Introdução: o Diabetes Mellitus é uma epidemia mundial de incidência crescente e alta morbi-mortalidade. Apesar de a neuropatia diabética ser a complicação neurológica mais comum, é crescente o conhecimento de que existe um acometimento do sistema nervoso central, notadamente no que concerne às alterações cognitivas. Objetivos: investigar, por meio de duas tarefas cognitivas objetivas, simples, rápidas, de baixo custo e de fácil aplicação, diferenças entre pacientes com Diabetes Mellitus Tipo 1 (DM1) e controles quanto a medidas de atenção e impulsividade, componentes-chave das funções executivas tradicionalmente avaliados por questionários subjetivos, longos, de difícil reprodutibilidade e que exigem psicólogos treinados; correlacionar as diferenças encontradas com características clínicas; explorar as correlações entre as duas tarefas. Métodos: Foram comparados os desempenhos de 20 pacientes com DM1 e 20 controles, de ambos os sexos, com idades entre 12 e 15 anos, utilizando a tarefa Agir-Não Agir e uma tarefa de Labirintos, e verificadas correlações entre eles. Resultados: o grupo DM1 teve mais respostas antecipatórias (RA) na tarefa Agir-Não Agir (p<0,05) e fez mais mudanças de trajetória nos Labirintos (p <0,01). Houve correlação entre hipoglicemias não-graves e RA (p=0,01), e entre hipoglicemias graves e número de toques nas paredes dos labirintos (p <0,05). HbA1c> 9% correlacionou-se com um maior número de becos sem saída nos labirintos (p <0,05). Os parâmetros mostraram-se coerentes dentro de cada tarefa e entre elas. Conclusões: Encontramos indicadores de desatenção e impulsividade coexistindo no DM1, o primeiro estando mais relacionado à hiperglicemia, e o último à hipoglicemia. Investigações adicionais são necessárias para estudar o declínio cognitivo associado ao diabetes por meio de avaliações mais objetivas, e avaliar a confiabilidade e as propriedades psicométricas das tarefas aqui propostas. / Background : Diabetes Mellitus is a worldwide epidemic of increasing incidence and high morbidity and mortality. Although diabetic neuropathy is the most common neurological complication, the knowledge that there is an involvement of the central nervous system is increasing, especially in relation to cognitive changes. Aims: To investigate with two simple, inexpensive, rapid, objective and easy-to-apply tasks, differences between patients with Type 1 Diabetes Mellitus (T1DM) and controls in outcome measures of attention and impulsivity, key-executive function components traditionally assessed by subjective and long questionnaires of difficult reproducibility that require trained psychologists; to correlate the alterations with clinical characteristics; to explore correlations between the tasks. Methods: We compared the scores of 20 T1DM to 20 controls, both sexes, aged 12 to 15 years, using a Go-NoGo and a Maze task, and verified correlations between them. Results: T1DM group had more anticipatory answers (AA) in Go-NoGo task (p<0,05) and made more direction changes in Mazes (p<0,01). There was correlation between non-severe hypoglycaemias and AA (p=0,01), and between severe hypoglycaemias and number of touches in Mazes’ walls (p<0,05). HbA1c>9% correlated to a greater number of alleys in Mazes (p<0,05). The tasks’ parameters were coherent among each task and between them. Conclusions: We found indicators of inattention and impulsivity coexisting in T1DM, the first more related to hyperglycaemia and the later to hypoglycemia. Further research is needed to study diabetes-associated cognitive decline with more objective parameters and evaluate the reliability and psychometric properties of the tasks herein proposed. / Dissertação (Mestrado)

La dégénérescence vasculaire et l’incapacité l’organisme à produire des vaisseaux sanguins de façon adéquate lors d’une condition ischémique est un fait saillant des rétinopathies ischémiques telles que la rétinopathie du prématuré (ROP). La ROP demeure la principale cause de défaillance visuelle et dans les cas extrêmes, de cécité chez les nourrissons prématurés. Elle présente deux phases distinctes soit une phase initiale clef de vasooblitération (VO) rétinienne et choroïdale qui entraînent la deuxième phase de néovascularisation (NV) rétinienne désorganisée et excessive. Au cours du développement normal, la NV oculaire a recours au phénomène d’angiogenèse qui consiste en la formation de nouveaux capillaires à partir de vaisseaux préexistants et de vasculogenèse qui consiste en la formation de nouveaux capillaires à partir de cellules endothéliales progénitrices dérivées de la moelle osseuse (BM-EPCs). Cette vasculogenèse implique la mobilisation des EPCs de la moelle osseuse vers la circulation afin d’être recrutées au site de NV pour contribuer de façon directe, soit en intégrant directement les structures vasculaires pour former des néovaisseaux, ou bien de façon indirecte par leur activité paracrine en libérant différents facteurs de croissance vasculaires. Toutefois, les mécanismes moléculaires impliqués dans la dysfonction des EPCs lors de la ROP sont encore mal compris. Au cours de mon mémoire, mes travaux ont ciblé la première phase de VO rétinienne afin de promouvoir la revascularisation par une thérapie basée sur une supplémentation d’EPCs natives ou reprogrammées. Compte tenu du rôle capital des EPCs dans la NV, mon mémoire s’est d’abord intéressé au rôle de Nogo-A (une protéine de la famille de réticulon), connue pour son action anti-angiogénique, sur l'activité fonctionnelle des EPCs en condition de ROP. Pour ce faire, nous avons utilisé un modèle de rétinopathie induite par l’oxygène (OIR) simulant