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Alterações da substância branca de pacientes com epilepsia parcial secundária à displasia cortical focal = estudo de imagem por tensor de difusão com análise voxel-a-voxel / White matter abnormalities in patients with partial epilepsy secondary to focal cortical dysplasia revealed by diffusion tensor : imaging (DTI) analysis in a voxelwise approachFonseca, Viviane de Carvalho 17 August 2018 (has links)
Orientador: Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T18:37:25Z (GMT). No. of bitstreams: 1
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Previous issue date: 2011 / Resumo: A epilepsia parcial secundária a displasia cortical focal (DCF), comumente se origina nos primeiros anos de vida, entretanto, alguns casos podem apresentar início após os 40 anos. Atualmente, a DCF é identificada em 20 - 25% de pacientes com epilepsia parcial extratemporal e aproximadamente 76% dos pacientes supostamente apresentam epilepsia refratária à medicação. Trata-se de uma malformação do desenvolvimento cortical (MDC), identificada por uma diferenciação anormal do córtex e neurônios displásicos na substância branca (SB). O exame de imagem por tensor de difusão (DTI) tem a capacidade de descrever a integridade da SB, através da quantificação da difusão e orientação das moléculas de água nos tecidos de forma não invasiva, podendo detectar anormalidades no tecido cerebral em estágios precoces em relação ao exame convencional de imagem por RM ponderado em T1 ou T2. Com o objetivo de detectar alterações microestruturais no tecido cerebral, utilizamos o exame de DTI para investigar a SB desses pacientes. Para isso, utilizamos uma medida de direcionamento da difusão, conhecida como anisotropia fracional (AF), que representa a orientação do eixo das estruturas dos feixes de fibras ao longo do qual as moléculas de água se movem de modo preferencial, indicando mudanças da microestrutura tissular. Foram analisados 53 sujeitos, sendo 22 pacientes e 31 indivíduos saudáveis. Todos os pacientes tinham diagnóstico clínico e eletroencefalográfico de epilepsia extratemporal (lobo frontal) secundária a provável DCF. Processamos o DTI com os programas: MRIcroN, FSL e TBSS (Tract-based Spatial Statistics). A comparação entre o grupo de pacientes e grupo controle foi realizada usando two-sample teste-t, com nível de significância de p <0,05. Identificamos áreas com redução da FA, nos lobos frontal, parietal, temporal e occipital, sendo elas: fórceps menor à direita (p=0,032), fórceps menor à esquerda (p=0,042), giro do cíngulo à esquerda (p=0,048), trato córtico-espinhal direito e esquerdo (p=0,022), fascículo fronto-occipital inferior direito (p=0,022), fascículo longitudinal superior e inferior esquerdo (p=0,034), radiação talâmica anterior à direita (p=0,034) e fascículo uncinado à esquerda (p=0,042). Nossos resultados mostraram um padrão extenso de anormalidades estruturais em regiões da SB que se estendem além do foco epileptogênico (lobo frontal), provavelmente decorrente da cronicidade da epilepsia. É possível que essas alterações sejam secundárias às descargas epilépticas muito freqüentes, associadas à generalização e bissincronia secundária / Abstract: Epilepsy secondary to FCD usually begins early in life, however, some cases may have onset after 40 years. Currently FCD has been identified in 20-25% of patients with extratemporal epilepsy and approximately 76% of patients with epilepsy refractory to antiepileptic drug treatment. FCD is a malformation of cortical development (MCD), identified by an abnormal differentiation of cortex and dysplastic neurons on the white matter. Diffusion tensor imaging (DTI) has a powerful ability to describe white matter integrity, through the quantification of the spread and direction of water molecules in tissues noninvasively, which can detect the abnormalities of the brain tissue in an earlier stage than conventional T2- or T1-weighted MRI. Aiming to detect microstructural changes in brain tissue, we used DTI to investigate the WM these patients. For this, we used a measure of diffusion direction, known as fractional anisotropy (FA), which represents the axis orientation of the structures of the fiber bundles along which the water molecules move preferentially, indicating changes in tissue microstructure. We analyzed 53 subjects, 22 patients and 31 healthy individuals. All the patients had clinical and EEG diagnosis of extratemporal epilepsy (frontal lobe), probably secondary to FCD. To process the DTI we used the following softwares: MRIcroN, FSL, TBSS. The comparison between the patients group and control group was performed using two-sample t-test, and the level of significance was set at <0.05. FA reduction in patients were identified in the frontal, parietal, temporal and occipital lobes, which were: right forceps minor (p =0.032), left forceps minor (p = 0.042), left cingulum (p = 0.048), right and left corticospinal tracts (p = 0.022), inferior right fronto-occipital fasciculus (p = 0.022),right and left superior longitudinal fasciculus (p = 0.034), right anterior thalamic radiation (p = 0.034) and the left uncinate fasciculus (p = 0,042). Our results showed a widespread pattern of WM micro structural abnormalities extending beyond the ictal onset zone (frontal lobe), probably due to the epilepsy chronicity. It is possible that this damage is secondary to persistent epileptic discharges with frequent generalization and secondary bilateral synchrony / Mestrado / Ciencias Biomedicas / Mestre em Ciências Médicas
