INTRODUÇÃO: Epilepsia do lobo temporal mesial (ELTM) por esclerose hipocampal (EH) é a forma de epilepsia focal mais comum na idade adulta e a causa mais frequente de refratariedade ao tratamento clínico. Apesar de se tratar de uma patologia da substância cinzenta, alguns estudos, por meio da imagem por tensor de difusão (diffusion tensor imaging-DTI), têm demonstrado alteração da substância branca temporal e extratemporal nestes pacientes. O corpo caloso (CC) é a maior comissura cerebral conectando áreas corticais homólogas de ambos os hemisférios cerebrais e tem sido implicado na propagação da atividade epiléptica. O objetivo principal do presente estudo foi avaliar possíveis alterações no CC de pacientes com ELTM-EH pela técnica de DTI e verificar se essas dependem da lateralidade da EH e da concordância entre os exames de ressonância magnética (RM) e os exames de vídeo-eletroencefalograma (EEG). Como objetivo secundário, também avaliou-se se estas alterações se correlacionavam com alguma variável clínica ou com as medidas volumétricas do CC. MÉTODOS: 42 pacientes com ELTM-EH (idades: 20-54 anos) e 30 voluntários saudáveis como grupo controle (idades: 18-53 anos) realizaram exame de RM de crânio, sendo obtidas sequências de DTI com 32 direções de gradiente e imagens volumétricas ponderadas em T1. Os pacientes foram também divididos em subgrupos: EH à direita e EH à esquerda, e em pacientes concordantes e discordantes. Os valores de anisotropia fracionada (AF), difusividade média (DM), difusividade axial (DA), difusividade radial (DR) e os dados volumétricos foram extraídos a partir de cinco segmentos obtidos automaticamente na secção sagital do CC. Foram realizadas comparações dos parâmetros de DTI no CC entre os grupos de pacientes e controles, e entre os subgrupos de pacientes. Foram investigadas correlações entre os parâmetros do tensor de difusão e as variáveis clínicas. As alterações volumétricas no CC dos pacientes com ELTM-EH bem como a correlação dessas alterações com as anormalidades de difusão também foram avaliadas. Considerou-se um valor de p < 0,05 como estatisticamente significativo. RESULTADOS: Nas regiões anterior, médio-posterior e posterior do CC dos pacientes, observaram-se redução da AF e aumento da DM e da DR, em relação aos controles. A DA manteve-se inalterada. Não foram demonstradas diferenças nos padrões de alteração de difusão entre os pacientes com EH à direita e com EH à esquerda, nem entre pacientes concordantes e discordantes. Não foram observadas correlações significativas entre os parâmetros do tensor de difusão com a idade ao evento inicial, idade de início da epilepsia, tempo de doença, tempo de epilepsia, período de latência e frequência de crises. No entanto, pacientes que apresentaram crise febril como evento precipitante inicial exibiram maior intensidade e extensão das alterações de difusão. Observou-se redução volumétrica difusa do CC, sendo demonstrada correlação negativa significativa entre DM e DR, e o volume nos segmentos central, médio-posterior e posterior, e, ainda, entre DA e volume do segmento posterior. Nós observamos, ainda, correlação negativa significativa entre o volume e o tempo de epilepsia, e o tempo de doença. CONCLUSÕES: Houve alteração dos parâmetros de DTI em áreas específicas do CC e redução volumétrica difusa desta estrutura. Tais anormalidades parecem ser secundárias à propagação das crises epilépticas ao longo de vias específicas anatômica ou funcionalmente relacionadas aos lobos temporais promovendo alterações secundárias na substância branca cerebral. O histórico de crise febril está relacionado a maior intensidade e extensão de acometimento do CC / INTRODUCTION: Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is the most common form of focal epilepsy in adults and it is frequently associated with refractoriness to medical treatment. Although epilepsy is considered a grey-matter disease, abnormalities in the temporal and extra-temporal white matter have been identified in these patients with diffusion tensor imaging (DTI). The corpus callosum (CC) is the major white matter tract connecting both cerebral hemispheres and has been implicated as an important route of spread of epileptic activity. The first goal of this study was to detect DTI abnormalities in specific areas of the CC in patients with MTLE-HS and to verify if these abnormalities depend on the laterality of the HS and on the concordance between the magnetic resonance imaging (MRI) and video-electroencephalogram (EEG). As a second goal we assessed if DTI results were correlated with any clinical variable or volumetric changes of the CC. METHODS: 42 patients (age: 20-54 years) and 30 healthy controls (age:18-53 years) were submitted to brain MRI. DTI sequences with 32 gradient encoding directions and volumetric T1-weighted images were obtained. Additionally, we grouped the patients in left sided and right sided HS and in concordant and discordant HS. Mean values of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and volumetric results were extracted from five segments at the midsagittal section of the CC obtained through automatic segmentation. Comparisons of DTI parameters of the CC were performed between patients and controls and between subgroups of patients. Correlations between DTI parameters and clinical findings were calculated. We also evaluated volume abnormalities of the CC in MTLE-HS patients and the correlations between these abnormalities and DTI changes. We considered a value of p <0.05 statistically significant. RESULTS: Our study showed that, when HS patients was compared to controls, the FA was lowest in the anterior, mid-posterior and posterior subregions of the CC. MD and RD were higher in these same segments. No changes were observed in AD. No differences in the CC DTI parameters were detected between right-sided HS and left-sided HS or between concordant and discordant HS patients. Age at initial event, age at epilepsy onset, duration of disease, duration