automated surface registration system based on surface conformal parameterization with holomorphic 1-forms and surface fluid registration. In this system, we automatically segmented and constructed hippocampal surfaces from MR images at many different time points, such as 6 months, 1- and 2-year follow up. Between the two different hippocampal surfaces, we did the high-order correspondences, using a novel inverse consistent surface fluid registration method. At each time point, using Hotelling's T^2 test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the non-demented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes. / Dissertation/Thesis / Masters Thesis Computer Science 2015

abstract: Alzheimer’s disease (AD), despite over a century of research, does not have a clearly defined pathogenesis for the sporadic form that makes up the majority of disease incidence. A variety of correlative risk factors have been identified, including the three isoforms of apolipoprotein E (ApoE), a cholesterol transport protein in the central nervous system. ApoE ε3 is the wild-type variant with no effect on risk. ApoE ε2, the protective and most rare variant, reduces risk of developing AD by 40%. ApoE ε4, the risk variant, increases risk by 3.2-fold and 14.9-fold for heterozygous and homozygous representation respectively. Study of these isoforms has been historically complex, but the advent of human induced pluripotent stem cells (hiPSC) provides the means for highly controlled, longitudinal in vitro study. The effect of ApoE variants can be further elucidated using this platform by generating isogenic hiPSC lines through precise genetic modification, the objective of this research. As the difference between alleles is determined by two cytosine-thymine polymorphisms, a specialized CRISPR/Cas9 system for direct base conversion was able to be successfully employed. The base conversion method for transitioning from the ε3 to ε2 allele was first verified using the HEK293 cell line as a model with delivery via electroporation. Following this verification, the transfection method was optimized using two hiPSC lines derived from ε4/ε4 patients, with a lipofection technique ultimately resulting in successful base conversion at the same site verified in the HEK293 model. Additional research performed included characterization of the pre-modification genotype with respect to likely off-target sites and methods of isolating clonal variants. / Dissertation/Thesis / Masters Thesis Bioengineering 2017

abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 5.4 million Americans. AD leads to memory loss, changes in behavior, and death. The key hallmarks of the disease are amyloid plaques and tau tangles, consisting of amyloid-β oligomers and hyperphosphorylated tau, respectively. Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals. Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage. Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2017

abstract: An in vitro model of Alzheimer’s disease (AD) is required to study the poorly understood molecular mechanisms involved in the familial and sporadic forms of the disease. Animal models have previously proven to be useful in studying familial Alzheimer’s disease (AD) by the introduction of AD related mutations in the animal genome and by the overexpression of AD related proteins. The genetics of sporadic Alzheimer’s is however too complex to model in an animal model. More recently, AD human induced pluripotent stem cells (hiPSCs) have been used to study the disease in a dish. However, AD hiPSC derived neurons do not faithfully reflect all the molecular characteristics and phenotypes observed in the aged cells with neurodegenerative disease. The truncated form of nuclear protein Lamin-A, progerin, has been implicated in premature aging and is found in increasing concentrations as normal cells age. We hypothesized that by overexpressing progerin, we can cause cells to ‘age’ and display the neurodegenerative effects observed with aging in both diseased and normal cells. To answer this hypothesis, we first generated a retrovirus that allows for the overexpression of progerin in AD and non-demented control (NDC) hiPSC derived neural progenitor cells(NPCs). Subsequently, we generated a pure population of hNPCs that overexpress progerin and wild type lamin. Finally, we analyzed the presence of various age related phenotypes such as abnormal nuclear structure and the loss of nuclear lamina associated proteins to characterize ‘aging’ in these cells. / Dissertation/Thesis / Masters Thesis Bioengineering 2017

