O mecanismo de controle da secreção de GnRH inclui diversas vias neuronais. Estudos em modelos animais identificaram genes que codificam fatores de transcrição, tais como TTF-1 (thyroid transcription factor 1) e EAP1 (enhanced at puberty), que atuam no controle transcricional de genes codificadores de fatores excitatórios (KiSS1 e GnRH) e inibitórios (preproencefalinas) regulando a secreção de GnRH. Em primatas, a expressão de EAP1 e TTF-1 aumenta, no início da puberdade, nas regiões hipotalâmicas envolvidas na secreção de GnRH. Nos modelos animais, a deleção pós-natal de TTF-1 e o silenciamento do EAP1 provocam atraso puberal e prejuízo na função reprodutiva. TTF-1 também está envolvido na morfogênese diencefálica, por meio da via de sinalização da família Sonic-Hedgehog. Anormalidades na secreção de GnRH resultam em distúrbios puberais, que variam de puberdade precoce central (PPC) a hipogonadismo hipogonadotrófico. Hipotetizamos que anormalidades genéticas no TTF-1 e EAP1 estejam envolvidas na patogênese dos distúrbios puberais centrais. A PPC pode ser idiopática ou devido a causas orgânicas, sendo o hamartoma hipotalâmico, uma malformação congênita não neoplásica, a mais conhecida. Os pacientes com PPC devido a hamartoma hipotalâmico podem cursar com alterações neurológicas e cognitivas. Nossos objetivos foram: estudar as regiões codificadora do TTF-1 e do EAP1 e a região promotora do TTF-1 em pacientes com distúrbios puberais centrais; estabelecer a prevalência, taxa de penetrância e modo de herança da forma familial de PPC e caracterizar as manifestações neurológicas e neurocognitivas de pacientes com PPC devido a hamartoma hipotalâmico. Foram selecionados 133 pacientes com distúrbios puberais centrais - PPC idiopática (n=71), PPC devido a hamartoma hipotalâmico (n=15) e hipogonadismo hipogonadotrópico isolado normósmico (HHIn) (n=47) - e controles (n=53). Os genes TTF-1 e EAP1 foram amplificados e submetidos a sequenciamento automático. Os tratos de poliglutamina e polialanina no EAP1 foram estudados por software de análise de tamanho de fragmento (GeneScan). A avaliação neurológica e neurocognitiva dos pacientes com PPC devido a hamartoma hipotalâmico consistiu de exame neurológico, eletroencefalograma, ressonância magnética de encéfalo e aplicação da escala de inteligência (WISC-III, WAIS-III, WPPSIR). Identificamos 25% de casos familiais de PPC, com modo de herança autossômica dominante e taxa de penetrância de 67,5%. Variantes alélicas no TTF-1 não foram identificadas nos pacientes estudados. No gene EAP1 foram identificadas quatro variantes alélicas sinônimas: p.E87E, p.A163A, p.Y415Y e uma nova variante alélica p.C758C, encontradas em pacientes com PPC e HHIn. A distribuição das frequências alélica e genotípica das variantes alélicas do EAP1 não diferiram entre pacientes com PPC, HHIn e controles (p >0,05). Nas regiões poliglutamina e polialanina 5 distal foi identificada variação similar no número de repetições glutamina e alanina em pacientes e controles. Não houve diferença significativa da frequência alélica em relação ao número de repetições glutamina e alanina entre os grupos PPC e HHIn (p >0,05). A avaliação neurológica dos pacientes com PPC devido a hamartoma hipotalâmico revelou epilepsia gelástica e crises focais com generalização em 3/15 (20%) pacientes. Não houve diferença significativa entre a mediana do maior diâmetro dos hamartomas dos pacientes com PPC com e sem epilepsia (13 e 10 mm, respectivamente). Quanto à forma, 10 hamartomas eram sésseis e 5 pedunculados, sendo que a forma pedunculada foi detectada exclusivamente em pacientes sem epilepsia. A avaliação neurocognitiva em 11 dos 15 pacientes com PPC devido a hamartoma hipotalâmico detectou 2 pacientes com epilepsia com QI significativamente menor que o grupo sem epilepsia (p <0,05). Em conclusão, (i) a considerável prevalência de casos familiais de PPC reforça a influência dos fatores genéticos na puberdade humana; (ii) mutações germinativas no TTF-1 e no EAP1 não estão envolvidas na patogênese dos distúrbios puberais centrais; (iii) a função neurocognitiva reduzida nos pacientes com hamartoma e epilepsia sugere um efeito