Introdução: Apesar de ser uma intervenção potencialmente promissora para melhorar a cognição em sujeitos com comprometimento cognitivo leve (CCL), os efeitos do treinamento aeróbio (TA) no metabolismo regional de glicose (MRG) no cérebro ainda são pouco conhecidos. Objetivo: Avaliar os efeitos do TA na cognição e no MRG cerebral em sujeitos com CCL, usando tomografia por emissão de pósitrons com 18F - fluordesoxiglicose (PET-18FDG). Métodos: Sessenta e cinco sujeitos com CCL realizaram um programa de TA de intensidade moderada, duas vezes por semana, durante 24 semanas. Uma avaliação cognitiva com a escala Alzheimer\'s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) e outra do metabolismo cerebral em repouso com o PET-18FDG foram realizadas antes e depois da intervenção. A capacidade aeróbia foi comparada utilizando o consumo máximo de oxigênio (VO2 máx.) medido em mL/kg/min. Os dados de PET-18FDG foram analisados voxel por voxel com o programa SPM8 (limiar: p < 0,001 não corrigido, tamanho de agrupamento >= 50 voxels). Uma técnica de modelação de equações estruturais foi usada para criar um modelo para explorar as mudanças no MRG cerebral em repouso depois do programa de TA. Resultados: Comparações com testes t pareados revelaram melhora nos valores da escala ADAS-Cog (diferença média: -2,4 (3,5), p < 0,001) e no VO2 máx. (diferença média: 1,4 (2,3) mL/kg/min, p < 0,001). A análise metabólica do cérebro constatou uma redução bilateral do MRG em ambos os polos temporais anteriores, no giro frontal inferior esquerdo, no giro do cíngulo anterior esquerdo, no hipocampo direito, no giro frontal médio esquerdo e nos núcleos caudados bilaterais. Em contraste, houve um aumento do MRG no precuneus direito e no giro frontal inferior esquerdo. Um modelo de confirmação de fatores foi usado para criar variáveis latentes que refletem a rede de saliência (RS) e a rede de modo padrão (default mode network (DMN)) com base em regiões com mudanças no MRG encontradas depois do TA. Uma análise de caminhos foi utilizada para testar a hipótese de que o TA poderia induzir mudanças (diminuição) do MRG em regiões da RS. Essa redução pode refletir um aumento da eficiência da rede e, consequentemente, um melhor controle sobre outras redes. Em última instância, essa mudança induziria um aumento do MRG no precuneus, um importante nó da DMN. Os valores de adequação do modelo atingiram significância estatística, demonstrando que esse modelo explica a variância dos dados medidos. Conclusão: O TA melhorou a cognição e alterou o MRG em regiões da DMN e da rede de saliência em sujeitos com CCL / Background: Despite being a potentially promising intervention to improve cognition in subjects with mild cognitive impairment (MCI), the effects of aerobic training (AT) on regional brain glucose metabolism (rBGM) are not yet entirely understood. Objective: To evaluate the effects of AT on cognition and rBGM in subjects with MCI using 18FDG-PET. Methods: Sixty-five subjects with MCI performed a twice-a-week, moderate intensity, AT program for 24 weeks. Assessment with the ADAS-Cog (Alzheimer\'s Disease Assessment Scale - Cognitive Subscale) and evaluation of rBGM with 18FDG-PET were performed before and after the intervention. Aerobic capacity was compared using the relative maximal oxygen consumption (VO2 max) measured in mL/Kg/min. 18FDG-PET data were analyzed on a voxel-by-voxel basis with SPM8 (threshold: uncorrected p < 0.001, cluster size >= 50 voxels). Structural equation modeling was used to create a model to explore the changes of resting-state rBGM after the AT program. Results: Comparisons using paired t-tests revealed improvements in the ADAS-Cog (mean difference: -2.4 (3.5), p < 0.001) and VO2 max scores (mean difference: 1.4 (2.3) mL/kg/min, p < 0.001). Brain metabolic analysis revealed