of epilepsy, latency period and seizure frequency were not significantly correlated with the DTI parameters. However, patients who had febrile seizures as initial event exhibited greater intensity and extent of DTI changes. All segments demonstrated volume reduction compared to controls. Significant negative correlation was demonstrated between MD and RD and the volume in the central, midposterior and posterior segments of the CC, and between AD and volume of the posterior segment. We also demonstrated negative correlation between volume and duration of disease and duration of epilepsy. CONCLUSIONS: This study showed diffusion abnormalities in specific areas of the CC and diffuse atrophy in patients with unilateral HS, which may be secondary to seizures propagation along specific pathways leading to secondary changes in brain white matter. The history of febrile seizure is related to greater involvement of the CC

A esquizofrenia é um transtorno mental de alta complexidade e até o presente momento nenhuma teoria conseguiu explicar completamente sua etiologia. Uma dessas teorias acredita que a transferência de informações entre os hemisférios de pacientes com esquizofrenia, que ocorre através do corpo caloso, comissura anterior e posterior, pode estar comprometida. Os objetivos do nosso estudo foram avaliar se existem alterações de conectividade inter-hemisférica (IH) e se essas alterações sofrem influência do gênero, em pacientes portadores de esquizofrenia quando comparados com seus parentes em primeiro grau e controles saudáveis, utilizando-se da imagem de ressonância magnética por tensor de difusão (IRMTD). Participaram do estudo 30 pacientes portadores de esquizofrenia, diagnosticados pelos critérios do Manual diagnóstico e estatístico das doenças mentais em sua quarta edição, os quais foram selecionados entre os pacientes do grupo de medicações atípicas do ambulatório de esquizofrenia e da enfermaria psiquiátrica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo; 30 parentes em primeiro grau desses pacientes; e 30 voluntários saudáveis. Todos os sujeitos do estudo foram submetidos a um exame de ressonância magnética, realizado no Centro de Ciências das Imagens e Física Médica de nossa instituição, onde foram adquiridas as sequências volumétricas e difusionais utilizadas em nosso estudo. Em posse das imagens de ressonância magnética dos 90 sujeitos do estudo, realizamos o pós-processamento dessas imagens, utilizando o software BrainVoyager QX® versão 2.4, com o intuito de obtermos, por meio dos dados provenientes da IRMTD, os mapas de anisotropia fracional (AF) e difusibilidade média (DM). Com esses mapas em mãos, procedemos à análise estatística do estudo, denominada de análise de covariância voxel a voxel (VANCOVA), no cérebro todo. Nessa análise, utilizamos a idade como covariável e verificamos a influência do gênero nos resultados encontrados. Nossos resultados 6 evidenciaram que os pacientes portadores de esquizofrenia apresentaram valores de AF e DM alterados em estruturas homólogas ao corpo caloso e áreas frontais adjacentes. Assim, podemos afirmar que descobrimos perda de conectividade IH nesses mesmos pacientes. Por meio de nosso estudo, descobrimos também a influência do gênero nos valores de AF e DM encontrados e então, consequentemente, podemos dizer que a conectividade IH de pacientes portadores de esquizofrenia sofreu influência do sexo. A idade também mostrou influenciar a conectividade IH de nossos pacientes. Com o atual conceito de que alterações de AF e DM podem ser encaradas como indicativos de comprometimento da mielina, e sabendo que a mielina participa diretamente das reações neuroquímicas do sistema glutamatérgico cerebral, também podemos dizer que o sistema glutamatérgico que participa da conectividade IH desses pacientes encontrava-se comprometido. / Schizophrenia is a highly complex mental disorder and no theory to date was able to fully explain the etiology of this disorder. One of the existing theories advocates that interhemispheric communication, which occurs through the corpus callosum and the anterior and posterior commissures, might be impaired in schizophrenia. Our study was designed to investigate whether there are interhemispheric connectivity (IC) alterations in schizophrenia and whether these alterations are influenced by gender through the comparison of schizophrenia patients with their first-degree relatives and healthy controls using diffusion tensor imaging (DTI). We enrolled 30 schizophrenia patients diagnosed according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and selected from the Group of Atypical Medications of the Schizophrenia Outpatient Clinic and the psychiatric ward of the Ribeirão Preto Medical School University Hospital, 30 first-degree relatives of these patients and 30 healthy volunteers. All subjects underwent magnetic resonance imaging (MRI) scans for the acquisition of volumetric and diffusion sequences. The images were post-processed using BrainVoyager QX® version 2.4 to create fractional anisotropy (FA) and mean diffusivity (MD) maps from DTI data. The resulting data were analyzed using voxel-to- voxel analysis of covariance (VANCOVA) for the whole brain. In this analysis, we used age as a co-variable and assessed the influence of gender. Our results showed that schizophrenia patients had altered FA and MD values in structures homologous to the corpus callosum and adjacent frontal areas, suggestive of IC loss in the patients. We also found that gender influenced FA and MD values and, therefore, that IC in schizophrenia patients is influenced by gender. Age was also found to influence IC in our patients. Based on the current conception that FA and MD alterations may indicate myelin impairment and knowing that myelin participates directly in neurochemical reactions of the glutamatergic system in the brain, we can infer that the glutamatergic system, which is implicated in IC, is affected in schizophrenia and is influenced by gender.