deletério das crises convulsivas no sistema nervoso central / GnRH secretion control involves multiple neuronal pathways. Animal studies have identified genes which codifies transcription factors, such as TTF-1 (thyroid transcription factor 1) and EAP1 (enhanced at puberty), that act in the transcriptional control of genes that codifies excitatory (KiSS1 and GnRH) and inhibitory factors (preproenkephalines) regulating GnRH secretion. In nonhuman primates, expression of EAP1 and TTF-1 are increased at the hypothalamic regions involved in GnRH secretion, at the beginning of puberty. In animal models, post-natal TTF-1 deletion and silencing of EAP1 lead to pubertal delay and damage of reproductive function. TTF-1 is also involved in diencephalic morphogenesis, through signalization via Sonic-Hedgehog family. Abnormalities in GnRH secretion are responsible for pubertal disorders, varying from central precocious puberty (CPP) to hypogonadotropic hypogonadism. We hypothesized that genetic anomalies at TTF-1 and EAP1 are involved in the pathogenesis of central pubertal disorders. CPP may be idiopathic or due to organic alterations and hypothalamic hamartoma, a non-neoplasic congenital malformation, is the most frequent known organic cause. Patients with CPP due to hypothalamic hamartoma may have neurological and cognitive disfunctions. Our aims were: to evaluated the codifying region of TTF-1 and EAP1 and the promoter region of TTF-1 in patients with central pubertal disorders; to establish the prevalence, penetrance rate and inheritance mode of familial CPP and to characterize neurologic and neurocognitive aspects of patients with CPP due to hypothalamic hamartoma. We selected 133 patients with central pubertal disorders idiopathic CPP (n=71), CPP due to hypothalamic hamartoma (n=15) and normosmic isolated hypogonadropic hypogonadism (nIHH) (n=47) - and controls (n=53). TTF-1 and EAP1 genes were amplified and sequenced. Polyglutamine and polyalanine tracts of EAP1 were studied by a fragment size analyser software (GeneScan). Neurologic and neurocognitive evaluation of CPP patients due to hypothalamic hamartoma consisted of neurologic exam, electroencephalogram, brain magnetic resonance and application of intelligence scale (WISC-III, WAIS-III, WPPSI-R). We identified 25% of familial CPP cases with autosomal dominant mode of inheritance and penetrance rate of 67.5%. No TTF-1 allelic variants were identified in the patients analysed. At EAP1 gene, four synonimous allelic variants were identified: p.E87E, p.A163A, p.Y415Y and a new allelic variant p.C758C, found in CPP and nIHH patients. The allelic and genotypic distribution of theses variants of EAP1 did not differ among patients with CPP and nIHH, and controls (p >0.05). At polyglutamine and 5 distal polyalanine region, similar glutamine and alanine repeats variation was found. No significative difference of allelic frequency distribution regarding the number of glutamines and alanines repeats was found among the studied groups (p >0.05). Neurologic evaluation of CPP patients due to hypothalamic hamartoma revealed epilepsy and focal crisis with generalization in 3/15 (20%) of the patients. No significant difference between the median of the larger diameter of hypothalamic hamartoma of CPP patients with and without epilepsy was found (10 mm and 13 mm, respectively). Regarding the shape, 10 hamartomas were sessile and 5 pedunculated, and the pedunculated shape was found only in non epileptic patients. Neurocognitive evaluation performed in 11 of the 15 patients with CPP due to hypothalamic hamartoma detected 2 patients with epilepsy whose IQ were significantly lower than the IQ found in the group without epilepsy (p <0.05). In conclusion, (i) the considerable prevalence of familial CPP cases reinforce the influence of genetic factors in human puberty; (ii) germinative mutations in TTF-1 and EAP1 are not involved in the pathogenesis of central pubertal disorders; (iii) reduced neurocognitive function in patients with hypothalamic hamartoma and epilepsy suggests a deleterious effect of crisis at the central nervous system