la ROP. L’objectif global de ce projet consiste à évaluer l’interrelation entre l’effet de l’hyperoxie (une condition clef de la ROP) sur la voie de signalisation Nogo-A et de son récepteur NgR1 sur la fonction des EPCs. Premièrement, les résultats obtenus montrent une augmentation de l’expression de Nogo-A et NgR1 chez les BM-EPCs soumis ex vivo à l’hyperoxie, mais aussi dans les EPCs extraites des rats OIR. En addition, l’augmentation de l’expression de Nogo-A/NgR1 par l’hyperoxie corrèle avec la dysfonction angiogénique des EPCs caractérisées par une diminution de leurs capacités de migration et de tubulogenèse. De façon intéressante, l’inhibition de Nogo-A (par un peptide neutralisant) améliore la capacité migratoire et tubulogénique des EPCs, et protège leur fonction contre l’hyperoxie. Également, l’inhibition de Nogo-A induit l’expression du facteur angiogénique et mobilisateur d’EPCs, SDF-1, suggérant que NgR1 régule négativement l’expression de SDF-1. Par ailleurs, nous avions également pour objectif final d’évaluer l’efficacité protectrice d’une supplémentation d’EPCs natives ou reprogrammées (Nogo-/-) pour améliorer la revascularisation rétinienne dans un modèle de rat OIR. Les résultats montrent qu’une supplémentation intrapéritonéale d’EPCs natives diminue significativement la VO rétinienne, mais que cet effet pro-angiogénique devient plus prononcé par le traitement d’EPCs préconditionnées (reprogrammées par l’inhibition de Nogo-A) chez les rats OIR. Collectivement, nos résultats démontrent que : 1) l’hyperoxie cause une dysfonction angiogénique des BM-EPCs en induisant Nogo-A ce qui contribue à la VO rétinienne chez les rats OIR, et que 2) une supplémentation d’EPCs conditionnées (reprogrammées par l’inhibition de Nogo-A) est plus efficace qu’une supplémentation d’EPCs natives pour améliorer la réparation vasculaire rétinienne. Pour conclure, nous mettons donc en évidence une cible potentielle qui est la protéine Nogo-A afin de préserver l’activité biologique des EPCs et ultimement, l’intégrité vasculaire chez les rats OIR. / Vascular degeneration and the inability of the body to produce adequate blood vessels during an ischemic condition is a salient feature of ischemic retinopathies such as retinopathy of prematurity (ROP). ROP remains the leading cause of visual impairment and in extreme cases, blindness in premature infants. It presents two distinct phases: a key initial phase of retinal and choroidal vasoobliteration (VO) which leads to the second phase of disorganized and excessive retinal neovascularization (NV). During normal development, ocular NV uses the phenomenon of angiogenesis which consists of the formation of new capillaries from pre-existing vessels and vasculogenesis which consists of the formation of new capillaries from progenitor endothelial cells derived from the marrow bone (BM-EPCs). This vasculogenesis involves the mobilization of EPCs from the bone marrow to the circulation in order to be recruited at the NV site to contribute directly, either by directly integrating the vascular structures to form new vessels, or indirectly by their paracrine activity by releasing different vascular growth factors. However, the molecular mechanisms involved in the dysfunction of EPCs during ROP are still poorly understood. During my thesis, my work targeted the first phase of retinal VO in order to promote revascularization by therapy based on supplementation of native or reprogrammed EPCs. Given the capital role of EPCs in NV, my thesis was first interested in the role of Nogo-A (a protein of the reticulon family), known for its anti-angiogenic action, on the functional activity of EPCs in ROP condition. To do this, we used an oxygen-induced retinopathy (OIR) model simulating ROP. The overall objective of this project is to assess the interrelationship between the effect of hyperoxia (a key condition of ROP) on the Nogo-A signaling pathway and its NgR1 receptor on the function of EPCs. First, the results obtained show an increase in the expression of Nogo-A and NgR1 in BM-EPCs subjected to hyperoxia ex vivo, but also in EPCs extracted from OIR rats. In addition, the increase in the expression of Nogo-A / NgR1 by hyperoxia correlates with the angiogenic dysfunction of EPCs characterized by a decrease in their capacity for migration and tubulogenesis. Interestingly, inhibition of Nogo-A (by a neutralizing peptide) improves the migratory and tubulogenic capacity of EPCs, and protects their function against hyperoxia. Also, inhibition of Nogo-A induces expression of the angiogenic and mobilizing factor of EPCs, SDF-1, suggesting that NgR1 negatively regulates the expression of SDF-1. In addition, our final objective was also to evaluate the protective efficacy of supplementation of native or reprogrammed EPCs (Nogo - / -) to improve retinal revascularization in an OIR rat model. The results show that intraperitoneal supplementation of native EPCs significantly decreases retinal VO, but that this pro-angiogenic effect becomes more pronounced by treatment of preconditioned EPCs (reprogrammed by inhibition of Nogo-A) in OIR rats. Collectively, our results demonstrate that: 1) hyperoxia causes angiogenic dysfunction of BM-EPCs by inducing Nogo-A which contributes to retinal VO in OIR rats, and that 2) supplementation of conditioned (reprogrammed by inhibition of Nogo-A) is more effective than supplementation of native EPCs in improving retinal vascular repairs. To conclude, we therefore highlight a potential target which is the Nogo-A protein in order to preserve the biological activity of EPCs and ultimately, vascular integrity in OIR rats.