The present study was conducted to help understand the impact of living with multiple sclerosis (MS), an unpredictable, chronic illness that is widely known to have a large influence on psychosocial functioning, mental health, and life satisfaction (Motl & Gosney, 2007; Weiner, 2004). Recent research has begun to position certain chronic illnesses, such as MS, as traumatic events that influence mental health in both beneficial and detrimental ways. Thus, the present study investigated the positive and negative consequences of centralizing one’s identity within their MS experiences as related to trauma, growth, and psychosocial influences via a path model with 616 individuals with MS. The results indicate strong support for the hypothesized paths between the variables of interest—centrality of MS, posttraumatic stress, posttraumatic growth, social support, personal mastery, depression, and life satisfaction. Specifically, results indicate that posttraumatic stress and posttraumatic growth partially mediated the relations between centrality of MS with depression and life satisfaction. Moderation analyses indicated that social support and personal mastery did not moderate any relations between centrality of MS with depression and life satisfaction. Rather, additional analyses suggest social support and personal mastery may be viewed as additional mediators between centrality and posttraumatic stress and posttraumatic growth. The results of the present study is the first known study to extend trauma literature to the population of MS in order to provide an approach to help understand the high rates of depression and inconsistent findings on quality of life for this population. Implications for practice, theory and research are discussed.

Na última década diferentes modalidades e técnicas quantitativas de neuroimagens aplicadas ao estudo de doenças neuro-degenerativas vêm fornecendo um volume cada vez maior de dados, tornando sua utilização uma tarefa complexa. Paralelamente, técnicas computacionais de reconhecimento de padrões vêm sendo desenvolvidas para apoiar a tomada de decisão humana. O propósito geral do presente estudo é aplicar técnicas de reconhecimento de padrões em dados quantitativos de neuroimagens adquiridas por ressonância magnética (RM) em pacientes com Esclerose Múltipla (EM). Especificamente foram avaliados dados retrospectivos de um grupo de 203 sujeitos controle sem doenças neurológicas e um grupo de 144 pacientes portadores de Esclerose Múltipla. Os dados usados foram provenientes da combinação de ferramentas computacionais de processamento de imagens e neuroimagens adquiridas em um aparelho de RM de 3 Tesla usando diferentes técnicas quantitativas: Difusão, Relaxometria, Taxa de Transferência de Magnetização (MTR) e Volumetria. Os dados das diferentes técnicas quantitativas em 126 regiões cerebrais não excludentes foram processados no programa de mineração de dados WEKA. Os algoritmos: k-nearest-neighbor (KNN) com diferentes números de vizinhos e Support vector machine (SVM) foram utilizados para a classificação e agrupamento desses dados. As regiões com maior contribuição na separação de ambos os grupos foram encontradas na substância branca (SB) nas seguintes estruturas: corpo caloso, precúneo, cerebelo e fusiforme esquerdos. Outro atributo significante foi o de hipo-intensidades que pode ser associado à presença de lesões, também na substância branca. Dentre as técnicas, a mais relevante foi a MTR com 92,9% de valor médio de área sob a curva ROC (Receiver Operating Characteristic), considerando os diferentes algoritmos de classificação e métodos de seleção de atributos, porém uma análise global incluindo os dados de todas as técnicas elevou esta área para 96,2%. O algoritmo KNN com 5 vizinhos foi considerado o melhor classificador geral para o conjunto de dados e tarefas aqui explorados resultando em 91,7% de valor médio de área sob a curva ROC, seguido por KNN3 com 90,8%, KNN1 com 87,1% e SVM com 85,8%. Uma classificação restrita, com áreas reconhecidamente afetadas pela EM e com KNN5 trouxe resultados de classificação 2,1% de valor médio de área sob a curva ROC inferiores à classificação principal sem restrições. O uso de técnicas de reconhecimento de padrões a partir dos dados de técnicas quantitativas de neuroimagem aplicadas à amostra estudada, demonstrou que a substância branca do cérebro é a mais afetada pela EM seguindo um padrão global com maior envolvimento no hemisfério esquerdo. A estratégia sugerida neste problema de classificação seria o uso dos dados de todas as técnicas quantitativas aqui discutidas provenientes das regiões envolvidas na classificação restrita conjuntamente com o precuneus e o fusiform, aplicando o KNN5 com seleção de melhores atributos. / In the last decade different modalities and quantitative neuroimaging techniques applied to the study of neurodegenerative diseases have been providing an increasing volume of data, making use of such a complex task. At the same time, computational techniques of pattern recognition