Abstract Salla disease (SD) is a rare lysosomal storage disorder, belonging to the Finnish disease heritage. The condition leads to intellectual disabilities. Two main categories of the disease have been identified – a conventional subtype and a severe subtype. The gene locus of SD has been assigned to a restricted region on the long arm of chromosome 6. The gene SLC17A5 is responsible for lysosomal-membrane sialic acid transport. The objective of this study was to describe the neurocognitive developmental spectrum of SD in a long follow-up study. In the original study (1997–1999), the sample consisted of 41 Finnish patients with Salla disease. They were examined by a paediatric neurologist, a psychologist and a speech therapist. The follow-up study (2010–2012) concerned of 27 (66%) patients from the original SD patient sample. The study included neurological and neuropsychological investigations. A case study of a mildly affected female patient was also reported. In the first study, the typical neurocognitive profile of SD was outlined and the different phenotypes confirmed. The neurocognitive profile of SD consisted of a strong motor handicap, but also well-developed skills in verbal comprehension and interaction. In the follow-up study, the main finding was that the verbal skills related to comprehension did not diminish over time. However, the skills that demanded productive speech were worsened by both dyspraxia and dysarthria, markers of dysfunction of the cerebellum. The neurocognitive and neurological status of the mildly affected female patient remained stable during the long follow-up time. In addition the MRI findings revealed mild dysfunction. The results indicate that the neurocognitive deficits related to SD are clear in childhood, but the illness does not have a rapid progressive nature after teenage years. The motor handicap is strong but the cognitive skills related to verbal comprehension, and interactive skills, do not deteriorate in adulthood. Four different neurodevelopmental periods can be outlined. / Tiivistelmä Tämän tutkimuksen tavoitteena oli kuvata Sallan tautiin liittyvä neurokognitiivisen kehityksen kulku pitkän seurantatutkimuksen aikana. Sallan tauti, erittäin harvinainen lysosomaalinen kertymäsairaus, kuuluu suomalaiseen tautiperimään. Nämä perinnölliset sairaudet ovat Suomessa yleisempiä kuin muissa maissa. Sallan tauti etenee älylliseen kehitysvammaisuuteen. Kaksi taudin päätyyppiä, tavanomainen ja vakava-asteinen fenotyyppi, on tunnistettu. Sallan taudin aiheuttavan geenin sijainti on paikallistettu kromosomiin 6. SLC17A5-geeni vastaa sialihapon kuljetuksesta solujen lysosomeissa. Ensimmäisen tutkimuksen (1997–1999) aineisto koostui 41 suomalaisesta Sallan tautia sairastavasta potilaasta. Neurologi, psykologi sekä puheterapeutti tutkivat jokaisen potilaan. Seuranta-aineisto (2010–2012) koostui 27 (66&#160;%) potilaasta. Tutkimukseen kuului neurologin sekä neuropsykologin tutkimus. Lieväoireisen naispotilaan kehityskulku julkaistiin erillisenä tapaustutkimuksena. Ensimmäisessä tutkimuksessa selvitettiin Sallan taudille ominainen neurokognitiivinen profiili, lisäksi vahvistettiin kahden eri fenotyypin olemassaolo. Neurokognitiivisiin tyyppioireisiin kuuluivat vahvat motoriset defektit, mutta toisaalta hyvin kehittyneet kielelliset taidot puheen ymmärtämisen osalta. Myös vuorovaikutustaidot olivat vahvat. Seurantatutkimuksen päätulos oli puheen ymmärtämisen taitojen säilyminen taudin edetessä. Puheen tuottamiseen liittyvien vaikeuksien osalta sekä dyspraksia että dysartria heikensivät kielellistä toimintakykyä. Nämä kielelliset defektit liittyvät pikkuaivojen toimintahäiriöihin. Lieväoireisen naispotilaan neurologiset ja neurokognitiiviset löydökset eivät olleet edenneet pitkän seurantatutkimuksen aikana. Myös aivojen kuvantamistutkimuksen tulokset olivat lievät. Sallan tautiin liittyvät neurokognitiiviset muutokset ovat selkeät lapsuusiässä, mutta sairauden luonne aikuisiällä ei ole nopeasti etenevä. Motorisen toimintakyvyn defektit ovat vahvat, mutta kielellisen ymmärtämisen ja vuorovaikutuksen taidot eivät heikkene aikuisilla potilailla. Taudista voidaan erotella neljä erilaista kehityksellistä vaihetta.

