O presente estudo consistiu-se na avaliação clínica e aplicação de testes cognitivos, além da realização de ressonância magnética (RM), de 3 tesla, do cérebro, processada com a técnica de \"Voxel-based Morphometry\" (VBM) e \"Skull Strip\", e 18F-FDG PET -CT processado com \"Statistical Parametric Mapping\" (SPM8) e correção de volume parcial (PVELab), em idosos sem déficits cognitivos (CDR=0), com comprometimento cognitivo leve amnéstico (CCL) (CDR=0,5) e com Doença de Alzheimer leve (DA leve)(CDR de 0,5 a 1). Os objetivos foram comparar os padrões de neuroimagem estrutural e metabólica entre os grupos, assim como correlacionar alterações estruturais volumétricas da RM e alterações metabólicas cerebrais do PET-CT, a um teste funcional, o \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE), nessa mesma amostra. Cada um dos grupo 3 grupos, pareados por idade, contém 30 indivíduos, totalizando amostra de 90. Os resultados dos exames de Neuroimagens, divididos por comparações entre os grupos, e corrigidos pela escolaridade, foram considerados significativos todos os achados nos quais a significância corrigida for <= 0,05 (p-FWEcorr <= 0,05). No CCL x DA foi observado hipometabolismo Giro do Cíngulo à Direita. No grupo DA x CCL foram observados hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Esquerdo, Precuneus Direito e na parte inferior do Lobo Parietal Esquerdo. Na DA x Controle, utilizando-se pesquisa de área a priori e filtros gaussiano de 8mm e 4mm, foi observada redução estatisticamente significante quanto ao volume de substância cinzenta na Amígdala Esquerda e na Amígdala Direita. No PET - CT, da DA, em relação ao grupo controle foram observadas áreas de hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Direito e no Giro Temporal Medial Direito. Na correlação direta do IQCODE, na comparação DA x Controle, no PET - CT evidenciou-se hipometabolismo no Giro Fusiforme Direito. Em conclusão, os resultados das comparações entre os grupos foram semelhantes ao encontrado na literatura para fases iniciais (leves) da patologia e mostraram, ainda, uma tendência a um \"continuum\" do controle até a DA. Por outro lado à correlação do IQCODE no DA x Controle carece de comprovação por outros trabalhos e com outros constructos estatísticos / This study consisted in the clinical evaluation and application of cognitive tests, in addition to magnetic resonance imaging (MRI) of 3 Tesla, of brain, processed with the technique of \"Voxel-based Morphometry\" (VBM) and \"Skull Strip\", and 18F-FDG PET-CT processed by \"Statistical Parametric Mapping\" (SPM8) and partial volume correction (PVELab) in subjects without cognitive impairment (CDR = 0), with amnestic mild cognitive impairment (MCI)(CDR = 0.5) and with mild Alzheimer \'s disease (AD mild)(CDRs of 0.5 to 1). The objectives were to compare the patterns of structural and metabolic neuroimaging between groups, as well as correlate MRI\'s volumetric structural changes and PET-CT\'s metabolic brain with a functional test, the \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE) in this same sample. Each one of three groups, matched by age, contains 30 subjects, totaling 90. The test results of neuroimaging, divided by comparisons between groups, and corrected by education, were considered significant the findings that corrected significance is <= 0.05 (p-FWEcorr <= 0.05). In CCL x DA was observed hypometabolism right cingulate gyrus. In DA x CCL hypometabolism were observed in the left cingulate gyrus, the left precuneus, right precuneus and left inferior parietal lobe. In DA x Control, using the \"a priori\" research area and gaussian filters 8mm and 4mm was observed statistically significant reduction on the volume of gray matter in the left and right amygdala. In PET - CT of DA relative to control group were observed areas of hypometabolisms in left cingulate, right precuneus and in the right medial temporal gyrus. In direct correlation of the IQCODE, compared DA x Control on PET - CT revealed a hypometabolism in the right fusiform gyrus. In conclusion, the results of the comparisons between groups were similar to those found in the literature for early (mild) pathology and showed a \"continuum\" of control to the DA. On the other hand the correlation of the IQCODE in DA x Control lacks confirmation by other studies and other statistical constructs

<p>Adrenocortical cancer (ACC) is a rare disease that is often difficult to diagnose, and therefore often presents at an advanced stage. Various cytotoxic treatments have been tried with little success. Evaluation of new diagnostic methods and improvement of medical therapies are therefore crucial.</p><p>The diagnostic potential of 11C-metomidate positron emission tomography (PET) was evaluated in eleven ACC patients. PET visualized all viable tumors with high tracer uptake, including two lesions that CT failed to detect. Necrotic or fibrotic tumors were PET negative. Medication with adrenal steroid inhibitors and chemotherapy may decrease the tracer uptake.</p><p>We performed a phase-II study with streptozocin and o,p’-DDD (SO) combination therapy in 40 ACC patients. The SO therapy was found to have impact on the disease-free interval (P = 0.02) as well as on survival (P = 0.01) in patients who received adjuvant therapy after curative resection. Complete or partial response was obtained in 36.4% of patients with measurable disease.</p><p>The efficacy and tolerability of combination therapy with vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) were evaluated in eleven patients with advanced ACC after failure of SO therapy. The median survival was 21 months from the start of treatment. A partial response was achieved in two patients. Adverse events were mainly restricted to grade 1-2 toxicities, and grade 3 toxicities were observed in only two cycles.</p><p>We tested 21 ACC tumors to analyze the expression of receptor tyrosine kinases and 15 ACC for mutation analysis of c-Kit exon 11, which can be targeted by antagonists such as imatinib. All ACCs expressed one or more kinases: c-Kit in 19 ACC and phospho-c-Kit in three while 14 ACCs expressed PDGFR-beta, suggesting the potential usefulness of tyrosine kinase inhibitors. No c-Kit mutations were detected in exon 11. Further evaluation of other mutations targeted by this drug may be needed.</p>

