Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.

Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.

Les tumeurs de la fosse postérieure (PFT) représentent les deux tiers des tumeurs cérébrales pédiatriques. Les PFT malignes les plus fréquentes sont le médulloblastome (40%), suivie de l'épendymome (10%). La chirurgie, la radiothérapie et/ou la chimiothérapie sont les approches thérapeutiques utilisées à l’heure actuelle. En raison de l'amélioration des traitements, la survie a augmenté de façon significative. Cependant, ces enfants souffrent de déficiences cognitives variées en partie attribuées à la radiothérapie et ce d’autant plus qu’ils sont jeunes. Atténuer les séquelles neurocognitives est devenu ces dernières années un des enjeux majeurs de l'oncologie pédiatrique. Dans cette optique, ce travail examine chez des enfants traités pour une PFT, les relations entre doses de radiothérapie reçues et performances neuropsychologiques en fonction de l’âge, au moyen d’une approche associant la neuroimagerie et la neuropsychologie. La contribution expérimentale s’articule autour de deux principaux axes. Le 1er axe utilise une approche exploratoire pour rendre compte des relations entre l’irradiation des régions cérébrales et le déclin cognitif chez les enfants traités pour une PFT. L’analyse des données met en relation des patterns spatiaux de répartition des doses dans le cerveau avec la variation des scores neuropsychologiques dans le temps (Mémoire de travail, vitesse de traitement, QI). Nos principaux résultats suggèrent une association entre la diminution des capacités en mémoire de travail et l’augmentation des doses (Dose uniforme équivalente, EUD) délivrées aux régions orbitofrontales ; alors qu’un ralentissement de la vitesse de traitement semble être lié à une dose élevée dans les lobes temporaux et la fosse postérieure. Le 2nd axe utilise une approche a priori pour déterminer l’impact de la maladie et des traitements sur le développement de la mémoire épisodique (ME) et des hippocampes, chez de jeunes enfants (2-13 ans). Cette partie se structure autour d’une part de l’analyse des performances des patients lors d’une tâche expérimentale mesurant la ME et d’autre part, d’une analyse longitudinale des volumes hippocampiques de ces enfants pendant le traitement. Nous avons a mis en évidence chez les enfants avec PFT une altération de la ME dépendant de l’âge : Chez les patients plus jeunes (<7 ans), l'altération était globale tandis que chez les plus âgés, elle ne concernait que la reconnaissance à long terme des détails temporels (c'est-à-dire «quand»). L’analyse des données volumiques hippocampiques n’a pas pu être achevée dans le temps de cette thèse, compte tenu de plusieurs difficultés méthodologiques liées notamment au recalage longitudinal des cerveaux en croissance. Ce travail apporte des connaissances nouvelles sur le rôle de certains facteurs dans l’émergence de difficultés cognitives spécifiques. La prévention des séquelles à long terme de ces enfants reste un défi pour les années à venir. / Pediatric posterior fossa tumors (PFT) account for two-thirds of all pediatric brain tumors. The most common malignant PFT is medulloblastoma (40%), followed by ependymoma (10%). Surgery, radiotherapy and/or chemotherapy are the current therapeutic approaches. As a result of the progress of treatment, event-free survival has significantly improved. Unfortunately, these children suffer from many cognitive impairments partly attributed to radiotherapy, especially in young children. Alleviating neurocognitive impairments has become one of the major challenges of pediatric oncology. Using an approach combining neuroimaging and neuropsychology, this work examines the relationship between treatments and neuropsychological performances as a function of age in children treated for PFT. The experimental contribution is based on two main axes. The first axis uses an exploratory approach to investigate the relationship between the decline of intellectual functioning and radiation dose distribution. For this purpose, we analyze, with a whole brain analysis, the relation between regional biological dose and changes over time of different cognitive scores (IQ, processing speed and working memory). Our results suggest a positive association between working memory decline and high dose (Equivalent Uniform Dose, EUD) delivered to the orbitofrontal regions, whereas decline of processing speed seems more related to EUD in the temporal lobes and posterior fossa. The 2nd axis uses a hypothesis-driven approach to determine the susceptibility of episodic memory (EM) impairment and hippocampal alteration in young child PFT patients (2-13yo). This part is structured around two aims: First, the assessment of PFT EM performances, thanks to an EM task, in comparison to Controls; second, the exploration of longitudinal patterns of hippocampal volume as a potential neural substrate underlying EM performance. The main results support the evidence of EM impairment in the PFT condition, which varied according to age: in the younger patients (<7yo) impairment was global while in the older it involved only the long term recognition of temporal details (i.e. ‘When’). However, at this stage of the work, several methodological difficulties mainly related to the registration parameters of the segmentation algorithm prevent us from achieving hippocampal volume analysis. This work brings new knowledge about the role of some risk factors on specific cognitive difficulties. Preventing long-term impairments of these children remains a challenge for years to come.