With the increase in survival for children with cancer, part of the focus of current research is aimed towards evaluating how these children are adapting psychosocially. Neurocognitive deficits have been well established. However, there are multiple facets encompassing quality of life, including general mental health, lifestyles and health behaviors, and academic and cognitive functioning. The relationship between neurocognitive and psychosocial functioning has yet to be thoroughly evaluated. The purpose of this study was to investigate the relationship between neurocognitive and psychosocial functioning in survivors of brain tumors and acute lymphoblastic leukemia. Data was collected from existing archival database comprised of patients of the at Cook Children's Medical Center in Texas. The sample consisted of 177 patients between the ages of 3 and 12 who were at least two years post-diagnosis. Measures used included the NEPSY and the Behavioral Assessment for Children. Statistical analyses included a several one-way analysis of variances, an independent samples t-test, a univariate analysis of variance, a hierarchical multiple regression, and odds ratio analyses. Results indicated survivors treated with neurosurgery alone appear to be less at risk for developing behavior problems than other treatment modalities. Also, brain tumor survivors demonstrate more problematic behaviors than survivors of acute lymphoblastic leukemia. Visuospatial functioning, diagnosis, and type of treatment were found to be predictive variables of behavior problems. Attention, and perhaps language, deficits may predispose children to more problems in their behavior. It is concluded that there are other factors affecting behavior in this population that were not accounted for in this analysis. It is recommended for future studies to research the individual clinical scales of the Behavior Assessment System for Children, obtain information from multiple informants, study this relationship longitudinally, and research additional factors that may be influencing the relationship between neurocognitive and psychosocial functioning. This provides evidence of risk factors that should be monitored as the child returns home and to school.

Abstract: Many regions of the cortex have been identified to be specifically selective for different features. For example, visually presented stimuli proceed, via both the dorsal “where” and ventral “what” streams, before converging in the frontal cortex for decision making processes. However, several subregions of both streams have been identified that demonstrate selectivity on many semantic dimensions, such as size. Most of the studies examining regions selectively activated in maintenance of semantic size have employed the use of visually presented images. In the present, however, study we provide a review of relevant literature, proposed techniques, and a list of word stimuli that may help elucidate the multivariate neural processing of several semantic dimensions.

<p>This dissertation combines stakeholder and analytical intelligence for consensus decision-making via an interactive optimization process. This dissertation outlines techniques for developing user models of subjective criteria of human stakeholders for an environmental decision support system called WRESTORE. The dissertation compares several user modeling techniques and develops methods for incorporating such user models selectively for interactive optimization, combining multiple objective and subjective criteria. </p><p>This dissertation describes additional functionality for our watershed planning system, called WRESTORE (Watershed REstoration Using Spatio-Temporal Optimization of REsources) (http://wrestore.iupui.edu). Techniques for performing the interactive optimization process in the presence of limited data are described. This work adds a user modeling component that develops a computational model of a stakeholder’s preferences and then integrates the user model component into the decision support system. <br></p><p>Our system is one of many decision support systems and is dependent upon stake- holder interaction. The user modeling component within the system utilizes deep learning, which can be challenging with limited data. Our work integrates user models with limited data with application-specific techniques to address some of these challenges. The dissertation describes steps for implementing accurate virtual stakeholder models based on limited training data. </p><p>Another method for dealing with limited data, based upon computing training data uncertainty, is also presented in this dissertation. Results presented show more stable convergence in fewer iterations when using an uncertainty-based incremental sampling method than when using stability based sampling or random sampling. The technique is described in additional detail. </p><p>The dissertation also discusses non-stationary reinforcement-based feature selection for the interactive optimization component of our system. The presented results indicate that the proposed feature selection approach can effectively mitigate against superfluous and adversarial dimensions which if left untreated can lead to degradation in both computational performance and interactive optimization performance against analytically determined environmental fitness functions. </p><p>The contribution of this dissertation lays the foundation for developing a framework for multi-stakeholder consensus decision-making in the presence of limited data.</p>