abstract: Alzheimer’s disease is a major problem affecting over 5.7 million Americans. Although much is known about the effects of this neurogenerative disease, the exact pathogenesis is still unknown. One very important characteristic of Alzheimer’s is the accumulation of beta amyloid protein which often results in plaques. To understand these beta amyloid proteins better, antibody fragments may be used to bind to these oligomers and potentially reduce the effects of Alzheimer’s disease. This thesis focused on the expression and crystallization the fragment antigen binding antibody fragment A4. A fragment antigen binding fragment was chosen to be worked with as it is more stable than many other antibody fragments. A4 is important in Alzheimer’s disease as it is able to identify toxic beta amyloid. / Dissertation/Thesis / Masters Thesis Chemical Engineering 2018

A Doença de Alzheimer (DA) vem apresentando aumento progressivo, sendo a causa de demência mais comum nos idosos (acima de 60 anos). Diante disso, há preocupação com alterações do estado de saúde dos cuidadores que compreendem na sua maioria familiares. Cuidar dos pacientes com demência por Doença de Alzheimer pode levar ao estresse crônico e má qualidade de vida. O presente estudo teve como objetivo avaliar fatores de risco cardiovascular, cognição e humor em cuidadoras idosas de pacientes com demência por Doença de Alzheimer, comparando-as com as não cuidadoras. As cuidadoras foram selecionadas por meio da revisão de prontuários do Hospital das Clínicas e do Centro de Saúde Escola da FMRP-USP. As idosas do grupo controle foram selecionadas na mesma área de moradia das idosas cuidadoras. Todas as participantes assinaram o Termo de Consentimento Livre e Esclarecido. Foram realizadas visitas previamente agendadas na casa de todas as participantes. Critérios de exclusão: diabetes; neoplasias malignas e doenças autoimunes, além de outras doenças debilitantes. Foram avaliadas idade, escolaridade, peso, altura, circunferência abdominal e Indice de Massa corpórea (IMC). Foi realizada avaliação laboratorial: dosagem de insulina de jejum; glicemia de jejum; colesterol total e HDL; triglicérides; creatinina; ureia; sódio; potássio; cálcio e TSH. Além disso, foi feita a avaliação da pressão arterial (PA) em domicílio pela pesquisadora e com a Medida Residencial de Pressão Arterial (MRPA), além da avaliação da cognição e humor, com a Escala de Depressão Geriátrica (EDG), Mini Exame do Estado Mental (MEEM) e Mini International Neuropsychiatric Interview (M.I.N.I.). A análise estatística foi realizada com o Teste Quiquadrado, Teste \"t\" de Student, Mann-Whiney e regressão logística simples e múltipla para a estimação do Odds Ratio bruto e ajustado (ORA). Foram avaliadas 62 idosas, sendo 31 cuidadoras de pacientes com Doença de Alzheimer e 31 do grupo controle. Verificou-se que os níveis de colesterol total foram mais elevados em idosas cuidadoras. Não houve diferenças entre os valores de PA sistólica e diastólica entre os grupos em relação às medidas realizadas pela pesquisadora e com a MRPA. De acordo com os resultados, as idosas cuidadoras apresentaram rastreio positivo para depressão em 58%, enquanto que o grupo controle apresentou apenas 16% (ORA=6,62, p<0,01). Em relação ao diagnóstico feito pelo M.I.N.I, 38,7% das cuidadoras apresentaram episódio depressivo, sendo superior ao controle (9,7%) (ORA=5,42, p=0,02). Verificouse que 35,5% das cuidadoras apresentaram transtorno de ansiedade diagnosticado, com 16% no grupo controle (ORA=4,79, p=0,03). A presença do companheiro interferiu para que as cuidadoras apresentassem mais transtorno de ansiedade (p=0,04). Não houve diferença entre a cognição dos grupos pela avaliação do MEEM. Cuidadoras idosas de pacientes dementados com Doença de Alzheimer apresentaram níveis de colesterol mais elevados, mais episódios depressivos e mais transtorno de ansiedade do que as não cuidadoras. A presença do companheiro interferiu para que apresentassem mais transtorno de ansiedade / Alzheimer´s disease (AD) has shown a progressive increase in incidence, being the most common cause of dementia in the older individuals (above 60 years old). Therefore, there is concern with health status change in caregivers, who are mostly relatives. Taking care of AD patients with dementia can lead to chronic stress and poor quality of life. This study aimed to evaluate cardiovascular risk factors, cognition and mood in older caregivers of patients with AD dementia, comparing them with non-caregivers. The caregivers were selected through the review of the Hospital\'s medical records and School Health Center of FMRP-USP. Control group of elderly women were selected in the same housing area of older caregivers. All participants signed a consent form. Visits were previously scheduled and were at the home of all participants. Exclusion criteria: diabetes; malignancies and autoimmune diseases, and other debilitating diseases. Were evaluated: age, education, weight, height, waist circumference and body mass index (BMI). Laboratory testing was performed: fasting insulin; fasting glucose; Total and HDL cholesterol; triglycerides; creatinine; urea; sodium; potassium; calcium and TSH. In addition, blood pressure (BP) evaluation was made at home by the researcher and by the Home Blood Pressure Monitoring (HBPM), and the assessment of cognition and mood, with the Geriatric Depression Scale (GDS), Mini Exam Mental State Examination (MMSE) and Mini International Neuropsychiatric Interview (MINI). Statistical analysis was performed with Chi-square test, test \"t\" test, Mann-whiney and multiple logistic regression and simple to estimate the gross and adjusted Odds Ratio (AOR). 