have been developed to favor the human performance. The purpose of this study is to apply techniques of pattern recognition in quantitative data of neuroimaging acquired by magnetic resonance (MR) in patients of multiple sclerosis (MS). There were evaluated retrospective data from a control group of 203 people without neurological diseases and a group of 144 patients with MS. The data used were from the combination of computational tools of image processing and neuroimaging acquired in an MR apparatus of 3 Tesla using different quantitative techniques: diffusion, relaxometry, magnetization transfer rate (MTR) and volumetry. The data of the different quantitative techniques in 126 regions of the brain not mutually excludent were processed in the software WEKA of data mining. The algorithms: k-nearest-neighbor (KNN) with different numbers of neighbors and support vector machine (SVM) were used for the classification and grouping of the data. The regions with the highest contribution to the separation of both groups were found in the white matter of the following structures: corpus callosum, precuneus, cerebellum and left spindle. Another significant attribute was the hypo-intensities that can be associated to the presence of lesions in the white matter also. The most relevant technique was the MTR with 92.9% of average area under ROC, considering the different algorithms of classification and methods of feature selection, however a global analysis including data from all techniques increased this area under ROC to 96.2%. The KNN algorithm for k = 5 is considered the best overall classifier for the dataset resulting in 91.7% average area under ROC, followed by KNN for k = 3 with 90.8%, KNN for k = 1 with 87.1%, and SVM with 85.8%. A restricted classification with known affected areas by MS and KNN for k = 5 brought results of classification of average area under ROC of 2.1% inferior to the main classification without restrictions. The use of techniques of pattern recognition from the data of quantitative techniques of neuroimaging showed that the white matter of the brain is the most affected by MS following a global pattern with higher involvement in the left hemisphere. The strategy suggested in this classification issue would be the use of data from all quantitative techniques discussed from the regions involved in restricted classification jointly with precuneus and fusiform, applying KNN for k = 5 with selection of best features.

Introdução: a descrição tradicional da Esclerose Múltipla (EM) enfatiza ser esta uma doença desmielinizante inflamatória acometendo a substância branca (SB) do sistema nervoso central. Porém, nas últimas décadas vêm sendo acumuladas evidências de acometimento da substância cinzenta (SC), tanto em estudos anátomo-patológicos como de imagem quantitativa de ressonância magnética (IRM-q). Este comprometimento da SC é mais evidente na fase crônica progressiva da doença, onde a atrofia predomina, sendo as alterações cognitivas entendidas como algo restrito a esta fase. No entanto, como foi provada a existência de dano axonal precoce na EM, nós hipotetizamos que existe comprometimento de funções superiores detectáveis por exames neuropsicológicos mesmo em pacientes com déficit mínimo. Objetivo: testar a hipótese de que existem alterações cognitivas precoces na EM mesmo com disabilidade mínima e dano tecidual discreto. Método: foram avaliados com bateria neuropsicológica extensiva e exames de IRM-q pormenorizados 17 indivíduos (6 homens e 11 mulheres) com EM recorrente remitente (RR), com diagnóstico clinicamente definido e comprovado por imagem de acordo com os critérios de McDonald. O tempo de doença foi igual ou inferior a cinco anos, contados a partir do diagnóstico e com disabilidade mínima (EDSS menor que 3). Um grupo controle de 17 voluntários normais pareados foi avaliado para comparação. Resultados: os pacientes apresentaram disfunção de funções superiores estatisticamente significantes que incluíram dificuldades de atenção, memória, velocidade de processamento de informação, habilidades visuoespaciais, planejamento, abstração verbal, raciocínio numérico, flexibilidade mental, controle inibitório, compreensão verbal e escores de QI (tanto de QI geral, quanto de QI de execução e verbal). Apresentaram-se preservados com relação aos controles: a capacidade de nomeação, a velocidade de processamento motor e o raciocínio lógico. Na IRM-q houve alterações significativas discretas, compatíveis com a fase inicial da doença. Conclusão: nossos achados sugerem que existe déficit cognitivo precoce na EMRR, mesmo quando a debilidade é incipiente ou ausente. / Introduction: the traditional description of Multiple Sclerosis (MS) emphasizes that this is an inflammatory demyelinating disease affecting the white matter (WM) of the central nervous system. However, in recent decades has been accumulated evidence of involvement of gray matter (GM), both in anatomical and pathological studies as a quantitative magnetic resonance imaging (MRI-q). This impairment