<p>Premenstrual dysphoria, so severe that it affects the lives of the women afflicted, is the condition studied in this thesis. Physiological and pharmacological mechanisms of pathogenetic relevance were investigated. </p><p>Women with premenstrual dysphoria showed a stronger and less dampened response of LH to an estradiol challenge than asymptomatic women, indicating an altered neuroendocrine regulation. In women with premenstrual dysphoria, the LH response was correlated to the severity of irritability and bloating, and the early FSH response was correlated to the severity of depressed mood. </p><p>The positron-emission study showed strong, consistent correlations between worsening of mood symptoms and a decrease in brain trapping of the immediate serotonin precursor, from the mid-follicular to the late luteal phase in women with premenstrual dysphoria. The strongest correlations were seen for the cardinal mood symptoms of premenstrual dysphoria, and for their opposites. Physical symptoms showed weaker or no correlations with the exception of nociceptive symptoms from erogenous body regions which showed positive correlations to serotonin precursor trapping in the right caudate nucleus. The findings are consistent with the serotonin hypothesis of premenstrual dysphoria, and might possibly explain the observed effects of serotonin-augmenting drugs in this condition.</p><p>The partial 5-HT_1A receptor agonist buspirone was superior to placebo in the treatment of premenstrual dysphoria. The weak SRI and 5-HT₂ receptor antagonist nefazodone was not superior to placebo. For women with premenstrual dysphoria in need of medication and who do not tolerate SRIs because of the sexual sideeffects, buspirone may be an alternative drug, since it had no adverse effects on sexual function. </p><p>The prevalence of polycystic ovaries and serum levels of androgens were not higher in women with premenstrual dysphoria than in their asymptomatic counterparts. The findings are not consistent with the hypothesis that irritability in women with premenstrual dysphoria is induced by elevated testosterone levels. </p><p>Thesis results, which are in line with the serotonin hypothesis of premenstrual dysphoria, may imply that increased brain sensitivity is one of the factors underlying severe premenstrual mood symptoms, thereby further supporting a common serotonergic dysregulation in this condition.</p>

SUMMARY Non Rapid Eye Movement (NREM) sleep in humans is defined by spontaneous neural activities organized by specific rhythms or oscillations. The aim of this thesis is to characterize, by means of neuroimaging techniques, the shaping of brain function by these physiological rhythms. The studied oscillations are sleep spindles, delta waves and slow oscillation, representing the main identifiable neurophysiological events of human NREM sleep. Sleep spindles are a hallmark of light NREM sleep. They are commonly described on electroencephalographic (EEG) recordings as 11-15 Hz oscillations, lasting more than 0.5 sec and with a typical waxing-and-waning waveform. During deeper stages of NREM sleep, spindles are progressively replaced by a slow wave activity (SWA; 0.5-4 Hz), which encompasses delta waves (1-4 Hz) and slow oscillations (0.5-1 Hz). In combination with EEG, we studied these rhythms using two different functional brain imaging techniques : positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These studies originally contribute to the understanding of the generating mechanisms and functional roles of NREM sleep oscillations, which are a hallmark of sleep architecture in healthy humans. Neural correlates of NREM sleep oscillations assessed by EEG / PET In this section, we report the analyses of PET data devoted to the study of NREM sleep oscillations. We characterized the brain areas in which activity, measured in terms of regional cerebral blood flow (rCBF), was correlated with EEG spectral power in the spindle (11-15 Hz), delta waves (1-4 Hz) and slow oscillation (0.5-1 Hz) frequency bands, in 23 non-sleep-deprived young healthy volunteers. EEG activity in the spindle frequency band was negatively correlated with rCBF in the thalamus. This result was in agreement with data suggesting the generation of spindles within cortico-thalamo-cortical loops (Steriade, 2006). Spectral power in the delta band was negatively correlated with rCBF in the medial prefrontal cortex, striatum, insula, anterior cingulate cortex, precuneus and basal forebrain, which are structures potentially involved in the modulation of cortical delta waves (Dang-Vu et al., 2005b). The functional brain mapping of slow oscillations was highly similar to the one of delta waves, in keeping with the hypothesis that both types of oscillations share common physiological mechanisms. These results consisted in negative correlations, which means that the cerebral blood flow in