62 older women were assessed, 31 caregivers of demented AD patients and 31 control group It was found that the total cholesterol levels were higher in elderly caregivers (AOR = 3.57, p = 0.03). There was no difference between the systolic and diastolic values between the groups in relation to the measures carried out by the researcher and HBPM. According to the results, older caregivers had a positive screening for depression in 58%, while the control group showed only 16% (AOR = 6.62, p <0.01). Regarding the diagnosis made by M.I.N.I, 38.7% of caregivers had depressive episode, higher than the control (9.7%) (AOR = 5.42, p = 0.02). It was found that 35.5% of caregivers had diagnosis of anxiety disorder, with 16% in the control group (AOR = 4.79, p = 0.03). The presence of the companion interfered, so that the caregivers presented more anxiety disorder (p = 0.04). There was no difference between cognition groups by assessing the MMSE. Concluding, caregivers of patients with AD have higher cholesterol levels, more depressive episodes and anxiety disorder than non-caregivers. The presence of the companion interfered to submit more anxiety disorder

The standard extract of Ginkgo biloba leaves (EGb761) is being clinically used in Europe for the treatment of impaired cerebral function in primary degenerative disorders such as Alzheimer disease (AD) and vascular dementia. The abnormal production and aggregation of amyloid β peptide (Aβ) and the deposition of fibrils in the brain is considered as key steps in the onset of AD. For this reason, the inhibition of Aβ aggregation and the destabilization of preformed fibrils have been identified as effective approaches for the prevention and treatment of AD. EGb761 mainly contains three categories of components: flavonol glycosides (FGs), terpene trilactones (TTLs), and catechins and procyanidins. Among them, only TTLs have been evaluated for the inhibition towards Aβ aggregation, and the effects were much weaker than that of the extract. It was suggested that EGb761 should contain several other compounds that are responsible for this activity. In the current study, we have conducted a comprehensive investigation of the generally chemical and bioactive properties of the compounds belonging to all three of the major component categories present in EGb761. We aimed to identify the compounds responsible for the inhibitory activity exhibited by EGb761 towards Aβ42 aggregation and the destabilization of preformed fibrils. The results can be summarized as follows. Seven major FGs were isolated from EGb761 and determined to be quercetin 3-O-α-(6′′′-p-coumaroyl glucopyranosyl-β-1,2-rhamnopyranoside (1), kaempferol 3-O-α-(6′′′-p-coumaroyl glucopyranosyl-β-1,2-rhamnopyranoside) (2), quercetin 3-O-β-D-rutinoside (3), quercetin 3-O-α-L-(β-D-glucopyranosyl)-(1,2)-rhamnopyranoside (4), isorhamnetin 3-O-β-D-rutinoside (5), kaempferol 3-O-β-D-rutinoside (6), and kaempferol 3-O-α-L-(β-D-glucopyranosyl)-(1,2)-rhamnopyranoside (7) by structural analysis. Four catechins and two procyanidins were also found in EGb761 and identified as catechin, epicatechin, gallocatechin, epigallocatechin, procyanidins B1 and B3. The inhibitory activities of these compounds and four major TTLs (i.e., ginkgolides A, B, and C and bilobalide) towards Aβ42 aggregation were evaluated using a thioflavin T fluorescence assay. The results revealed that catechins and procyanidins compounds exhibited significant inhibitory activities with IC50 values in the range of 3-16 μM, and those of the procyanidins were stronger. Three of the FGs (FG1, FG3 and FG4) showed moderate inhibitory activities, with IC50 values in the range of 30-70 μM, whereas the other four FGs (i.e., FG2, FG5, FG6 and FG7) and the four TTLs showed much weaker activity. The catechins and procyanidins also showed potent activities towards the destabilization of preformed Aβ fibrils. Based on these results, we established several structure-activity relationships (SARs) that specific structural groups, as well as the number and position of hydroxyl groups, the linking sequences of the sugar moieties, and the three