The preterm delivery (<37 weeks gestation) rates are generally 5-9% in Europe, 12-13% in the US, and each year about 13 millions preterm infants are born worldwide (MacDorman and Mathews, 2009; Slattery and Morrison, 2002). The early exposure to the extra-uterine environment increases the risks of perinatal brain injury, involving more often the white matter. The white matter injury is characterized by a potential subsequent occurrence of cognitive problems, of developmental delay and of major motor deficits (e.g. cerebral palsy). <p>The most widely used imaging technique for studying neonatal brain is cranial ultrasound that can be performed at bedside and detects major brain abnormalities (hemorrhage, infarctions, cysts, dilatation of the lateral ventricles). However, it has a poor sensitivity for non-cystic or diffuse white matter abnormalities (WMA), the most common form of white matter injury in preterm infants. In comparison to ultrasound, MR (magnetic resonance) imaging has been reported to be superior in detecting WMA and is considered as an essential modality for imaging the neonatal brain. The standard sequences (e.g. T1-, T2-weighted imaging) are routinely performed for assessing not only brain anatomy, but also for evaluating brain lesions. Nevertheless, ¡§conventional MR imaging¡¨ has been criticized because it is limited in qualitative assessment and it does not provide information on the extent of specific white matter pathways injuries. <p>Currently, diffusion tensor imaging (DTI) enables more detailed exploration of white matter microstructure. Furthermore, DTI is now the best in vivo technique capable of delineating white matter pathways and quantifying microstructural changes not visible on conventional MR imaging. Diffusion tensor tractography allows the reconstruction of the principal white matter fibers. Moreover, it also provides diffusion indices like fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (£f//), transverse diffusivity (£f¢r) that help assess the changes in fiber tracts, even before myelination becomes histologically evident. <p>Structural MR imaging studies performed in neonates are scarce. A number of essential questions are still under debate, concerning the normal white matter structure, as well as premature brain injury. First, left language lateralization and right handedness are complex phenomena incompletely understood and the question rises whether structural lateralization already exist in healthy preterm neonates at term-equivalent age. Second, it is of interest to know whether gender-related structural differences exist in healthy preterm neonates. Finally, in the assessment of preterm brain injury, the relationship between WMA on conventional imaging and altered diffusion indices in fiber tracts is still unclear. Therefore, the aims of the thesis were to investigate the brain structure in a population of preterm neonates at term-equivalent age by DTI and probabilistic tractography.<p>The first part of this thesis (Study I and Study II) was devoted to the study of white matter structural characteristics in healthy preterm neonates. Previous studies have shown that structural asymmetries in language and motor related fibers are present in adults and in infants (Dubois et al. 2009; Westerhausen et al. 2007). Our hypothesis was that these structural asymmetries are already present in preterm neonates at term-equivalent age. In Study I, DTI and probabilistic tractography were performed and we found volume and microstructural asymmetries in the language related parieto-temporal superior longitudinal fasciculi (SLF), in the motor related corticospinal tract (CST) and in the motor part of the superior thalamic radiation (STR) as well. In Study II, we found that compared to boys, girls have larger relative tract volumes and an advanced maturation in language and motor related fiber tracts. <p>The second part of this thesis (Study III) investigated whether WMA on conventional MR imaging are related to abnormalities within the fiber tract microstructures. WMA were classified as normal, mild, moderate and severe according to Woodward¡¦s classification (Woodward et al. 2006). Woodward and colleagues studied a large population (167 infants) of preterm infants at term equivalent age with MRI. They demonstrated that WMA were important predictors of neurological outcomes by comparing their results with the neurological outcomes of those infants at corrected age of two. We found that compared to neonates with no abnormalities, infants with mild abnormalities have significantly higher ƒÜ¢r in the right CST, the left anterior thalamic radiation (ATR), the left sensory STR and bilateral motor STR. Those findings might be related to injuries of premyelinating oligodendrocytes resulting in subsequent failure of both development and ensheathment of axons. Considering that those fiber tracts connect important cortical zones, microstructural changes in those fiber tracts might be responsible for the later neurodevelopment deficits in motor and cognitive functions. <p>We concluded that structural asymmetries and gender differences in motor and language related fibers are present in healthy preterm neonates at term-equivalent age well before the development of speech and hand preference. Structural asymmetries and gender differences have to be considered in neonatal white matter assessment. Finally, altered DTI indices are associated with WMA on conventional MR imaging in preterm neonates. Our results suggest that disrupted premyelination is the major correlate with WMA rather than axonal pathology. Non-invasive DTI and tractography constitute an additional tool for the assessment of white matter injuries, as it could provide more adequate diagnostic information on brain microstructure in preterm neonates at term-equivalent age. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Abstract Recognition of individuals at highest risk for psychosis is challenging and no definitive biomarkers are yet available. Physical illnesses associated with a sedentary lifestyle are common in patients with severe mental illness. Both, bodyweight and risk for psychosis are associated with brain white matter (WM) abnormalities. There are several dysregulated pathways which are common in psychiatric illnesses and weight-related processes, but it is not known how weight and vulnerability for psychosis interact in the brain. The present study examines brain WM microstructure and its association to body mass index (BMI) in young adults with a familial risk for psychosis (FR). In addition, the level of physical activity and cardiorespiratory fitness in individuals vulnerable to psychosis was examined. Participants of the present study are members of the Northern Finland Birth Cohort 1986. Two separate clinical substudies were conducted. The first having been done when the participants were at age 15–16. At that time, physical activity was defined by postal questionnaire (n=6,987) and cardiorespiratory fitness was measured by a submaximal cycle ergometer test (n=4,803). Risk for psychosis was viewed from three perspectives, with possible overlap between groups: having familial risk for psychosis, existing prodromal symptoms at age 15–16, and development of hospital treated psychosis between the ages of 16 and 20 years. The latter substudy was conducted when the participants were aged between 20 and 25 years. Diffusion tensor imaging was performed on 108 participants. Our study showed that there was no difference in WM microstructure between FR and control groups suggesting that WM abnormalities are not a genetic feature for risk of psychosis in all populations. However, the association between BMI and WM microstructure differed significantly between the FR and control groups. We also demonstrated that the level of physical activity was lower before the onset of psychotic illness. Therefore, these results imply that it would be of great importance to consider weight and physical activity levels in subjects at risk for psychosis, in order to avoid the detrimental effects of a sedentary lifestyle on overall health. / Tiivistelmä Korkeimmassa psykoosiriskissä olevien tunnistaminen on haastavaa, eikä kunnollisia biomarkkereita ole käytettävissä. Vähäiseen liikunta-aktiivisuuteen liitetyt fyysiset sairaudet ovat yleisiä vakavaa mielenterveyshäiriötä sairastavilla. Sekä kehonpaino että psykoosialttius on yhdistetty aivojen valkean aineen rakenteen poikkeavuuksiin. Useat kehon säätelymekanismien poikkeavuudet liittyvät sekä psykiatrisiin sairauksiin että painoon liittyviin prosesseihin, mutta ei ole olemassa tutkimustietoa siitä, miten paino ja psykoosialttius vaikuttavat yhdessä aivojen rakenteeseen. Tässä osajulkaisuväitöskirjassa tutkitaan aivojen valkean aineen mikrorakennetta nuorilla aikuisilla, jotka ovat sukuriskissä sairastua psykoosiin, sekä painon vaikutusta valkean aineen rakenteeseen psykoosiriskissä. Lisäksi tutkitaan psykoosialttiiden nuorten liikunta-aktiivisuutta ja kuntoa. Tutkittavat kuuluvat Pohjois-Suomen vuoden 1986 syntymäkohorttiin. Kaksi osatutkimusta toteutettiin, joista aikaisempi kliininen tutkimus tutkittavien ollessa 15–16-vuotiaita. Tuolloin selvitettiin liikunta-aktiivisuus postikyselyn avulla (n=6,987) ja aerobinen kunto mittaamalla hapenottokyky polkupyöräergometrilla (n=4,803). Psykoosialttiutta tarkasteltiin kolmella tavalla, ja ryhmien välillä esiintyi osittaista päällekkäisyyttä: sukurasitus, 15–16 v. iässä raportoidut psykoosinkaltaiset oireet ja sairaalahoitoon johtanut psykoosi 16–20 v. iässä. Toinen kliininen osatutkimus toteutettiin tutkittavien ollessa 20–25-vuotiaita. Tutkimuksen yhteydessä tehtiin aivojen diffuusiotensorikuvaus 108 osallistuneelle. Aivojen valkean aineen mikrorakenteessa ei havaittu eroa sukuriskissä olevien ja kontrollien välillä viitaten siihen, että poikkeavuudet valkean aineen rakenteessa eivät olisi psykoosiriskin geneettinen piirre kaikissa populaatioissa. Havaitsimme kuitenkin, että assosiaatio painoindeksin ja valkean aineen rakenteen välillä oli erilainen sukuriski- ja kontrolliryhmissä. Tutkimus osoitti myös, että liikunta-aktiivisuus on alentunut jo ennen psykoosisairauden puhkeamista. Psykoosiriskissä olevien liikuntatottumuksiin ja painoon tulisi kiinnittää erityistä huomiota jo varhaisessa vaiheessa elimellisten sairauksien ehkäisemiseksi.

L'érythropoiétine (Epo) est une protéine ubiquitaire dans les tissus de l'organisme. Elle est dotée d'une fonction endocrine, autocrine et paracrine. Elle favorise les activités anti-apoptotiques des tissus soumis à un stress hypoxique. Dans de nombreux modèles animaux de traumatisme ou d'agression du système nerveux central et quelques études cliniques, l'Epo recombinante humaine (Epo-rh) a révélé des propriétés neuroprotectrices. L'objectif principal de ce travail est d'améliorer les connaissances sur l'Epo afin de favoriser l'inclusion de l'Epo-rh dans l'arsenal thérapeutique chez l'homme après traumatisme du système nerveux central. Deux axes de travail ont été explorés : dans un première partie, pour expliquer l'échec de la mise en oeuvre d'une étude de la tolérance et d'efficacité biologioque de l'Epo-rh dans le Traumatisme Médullaire Déficitaire (TMD) chez l'homme, nous avons étudié l'épidémiologie des TMD sur la période 1997-2006, à partir du Registre des accidents du Rhône. Ensuite nous avons étudié l'évolution de cette incidence entre 2 périodes de 6 ans : 1995-2001 et 2003-2008. Parallèlement, compte tenu d'une incidence de traumatisme crânien (TC) 20 fois plus élevée que celle du TMD chez l'homme, nous avons entrepris de caractériser les effets d'un TC expérimental par