these areas was lower when the power in the corresponding frequency band was higher. The different rhythms of NREM sleep are synchronized by the slow oscillation, which alternates a hyperpolarization phase during which cortical neurons remain silent, and a depolarization phase associated with important neuronal firing. The prominent effect of hyperpolarization phases could account for the decrease in blood flow found in PET studies. Indeed, PET has a limited temporal resolution, around one minute, and therefore averages brain activity over relatively long periods, during which hyperpolarization phases predominate. Thus PET imaging does not allow to directly study brief events, lasting one second or so, such as NREM sleep oscillations. Besides, the spectral power values used in PET studies are just an indirect reflection of the appearance of these rhythms during sleep. These considerations justify the use of fMRI because, together with improved spatial resolution, its temporal resolution around one second allows to assess brain responses associated to the occurrence of NREM sleep oscillations, taken as identifiable events. Neural correlates of NREM sleep oscillations assessed by EEG / fMRI The largest section of the thesis is devoted to the use of fMRI in the study of NREM sleep oscillations. We characterized the brain areas in which activity, measured in terms of blood oxygen level dependent (BOLD) signal, was correlated with the occurrence of NREM sleep oscillations. Compared to EEG with PET, EEG recording with simultaneous fMRI was technically much more challenging. In particular, the analysis of EEG data acquired simultaneously with fMRI required a complex signal processing in order to remove all artefacts induced during the scanning procedure. After clean EEG data had been obtained, automatic detection of spindles (Molle et al., 2002), delta waves and slow oscillations (Massimini et al., 2004) was performed according to published criteria, and provided the series of events to be used as regressors in the statistical analysis of fMRI data. The latter assessed the main effects of spindles, delta waves and slow oscillations on BOLD signal changes across the 14 non-sleep-deprived young healthy volunteers selected for this study. Spindles were analysed considering 2 potential subtypes. Indeed, in humans, while most spindles are recorded in central and parietal regions and display a frequency around 14 Hz (fast spindles), others are prominent on frontal derivations with a frequency around 12 Hz (slow spindles). Previous data also show differences between both subtypes in their modulation by age, circadian and homeostatic factors, menstrual cycle, pregnancy and drugs (De Gennaro and Ferrara, 2003). However, no clear evidence of a distinct neurobiological basis for these two subtypes of spindles has been demonstrated so far. After automatic detection of spindles and their differentiation as fast and slow, we showed that the two subtypes were associated with activation of partially distinct thalamo-cortical networks. These data further support the existence of 2 subtypes of sleep spindles modulated by segregated neural networks (Schabus et al., 2007). Slow oscillation has initially been described at the cellular level in animals as an oscillation <1 Hz of membrane potential, alternating a hyperpolarization phase (down) during which cortical neurons are silent and a depolarization phase (up) associated with intense neuronal firing (Steriade, 2006). At the macroscopic level, this slow rhythm is found on human EEG recordings as high amplitude slow waves, defined by a peak-to-peak amplitude of more than 140 µV (Massimini et al., 2004). The slow oscillation also synchronizes other NREM sleep rhythms such as spindles (Molle et al., 2002) and delta waves (defined here as waves of lower peak-to-peak amplitude : between 75 and 140 µV). The organization of NREM sleep by the slow oscillation suggests that NREM sleep should be characterized by increased brain activities associated with the up state of slow oscillation. Indeed, we observed significant BOLD signal changes in relation to both slow waves and delta waves in specific brain areas including inferior and medial frontal gyrus, parahippocampal gyrus, precuneus, posterior cingulate cortex, ponto-mesencephalic tegmentum and cerebellum. All these responses consisted in brain activity increases. These results stand in sharp contrast with earlier sleep studies, in particular PET studies, reporting decreases in brain activity during NREM sleep. Here we showed that NREM sleep cannot be reduced to a state of global and regional brain activity decrease, but is actually an active state during which phasic increases in brain activity are synchronized to the slow oscillation. We then compared brain responses to delta and slow waves respectively and found no significant difference. In agreement with our PET data, this result suggests that slow waves and delta waves share common neurobiological mechanisms. However, when effects of slow and delta waves were tested separately, we observed that slow waves were specifically associated with activation of brainstem and mesio-temporal areas, while delta waves were associated with activation of inferior and medial frontal areas. This result is important in regard to the potential role of slow oscillation in memory consolidation during sleep (Marshall et al., 2006). Indeed, the preferential activation of mesio-temporal areas with high amplitude slow waves suggests that the amplitude of the wave is a crucial factor in the recruitment during sleep of brain structures involved