dimensional conformations of the compounds were important to their inhibitory activity. We also established quantitative analysis of all these tested compounds and simultaneously determined their contents in the Ginkgo extracts. In addition, total FGs, total TTLs, and total catechins and procyanidins were prepared by column chromatography. Similarly, they were also quantitatively analyzed and their inhibitory activities towards Aβ42 aggregation were evaluated. The results showed that total catechins and procyanidins exerted much stronger activity than total FGs and total TTLs. Comprehensive assessment of their activities and contents in the extract indicated that the contribution of the FGs was almost twice that of the catechins and procyanidins, which indicated that they played an important role in the effect of the extract. TTLs alone could barely contribute to the EGb’ effect and probably exerted their influence through the synergistic effect with FGs, which was speculated from the study. In conclusion, the current study has shown that the catechins and procyanidins present in EGb761 possessed potent ability to inhibit Aβ aggregation and destabilize preformed fibrils. FGs made a significant contribution to EGb761’s inhibitory activity towards Aβ aggregation and its neuroprotective effects. Furthermore, the SAR study provide evidences for further research and development of Ginkgo products and drugs designed to target Aβ aggregation or the destabilization of preformed fibrils. Despite their low contents in EGb761 and related products, catechins and procyanidins, and even proanthocyanidins deserve further study because of their potent effects towards Aβ aggregation and the destabilization of preformed fibrils, which could have a significant impact on the quality control of Ginkgo leaves and Ginkgo products.

abstract: Mathematical modeling and decision-making within the healthcare industry have given means to quantitatively evaluate the impact of decisions into diagnosis, screening, and treatment of diseases. In this work, we look into a specific, yet very important disease, the Alzheimer. In the United States, Alzheimer’s Disease (AD) is the 6th leading cause of death. Diagnosis of AD cannot be confidently confirmed until after death. This has prompted the importance of early diagnosis of AD, based upon symptoms of cognitive decline. A symptom of early cognitive decline and indicator of AD is Mild Cognitive Impairment (MCI). In addition to this qualitative test, Biomarker tests have been proposed in the medical field including p-Tau, FDG-PET, and hippocampal. These tests can be administered to patients as early detectors of AD thus improving patients’ life quality and potentially reducing the costs of the health structure. Preliminary work has been conducted in the development of a Sequential Tree Based Classifier (STC), which helps medical providers predict if a patient will contract AD or not, by sequentially testing these biomarker tests. The STC model, however, has its limitations and the need for a more complex, robust model is needed. In fact, STC assumes a general linear model as the status of the patient based upon the tests results. We take a simulation perspective and try to define a more complex model that represents the patient evolution in time. Specifically, this thesis focuses on the formulation of a Markov Chain model that is complex and robust. This Markov Chain model emulates the evolution of MCI patients based upon doctor visits and the sequential administration of biomarker tests. Data provided to create this Markov Chain model were collected by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The data lacked detailed information of the sequential administration of the biomarker tests and therefore, different analytical approaches were tried and conducted in order to calibrate the model. The resulting Markov Chain model provided the capability to conduct experiments regarding different parameters of the Markov Chain and yielded different results of patients that contracted AD and those that did not, leading to important insights into effect of thresholds and sequence on patient prediction capability as well as health costs reduction. The data in this thesis was provided from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). ADNI investigators did not contribute to any analysis or writing of this thesis. A list of the ADNI investigators can be found at: http://adni.loni.usc.edu/about/governance/principal-investigators/ . / Dissertation/Thesis / Masters Thesis Industrial Engineering 2018