Made available in DSpace on 2014-12-17T15:38:51Z (GMT). No. of bitstreams: 1 DanielleFG_DISSERT.pdf: 5162066 bytes, checksum: d43c54235f8f5b351fac7f8338c0b332 (MD5) Previous issue date: 2011-04-01 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Central Nervous System are the most common pediatric solid tumors. 60% of these tumors arise in posterior fossa, mainly in cerebellum. The first therapeutic approach is surgical resection. Malignant tumors require additional strategies - chemotherapy and radiotherapy. The increasing survival evidences that childhood brain tumors result in academic and social difficulties that compromise the quality of life of the patients. This study investigated the intellectual functioning of children between 7 to 15 years diagnosed with posterior fossa tumors and treated at CEHOPE - Recife / PE. 21 children were eligible - including 13 children with pilocytic astrocytoma (G1) who underwent only surgery resection, and eight children with medulloblastoma (G2) - submitted to surgical resection, chemotherapy and craniospinal radiotherapy. Participants were evaluated by the Wechsler Intelligence Scale for Children - WISC-III. Children of G1 scored better than children of G2. Inferential tools (Mann-Whitney ? Test) identified significant diferences (p &#8804; 0.05) between the Performance IQ (PIQ) and Processing Speed Index (PSI) as a function of treatment modality; Full Scale IQ (FSIQ), PIQ and PSI as a function of parental educational level; PIQ, FSIQ, IVP and Freedom from Distractibility (FDI) as a function of time between diagnosis and evaluation. These results showed the late and progressive impact of radiotherapy on white matter and information processing speed. Furthermore, children whose parents have higher educational level showed better intellectual performance, indicating the influence of xxii socio-cultural variables on cognitive development. The impact of cancer and its treatment on cognitive development and learning should not be underestimated. These results support the need to increase the understanding of such effects in order to propose therapeutic strategies which ensure that, in addition to the cure, the full development of children with this pathology / Os tumores de Sistema Nervoso Central s?o as neoplasias s?lidas mais frequentes na inf?ncia. 60% desses tumores ocorrem na fossa posterior, cujo principal componente ? o cerebelo. A primeira interven??o ? a ressec??o cir?rgica; tumores malignos requerem estrat?gias terap?uticas complementares quimioterapia e radioterapia. O aumento da sobrevida evidenciou que crian?as com tumores cerebrais apresentam dificuldades acad?mico-sociais que comprometem sua qualidade de vida. O objetivo deste estudo foi investigar a capacidade intelectiva de crian?as de 6 a 16 anos com tumores de fossa posterior. Participaram 21 crian?as atendidas pelo CEHOPE Recife/PE sendo 13 crian?as com astrocitoma piloc?tico (G1) - submetidas ? cirurgia de ressec??o e; oito crian?as com meduloblastoma (G2) submetidas a cirurgia de ressec??o, quimioterapia e radioterapia de cr?nio e neuro-eixo. Os participantes foram avaliados pelas Escalas Wechsler de Intelig?ncia para Crian?as WISC-III. Crian?as de G1 obtiveram desempenho superior ao de crian?as de G2. An?lises estat?sticas inferenciais (Teste ? de Mann-Whitney) identificaram contrastes estatisticamente significativos (p&#8804;0,05), entre o QI de Execu??o (QIE) e ?ndice Fatorial Velocidade de Processamento (IVP) em fun??o da modalidade de tratamento; QI Total, QIE e IVP em fun??o do n?vel de escolaridade dos pais; QIE, QIT, IVP e ?ndice Fatorial Resist?ncia ? Distra??o (IRD) em fun??o do tempo entre o diagn?stico e a avalia??o. Sugere-se o impacto tardio e progressivo da radioterapia sobre a subst?ncia branca e sobre a velocidade de processamento; crian?as cujos pais possuem maior n?vel de instru??o formal apresentam melhor capacidade intelectiva, sugerindo a influ?ncia de vari?veis s?cio-culturais sobre o desenvolvimento cognitivo. O impacto do c?ncer e seu tratamento sobre o desenvolvimento e a aprendizagem n?o deve ser subestimado. Tais resultados refor?am a necessidade de aprofundar a compreens?o sobre tais efeitos, visando propor estrat?gias terap?uticas que garantam, al?m da reabilita??o cl?nica, o pleno desenvolvimento das crian?as com esta patologia.