in the processing of memory traces. RESUME Le sommeil lent de lhomme est défini par la présence dactivités neuronales spontanées, organisées sous forme de rythmes ou oscillations spécifiques. Lobjectif des travaux réalisés dans le cadre de cette thèse est de caractériser, par des méthodes de neuroimagerie, le fonctionnement cérébral au cours de ces rythmes physiologiques. Les oscillations que nous avons étudiées sont les fuseaux du sommeil, les ondes delta et les oscillations lentes, représentant les principales activités neurophysiologiques identifiables chez lhomme au cours du sommeil lent. Les fuseaux du sommeil constituent un élément essentiel du sommeil lent léger. Ils sont communément décrits sur les enregistrements électroencéphalographiques (EEG) comme des oscillations de fréquence comprise entre 11 et 15 Hz, dune durée dau moins 0,5 sec, et de morphologie caractéristique daugmentation puis de diminution damplitude. Au cours des stades plus profonds de sommeil lent, les fuseaux sont en grande partie remplacés par une activité donde lente (SWA; 0,5-4 Hz) qui recouvre les ondes delta (1-4 Hz) et les oscillations lentes (0,5-1 Hz). En combinaison à lEEG, nous avons utilisé deux techniques dimagerie fonctionnelle différentes pour étudier ces rythmes: la tomographie par émission de positons (PET) et limagerie en résonance magnétique fonctionnelle (fMRI). Ces études apportent une contribution originale à notre compréhension du sommeil lent chez lhomme sain, par lexploration des mécanismes générationnels de ces oscillations, piliers de larchitecture du sommeil. Corrélats cérébraux des rythmes du sommeil lent en EEG / PET Dans cette section, nous décrivons lutilisation de la PET dans létude des rythmes du sommeil lent. Nous avons caractérisé les régions cérébrales dans lesquelles lactivité, mesurée en terme de débit sanguin cérébral régional (rCBF), était corrélée à la puissance spectrale EEG dans la bande de fréquence des fuseaux (11-15 Hz), des ondes delta (1-4 Hz) et des oscillations lentes (0.5-1 Hz), chez 23 jeunes volontaires sains et non privés de sommeil. Lactivité EEG dans la bande des fuseaux était corrélée négativement avec le rCBF dans le thalamus. Ce résultat est en accord avec les données suggérant la genèse des fuseaux par des boucles dinteraction cortico-thalamo-corticale (Steriade, 2006). La puissance spectrale dans la bande delta était négativement corrélée avec le rCBF au niveau du cortex préfrontal médial, du striatum, de linsula, du cortex cingulaire antérieur, du précuneus et du télencéphale basal, régions potentiellement impliquées dans la modulation des ondes delta corticales (Dang-Vu et al., 2005b). La carte des oscillations lentes était superposable à celle des ondes delta, ce qui suggère que ces deux types doscillations relèvent chez lhomme de mécanismes physiologiques communs. Ces résultats démontraient donc des corrélations négatives, ce qui signifie que le débit sanguin cérébral dans ces régions était dautant plus faible que la puissance dans la bande de fréquence correspondante était élevée. Linterprétation de ce phénomène doit intégrer le fait que les différents rythmes du sommeil lent sont sculptés par loscillation lente, laquelle alterne une phase dhyperpolarisation au cours de laquelle les neurones corticaux sont silencieux, et une phase de dépolarisation au cours de laquelle ils déchargent en bouffées. Leffet prépondérant des phases dhyperpolarisation pourrait expliquer la baisse de débit cérébral démontrée en PET. En effet, cette dernière présente une résolution temporelle limitée, de lordre de la minute, ce qui a pour effet dintégrer lactivité cérébrale sur des périodes de temps relativement longues, au cours desquelles les phases dhyperpolarisation corticale prédominent. Limagerie en PET ne permet pas donc pas détudier directement des événements brefs de lordre de la seconde, tels que les oscillations du sommeil lent. En outre, les valeurs de puissance spectrale utilisées pour caractériser ces rythmes en PET ne reflètent quindirectement leur survenue au cours du sommeil. Ces considérations justifient le recours à limagerie en fMRI, dont la résolution temporelle de lordre de la seconde permet dévaluer les réponses cérébrales associées à la survenue des oscillations du sommeil lent, considérées cette fois comme des événements identifiables. Corrélats cérébraux des rythmes du sommeil lent en EEG / fMRI Dans cette partie, la plus importante, nous décrivons lanalyse en fMRI des rythmes du sommeil lent. Nous avons caractérisé les régions cérébrales dont l'activité, mesurée par le signal BOLD, était corrélée à la survenue des oscillations du sommeil lent. Par rapport à la situation rencontrée en PET, lenregistrement des données EEG nécessaire à la détection des rythmes du sommeil lent, simultanément à lacquisition fMRI, a posé des difficultés techniques considérablement plus grandes. En particulier, linterprétation de lEEG dans ces conditions a nécessité un traitement précis du signal afin den éliminer les éléments artéfactuels qui le contaminent. Ce nest quaprès ce processus que la détection automatique des fuseaux (Molle et al., 2002), des ondes delta et des oscillations lentes (Massimini et al., 2004) selon des critères publiés a pu seffectuer, permettant dobtenir les séries dévénements qui furent entrés comme régresseurs dans lanalyse statistique des données fMRI. Cette dernière évalue leffet principal des fuseaux, ondes delta et oscillations lentes sur les variations du signal BOLD chez lensemble des 14 jeunes volontaires sains et non privés de sommeil sélectionnés pour létude. En ce qui concerne