a bilateral reduction of rBGM in both anterior temporal poles, left inferior frontal gyrus, left anterior cingulate cortex, right hippocampus, left middle frontal gyrus and bilateral caudate nuclei. In contrast, there was an increase in rBGM in the right precuneus and left inferior frontal gyrus. Confirmatory factor analysis was used to create latent variables reflecting the salience network (SN) and default mode network (DMN) based on regions with rBGM changes found after the AT. A path model analysis was used to test the hypothesis that AT would induce rBGM changes (decrease) in regions of the SN. This decrement may reflect improved efficacy and consequently, better control over other networks. Ultimately, these changes would induce an increment in rBGM in the precuneus, an important node of the DMN. Values of model fit reached statistical significance, demonstrating that this model explain the variance of the measured data. Conclusion: AT improved cognition and changed rBGM measured with 18FDG-PET in nodes od the DMN and SN in subjects with MCI

Falhas na conectividade cerebral e na atividade córtico-límbica podem estar envolvidas no Transtorno Depressivo Maior (TDM). O uso simultâneo da Estimulação Magnética Transcraniana (EMT) e a Tomografia por Emissão de Pósitrons (PET) é um eficiente método não-invasivo para estudar a conectividade funcional interregional do cérebro humano e os mecanismos envolvidos na ação precisa da EMT sobre o córtex préfrontal dorso-lateral (CPFDL), componente do modelo neuroanatômico da depressão. O presente estudo avaliou o padrão de ativação das áreas envolvidas neste modelo, como o CPFDL, tálamo, hipocampo, amígdala, giro do cíngulo e cerebelo, em pacientes com Transtorno Depressivo Maior (TDM), comparados a controles. Dezessete pacientes com TDM e 17 controles foram estudados. A EMT foi aplicada em uma frequência de 3 Hz no CPFDL esquerdo. Um braço robótico para localização precisa do estímulo foi utilizado. Cada indivíduo foi submetido a duas sessões de EMT em três intensidades (90% do Limiar Motor (LM), 100% do LM e 110% do LM) e duas sessões de EMT \"placebo\" (aplicadas como clicks auditivos). Durante a EMT, as imagens foram realizadas em uma câmera GE 4096 e o fluxo sanguíneo cerebral foi medido através da PET utilizando H2 15O. Imagens por Ressonância Magnética (RMI) foram adquiridas para co-registro da PET-RMI, possibilitando a localização precisa do CPFDL. Mudanças significativas no Fluxo Sanguíneo Cerebral (FSC) indicando atividade neural foram detectadas utilizando uma estratégia de subtração sem áreas de interesse prévias. Os pacientes, comparados a controles, apresentaram uma resposta diminuída do FSC na área estimulada (CPFDL esquerdo) na intensidade de 100% do LM. Áreas não diretamente estimuladas que apresentaram uma diminuição do FSC, em pacientes, foram o giro do cíngulo anterior direito (90% do LM) e, dentre as regiões sub-corticais, globo pálido esquerdo (90% e 110% do LM) e tálamo direito (100% do LM). O giro do cíngulo posterior, bilateralmente, e a vermis cerebelar direita apresentaram aumento do FSC em todas as intensidades de estimulação. Este estudo sugere que pacientes com depressão maior podem apresentar um limiar mais alto para a estimulação com EMT do CPFDL esquerdo, e uma resposta córtico-límbica distinta à EMT, quando comparados aos resultados dos indivíduos controles. Estes achados devem ser considerados em estudos que utilizarem EMT para tratamento da depressão. Este estudo sugere que a fisiopatologia do TDM envolve um prejuízo da conectividade córtico-límbica. / Disturbed corticolimbic activity and connectivity may underlie major depressive disorder. The simultaneous use of transcranial magnetic stimulation (TMS) and positron emission tomography (PET) is a powerful noninvasive method to study