of the GM is more evident in chronic progressive disease, where atrophy predominates, and cognitive changes seen as something restricted to this phase. However, as has proven the existence of early axonal damage in MS, we hypothesized that there is impairment of higher functions detectable by neuropsychological tests, even in patients with minimal deficit. Objective: to test the hypothesis that there are early cognitive changes in MS even with disabled with minimal tissue damage and discreet. Methods: we evaluated extensive neuropsychological and MRI scans q-detailed 17 subjects (6 men and 11 women) with relapsing remitting (RR), defined clinically diagnosed and confirmed by the image according to the McDonald criteria. Disease duration was equal to or less than five years, starting from the diagnosis and disabled with minimal (EDSS less than 3). A control group of 17 matched normal volunteers were evaluated for comparison. Results: patients showed impairment of higher functions were statistically significant, which included attention deficit, memory, speed of information processing, visuospatial abilities, planning, verbal abstraction, numerical reasoning, mental flexibility, inhibitory control, verbal comprehension and IQ scores (both IQ general, the implementation of IQ and verbal). Presented are preserved with respect to controls: the ability of appointment, the speed of motor processing and logical reasoning. In MRI-q discrete significant changes consistent with early disease was finding. Conclusion: our findings suggest that cognitive deficits exist in early RR-MS, even when the disability is weak or absent.

In the brain, axons are wrapped by myelin sheaths which ensure fast saltatory conduction of impulses and provide metabolic support. In multiple sclerosis (MS), the myelin sheaths are lost which leaves the axon denuded. This not only results in slower conduction of action potentials, but if prolonged, can also lead to axon death due to the loss of metabolic support. This neurodegeneration is the main cause of permanent disability in multiple sclerosis patients. The axon death and disability which stem from it could be prevented by restoring the myelin wrap before axon damage has occurred. This remyelination process is carried out by oligodendrocyte precursor cells which are present throughout life. To remyelinate, OPCs migrate to the area of damage and differentiate into myelinating oligodendrocytes which ensheathe axons with new myelin. In multiple sclerosis, this process occurs but is insufficient to overcome the damage. Therefore, central to the therapeutic efforts in multiple sclerosis is the aim to improve endogenous remyelination. Enhancing recruitment of oligodendrocyte precursor cells (OPCs) to the areas of damage is a clinically unexplored target. To investigate the therapeutic potential of OPC recruitment modulators, I have looked at 2 different targets involved in migration NDST1/HS and Sema3A/NP1. The first target, heparan sulfate (HS) is a proteoglycan which is important to OPC migration, investigated by Pascale Durbec's group in France. In a demyelinating mouse model, its key synthesising enzyme, NDST1, is upregulated by oligodendroglia in a belt around the lesion to aid OPC recruitment. Loss of NDST1 in oligodendrocytes was found to impair remyelination and reduce OPC migration in mice. In collaboration with them, I investigated the relevance of this molecule in post-mortem MS human tissue. I found that in human as well as mouse, NDST1 was primarily expressed by oligodendroglia. The protein level and the proportion of oligodendroglia expressing NDST1 was increased in MS compared to control indicating NDST1 upregulation as a disease response in human. We also found that low numbers of NDST1+ oligodendroglia correlate with bigger sizes of lesions and chronic lesion types that fail to repair, highlighting its importance in repair. Moreover, high numbers of NDST1+ cells in a patient correlated with increased remyelination potential. This indicates that in human, intra-patient variation in NDST1 level may explain differences in potential for endogenous repair. Secondly, I looked at Sema3A, a chemorepulsive molecule which is upregulated in demyelinated injury rodent models aswell as multiple sclerosis lesions, particularly in OPC-depopulated chronic active lesions. Research has consistently found that the level of Sema3A negatively correlates to remyelination because Sema3A hinders OPC migration. This has highlighted Sema3A as a potential target to improve OPC recruitment in MS however the size and shape of the molecule make it hard to design therapeutics against it. Therefore, I looked at its druggable receptor, Neuropilin 1 (NP1), to see whether inhibition of NP1 had the same positive effect on OPC recruitment and remyelination as lowering the level of Sema3A. NP1 is a tyrosine kinase receptor for both Sema3A and vascular endothelial growth factor (VEGF) and is found in many cell types. To check if NP1 inhibition is beneficial, I assessed remyelination