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Compréhension des mécanismes physiopathologiques des malformations du développement cortical associées à des mutations dans les gènes KIF2A et NEDD4L / Understanding the pathophysiological mechanisms of malformations of cortical development associated with mutations in KIF2A and NEDD4L genesBroix, Loïc 24 November 2016 (has links)
Les malformations du développement cortical (MDC) résultent d’altérations au niveau de différentes étapes de la corticogénèse telles que la prolifération, la migration et la différenciation neuronale et sont généralement associées à des épilepsies pharmaco-résistantes et à des déficiences intellectuelles sévères. Les causes génétiques des MDC restent encore inconnues dans de nombreux cas, nous avons donc réalisé le séquençage de l’exome entier de nombreux patients présentant des MDC et les analyses ont permis de mettre en évidence l’implication des gènes KIF2A et NEDD4L dans les MDC. Dans le cadre de ma thèse, nous proposons de focaliser sur les conséquences cellulaires et neurodéveloppementales résultant des mutations dans les gènes KIF2A et NEDD4L retrouvées chez les patients atteints de MDC. KIF2A code pour une kinésine-13 qui a pour fonction de réguler la dynamique des microtubules (MT) via son activité MT dépolymérase ATP-dépendante aux niveaux des extrémités des MT. L’approche basée sur la technique d’électroporation in utero nous a permis de mettre en évidence le rôle crucial joué par KIF2A dans la régulation de la neurogénèse, la migration neuronale et le positionnement des neurones dans le cortex. En particulier, nos données révèlent que l’expression des mutants KIF2A responsables de MDC entraîne une augmentation du nombre de cellules à l’état de progéniteurs qui est conséquente à un allongement du temps passé dans le cycle cellulaire. Nos premières données cellulaires et au cours du développement montrent que l’expression des mutants KIF2A induit des altérations dans l’intégrité du fuseau mitotique, dans la progression mitotique et également une localisation anormale de KIF2A au niveau du cil primaire. NEDD4L code pour une E3 ubiquitine ligase qui joue un rôle dans l’ubiquitination de nombreux substrats permettant la régulation de leur dégradation et de leur localisation subcellulaire. Dans un premier temps, nos données cellulaires ont montré que les mutants associées à des MDC ont une sensibilité accrue pour la dégradation par le protéasome. De plus, l’approche d’électroporation in utero a permis de montrer que l’expression des mutants NEDD4L ainsi qu’un excès de NEDD4L WT dérégulent la neurogenèse, le positionnement des neurones et le processus de translocation terminal. Des études complémentaires, incluant le traitement à la rapamycine, ont révélé qu’un excès de NEDD4L WT mène à la dérégulation des voies de signalisations mTORC1 et Dab1 tandis que l’expression des mutants est associée à une dérégulation des voies mTORC1 et Akt. L’ensemble de ces résultats renforce donc dans un premier temps l’importance des protéines liées aux MT dans le développement cortical en décrivant le rôle crucial de la kinésine KIF2A dans des mécanismes tels que la dynamique de migration neuronale et dans la régulation du cycle cellulaire des progéniteurs neuronaux. D’autre part, nous fournissons également de nouvelles données permettant de mieux comprendre le rôle critique de NEDD4L dans la régulation des voies mTOR et de leurs contributions dans le développement cortical. / Malformations of cortical development (MCD) result from alterations in different stages of corticogenesis such as proliferation, migration and neuronal differentiation, and are generally associated with drug-resistant epilepsy and severe intellectual disabilities. The genetics causes of MCD remain largely unknown, we have thus performed the whole-exome sequencing of many patients with MCD and reported the identification of multiple pathogenic missense mutations in KIF2A and NEDD4L genes. Within the frame of my thesis project, we propose to focus on the cellular and neurodevelopmental consequences resulting from KIF2A and NEDD4L mutations shown to be involved in MCD. KIF2A is a member of the kinesin-13 family, which rather than regulating cargos transport along microtubules (MT), regulates MT dynamics by depolymerizing MTs. The in utero electroporation approach allowed us to highlight the crucial