interregional functional connectivity of the dorsolateral prefrontal cortex (DLPFC), a major component of the neuroanatomic model of depression. Seventeen unmedicated patients with recurrent major depression and 17 healthy volunteers were studied. TMS was delivered at 3 Hz to the left DLPFC by image guided robotic TMS (irTMS) system. Each subject underwent two trials of TMS at each of three intensities (90% MT (motor threshold), 100% MT, 110% MT), and two trials of sham TMS (delivered as auditory clicks). During the TMS, cerebral blood flow (CBF) was measured with H2 15O-Positron Emission Tomography (PET). An anatomical MR scan was acquired for PET-MRI co-registration to facilitate precise location of the DLPFC. Significant changes in cerebral blood flow indicating neural activity were detected using a ROI-free image subtraction strategy. Patients had a decreased response in regional CBF (rCBF) in left DLPFC in the intensity of 100% of MT. Left and right posterior cingulate demonstrated increased CBF across all intensities in depressed patients. Patients also had a decreased response in the right anterior cingulate at 90% of MT and right cerebellar vermis in response to left DLPFC stimulation across all intensities, compared to healthy volunteers. Among subcortical regions, only left globus pallidus and right thalamus showed a significant de-activation across varying TMS intensities. Patients with major depression may have a higher threshold for the TMS stimulation of the left DLPFC and a different corticolimbic response to TMS stimulation than healthy controls, a finding that must be taken into consideration in studies utilizing TMS as a treatment for depression. These findings suggest impaired cortico-limbic connectivity in unipolar depression, which could underlie illness pathophysiology.

INTRODUÇÃO: Cerca de 80% dos nódulos de tireóide com citologia indeterminada são benignos. É possível que a tomografia por emissão de pósitrons (PET) com 2-[18F]- fluoro-2-desoxi-D-glicose (FDG) ajude a identificar quais dessas lesões são malignas. A captação de FDG depende da expressão de GLUTs (transportadores de glicose transmembrana) e hexoquinases. Captação difusa de FDG no leito tireoidiano tem ainda sido associada à tireoidite autoimune crônica (TAC), embora haja evidências de que pacientes com parênquima tireoidiano aparentemente sadio possam ter essa alteração. OBJETIVOS: (1) Determinar a sensibilidade e especificidade da PET-FDG no diagnóstico pré-operatório de malignidade dos nódulos tireoidianos, especialmente daqueles com resultados citológicos indeterminados, e avaliar esse desempenho no subgrupo de pacientes com TAC. (2) Determinar a correlação entre o achado de captação difusa tireoidiana da FDG à PET com o diagnóstico histopatológico de TAC e compará-la às concentrações plasmáticas dos anticorpos antitireoidianos. (3) Determinar a correlação entre a expressão dos marcadores imuno-histoquímicos GLUT 1, GLUT 3, GLUT 12, hexoquinase 2 e hexoquinase 3 com o diagnóstico histopatológico dos nódulos e com a captação de FDG apresentada pelos mesmos. MÉTODOS: 56 pacientes com nódulo de tireóide (42 com citologia indeterminada, 10 compatíveis com carcinoma papilífero e 4 com citologia benigna) realizaram PET-FDG e foram submetidos à tireoidectomia. Os resultados da PET-FDG foram comparados com o diagnóstico histopatológico do nódulo, com o infiltrado linfocitário no parênquima tireoidiano, com o diagnóstico de TAC e com os resultados do estudo imuno-histoquímico de micromatriz tecidual de tecido correspondente ao nódulo tireoidiano puncionado e ao tecido tireoidiano não nodular. RESULTADOS: 1) Todos os 21 pacientes com câncer de tireóide (11 com citologia indeterminada) apresentaram captação focal de FDG na tireóide. 2) Captação focal de FDG correlacionou-se com maior risco de malignidade (p<0,001). 