percussion fluide latérale (LFPI) chez le rat afin de mieux comprendre la pharmacologie et les mécanismes d'action moléculaires, en particulier anti-inflammatoires et neuroprotecteurs, de l'Epo-rh / Erythropoietin (Epo) is an ubiquitous cytokine. It has endocrine, paracrin and autocrin functions. It improves antiapoptotic mechanisms on all tissues subjected to hypoxic stress. In many animal models of brain trauma but also in other brain injury models, and some human clinical studies, recombinant Human Epo (Epo-rh) has proven neuro-protective properties. The main goal of this work was to improve and incorporate Epo-rh in the pharmacological arsenal of treatment in brain and spinal cord traumatic injuries in human. In a first part, to explore the reasons of failure of inclusion in a Spinal Cord Injury (SCI) study to test the thrombo-embolic tolerance and efficacy of Epo-rh, we studied the epidemiology of SCI using the road crash Rhône registry in the period 1997-2006. Then we compared the epidemiological trends of the SCI incidence, associated trauma, mortality and fatality rates in two periods of 6 years: 1995-2001 and 2003-2008. In a second part, due to the 20-fold higher incidence of traumatic brian injury (TBI) in comparison to SCI, we characterized the effects of a moderate (1.6-1.8 atm) lateral fluid percussion injury (LFPI) in order to understand and characterize the pharmacological, anti-inflammatory and neuroprotective mechanisms of action of Epo-rh in such a brain injury

Les troubles mnésiques sont fréquents dans la sclérose en plaques (SEP) mais leurs substrats anatomique et biologique sont mal connus. L’objectif de cette thèse translationnelle était de comprendre les mécanismes physiopathologiques des troubles mnésiques à la phase précoce de la SEP, avec pour perspective de trouver de nouvelles cibles thérapeutiques et de définir de nouveaux marqueurs d’imagerie. Nous avons réalisé une analyse neuropsychologique et IRM de patients atteints de forme précoce de SEP et nous avons étudié des souris à la phase précoce d’une encéphalomyélite auto-immune expérimentale (EAE, le modèle animal de la SEP) avec une combinaison d’expériences comportementales, d’IRM, histologiques, électrophysiologiques et pharmacologiques. Nous avons démontré que l’atteinte hippocampique était précoce dans l’histoire de la maladie et qu’elle était corrélée au déclin mnésique des patients atteints de SEP. Nous avons identifié chez les souris EAE que la structure et la fonction du gyrus denté étaient plus vulnérables que les autres sous-champs de l’hippocampe au stade précoce de la maladie et nous avons transposé cette découverte à la pathologie humaine en démontrant une perte des capacités de pattern separation chez des patients atteints de forme précoce de SEP. Du point de vue mécanistique, nous avons démontré que l’activation microgliale précoce était responsable de l’atteinte du gyrus denté et des troubles mnésiques dans l’EAE et que cette cascade physiopathologique pouvait être prévenue grâce à un traitement par minocycline. Du point de vue de l’imagerie, nous avons également démontré que l’atteinte microstructurale de l’hippocampe ainsi que la neurodégénérescence précoce du gyrus denté pouvaient être étudiées in vivo en tenseur de diffusion (DTI). Nous travaillons à la mise en place de méthode encore plus spécifique par l’imagerie de densité neuritique et d’orientation/dispersion (NODDI). Nos résultats relient l’atteinte mnésique précoce de la SEP à une neurodégénérescence sélective du gyrus denté. Ce processus physiopathologique peut être prévenu en inhibant l’activation microgliale chez les souris EAE et peut être étudié in vivo grâce au DTI chez la souris comme chez l’homme, offrant d’évidentes perspectives cliniques dans la prise en charge des patients atteints de SEP. / Memory impairment is frequent in multiple sclerosis (MS) but its anatomical and biological substrates are poorly understood. The objective of this translational thesis was to understand the pathophysiological mechanisms of early memory impairment in MS, to find new potential therapeutic targets and to define new imaging biomarkers related to memory impairment. We used neuropsychological and MRI experiments in patients with early MS and we explored experimental autoimmune encephalomyelitis (EAE) mice (a mouse model of MS) at the early stage of the disease with a combination of behavioral, in vivo MRI, histological, electrophysiological and pharmacological approaches. In patients with MS, we demonstrated that hippocampal damage occurs early during the course of the disease and that it correlates with memory impairment. In EAE-mice, we identified that dentate gyrus structure and function are more vulnerable than other hippocampal subfields at the early stage of the disease and we translated this finding back to humans by demonstrating loss of pattern separation performances in patients with early MS. From a mechanistic point of view, we demonstrated that early microglial activation causes dentate gyrus disruption and memory impairment in EAE-mice and that this pathophysiological cascade can be prevented with minocycline. From the imaging point of view, we demonstrated that hippocampal microstructural damage and early dentate gyrus degeneration can be monitored in vivo with diffusion tensor imaging (DTI). We are currently developing more specific imaging approaches with optimization of the Neurite Orientation Dispersion and Density Imaging (NODDI) to assess hippocampal subfields. Our results link early memory impairment in MS to a selective disruption of the dentate gyrus. We were able to prevent this neurodegenerative process with microglial inhibitors in EAE-mice and to capture these features non-invasively with DTI in both humans and rodents, paving the way toward new clinical perspectives in MS.