role of KIF2A in the regulation neurogenesis, neuronal migration and the neuronal positioning in the cortex. Particularly, our data show that the expression of the KIF2A mutants involved in MDC lead to an increase in the number of cells in proliferative state which is a consequence of a prolonged time spent in the cell cycle. Our first cellular data and during development show that the expression of pathogenic KIF2A mutations induce alterations in the mitotic spindle integrity, in the mitotic progression and also an abnormal localization of KIF2A in the primary cilium. NEDD4L encodes a member of the NEDD4 family of HECT-type E3 ubiquitin ligases known to regulate the turnover and function of a number of proteins involved in fundamental cellular pathways and processes. Firstly, cellular and expression data showed sensitivity of MCD-associated mutants to proteasome degradation. Moreover, the in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while MCD-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these results reinforce the importance of MT-related proteins in cortical development describing the crucial role of KIF2A kinesin in mechanisms such as neuronal migration dynamics and neuronal progenitor’s cell cycle regulation. On the other hand, we also provide new data to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.
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Identification and Epidemiological Delineation of Rare Genetic EpilepsiesLopez Rivera, Javier A. 26 August 2022 (has links)
No description available.
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Arrêt précoce de la migration neuronale corticale : conséquences cellulaires et comportementales / Premature arrest of cortical neuronal migration : cellular and behavioral consequencesMartineau, Fanny 27 November 2017 (has links)
La migration radiaire est un des processus clefs de la corticogenèse menant à l’établissement d’un cortex en six couches chez les mammifères. La compréhension de ce mécanisme complexe est nécessaire à une meilleure appréhension du développement cortical. Dans ce travail de thèse, j’ai étudié la migration des neurones pyramidaux du cortex sous deux angles distincts. La 1ère partie se place d’un point de vue développemental en appréciant comment le positionnement laminaire résultant d’une migration normale ou anormale affecte la maturation neuronale. La 2nde partie se concentre sur une pathologie migratoire, l’hétérotopie en bande sous-corticale, et les altérations cognitives parfois associées à cette malformation. Pour ces deux projets, la migration neuronale a été altérée chez le rat par knockdown (KD) in utero de la doublecortine (Dcx), un effecteur majeur de la migration. Les neurones positionnés anormalement présentent une orientation incorrecte, un arbre dendritique moins développé, une spinogenère réduite et une altération morpho-fonctionnelle de la synaptogenèse glutamatergique. De plus, notre étude a mis en évidence l’implication de Dcx dans la dendritogenèse et la régulation fine des synapses glutamatergiques in vivo. Enfin, nous avons utilisé les rats Dcx-KD comme modèle d’hétérotopie en bande afin d’étudier comment un déficit de migration neuronale impacte le fonctionnement du cortex. La caractérisation comportementale, réalisée à l’aide d’une large gamme de tests, n’a pas mis en évidence de déficits majeurs des capacités motrices, somatosensorielles ou cognitives chez ces animaux. / Radial migration is one of the key processes leading to the formation of a six-layered cortex in mammals. Understanding this mechanism is necessary to get a better grasp of cortical development. During my PhD, I studied neuronal migration of pyramidal neurons from two different points of views. The 1st part is related to fundamental biology and assesses how laminar misplacement resulting from migration failure influences neuronal maturation. The 2nd one focuses on pathology by investigating a migration disorder, subcortical band heterotopia, and associated cognitive deficits. For both projects, neuronal migration was impaired in rat through in utero knockdown (KD) of doublecortin (Dcx), a major effector of cortical migration. Misplaced neurons display an abnormal orientation, a simplified dendritic arbor, a decreased spinogenesis and morpho-functional alterations of glutamatergic synaptogenesis. Moreover, our study shows that Dcx plays a role in dendritogenesis, in shaping spine morphology and in fine-tuning glutamatergic synaptogenesis. Finally, we used Dcx-KD rats as an animal model of subcortical band heterotopia to assess how migration failure would impact cortical functions. The behavioral characterization carried out through a wide range of tests did not bring to light any major shortcoming regarding motor, somatosensory or cognitive abilities in these animals. Therefore, although Dcx-KD rats display a SBH and develop spontaneous seizures, it does not seem to recapitulate cognitive deficits found in patients.