3) Dos 31 pacientes com nódulos benignos com citologia indeterminada, 12 não tinham captação focal de FDG (especificidade de 39%). 4) Captação difusa no leito tireoidiano à PET-FDG foi associada à presença de TAC no exame histopatológico (p=0,019). Porém, 5 pacientes, sem sinais de infiltrado linfocitário, apresentaram captação difusa à PET-FDG. 5) Imunoexpressão dos anticorpos contra GLUTs 1, 3 e 12 e hexoquinases 2 e 3 nas células epiteliais dos nódulos não esteve positivamente associada com captação de FDG e com malignidade. 6) Não houve associação entre captação difusa de FDG no leito tireoidiano e imunoexpressão desses marcadores no parênquima tireoidiano não nodular. CONCLUSÕES: 1) A PET-FDG tem alta sensibilidade para diagnóstico de lesões malignas de tireóide, com especificidade de 39% para nódulos com citologia indeterminada. 2) Captação difusa de FDG no leito tireoidiano está associada à presença de TAC, mas pode ocorrer em pacientes sem infiltrado linfocitário. 3) A imuno-histoquímica para os anticorpos contra GLUTs 1, 3 e 12 e hexoquinases 2 e 3 não contribui para a diferenciação de nódulos malignos dos benignos e não se associa com a captação de FDG pelos nódulos / INTRODUCTION: Around 80% of thyroid nodules with indeterminate cytological result are benign. Positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy- D-glucose (FDG) might help to identify malignant thyroid lesions. FDG uptake depends on GLUTs expression (transmembranous glucose transporters) and on hexokinases. Although diffuse FDG thyroid uptake has been associated with chronic autoimmune thyroiditis (CAT), there is some evidence that patients with apparently normal thyroid parenchyma can display this pattern of FDG uptake. OBJECTIVES: (1) To assess the sensitivity and specificity of FDG PET in identifying thyroid malignancy in the preoperative evaluation of thyroid nodules and evaluate these results in the subgroup of patients with indeterminate cytological results and in the subgroup with CAT. (2) To compare the finding of diffuse FDG thyroid uptake with the histopathologic diagnosis of CAT and with the serum levels of antithyroid antibodies. (3) To evaluate the immunoexpression by thyroid nodules of GLUT 1, GLUT 3, GLUT 12, hexokinase 2 and hexokinase 3 and to compare it with the histopathologic diagnosis of these nodules and with FDG uptake. METHODS: 56 patients with thyroid nodules (42 with indeterminate cytological result, 10 with papillary carcinoma and 4 with benign cytological result) underwent FDG PET and, subsequently, thyroidectomy. FDG PET results were compared with the histopathologic diagnosis of the nodule, lymphocytic infiltrate of thyroid parenchyma, CAT diagnosis and immunohistochemical results of tissue microarray of the tissue from the thyroid nodule and the normal thyroid parenchyma. RESULTS: 1) All the 21 patients with thyroid cancer (11 with indeterminate cytological result) had focal thyroid FDG uptake. 2) Focal FDG uptake was associated with malignancy (p<0.001). 3) From 31 patients with benign nodules whose cytological result was indeterminate, 12 did not display focal FDG uptake (specificity of 39%). 4) Diffuse FDG uptake in thyroid bed was associated with CAT in the histopathologic exam (p=0.019). However, 5 patients without lymphocytic infiltrate had diffuse FDG uptake. 5) Immunoexpression of GLUTs 1, 3 and 12 and hexokinases 2 and 3 by epithelial cells of thyroid nodules was not positively associated with FDG uptake and malignancy. 6) There was no association between diffuse FDG uptake in thyroid bed and immunoexpression of these markers in the normal thyroid tissue. CONCLUSIONS: 1) FDG PET has high sensitivity to the diagnosis of malignancy in thyroid bed, with a specificity of 39% for thyroid nodules with indeterminate cytological result. 2) Diffuse FDG uptake in the thyroid bed is associated with CAT, but can be found in patients without lymphocytic infiltrate. 3) Immunohystochemistry against GLUTs 1, 3 and 12 and hexokinases 2 and 3 does not add in the differentiation of malignant and benign thyroid nodules and is not associated with FDG uptake by these nodules