Ce travail de thèse présente une approche clinique et thérapeutique visant à fournir de nouvelles techniques de soins pour les patients atteints de troubles neurocognitifs et notamment de maladie d’Alzheimer. Les serious exergames sont des jeux vidéo sérieux intégrant une activité physique. Ils peuvent constituer des outils de production d’environnement enrichi pour les utilisateurs, en associant notamment exercice physique et entraînement cognitif. L’objectif de cette thèse est d’explorer en quoi les serious exergames peuvent contribuer à la prise en charge non médicamenteuse des troubles neurocognitifs. Dans ce travail, nous avons réalisé deux types de contribution. Les premières contributions sont générales, l’une présente notre approche clinique intégrative combinant exercice physique et entraînement cognitif via l’utilisation de serious exergames, et l’autre présente des recommandations concernant l’usage des serious games. Les secondes contributions sont de nature expérimentale. La première expérimentation vise à vérifier une des bases théoriques de notre approche clinique. Les deux expérimentations suivantes constituent une évaluation de la mise en œuvre de notre approche. / This thesis presents a clinical and therapeutic approach aiming to create new care for patients with neurocognitive disorder. Serious exergames are serious video games integrating physical activity. Serious exergames could be tools to product enriched environment associating physical exercise and cognitive training. The aim of this thesis is to investigate whether serious exergames can contribute to the non-pharmacological management of neurocognitive disorders. In this thesis we have made two types of contributions. The first type are general contributions. One presents our integrative clinical approach associating physical exercise and cognitive training using serious exergames. The other one presents recommendations concerning the use of serious exergames. The second type of contributions are experimental. The first one aims to confirm a theoretical base of our clinical approach. The two other experiments assess the implementation of our approached in a population of patients with neurocognitive disorder.

Le rôle de proche aidant est essentiel pour soutenir l’autonomie de la personne ayant la maladie d’Alzheimer (ou un autre trouble neurocognitif). Or, bien que la perception du proche aidant quant au statut fonctionnel de l’aîné à qui il offre du soutien ait déjà été étudiée, il n'existe pas de revue de littérature ayant abordé la correspondance entre l'évaluation d'un professionnel et la perception du statut fonctionnel par les proches aidants. L’objectif de cette étude est donc de comparer la perception du proche aidant et celle du professionnel de la santé quant au statut fonctionnel des aînés ayant la maladie d’Alzheimer (ou d’autres troubles neurocognitifs). Pour ce faire, un examen de la portée a été réalisé. Seize articles répondant aux critères d'inclusion ont été inclus dans l’étude. Toutes les études sélectionnées étaient non-expérimentales (transversale, longitudinale, cohorte avec groupe conrôle, cohorte, qualitative et mixte), et représentaient des échantillons hétérogènes concernant la dimension cognitive des sujets. La majorité des études (n=10) comptaient plus de femmes que d’hommes parmi ses participants. L’âge des aînés ayant un trouble neurocognitif variait entre 62,4 (±6,8) ans et 82,7 (±6,4) ans et celui des proches aidants variait de 48,2 (±15,2) ans à 79,6 (±8,5) ans. Les conjoints de personnes ayant la maladie d’Alzheimer ou un trouble neurocognitif sont les principaux dispensateurs d’aide parmi les proches aidants, suivi des enfants. Les milieux d'évaluation variaient entre le domicile, les milieux cliniques ou les laboratoires de centres de recherche. Les résultats de 75 % des études montrent que les évaluations faites par les professionnels donnent des résultats divergents avec la perception des proches aidants. Aussi, dans 31 % des études, la tendance était la sous-estimation des capacités par les proches aidants comparativement aux professionnels alors que dans 25 % des études, la tendance allait dans le sens de la surestimation des capacités. Enfin, dans 19 % des études, ou ne précisait pas la nature des divergences (sous-estimation ou surestimation). Des résultats portant sur la nature de la relation entre la personne ayant un trouble neurocognitif et son proche suggèrent que les conjoints ont tendance à surestimer les