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Alterações de linguagem em familias com sindome perisylviaia / Language disrder in families with Perisylvian SyndomeOliveira, Ecila Paula dos Mesquita de 18 August 2006 (has links)
Orientador: Marilisa Mantovani Guerreiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T04:56:07Z (GMT). No. of bitstreams: 1
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Previous issue date: 2006 / Resumo:Distúrbio específico do desenvolvimento da linguagem (DEDL) se refere à aquisição inadequada da linguagem em crianças que não tenham outras alterações do desenvolvimento, ou seja, o prejuízo no desenvolvimento da linguagem é a principal dificuldade do paciente, mesmo havendo queixas secundárias de menor relevância. O quadro de manifestações lingüísticas de crianças com DEDL pode ser freqüentemente correlacionado com a presença de polimicrogiria perisylviana em exames de neuroimagem (síndrome perisylviana). O objetivo do presente estudo foi investigar famílias de crianças que possuem um quadro de DEDL associado à polimicrogiria e caracterizar as manifestações lingüísticas nos membros (crianças e adultos) dessas famílias, além de correlacionar os achados com exames de neuroimagem. Foram selecionadas três famílias com história de alterações no desenvolvimento da linguagem e com exames de neuroimagem evidenciando polimicrogiria na região sylviana. Os pacientes foram submetidos à avaliação psicológica e fonoaudiológica (audiológica e específica de linguagem). Os nossos dados confirmaram que quadros de alterações específicas de linguagem fazem parte do espectro da síndrome perisylviana; o presente estudo verificou a presença de distúrbios do desenvolvimento de linguagem co-ocorrendo com alterações na leitura e/ou escrita em membros de uma mesma família; os nossos achados mostraram que na síndrome perisylviana, em crianças, observa-se predominantemente alterações na linguagem oral e, em adultos, observa-se predominantemente alterações na linguagem escrita; os nossos resultados confirmaram que sujeitos com envolvimento cortical extenso apresentam manifestações clínicas mais graves, enquanto sujeitos com imagens evidenciando comprometimento cortical posterior e/ou focal apresentam manifestações clínicas mais sutis; ressalta-se finalmente que o exame de ressonância magnética realizado com critério e dirigido para a hipótese diagnóstica, frente a uma criança com atraso na aquisição e desenvolvimento da linguagem associado a sinais clínicos de disfunção oromotora e/ou sinais pseudobulbares é bem indicado / Abstract: Specific language impairment (SLI) refers to inadequate language development in a child without other development disorder, that is, inadequate language acquisition is the main difficulty, even if the child may present with other symptoms. SLI may occur in patients who have polymicrogyria around Sylvian fissure on neuroimaging studies (perisylvian syndrome). The aim of this study was to investigate family members of children with perisylvian syndrome and characterize the linguistic profile found in those families. We selected three families with perisylvian syndrome. Patients underwent a psychological assessment and a comprehensive phonologic evaluation (audiologic evaluation and language evaluation). This study found that SLI and reading/writing impaiment may co-occur in different members of the same family; our data showed that children with perisylvian syndrome present mostly with SLI while adults with perisylvian syndrome present mostly with reading/writing impairment; our results confirmed that clinical picture is correlated with the extent of cerebral involvement; and finally, MRI imaging is indicated when a child has SLI and pseudobulbar signs / Mestrado / Ciencias Biomedicas / Mestre em Ciências Médicas
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