La tomographie par émission de positons (TEP) est une technique d’imagerie moléculaire avec de meilleures performances que la tomographie par émission monophotonique. Son utilisation contribue à l’amélioration des prises en charge des patients. Dans les centres dépourvus de cyclotrons, le 68Ga disponible à partir d’un générateur constitue une alternative pour le développement de traceurs TEP. Pour pouvoir développer des 68Ga-traceurs, un travail de caractérisation de la qualité des éluats a été effectué. Des méthodes de marquage adaptées ont été mises en place et validées. Nous nous sommes intéressés à trois cibles moléculaires particulièrement intéressantes dans les pathologies cardiovasculaires: les récepteurs de la somatostatine (SSTR) surexprimés dans les tumeurs neuroendocrines (TNE) mais constituant aussi une cible d’intérêt dans les pathologies cardiovasculaires à composante inflammatoire ; la phosphatidylsérine (PS), un marqueur de l’apoptose cellulaire et de l’activation plaquettaire ; la P-sélectine, un marqueur des activations plaquettaire et endothéliale. Les traceurs suivants ont été développés: 1) Analogues de la somatostatine ciblant les SSTR: a)68Ga-DOTANOC validé pour l’imagerie des TNE-Gastroentéropancréatiques dans le cadre d’un essai clinique multicentrique. b) 68Ga-NODAGANOC testé in vitro sur des cellules d’adénocarcinome pancréatique. Cette validation initiale dans l’application la plus fréquente(oncologie) a pour objectif de faciliter le passage vers des applications cardiovasculaires futures (athérosclérose, myocardite...) ; 2) Un peptide ciblant la PS : le 68Ga-P04087 ; 3) Un polysaccharide ciblant la P-sélectine: 68Ga-NODAGA-Asphy. Les deux derniers traceurs ont été testés sur un modèle d’endocardite infectieuse chez le rat. / The Positron emission tomography (PET) is a molecular imaging technique with usually better performances than Single-Photon Emission Computed Tomography. Consequently, the use of PET and appropriate tracers could enable clinicians to make a better therapeutic decision, thus improving the management of patients. In centers without cyclotrons, 68Ga available from a generator is an alternative for the development of PET tracers. In order to develop 68Ga labeled-molecules, a characterization of the quality of the eluates was performed. Radiolabeling techniques adapted to the quality of the starting material were developed and validated. In this thesis we focused on three particularly interesting molecular targets in cardiovascular pathologies: somatostatin receptors (SSTR), overexpressed in neuroendocrine tumors (NETs) but also constituting a target of interest in cardiovascular diseases with an inflammatory component; phosphatidylserine (PS), a marker of cell apoptosis and platelet activation; P-selectin, a marker of platelet and endothelial activation.The following tracers have been developed: 1) Somatostatin analogues which target SSTR: a) 68Ga-DOTANOC validated for Gastroenteropancreatic-NETs imaging and used in a multicenter clinical trial. b) 68Ga-NODAGANOC tested in vitro on pancreatic adenocarcinoma cells. This initial validation in the most common application (oncology) aims to facilitate the transition to future cardiovascular applications (atherosclerosis, myocarditis ...) 2) A peptide for PS targeting: 68Ga-P04087; 3) A polysaccharide for P-selectin targeting: 68Ga-NODAGA-Asphy. The last two radiolabeled molecules were tested in a rat model of infective endocarditis.