Made available in DSpace on 2015-05-14T12:43:02Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1570765 bytes, checksum: 762e1a257e5a08c0c5aeb8f232a29d0f (MD5) Previous issue date: 2012-10-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This research, entitled Coreferential Processing by the Elderly Subjects With and Without Alzheimer's Disease, aimed to analyze and compare the coreferential processing by the elderly subjects with and without Alzheimer's disease (AD) in Brazilian Portuguese. To achieve our goals and respond to our hypotheses, we supported on the Mini-Mental State Examination (MMSE) in order to classify the dementia degree affecting the AD elderly subjects and to qualify the level of understanding, enabling them to respond to the on-line tests. We used the self-paced reading technique and we selected 12 elderly subjects without pathologies (ESWP), and 06 elderly subjects with Alzheimer's Disease (ESAD), a total sample of 18 subjects. As results of the first experiment, we found, in the ESWP group, pronouns being processed faster than repeated names, which agrees with studies on adults without pathology in Brazilian Portuguese (LEITÃO, 2005; QUEIROZ, LEITÃO, 2008; LEITÃO, SIMÕES, 2011). And in the ESAD group, volunteers were faster when retrieving the repeated name, confirming the findings that have been found in literature regarding the pathologies that have some impairment of the working memory (ALMOR et al., 2000) and (ALBUQUERQUE, 2008). In order to analyze the level of semantic impairment in subjects with AD mild impairment during coreferential processing, we carried out a second experiment which focuses on the coreference processing from retrievals with hypernyms and hyponyms. Results showed that the elderly control group preferred, during the anaphoric retrieval, the superordinate NPs. But the elderly subjects with Alzheimer's disease showed no significant differences between conditions (hyponym and hyperonym). We concluded that it is apparent that pronouns and hypernyms are processed more quickly by the elderly subjects without pathologies because they contain less semantic features required to identify their antecedents; and the repeated names as well as hyponyms are processed more slowly because they contain more semantic features. In the AD elderly subjects cases, we believe that the lack of significant difference between hyponyms and hypernyms, in this kind of anaphoric retrieval, is resulting from the impaired working memory, featuring that the AD elderly subjects need that words be restated as activating that memory. / Esta pesquisa intitulada Processamento Correferencial em Idosos com e Sem Doença de Alzheimer, objetivou analisar e comparar o processamento correferencial, em idosos com e sem a Doença de Alzheimer (DA) no Português Brasileiro. Para atingirmos os nossos objetivos e respondermos as nossas hipóteses, tomamos como base o Mini-Mental State Examination (MMSE) com o intuito de classificarmos o grau da demência que acomete os idosos com a DA e qualificarmos o nível de compreensão, viabilizando a participação desses sujeitos para responderem aos testes on-line. Foi utilizada a técnica de leitura automonitorada, e selecionados 12 idosos sem patologias (ISP), e 06 idosos com a Doença de Alzheimer (IDA), totalizando uma amostra de 18 sujeitos. Como resultados do primeiro experimento, encontramos, no grupo ISP, pronomes sendo processados mais rapidamente do que nomes repetidos, o que corrobora com os estudos realizados com adultos em Português Brasileiro sem patologia (LEITÃO, 2005; QUEIROZ, LEITÃO, 2008; LEITÃO, SIMÕES, 2011). E no grupo IDA, os voluntários foram mais rápidos na retomada do nome repetido, confirmando os achados que vem sendo encontrado na literatura em relação a patologias que têm algum prejuízo da memória de trabalho (Almor et al., 2000) e (Albuquerque, 2008). Com o intuito de analisarmos o nível de comprometimento semântico em indivíduos com DA de grau leve, durante o processamento correferencial, elaboramos um segundo experimento, que focaliza o processamento da correferência a partir de retomadas com hiperônimos e hipônimos, os resultados demonstraram, que os idosos do grupo controle apresentaram preferência, na retomada anafórica, por SNs superordenados. Já os idosos com Doença de Alzheimer não apresentaram diferenças significativas entre as condições (hipônimo e hiperônimo). Concluímos que torna-se evidente que pronomes, assim como hiperônimos, são processados mais rapidamente, por idosos sem patologias, por conterem menos traços semânticos necessários para identificar os seus antecedentes; e nomes-repetidos, assim como hipônimos, são processados mais lentamente por conterem mais traços semânticos. Nos casos dos Idosos com DA, entendemos que a ausência de diferença significativa entre hipônimos e hiperônimos, nesse tipo de retomada anafórica, seja decorrente do comprometimento na memória de trabalho, caracterizando que os idosos com DA necessitam que palavras sejam reapresentadas como ativadoras dessa memória.