les fuseaux, ils furent subdivisés en 2 sous-types. Chez lhomme en effet, alors que la grande majorité des fuseaux sont enregistrés dans les régions centrales et pariétales, avec une fréquence denviron 14 Hz (fuseaux rapides), dautres fuseaux dits lents (environ 12 Hz) prédominent dans les régions frontales. Des données antérieures rapportent également des différences entre ces deux sous-types en ce qui concerne leur modulation par des paramètres comme lâge, les facteurs circadiens et homéostatiques, la phase du cycle menstruel, la grossesse et certains agents pharmacologiques (De Gennaro and Ferrara, 2003). Cependant, aucune description formelle dun substrat biologique distinct navait encore été établie pour ces 2 sous-types de fuseaux. Après détection automatique des fuseaux et leur ségrégation en fuseaux rapides et lents, nous avons pu démontrer que les 2 sous-types de fuseaux étaient associés à des activations dans des réseaux thalamo-corticaux partiellement distincts. Ces données apportent donc des arguments pour établir lexistence de 2 sous-types biologiquement différenciés de fuseaux du sommeil (Schabus et al., 2007). Loscillation lente du sommeil lent a été décrite initialement au niveau cellulaire chez lanimal comme une oscillation de fréquence <1Hz et qui alterne une phase dhyperpolarisation (ou down), au cours de laquelle les neurones corticaux sont silencieux, et une phase de dépolarisation (ou up) qui correspond à une période de décharges neuronales intenses (Steriade, 2006). Chez lhomme, cette oscillation lente est également retrouvée sur les enregistrements EEG de surface sous forme dondes lentes de haute amplitude, définies par une amplitude pic-à-pic de plus de 140 µV (Massimini et al., 2004). Loscillation lente synchronise aussi dautres rythmes du sommeil lent tels les fuseaux (Molle et al., 2002) et les ondes delta (définies ici par des ondes de plus basse amplitude pic-à-pic : entre 75 et 140 µV). Lorganisation du sommeil lent par ces oscillations lentes suggère que le sommeil lent devrait être marqué par des activations cérébrales survenant en synchronie avec les phases up des oscillations lentes. De fait, nous avons observé des variations significatives de signal BOLD en association avec les ondes lentes et delta dans des régions cérébrales spécifiques incluant le gyrus frontal inférieur et médial, le gyrus parahippocampique, le precuneus, le cortex cingulaire postérieur, le tegmentum ponto-mésencéphalique et le cervelet. Ces variations étaient positives dans toutes les régions mises en évidence, ce qui traduit une augmentation dactivité. Ces résultats sont originaux en ce quils suggèrent que le sommeil lent, contrairement à ce qui était conclu des précédentes études du sommeil chez lhomme (particulièrement en PET), ne se réduit pas à une hypoactivation cérébrale globale et régionale. Au contraire, nos données montrent que le sommeil lent saccompagne dune activation cérébrale phasique rythmée par la phase de dépolarisation des oscillations lentes. Nous avons ensuite comparé les réponses cérébrales aux ondes delta et celles aux ondes lentes. Aucune région cérébrale ne présentait dactivité significativement différente en fonction des 2 types dondes. En accord avec nos données PET, ce résultat suggère quil ny a pas de différence formelle sur le plan des mécanismes neurobiologiques entre ondes lentes et ondes delta. Toutefois, lorsque les effets des ondes lentes et delta furent testés séparément, nous avons observé que les ondes lentes activaient spécifiquement le tronc cérébral et le cortex mésio-temporal alors que les ondes delta activaient les aires frontales inférieure et médiale. Cet résultat est important si lon considère en particulier le rôle potentiel des oscillations lentes dans la consolidation des traces mnésiques au cours du sommeil (Marshall et al., 2006). Lactivation préférentielle des aires mésio-temporales avec les ondes lentes de haute amplitude suggère en effet que lamplitude de londe est un paramètre déterminant dans le recrutement au cours du sommeil de structures cérébrales impliquées dans le traitement des traces mnésiques.

RESUME: Le travail de recherche rapporté dans cette thèse concerne lamélioration de traceurs marqués au fluor-18 utilisés en routine clinique : la 2-[18F]fluoro-L-tyrosine et le 2-désoxy-2-[18F]fluoro-D-glucose. Les résultats relatifs à lacide aminé, de valeur confirmative pour les connaissances publiées antérieurement dans la littérature, consistent en une validation chez le rat qui entérine le potentiel de ce traceur pour létude de la vitesse de synthèse des protéines cérébrales in vivo. Les perspectives futures pour ce traceur sont dès lors lextension de son utilité dans le domaine de loncologie et son utilisation pour létude de phénomènes physiologiques neurologiques. Durant ce travail, des techniques décrites dans la littérature, mais non pratiquées au CRC ont fait lobjet dune implémentation et sont maintenant accessibles (modèle du rat vigile, méthodes de synthèse de polymères à empreinte moléculaire). La partie principale du travail concerne la récupération du [18F]fluorure et son utilisation pour le marquage nucléophile sans étape dévaporation. La synthèse du 2-désoxy-2-[18F]fluoro-D-glucose a servi de réaction témoin pour tester lapplicabilité des méthodes développées dans ce cadre. Deux stratégies différentes, lune utilisant des supports ioniques et des solvants protiques, lautre utilisant des supports non ioniques et des solvants non protiques, ont permis datteindre les buts fixés avec des rendements dincorporation du [18F]fluorure de même ordre de grandeur que ceux