L'imagerie en tenseur de diffusion (DTI) est basée sur la mesure de la mobilité des molécules d'eau permettant l'analyse de la microarchitecture du tissu cérébral. Le trajet des fibres blanches peut être alors reconstruit par des méthodes de tractographie déterministes basées sur la direction principale de la diffusion. Toutefois elle repose sur des outils mathématiques complexes donnant un regard indirect sur les structures anatomiques, et sa validation est un enjeu majeur. Notre objectif a été de concevoir un objet-Test (OT) tri-Dimensionnel permettant la validation de la diffusion dans des faisceaux de fibres imitant l'organisation cérébrale. Cet OT se compose de trois modules: BOITE, SOLUTION, FIBRE réalisés en impression 3D. Il se compose de solutions de glucose et de fibres de dyneema orientées dans les trois orientations de l’espace. Nous nous sommes intéressés au développement d'une méthode de contrôle qualité des mesures quantitatives de diffusion dans le module SOLUTION. / Diffusion Tensor Imaging (DTI) is based on the measurement of water diffusion mobility in order to investigate brain microarchitecture and white fiber connectivity. The trajectory of white fibers bundles can be reconstructed by deterministic tractography methods depending on the principal direction of diffusion in tissu. However, tractography consist to complex mathematical algorithms reflecting an indirect visualization of white fibers. Our goal consisted to design a 3D phantom which imitates brain's diffusion properties, offering different degrees of diffusion mobility and imitating the organization of brain fibers. The phantom consists of three components 3D-Printing: BOX, SOLUTION, FIBER. The phantom was composed of various glucose solutions and dyneema synthetical fibers organized in all 3 directions. We developed a quality control of quantitative measurements for the SOLUTION's component. We have lead a comparison of fibers reconstruction between tractography and ground truth in FIBER's component. Results show that : ADC values were ranged on those brain values with glucose solutions; FA,

The aim of this work was to establish a comprehensive processing pipeline of cervical spinal cord HARDI dMRI data and T2-weighted anatomical MRI images in high-resolution. In the research part we provide description of anatomical data processing, theoretical background of dMRI, description of current approaches to 3D anisotropic diffusion estimation as well as current imaging methods of spinal cord axonal bundles. As one of the first in the world, we are investigating multiple-direction diffusion models for human in-vivo spinal cord white matter minority bundles imaging. We designed our own processing pipeline utilizing Spinal Cord Toolbox (SCT), FSL, in-house developer scripts and TORQUE-based batch system for grid computation, tested on real data from cervical spinal cord area between segments C4-C6 from 26 healthy volunteers. Designed processing pipeline with one non-automatic step, works from pre-processing to parcelation of selected spinal cord structures based on co-registration with anatomical spinal cord template for 25 subjects. One person data includes motion artifacts for which the proces failed. There are visible waves in sagittal images of some subjects caused probably by blood-vessel pulsing. Local quantification metrics of spinal cord anatomy (fractional anisotropy – FA, fractional volumes of first – f1 and second – f2 direction of anisotropic diffusion) from different parts (white matter, gray matter, cortico-spinal tract) and from different population groups (men vs. women), were extracted from dMRI data. As we expected, FA maps show visible decreases in areas of gray matter. We also detected second diffusion dirrection in slices, where the spinal roots come out. In some areas, fractional volume of second diffusion direction reaches up to 40% of the total component of the dMRI signal. All mentioned parameters probability density functions for all mentioned groups are non-normal distributions. Between male and female groups there were no significant distribution differences for f1 and f2 volumes. The distribution of FA values between men and women is statistically different. Unfortunatelly, there is a significant inter-subject variability in results, which has much higher dispersion than differences between different group distributions. Despite the inter-subject variability, this work significantly extends the knowledge about data acquisiton capabilities and MRI and dMRI data from cervical spinal cord image processing. This work also lays down foundations for utilization of the imaging method in future and planned clinical research, where it will be possible to test the alteration of the spinal cord anatomy on the minor secondary bundles separately.

<div>Adolescent collision-sport athletes may be exposed to repetitive head impacts over years of practices and competitions without immediately observable symptoms. Despite the growing concerns, these athletes often continue play while at risk. Concrete objective measurements are desired to inform prompt and effective preventative strategies for this vulnerable population. However, adolescent brains are rapidly developing and the accrual of brain injury is often subtle. Prospective screening with sensitive biomarkers is challenging and requires advanced technologies, rigorous data processing, and the interdisciplinary expertise of engineering, neurobiology, and cognitive sciences.</div><div><br></div><div>To address the challenge, we first developed population-specific brain atlases to facilitate reproducible and meaningful statistical analyses. The atlases better characterized the neuroanatomy of early-to-middle adolescent (ages 13-19) collision-sport athletes, reduced deformation introduced during spatial normalization, and exhibited higher sensitivity in image analysis compared to standardized adult or age-appropriate brain templates. The atlases can be further applied to monitor the neuroanatomical trajectory and can serve as a coordinate reference system to retrospectively harmonize data collected from different sites and imaging acquisition parameters, facilitating group analysis at large scale.</div><div><br></div><div>Next, to assess whether the changes of white matter microstructure can be attributed to repetitive head impacts and are reflected by cognitive performance, we analysed the diffusion tensor imaging (DTI) data of high school men’s football and women's soccer across a single season, with accompanying data from head impact sensors and neurocognitive assessments. Within multiple brain regions, we observed significantly altered DTI metrics, both transiently over a season and chronically with more years of high school experience. For the football players, hits with peak translational acceleration over 37 <i>g</i> were sufficient to alter the distributions of DTI changes, and deficits in white matter microstructure correlated with poorer performance of anti-saccade task at one month post-season, suggesting increased vulnerability for inhibitory control. Monitoring repetitive head impacts thus provides a temporal profile for identifying at-risk individuals during the competitive season, informing prompt interventional strategies, therefore protecting the brain and cognitive health of early-to-middle adolescent collision-sport athletes in the long run.</div>