in a mouse where the Sema3A binding site of NP1 has been mutated to prevent Sema3A binding and exerting its effect. This is a proxy for a (currently unavailable) ideal NP1 inhibitor of the Sema3A site only. Contrary to my expectations, OPC recruitment and remyelination in the mutant mice were not improved. However, the NP1 mutation resulted in an altered immune response. To exclude the possibility that no improvement in the OPC recruitment and remyelination of those mice was seen because it was negated by the altered immune response, I explored a cell specific mutant mouse in which NP1 was deleted in oligodendroglia only. In this mutant as well, I did not see improvement of OPC recruitment and remyelination. I therefore propose that Neuropilin 1 is not imperative for Sema3As action in remyelination and is not suitable as a therapeutic target in multiple sclerosis. Loss of the whole NP1, but not loss of the Sema3A site also resulted in biggermyelinated and unmyelinated axons as well as a different myelin thickness post remyelination. This showed that VEGF and the VEGF site on NP1 in oligodendroglia have a previously unknown but important role in determining axon size and myelin thickness which should be further investigated. To further elucidate those results in a simple system, I looked at how Sema3A, NP1-Sema3A inhibitors, VEGF and NP1-VEGF inhibitor affect OPC behaviour. I confirmed Sema3As chemorepulsive effect but also showed that at different concentrations it can improve proliferation and survival of OPCs. Inhibiting the Sema3A site and the VEGF site of NP1 by specific blocking antibodies also affects OPC proliferation and maturation. This suggested that NP1s ligands are involved in more than just OPC migration. In summary, this work supports the relevance of the mouse findings that NDST1 is upregulated in demyelination and important for repair for human illustrating that it might be a suitable therapeutic target to investigate. However, despite the importance of Sema3A in MS models, its only reported receptor, NP1, is not essential for Sema3As action. Therefore, it is an unsuitable therapeutic target. The fact that NP1 is an inappropriate drug target for MS is further demonstrated by the involvement of its ligands in multiple OPC behaviours both in positive and negative aspects.

La plupart des signaux naturels peuvent être représentés par une combinaison linéaire de quelques atomes dans un dictionnaire. Ces représentations parcimonieuses et les méthodes d'apprentissage de dictionnaires (AD) ont suscité un vif intérêt au cours des dernières années. Bien que les méthodes d'AD classiques soient efficaces dans des applications telles que le débruitage d'images, plusieurs méthodes d'AD discriminatifs ont été proposées pour obtenir des dictionnaires mieux adaptés à la classification. Dans ce travail, nous avons montré que la taille des dictionnaires de chaque classe est un facteur crucial dans les applications de reconnaissance des formes lorsqu'il existe des différences de variabilité entre les classes, à la fois dans le cas des dictionnaires classiques et des dictionnaires discriminatifs. Nous avons validé la proposition d'utiliser différentes tailles de dictionnaires, dans une application de vision par ordinateur, la détection des lèvres dans des images de visages, ainsi que par une application médicale plus complexe, la classification des lésions de scléroses en plaques (SEP) dans des images IRM multimodales. Les dictionnaires spécifiques à chaque classe sont appris pour les lésions et les tissus cérébraux sains. La taille du dictionnaire pour chaque classe est adaptée en fonction de la complexité des données. L'algorithme est validé à l'aide de 52 séquences IRM multimodales de 13 patients atteints de SEP. / Most natural signals can be approximated by a linear combination of a few atoms in a dictionary. Such sparse representations of signals and dictionary learning (DL) methods have received a special attention over the past few years. While standard DL approaches are effective in applications such as image denoising or compression, several discriminative DL methods have been proposed to achieve better image classification. In this thesis, we have shown that the dictionary size for each class is an important factor in the pattern recognition applications where there exist variability difference between classes, in the case of both the standard and discriminative DL methods. We validated the proposition of using different dictionary size based on complexity of the class data in a computer vision application such as lips detection in face images, followed by more complex medical imaging application such as classification of multiple sclerosis (MS) lesions using MR images. The class specific dictionaries are learned for the lesions and individual healthy brain tissues, and the size of the dictionary for each class is adapted according to the complexity of the underlying data. The algorithm is validated using 52 multi-sequence MR images acquired from 13 MS patients.