obtenus en radiochimie usuelle du fluor-18. La méthode utilisant les supports non ioniques a par ailleurs démontré sa grande généralité vis-à-vis de précurseurs divers, aliphatiques et aromatiques, dans des conditions de marquage diverses, notamment à température modérée. Les perspectives de ces méthodes nouvelles pour la fabrication des traceurs TEP tirent parti de la possibilité de les implanter dans un automate miniaturisé (milli- ou micro-réacteur), à visée synthétique ou analytique. Lefficacité et la simplicité des méthodes de récupération sans évaporation mises au point dans ce travail les destinent à être utilisées aussi bien en développement des traceurs quen synthèse de routine. Elles sont applicables aussi bien à léchelle des automates courants quà celle des futures applications microfluidiques. Par ailleurs, nous sommes persuadés de lintérêt des polymères à empreinte moléculaire dans le créneau des méthodes analytiques. Egalement applicables à des systèmes miniaturisés, ils devraient aider à la réalisation danalyses automatisées des produits finis et à une libération accélérée. Le gain de temps et les moindres pertes de principe actif conduiront alors à une meilleure disponibilité des traceurs TEP et à leur participation accrue aux objectifs de la médecine personnalisée. Nous pensons dès lors avoir ouvert quelques pistes de recherche prometteuses pour la mise en application de ses nouvelles technologies au domaine de la tomographie à émission de positon. / SUMMARY: The results reported in this work concern the improvement of 18-fluorine labelled radiopharmaceuticals used in routine clinical applications: 2-[18F]fluoro-L-tyrosine and 2-deoxy-2-[18F]fluoro-D-glucose. The study of the metabolism of non carrier added 2-[18F]fluoro-L-tyrosine in rats confirms that this tracer is rapidly and extensively incorporated into cerebral proteins and is therefore well suited to the assessment of Protein Synthesis Rate (PSR) in vivo by PET. A correction for the appearance of metabolites is advised for quantitative interpretation of the data. An improvement in the radiosynthesis is necessary to make 2-[18F]fluoro-L-tyrosine widely available for its application in oncology and to envisage the extended use of this tracer for the study of the protein synthesis in other physiological or pathological processes. The second chapter deals with use of molecular imprints in the PET radiochemistry. The molecularly imprinted polymers were synthetized, characterized and tested for the production of specific PET tracers and the plasma analysis of the parent metabolites. The third part of the work consisted in a development of new methods for the [18F]fluoride recovery in order to permit the labelling of different precursors through nucleophilic substitution without the evaporation step classically performed in 18-fluorine radiochemistry. The synthesis of 2-deoxy-2-[18F]fluoro-D-glucose has been used as a tool for the evaluation of the developed methods. Two strategies were considered to concentrate and recover the [18F]fluoride. The first one used ionic solid supports and protic solvents. The second one relied on the use of non ionic solid supports and non protic solvents. Both strategies led us to reach [18F]fluoride incorporation yields as high as in classical radiosyntheses with evaporation. Ionic liquids and tertiary alcohols were also evaluated in order to improve the tolerance of the [18F]fluoride nucleophilic substitution to water. The molecularly imprinted polymers and the new methods for the recovery of [18F]fluoride will now be tested for the implementation of PET tracers radiosynthesis and quality control into microchip devices.

Adrenocortical cancer (ACC) is a rare disease that is often difficult to diagnose, and therefore often presents at an advanced stage. Various cytotoxic treatments have been tried with little success. Evaluation of new diagnostic methods and improvement of medical therapies are therefore crucial. The diagnostic potential of 11C-metomidate positron emission tomography (PET) was evaluated in eleven ACC patients. PET visualized all viable tumors with high tracer uptake, including two lesions that CT failed to detect. Necrotic or fibrotic tumors were PET negative. Medication with adrenal steroid inhibitors and chemotherapy may decrease the tracer uptake. We performed a phase-II study with streptozocin and o,p’-DDD (SO) combination therapy in 40 ACC patients. The SO therapy was found to have impact on the disease-free interval (P = 0.02) as well as on survival (P = 0.01) in patients who received adjuvant therapy after curative resection. Complete or partial response was obtained in 36.4% of patients with measurable disease. The efficacy and tolerability of combination therapy with vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) were evaluated in eleven patients with advanced ACC after failure of SO therapy. The median survival was 21 months from the start of treatment. A partial response was achieved in two patients. Adverse events were mainly restricted to grade 1-2 toxicities, and grade 3 toxicities were observed in only two cycles. We tested 21 ACC tumors to analyze the expression of receptor tyrosine kinases and 15 ACC for mutation analysis of c-Kit exon 11, which can be targeted by antagonists such as imatinib. All ACCs expressed one or more kinases: c-Kit in 19 ACC and phospho-c-Kit in three while 14 ACCs expressed PDGFR-beta, suggesting the potential usefulness of tyrosine kinase inhibitors. No c-Kit mutations were detected in exon 11. Further evaluation of other mutations targeted by this drug may be needed.