<p>Alchajmerova bolest je najče&scaron;ća demencija od svih demencija i karakteri&scaron;e je depozicija senilinih plakova i neurofibrilarnih klubadi u kortikalnim moždanim regionima, koje daljim razvojem bolesti postaju atrofične. Klinički se karakteri&scaron;e smetnjma na planu pamćenja, egzekutivnih funkcija, pažnje i ostalih kognitivnih funkcija uz odustsvo sposobnosti samostalnog funkcionisanja u svakodnevnom životu. Blagi kognitivni poremeća (BKP) je klinički entitet koji se smatra početnim stadijumom demencije u kom se registruju smetnje na planu pamćenja, ali i drugih kognitvnih funkcija, uz očuvanu funkcionalnost u svakodnevnom životu. Kod obe bolesti je utvrđeno da pored kortikalnog zahvatanja, patolo&scaron;kim procesom je zahvaćena i bela masa mozga. U dana&scaron;nje vreme se mirkostrukturno o&scaron;tećenje bele mase mozga može ispitati difuzionim tenzorskim imidžinogom (DTI) na magnentoj rezonanci mozga (MR). Cilj: Utvrditi razlike neuropsiholo&scaron;kih skorova i razlike DTI parametara između obolelih od AB, BKP i kontrolne grupe zdravih ispitanika, kao i utvrditi da li postoji korelacija između neuropsiholo&scaron;kih skorova i DTI parametara kod BKP i AB.&nbsp; Metode: U istraživanje je uključeno tri ispitivane grupe od po 30 ispitanika: oboleli od AB u blagom stadijumu bolesti, oboleli od amnestičkog multi-domen BKP i kontrolna grupa zdravih ispitanika. Dijagnoza kod obolelih u obe grupe je postavljena na osnovu kliničkih kriterijuma aktuelnih dijagnostičkih kriterijuma iz 2011. godine. Kod svih ispitanika je sprovedeno detaljno neuropsiholo&scaron;ko testiranje u cilju procene kognitivnih funkcija (smetnji na planu pamćenja, egzekutivnih funkcija, pažnje, govora, vizuospacijalnih i vizuokonstrukcionih sposobnosti), depresivnosti i drugih neuropsihijatrijskih simptoma i kvaliteta života. Samo je kod obolelih od AB dopunski vr&scaron;ena procena sposobnosti svakodnevnog funkcionisanja. Kognitivne funkcije su ispitane formiranjem kognitivnih domena, na osnovu pretpostavke o zajedničkom predmetu merenja kori&scaron;ćenih testova. Potom je načinjen MR mozga, u okviru koje je analiziran i DTI. Dalja obrada DTI je sprovedena primenom TBSS metode, čime su dobijene vrednosti DTI parametara: frakcione anizotropije (FA), srednje difuzivnosti (SD), radijalne difuzivnosti (RD) i aksijalne difuzivnosti (DA). Nakon toga je načinjena korelacija neuropsiholo&scaron;kog postignuća i DTI parametara kori&scaron;ćenjem Pirsonovog, odnosno Spirmanovog koeficijenta korelacije. Rezultati: Oboleli od AB su imali lo&scaron;ije postignuće na planu vizuelnog pamćenja, verbalnog pamćenja, neposrednog upamćivanja, odloženog prisećanja, pažnje, govora, egzekutivnih funkcija, mi&scaron;ljenja, radne memorije i vizuospacijalnih i vizuokonstrukcionih sposobnosti u odnosu na kontrolnu grupu zdravih. Oboleli od BKP su imali lo&scaron;ije postignuće u odnosu na kontrolnu grupu zdravih u domenima vizuelno pamćenje, neposredno upamćivanje, odloženo prisećanje, govor, mi&scaron;ljenje i vizuospacijalne i vizuokonstrukcione sposobnosti. Obe grupe obolelih su ispoljile vi&scaron;e depresivnih simptoma u odnosu na kontrolnu grupu zdravih ispitanika. Takođe, obe grupe obolelih ispoljavaju statistički značajno vi&scaron;e neuropsihijatrijskih simptoma u odnosu na zdrave ispitanike, gde se kod obolelih od AB registruju sumanute ideje, halucinacije, agitacija, euforija, dezinhibicija, ritabilnost i apatija, dok se kod obolelih od BKP registruju anksioznost i iritabilnost. Oboleli od AB imaju lo&scaron;iji kvalitet života u odnosu na zdrave ispitanike, dok između oboleli od BKP i zdravih ispitanika nema razlike u proceni kvaliteta života. &Scaron;to se tiče DTI parametara, oboleli od AB imaju niži FA i vi&scaron;u SD, RD i DA u odnosu na zdrave ispitanike na vi&scaron;e puteva bele mase: prednji krak kapsule interne, prednja korona radijata, telo korpusa kalozuma, cingulum, kapsula eksterna, fornix-strija terminalis, koleno korpusa kalozuma, donji fronto-okcipitalni fascikulus, zadnja korona radijata, gornji fronto-okcipitalni fascikulus, gornji longitudinalni fascikulus i fascikulus uncinatus. Oboleli od BKP imaju sniženu FA i povi&scaron;enu SD, RD i DA u regiji forniksa u odnosu na zdrave ispitanike. Kod obolelih od AB registrovane su značajne povezanosti mikrostrukturnog o&scaron;tećenja bele mase i o&scaron;tećenja svih kognitivnih domena, izuzev domena mi&scaron;ljenje, dok su kod obolelih od BKP registrovane značajne povezanosti mikrostrukturnog o&scaron;tećenja bele mase i o&scaron;tećenja svih kognitivnih domena, izuzev domena egzekutivne funkcije. U grupi obolelih od BKP je bilo vi&scaron;e registrovanih korelacija o&scaron;tećenja domena verbalno pamćenje, odloženo prisećanje i govor sa o&scaron;tećenjem bele mase mozga, dok je kod AB bilo vi&scaron;e registrovanih korelacija o&scaron;tećenja domena vizuelno pamćenje, neposredno upamćivanje, pažnja, radna memorija i vizuospacijalne i vizuokontrukcione sposobnosti sa o&scaron;tećenjem bele mase mozga. Depresivnost je jedino u grupi BKP značajno korelirala sa o&scaron;tećenjem određenih puteva bele mase mozga. Zaključak: U blagom stadijumu obolelih od AB se registruje kognitivno o&scaron;tećenje svih ispitivanih domena, vi&scaron;e su ispoljeni depresivni simptomi, utvrđen je veliki broj neuropsihijatrijskih simptoma i naru&scaron;en je kvalitet života u odnosu na zdrave ispitanike. Kod obolelih od BKP je registrovano kognitivno o&scaron;tećenje vi&scaron;e od pola procenjivanih kognitivnih funkcija, vi&scaron;e su ispoljeni depresivni simptomi i utvrđeno prisustvo anksioznosti i iritabilnosti, dok kvalitet života nije naru&scaron;en u ovoj fazi bolesti u odnosu na zdrave ispitanike. Rezultati vezani za mikrostrukturno o&scaron;tećenja mozga u najranijim fazama AB ukazuju da je neuronska mreža značajno o&scaron;tećena u najranijim kliničkim fazama bolesti, dok je u stadijumu BKP izolovana na o&scaron;tećenje u regiji forniksa. U grupi obolelih od BKP je bilo vi&scaron;e registrovanih korelacija o&scaron;tećenja domena verbalno pamćenje, odloženo prisećanje i govor sa o&scaron;tećenjem bele mase mozga, dok je kod AB bilo vi&scaron;e registrovanih korelacija o&scaron;tećenja domena vizuelno pamćenje, neposredno upamćivanje, pažnja, radna memorija i vizuospacijalne i vizuokontrukcione sposobnosti sa o&scaron;tećenjem bele mase mozga. Stepen depresivnosti i o&scaron;tećenje bele mase mozga je povezano isključivo na nivou BKP.