Na última década diferentes modalidades e técnicas quantitativas de neuroimagens aplicadas ao estudo de doenças neuro-degenerativas vêm fornecendo um volume cada vez maior de dados, tornando sua utilização uma tarefa complexa. Paralelamente, técnicas computacionais de reconhecimento de padrões vêm sendo desenvolvidas para apoiar a tomada de decisão humana. O propósito geral do presente estudo é aplicar técnicas de reconhecimento de padrões em dados quantitativos de neuroimagens adquiridas por ressonância magnética (RM) em pacientes com Esclerose Múltipla (EM). Especificamente foram avaliados dados retrospectivos de um grupo de 203 sujeitos controle sem doenças neurológicas e um grupo de 144 pacientes portadores de Esclerose Múltipla. Os dados usados foram provenientes da combinação de ferramentas computacionais de processamento de imagens e neuroimagens adquiridas em um aparelho de RM de 3 Tesla usando diferentes técnicas quantitativas: Difusão, Relaxometria, Taxa de Transferência de Magnetização (MTR) e Volumetria. Os dados das diferentes técnicas quantitativas em 126 regiões cerebrais não excludentes foram processados no programa de mineração de dados WEKA. Os algoritmos: k-nearest-neighbor (KNN) com diferentes números de vizinhos e Support vector machine (SVM) foram utilizados para a classificação e agrupamento desses dados. As regiões com maior contribuição na separação de ambos os grupos foram encontradas na substância branca (SB) nas seguintes estruturas: corpo caloso, precúneo, cerebelo e fusiforme esquerdos. Outro atributo significante foi o de hipo-intensidades que pode ser associado à presença de lesões, também na substância branca. Dentre as técnicas, a mais relevante foi a MTR com 92,9% de valor médio de área sob a curva ROC (Receiver Operating Characteristic), considerando os diferentes algoritmos de classificação e métodos de seleção de atributos, porém uma análise global incluindo os dados de todas as técnicas elevou esta área para 96,2%. O algoritmo KNN com 5 vizinhos foi considerado o melhor classificador geral para o conjunto de dados e tarefas aqui explorados resultando em 91,7% de valor médio de área sob a curva ROC, seguido por KNN3 com 90,8%, KNN1 com 87,1% e SVM com 85,8%. Uma classificação restrita, com áreas reconhecidamente afetadas pela EM e com KNN5 trouxe resultados de classificação 2,1% de valor médio de área sob a curva ROC inferiores à classificação principal sem restrições. O uso de técnicas de reconhecimento de padrões a partir dos dados de técnicas quantitativas de neuroimagem aplicadas à amostra estudada, demonstrou que a substância branca do cérebro é a mais afetada pela EM seguindo um padrão global com maior envolvimento no hemisfério esquerdo. A estratégia sugerida neste problema de classificação seria o uso dos dados de todas as técnicas quantitativas aqui discutidas provenientes das regiões envolvidas na classificação restrita conjuntamente com o precuneus e o fusiform, aplicando o KNN5 com seleção de melhores atributos. / In the last decade different modalities and quantitative neuroimaging techniques applied to the study of neurodegenerative diseases have been providing an increasing volume of data, making use of such a complex task. At the same time, computational techniques of pattern recognition have been developed to favor the human performance. The purpose of this study is to apply techniques of pattern recognition in quantitative data of neuroimaging acquired by magnetic resonance (MR) in patients of multiple sclerosis (MS). There were evaluated retrospective data from a control group of 203 people without neurological diseases and a group of 144 patients with MS. The data used were from the combination of computational tools of image processing and neuroimaging acquired in an MR apparatus of 3 Tesla using different quantitative techniques: diffusion, relaxometry, magnetization transfer rate (MTR) and volumetry. The data of the different quantitative techniques in 126 regions of the brain not mutually excludent were processed in the software WEKA of data mining. The algorithms: k-nearest-neighbor (KNN) with different numbers of neighbors and support vector machine (SVM) were used for the classification and grouping of the data. The regions with the highest contribution to the separation of both groups were found in the white matter of the following structures: corpus callosum, precuneus, cerebellum and left spindle. Another significant attribute was the hypo-intensities that can be associated to the presence of lesions in the white matter also. The most relevant technique was the MTR with 92.9% of average area under ROC, considering the different algorithms of classification and methods of feature selection, however a