habiletés fonctionnelles des personnes ayant des troubles neurocognitifs à un stade léger, tandis que les proches ayant un autre type de lien (enfant, ami) montrent généralement une tendance à la sous-estimation. De plus, les divergences entre les proches aidants et les professionnels sont davantage susceptibles de porter sur des activités en lien avec les activités instrumentales de la vie quotidienne. Des études additionnelles auprès des proches aidants devront être réalisées en parallèle à des évaluations standardisées par des professionnels de la santé afin de recueillir des données plus complètes qui aideront à mieux comprendre quelles sont les activités qui sont perçues de façon divergente selon ces deux points de vue. / The role of the caregiver is essential in supporting the autonomy of those with Alzheimer's disease (or another neurocognitive disorder). However, although the caregiver's perception of the functional status of the person to whom he or she provides support has already been studied, no literature review that has addressed the correspondence between a professional assessment and the perception of functional status by caregivers. The objective of this study is therefore to compare the caregiver's perception and evaluation of the healthcare professional regarding the functional status of seniors with Alzheimer's disease (or other neurocognitive disorders). To do so, a scope review was conducted. Sixteen articles meeting the inclusion criteria were included in the study. All studies were non-experimental (cross-sectional, longitudinal, cohort with control group, cohort, qualitative and mixed), and represented heterogeneous samples with respect to the cognitive dimension of the subjects. The majority of studies (n=10) had more female than male participants. The age of seniors with a neurocognitive disorder ranged from 62.4 (±6.8) y.o. to 82.73 (±6.4) y.o., and that of caregivers ranged from 48.2 (±15.2) y.o. to 79.6 (±8.5) y.o. Spouses of people with Alzheimer's disease or a neurocognitive disorder were the primary caregivers among family caregivers, followed by children. Assessment settings varied from home, clinical settings or research center laboratories. The results of 75 % of the studies show that the assessments made by professionals gave results that diverge from the perception of caregivers. In 31 % of the studies, there was a tendency for caregivers to underestimate abilities compared to professionals, while in 25 % of the studies, there was a tendency for caregivers to overestimate abilities. Finally, in 19 % of the studies, the nature of the discrepancies (underestimation or overestimation) was not specified Results on the nature of the relationship between the person with a neurocognitive disorder and his/her caregiver suggest that spouses tend to overestimate the functional abilities of people with mild neurocognitive disorders, while relatives in other types of relationships (child, friend) generally show a tendency to underestimate them. Moreover, differences between caregivers and professionals are more likely to be related to activities related to instrumental activities of daily living. Additional studies with caregivers will have to be conducted in parallel with standardized assessments by healthcare professionals in order to collect more data to better understand which activities of functional status are perceived in a divergent way.

Our lives become longer with new advancements in medicine and technology. As a result, cognition and memory impairments will become a growing concern[23]. To be able to treat cognitive decline, dementia and related diseases, the need for early detection of memory deficiencies increases. This study aimed to validate the use of a new digital interaction version of a common memory test, the Rey Auditory Verbal Learning Test (RAVLT), compared with norm from the traditional human-to-human interaction version of the same test. This was performed through userstudies with both test versions in a counterbalanced order. The results consisted of quantitative results from the tests together with qualitative data from interviews with the participants in connection to each test occasion. The results showed a slight difference in some aspects of the quantitative test results, but at the same time, no significant difference for most of the measured results. Further, the interviews demonstrated that the differences in interaction and experience between the versions of the tests could be the reason for some of the differences in the quantitative result. The conclusion from this study was that there are many difficult problems to solve for speech interfaces in neurocognitive tests like the RAVLT. In line with previous research [22], the results highlight the importance of a natural speech interaction that conforms with the basic principles of human conversation, to create a stress-free experience and test results that can be reliable and comparable.

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