Premenstrual dysphoria, so severe that it affects the lives of the women afflicted, is the condition studied in this thesis. Physiological and pharmacological mechanisms of pathogenetic relevance were investigated. Women with premenstrual dysphoria showed a stronger and less dampened response of LH to an estradiol challenge than asymptomatic women, indicating an altered neuroendocrine regulation. In women with premenstrual dysphoria, the LH response was correlated to the severity of irritability and bloating, and the early FSH response was correlated to the severity of depressed mood. The positron-emission study showed strong, consistent correlations between worsening of mood symptoms and a decrease in brain trapping of the immediate serotonin precursor, from the mid-follicular to the late luteal phase in women with premenstrual dysphoria. The strongest correlations were seen for the cardinal mood symptoms of premenstrual dysphoria, and for their opposites. Physical symptoms showed weaker or no correlations with the exception of nociceptive symptoms from erogenous body regions which showed positive correlations to serotonin precursor trapping in the right caudate nucleus. The findings are consistent with the serotonin hypothesis of premenstrual dysphoria, and might possibly explain the observed effects of serotonin-augmenting drugs in this condition. The partial 5-HT1A receptor agonist buspirone was superior to placebo in the treatment of premenstrual dysphoria. The weak SRI and 5-HT2 receptor antagonist nefazodone was not superior to placebo. For women with premenstrual dysphoria in need of medication and who do not tolerate SRIs because of the sexual sideeffects, buspirone may be an alternative drug, since it had no adverse effects on sexual function. The prevalence of polycystic ovaries and serum levels of androgens were not higher in women with premenstrual dysphoria than in their asymptomatic counterparts. The findings are not consistent with the hypothesis that irritability in women with premenstrual dysphoria is induced by elevated testosterone levels. Thesis results, which are in line with the serotonin hypothesis of premenstrual dysphoria, may imply that increased brain sensitivity is one of the factors underlying severe premenstrual mood symptoms, thereby further supporting a common serotonergic dysregulation in this condition.

Anxiety disorders are very common and the primary feature is abnormal or inappropriate anxiety. Fear and anxiety is often mediated by the amygdala, a brain structure rich in substance P (SP) and neurokinin 1 (NK1) receptors. To learn more about how the human amygdala is modulated by fear and anxiety in event-triggered anxiety disorders and to investigate if the SP/NK1 receptor system is affected, regional cerebral blood flow (rCBF) ([15O]-water; Study I and II) and the SP/NK1 receptor system ([11C]GR205171; Study III and IV) were studied with positron emission tomography (PET). In Study I we investigated the neural correlates of affective startle modulation in persons with specific phobia by measuring rCBF during exposure to fearful and non-fearful pictures, paired and unpaired with acoustic startle stimuli. Fear-potentiated startle was associated with activation of the affective part of the anterior cingulate cortex and the left amygdaloid–hippocampal area. In Study II short-term drug treatment effects on rCBF in patients diagnosed with social phobia was evaluated, comparing the NK1 receptor antagonist GR205171 to the selective serotonin reuptake inhibitor citalopram and placebo. Social anxiety and neural activity in the medial temporal lobe including the amygdala was significantly reduced by both drugs but not placebo. In Study III we investigated if activity in the SP/NK1 receptor system in the amygdala would be affected by fear provocation in individuals with specific snake or spider phobia. Fear provocation was associated with a decreased uptake of the NK1 antagonist [11C]GR205171 in the amygdala, possibly explained by an increase in endogenous SP release occupying the NK1 receptors. Study IV was conducted to explore the resting state NK1 receptor availability in PTSD patients as compared to healthy controls. Increased resting state binding of the tracer [11C]GR205171 in the amygdala of patients with PTSD suggested an increased amount of available receptors. In summary, fear and fear-potentiated startle modulates the human amygdala, possibly through the SP/NK1 receptor system.

The purpose of this experiment was to investigate skeletal muscle blood flow and glucose uptake in m. biceps (BF) and m. quadriceps femoris (QF) 1) during recovery from high intensity cycle exercise, and 2) while wearing a compression short applying ~37 mmHg to the thigh muscles. Blood flow and glucose uptake were measured in the compressed and non-compressed leg of 6 healthy men by using positron emission tomography. At baseline blood flow in QF (P = 0.79) and BF (P = 0.90) did not differ between the compressed and the non-compressed leg. During recovery muscle blood flow was higher compared to baseline in both compressed (P&lt;0.01) and non-compressed QF (P&lt;0.001) but not in compressed (P = 0.41) and non-compressed BF (P = 0.05; effect size = 2.74). During recovery blood flow was lower in compressed QF (P&lt;0.01) but not in BF (P = 0.26) compared to the non-compressed muscles. During baseline and recovery no differences in blood flow were detected between the superficial and deep parts of QF in both, compressed (baseline P = 0.79; recovery P = 0.68) and non-compressed leg (baseline P = 0.64; recovery P = 0.06). During recovery glucose uptake was higher in QF compared to BF in both conditions (P&lt;0.01) with no difference between the compressed and non-compressed thigh. Glucose uptake was higher in the deep compared to the superficial parts of QF (compression leg P = 0.02). These results demonstrate that wearing compression shorts with ~37 mmHg of external pressure reduces blood flow both in the deep and superficial regions of muscle tissue during recovery from high intensity exercise but does not affect glucose uptake in BF and QF. © 2013 Sperlich et al. / <p>:doi 10.1371/journal.pone.0060923</p>