global analysis including data from all techniques increased this area under ROC to 96.2%. The KNN algorithm for k = 5 is considered the best overall classifier for the dataset resulting in 91.7% average area under ROC, followed by KNN for k = 3 with 90.8%, KNN for k = 1 with 87.1%, and SVM with 85.8%. A restricted classification with known affected areas by MS and KNN for k = 5 brought results of classification of average area under ROC of 2.1% inferior to the main classification without restrictions. The use of techniques of pattern recognition from the data of quantitative techniques of neuroimaging showed that the white matter of the brain is the most affected by MS following a global pattern with higher involvement in the left hemisphere. The strategy suggested in this classification issue would be the use of data from all quantitative techniques discussed from the regions involved in restricted classification jointly with precuneus and fusiform, applying KNN for k = 5 with selection of best features.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2017-01-13T11:19:37Z No. of bitstreams: 2 Dissertação - Inez Janaina de Lima Amaral - 2016.pdf: 3470243 bytes, checksum: 505c91c5b53d230db5e57a0e95e981ab (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-01-16T11:00:26Z (GMT) No. of bitstreams: 2 Dissertação - Inez Janaina de Lima Amaral - 2016.pdf: 3470243 bytes, checksum: 505c91c5b53d230db5e57a0e95e981ab (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-01-16T11:00:26Z (GMT). No. of bitstreams: 2 Dissertação - Inez Janaina de Lima Amaral - 2016.pdf: 3470243 bytes, checksum: 505c91c5b53d230db5e57a0e95e981ab (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-11-09 / The control of the symptoms of dysphagia in patients with Multiple Sclerosis (MS) has been underestimated by clinicians, patients and caregivers. Dysphagia has a prevalence between 33-43% of this population. The evaluation of the swallowing has been a major challenge in clinical practice, and without a unified method of diagnosis in this population. Identify patients with dysphagia in the early stages of MS is fundamental in preventing complications such as malnutrition, dehydration and death. The aim of this study was to identify the presence or absence of swallowing desorders in patients diagnosed with MS in the Reference and Research Center for Multiple Sclerosisin the University Hospital of the Federal University of Goiás, in the midwest of Brazil. This was a cross-sectional study between july 2015 and march 2016, with 73 patients above 18 years old with definite diagnosis of MS. It was excluded patients from other health units, outside the scope of the suty period, without clinical conditions associated with other diseases or who did not agree to participate. The presence of dysphagia was found at 30.14% of the patients. This finding meets the results in other studies. The main manifestations were dificulties in qualifying and propel the food bolus, with changes in the oral and pharyngeal phases of swallowing. Thus, it is necessary the evaluation and monitoring of this population, guarateeing early intervention, reducing the risks to the quality of life. / O controle dos sintomas da disfagia nos pacientes com Esclerose Múltipla (EM) vem sendo subestimado pelos clínicos, pacientes e cuidadores. A disfagia tem prevalência conhecida entre 33-43% desta população. A avaliação da deglutição tem sido um grande desafio na prática clínica, e sem um método diagnóstico unificado para esta população. Identificar os pacientes com disfagia nos estágios iniciais da EM é fundamental na prevenção de complicações como desnutrição, desidratação e óbito. O objetivo deste estudo foi identificar a presença ou não de alterações da deglutição de pacientes com diagnóstico de EM em atendimento no Centro de Referência e Investigação em Esclerose Múltipla do Hospital das Clínicas da Universidade Federal de Goiás, no Centro-oeste do Brasil. Este foi um estudo transversal entre julho de 2015 e março de 2016, com 73 pacientes, acima de 18 anos de idade com diagnóstico definitivo de EM. Foram excluídos pacientes deoutras unidades de saúde, fora do período de abrangência do estudo, sem condições clínicas, com outras enfermidades associadas ou que não concordaram em participar do estudo. A presença de disfagia foi encontrada em 30,14% dos pacientes. Esse achado vem de encontro com outros estudos. As principais manifestações observadas foram dificuldades de qualificação e propulsão do bolo alimentar, demonstrando comprometimento da fase oral e faríngea da deglutição. Assim, faz-se necessário a avaliação e acompanhamento desta população, garantindo a intervenção de forma precoce, diminuindo os riscos para a qualidade de vida.