</p> / <p>Alzheimer&#39;s disease (AD) is the most common dementia of all dementia with deposition of senile plaques and neurofibrillary tangles in cortical brain regions, which become atrophic in the further disease development. It`s main clinical characteristics are impairment of memory, executive function, attention and other cognitive functions with impairment in daily living activities. Mild cognitive impairment (MCI) is a clinical entity considered as an initial stage of dementia with present memory impairment, as well as other cognitive functions, while maintaining the functionality of the everyday life. In both diseases, pathological processes affect also the white matter of the brain. Nowadays, microstructural damage of the brain white matter is diagnosed by using diffusion tensor imaging (DTI) in the brain magnetic resonance imaging (MR). Objective: The aim of this study was to determine differences in neuropsychological scores and differences in DTI parameters between patients with AD, MCI and control groups of healthy subjects, as well as to determine whether there is a correlation between scores and DTI parameters in MCI and AD.&nbsp; Methods: The study included three groups of 30 patients each: of AD patients in the mild stage of the disease, patients with multi-domain amnestic MCI, and healthy controls. The patient&rsquo;s diagnosis are based upon clinical criteria of current diagnostic criteria proposed in 2011. All patients had assessment of cognitive functions (impairment of memory, executive function, attention, language, visuospatial and construction abilities), depressive symptoms and other behavioral disorders and quality of life. Only in patients with AD, we also assessed ability of daily living activities. Cognitive functions were tested by forming cognitive domains, based on the assumption of a common object of measurement of analyzed tests. Further, participants had MRI scan, in which DTI was analyzed. DTI post-processing was carried out by using TBSS method, whereby the values of DTI parameters were: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (DA). We conducted correlation analysis of the neuropsychological achievements and DTI parameters using Pearson or Spearman&rsquo;s correlation coefficient, dependent on variable distribution. Results: The patients with AD had lower scores in the field of visual memory, verbal memory, immediate and delayed recall, attention, language, executive functions, reasoning, working memory and visuospatial and construction abilities compared to the control group. Patients with MCI had lower scores compared to the control group in the domains of visual memory, immediate and delayed recall, language, reasoning, and visuospatial and construction abilities. Both groups of patients have more depressive symptoms in relation to the control group of healthy subjects. In addition, both groups of patients exhibited a significantly higher degree of behavioral disorders as compared to healthy subjects, where AD patients experienced delusions, hallucinations, agitation, euphoria, disinhibition, irritability and apathy, while MCI patients experienced anxiety and irritability. Patients with AD had a poor quality of life compared to healthy subjects, whereas people with MCI did not. As for the parameters of DTI, AD patients had decrease of FA and increase of MD, RD, and DA compared to the healthy subjects in the multiple white matter tracts: anterior limb of internal capsule, anterior part of corona radiata, the body of the corpus callosum, cingulum, external capsule, fornix- striae terminalis, genu of the corpus callosum, inferior frontal-occipital fasciculus, posterior corona radiata, superior frontal-occipital fasciculus, superior longitudinal fasciculus and fasciculus uncinatus. Patients with MCI had decreased FA and increased MD, RD and DA in the fornix compared to healthy subjects. In AD patients, there was significant association between microstructural white matter brain damage and all cognitive domains, except domain reasoning, while in patients with MCI significant association was evident between microstructural white matter damage and all cognitive domains, except the domain of executive function. Results related to the microstructural white matter brain damage in mild AD indicates that wide neural network is significantly damaged at the earliest clinical stages of the disease, while in MCI stage only fornix shows microstructural white matter brain damage. Level of impairment of verbal memory, delayed recall and language correlates more frequently in MCI group compared to mild AD group, where impairment in the field of visual memory, immediate recall, attention, working memory and visuospatial and construction abilities correlates more frequently with white matter brain damage. Association of depressive symptoms and white matter brain damage was significant in MCI patients. Conclusion: In mild AD, cognitive impairment is present in all cognitive domains; patients experience more depressive symptoms and wider spectrum of behavioral disorders with compromised quality of life compared to healthy subjects. In MCI patients, cognitive impairment is present in more than half of the assessed cognitive functions; patients also experience more depressive symptoms, as well as anxiety and irritability without quality of life deterioration compared to healthy subjects. Results related to the microstructural white matter brain damage in mild AD indicates that wide neural network is significantly damaged at the earliest clinical stages of the disease, while in MCI stage only fornix shows microstructural white matter brain damage. Level of impairment of verbal memory, delayed recall and language correlates more frequently in MCI group compared to mild AD group, where impairment in the field of visual memory, immediate recall, attention, working memory and visuospatial and construction abilities correlates more frequently with white matter brain damage. The degree of depression correlated significantly with white matter brain damage solely at the level of MCI.</p>