Positron emission tomography (PET) is a well-established functional imaging method used in nuclear medicine. It allows for retrieving information about biochemical and physiological processes in vivo. The currently possible spatial resolution of PET is about 5 mm for brain acquisitions and about 8 mm for whole-body acquisitions, while recent improvements in image reconstruction point to a resolution of 2 mm in the near future. Typical acquisition times range from minutes to hours due to the low signal-to-noise ratio of the measuring principle, as well as due to the monitoring of the metabolism of the patient over a certain time. Therefore, patient motion increasingly limits the possible spatial resolution of PET. In addition, patient immobilisations are only of limited benefit in this context. Thus, patient motion leads to a relevant resolution degradation and incorrect quantification of metabolic parameters. The present work describes the utilisation of a novel motion compensation method for clinical brain PET acquisitions. By using an external motion tracking system, information about the head motion of a patient is continuously acquired during a PET acquisition. Based on the motion information, a newly developed event-based motion compensation algorithm performs spatial transformations of all registered coincidence events, thus utilising the raw data of a PET system - the so-called `list-mode´ data. For routine acquisition of this raw data, methods have been developed which allow for the first time to acquire list-mode data from an ECAT Exact HR+ PET scanner within an acceptable time frame. Furthermore, methods for acquiring the patient motion in clinical routine and methods for an automatic analysis of the registered motion have been developed. For the clinical integration of the aforementioned motion compensation approach, the development of additional methods (e.g. graphical user interfaces) was also part of this work. After development, optimisation and integration of the event-based motion compensation in clinical use, analyses with example data sets have been performed. Noticeable changes could be demonstrated by analysis of the qualitative and quantitative effects after the motion compensation. From a qualitative point of view, image artefacts have been eliminated, while quantitatively, the results of a tracer kinetics analysis of a FDOPA acquisition showed relevant changes in the R0k3 rates of an irreversible reference tissue two compartment model. Thus, it could be shown that an integration of a motion compensation method which is based on the utilisation of the raw data of a PET scanner, as well as the use of an external motion tracking system, is not only reasonable and possible for clinical use, but also shows relevant qualitative and quantitative improvement in PET imaging. / Die Positronen-Emissions-Tomographie (PET) ist ein in der Nuklearmedizin etabliertes funktionelles Schnittbildverfahren, das es erlaubt Informationen über biochemische und physiologische Prozesse in vivo zu erhalten. Die derzeit erreichbare räumliche Auflösung des Verfahrens beträgt etwa 5 mm für Hirnaufnahmen und etwa 8 mm für Ganzkörperaufnahmen, wobei erste verbesserte Bildrekonstruktionsverfahren eine Machbarkeit von 2 mm Auflösung in Zukunft möglich erscheinen lassen. Durch das geringe Signal/Rausch-Verhältnis des Messverfahrens, aber auch durch die Tatsache, dass der Stoffwechsel des Patienten über einen längeren Zeitraum betrachtet wird, betragen typische PET-Aufnahmezeiten mehrere Minuten bis Stunden. Dies hat zur Folge, dass Patientenbewegungen zunehmend die erreichbare räumliche Auflösung dieses Schnittbildverfahrens limitieren. Eine Immobilisierung des Patienten zur Reduzierung dieser Effekte ist hierbei nur bedingt hilfreich. Es kommt daher zu einer relevanten Auflösungsverschlechterung sowie zu einer Verfälschung der quantifizierten Stoffwechselparameter. Die vorliegende Arbeit beschreibt die Nutzbarmachung eines neuartigen Bewegungskorrekturverfahrens für klinische PET-Hirnaufnahmen. Mittels eines externen Bewegungsverfolgungssystems wird während einer PET-Untersuchung kontinuierlich die Kopfbewegung des Patienten registriert. Anhand dieser Bewegungsdaten führt ein neu entwickelter event-basierter Bewegungskorrekturalgorithmus eine räumliche Korrektur aller registrierten Koinzidenzereignisse aus und nutzt somit die als &amp;quot;List-Mode&amp;quot; bekannten Rohdaten eines PET Systems. Für die Akquisition dieser Daten wurden eigens Methoden entwickelt, die es erstmals erlauben, diese Rohdaten von einem ECAT Exact HR+ PET Scanner innerhalb eines akzeptablen Zeitraumes zu erhalten. Des Weiteren wurden Methoden für die klinische Akquisition der Bewegungsdaten sowie für die automatische Auswertung dieser Daten entwickelt. Ebenfalls Teil der Arbeit waren die Entwicklung von Methoden zur Integration in die klinische Routine (z.B. graphische Nutzeroberflächen). Nach der Entwicklung, Optimierung und Integration der event-basierten Bewegungskorrektur für die klinische Nutzung wurden Analysen anhand von Beispieldatensätzen vorgenommen. Es zeigten sich bei der Auswertung sowohl der qualitativen als auch der quantitativen Effekte deutliche Änderungen. In qualitativer Hinsicht wurden Bildartefakte eliminiert; bei der quantitativen Auswertung einer FDOPA Messung zeigte sich eine revelante Änderung der R0k3 Einstromraten eines irreversiblen Zweikompartment-Modells mit Referenzgewebe. Es konnte somit gezeigt werden, dass eine Integration einer Bewegungskorrektur unter Zuhilfenahme der Rohdaten eines PET Systems sowie unter Nutzung eines externen Verfolgungssystems nicht nur sinnvoll und in der klinischen Routine machbar ist, sondern auch zu maßgeblichen qualitativen und quantitativen Verbesserungen in der PET-Bildgebung beitragen kann.