In multiple sclerosis (MS), pathogenic T effector cells (Teff) are believed to orchestrate immune-mediated destruction of the central nervous system (CNS) myelin sheath. In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, CNS infiltration by regulatory T cells (Treg), producing the anti-inflammatory cytokine IL-10, promotes the resolution of disease. Currently, little is understood about how Treg function within the inflamed CNS and on which cells they exert their suppressive function. There is a debate as to whether Treg in MS patients are capable of infiltrating the CNS and if they do, it is unclear whether they are functional. Understanding Treg function in EAE and MS could open up new possibilities for treatment, as Treg could be modulated for immunosuppressive therapy. A key step in the development of EAE (and presumably MS) is the ability of Teff cells to cross the blood brain barrier (BBB) and enter the CNS parenchyma. The hypothesis of this work was that Treg facilitate resolution of the inflamed CNS by preventing entry of the pathogenic T cells into the CNS parenchyma, thus preventing further damage. As such, it is important to understand with which immune cells and CNS resident cells Treg communicate to achieve resolution of disease. The presence of Treg in MS lesions was investigated with double immunohistochemistry (IHC) in frozen post-mortem MS brain tissue. CD4+Foxp3+ Treg were present in a subset of patients and their presence was associated with perivascular retention of CD4+Foxp3- and CD8+Foxp3- T cells. Foxp3+ cells in MS lesions predominantly expressed IL-10, indicating regulatory activity, although low-level production of IL-17, TNF-α, IFN-γ and GM-CSF was observed as well. Generally, analysis of total cytokine expression identified distinct patterns of cytokine production between lesions. Nonetheless, these could not be used to discriminate individual patients. These studies were repeated in C57BL/6 mice in which the Treg population was depleted before onset of EAE to mimic lesions with and without Treg presence, as found in MS patients. An immunofluorescent technique to study up to 5 fluorochromes simultaneously was developed to study antigen presenting cell (APC), Teff and Treg location, spatial relationship and function (as measured by cytokine expression) in the CNS of EAE mice at different stages of disease. Using this technique it was found that CD4+Foxp3- Teff and CD4+Foxp3+ Treg were located within 50-100μm of CD11c+ APC in the CNS of EAE affected mice. CNS Teff and Treg predominantly produced IFN-γ or IL-10, although low levels of IL-17 were detected in Teff and Treg as well. IL-17+ Treg were close to IL-17+ Teff, IFN-γ+ Treg were close to IFN-γ+ Teff, but IL-10+ Treg were not in close proximity to IL-10+ T cells in the CNS during EAE. In conclusion, there is evidence for functional Treg in EAE and MS lesions, supporting the concept of enhancing Treg activity as a clinical intervention. Treg seem to be capable of retaining pathogenic T cells at the blood brain barrier in MS lesions. In addition, studies of cytokine expression in MS lesions indicated that there is no sound basis for patient stratification based on peripheral blood cytokine profile. This thesis advances our understanding of Treg location, function and spatial relationship with other immune cells within the inflamed CNS.

Regulatory T cells (Tregs), expressing the transcription factor Foxp3, form a key component of peripheral immune tolerance, guarding against auto-aggressive immune responses. Multiple Sclerosis is an inflammatory and demyelinating disease of the central nervous system (CNS) which is largely believed to be mediated by immune components reacting to the self myelin antigens that insulate the nerve fibres. Recent investigations have reported that regulatory T cells are dysfunctional in MS patients; therefore enhancing the regulatory T cell responses in MS is an attractive therapeutic target. Using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE) we have attempted to develop disease-relevant Treg-based therapies to prevent disease induction. This required an understanding of the antigenic-reactivity of Tregs during disease. Results described in this thesis show that a proportion of Tregs in the draining lymph nodes and CNS were reactive to the disease initiating antigen(s) and could suppress in vitro responses of naïve T cells bearing transgenic T cell receptors, recognising the same antigen. Adoptive transfer of antigen-reactive Tregs suppressed disease induced with the same antigen, but also reduced disease induced with a distinct myelin antigen. Peptide-based tolerance using a high affinity MHC binding peptide analogue expanded and maintained antigen-reactive T cells which were tolerant to antigenic restimulation, although these cells did not express Foxp3. Peptide-treated mice showed reduced incidence of disease relapses during EAE induced against a distinct myelin antigen. Thus, while EAE and MS will involve a polyclonal effector T cell response to many antigens, therapeutic targeting of Tregs reactive against one CNS component may be sufficient to reduce disease. Endogenous expression of myelin autoantigen did not grossly alter the response of antigenreactive Tregs in the periphery. However, expression of endogenously derived viral superantigen enhanced the proportion of superantigen-reactive Foxp3+ Tregs in the periphery. This observation was extended using exogenous superantigen, suggesting that prolonged exposure to low dose (super)antigen tips the balance of the immune system in favour of regulation. This has implications for the ability to successfully fight infection, as well as for the limitation of autoaggressive responses and may contribute to the understanding of the hygiene hypothesis.

Purpose: The systematic review explored whether self-management interventions improve patient activation in long-term conditions, and if any improvements are greater than the amount of change experienced by patients in usual care or active control conditions. It also aimed to determine if positive effects on activation are maintained at follow-up. The empirical study sought to explore relationships between patient activation, psychological factors (depression and valued living), perceived clinician empathy, perceived symptom severity, self-management and demographic variables. It also examined whether depression, valued living and perceived clinician empathy are unique predictors of activation, and if activation is a unique predictor of self-management for MS, when relevant confounding variables are controlled for. Methods: For the systematic review, a comprehensive search of multiple electronic databases was conducted to identify intervention research reporting on patient activation outcomes, as measured by the short-form Patient Activation Measure (PAM-13), in people with long-term conditions. For the empirical study, a cross-sectional survey of 118 people with MS explored patient activation, MS symptom severity, valued living, depression, perceived clinician empathy, self-management for MS and demographic factors. Correlation and hierarchical regression analyses were employed to explore relationships between variables. Results: Twenty-five studies were eligible for inclusion in the systematic review, reporting a wide range of long-term conditions. Twenty-one studies (10 RCTs; 1 non-randomised study; and 10 uncontrolled studies) found an improvement in patient activation at post-intervention. Nine studies reported a significantly greater improvement in activation in self-management conditions compared with usual care or an active control at post-intervention. In six out of eight studies, gains in patient activation were maintained in the intervention group at follow-up. However, in four of these six studies, patient activation in the control group also improved over time. Findings from the empirical study suggested that only valued living was a significant predictor of patient activation after controlling for demographic variables and MS symptom severity. Neither depression nor perceived clinician empathy significantly predicted activation. After controlling for valued living, depression and perceived clinician empathy, patient activation independently predicted 5.5% of variance in self-management for MS. Both activation and perceived clinician empathy were significant predictors of self-management for MS. Conclusions: Self-management interventions improve patient activation in long-term conditions compared with usual care or active control. Patient activation gains appear to be maintained longer-term; however, the impact of self-management interventions on activation is unclear due to increases in activation in control groups over time. Valued living is associated with patient activation in MS, while patient activation and perceived clinician empathy are associated with MS self-management. Self-management interventions targeting valued living and the patient-clinician relationship may be effective for addressing low levels of activation in some patients with MS.