<p>Neuroendocrine tumors (NET´s) are often characterized by overproduction of peptide hormones. In spite of pronounced clinical symptoms, the tumor lesions can be small and difficult to detect. The general aim of this thesis was to investigate, in vitro and in vivo, some of the potential monoamine pathways present in NET´s, using radiolabeled tracers for positron emission tomography (PET), with the intention to explore the value of PET-imaging in the management of NET´s.</p><p>We used the 11C-labeled serotonin precursor 5-hydroxy tryptophan (HTP) as the tracer for imaging of NET´s. More than 95% of the subjects displayed a high tracer uptake on PET and tumor detection rate with PET was higher in >50% of the patients compared both to computed tomography (CT) and somatostatin receptor scintigraphy (SRS). The primary tumor was imaged by PET in 84% (16/19), compared to 47% and 42% for SRS and CT, respectively. Tumor visibility was better with PET due to a higher tumor-to-background ratio and a better spatial resolution. There was a strong correlation (r = .907) between changes in urinary-5-hydroxy indole acetic acid and changes in transport rate of 11C-5-HTP during treatment, indicating the use of PET in treatment monitoring of NET´s. </p><p>Pretreatment with carbidopa decreased the urinary radioactivity concentration four-fold and significantly (p<0.001) increased the tumor tracer uptake. This greatly improved image interpretation and tumor lesion detection.</p><p>A screening for expression of monoamine pathways in NET´s revealed a high in vitro binding of the monoamineoxidase-A ligand harmine to tumor sections. PET examinations with 11C-harmine could visualize tumors in all patients, including non-functioning endocrine pancreatic tumors (EPT´s).</p><p>Finally, the in vitro turnover and in vivo distribution of the amino acids glutamate, glutamine and aspartate was investigated. Limited uptake in vivo indicates the lack of utility for these substances as PET-tracers for imaging and characterization of NET´s. </p>

<p>This thesis explored the epidemiology of Posttraumatic Stress Disorder (PTSD) and different aspects of the disorder. Firstly, we investigated the lifetime prevalence of traumatic experiences and PTSD in the general adult population in Sweden and evaluated the impact of different trauma types, trauma frequency, and perceived distress. The results show that traumatic experiences are common and PTSD is not rare; roughly one out of ten traumatic events results in PTSD, with a 5.6% lifetime prevalence. The female/male ratio is 2:1. The risk for PTSD increases considerably with a high trauma-associated emotional impact. The distressing impact of a given trauma appears to be higher in women than in men, indicating an increased vulnerability in women. Secondly, we hypothesized that traffic road accidents (TRA’s) are one of the most prevalent types of traumatic events in Swedish society; therefore, we examined the impact of event and response characteristics associated with TRA’s on PTSD development. The data demonstrate that of those who had experienced a TRA (n=1074, 58.9%), 6.1% reported lifetime PTSD. TRA’s associated with fatal accidents and injury to oneself and related to high distress more than double the risk for PTSD. Thirdly, we compared the relative merits of the DSM-IV’s three-factor solution for PTSD symptoms to alternative models. We found that the symptomatology is equally well accounted for using all factor analytic models as yet presented in the literature; the DSM-IV, we found, provides as good a fit to data as other models. Fourthly, we examined the neurofunctional correlates of PTSD symptoms and whether a treatment-induced (serotonin reuptake inhibitor - SSRI) reduction of PTSD symptoms is associated with altered rCBF during symptom provocation. Our results indicate that PTSD symptoms correlates with areas involved in memory, emotion, attention, and motor control and that SSRI treatment normalizes provocation-induced rCBF in these areas.</p>

This thesis explored the epidemiology of Posttraumatic Stress Disorder (PTSD) and different aspects of the disorder. Firstly, we investigated the lifetime prevalence of traumatic experiences and PTSD in the general adult population in Sweden and evaluated the impact of different trauma types, trauma frequency, and perceived distress. The results show that traumatic experiences are common and PTSD is not rare; roughly one out of ten traumatic events results in PTSD, with a 5.6% lifetime prevalence. The female/male ratio is 2:1. The risk for PTSD increases considerably with a high trauma-associated emotional impact. The distressing impact of a given trauma appears to be higher in women than in men, indicating an increased vulnerability in women. Secondly, we hypothesized that traffic road accidents (TRA’s) are one of the most prevalent types of traumatic events in Swedish society; therefore, we examined the impact of event and response characteristics associated with TRA’s on PTSD development. The data demonstrate that of those who had experienced a TRA (n=1074, 58.9%), 6.1% reported lifetime PTSD. TRA’s associated with fatal accidents and injury to oneself and related to high distress more than double the risk for PTSD. Thirdly, we compared the relative merits of the DSM-IV’s three-factor solution for PTSD symptoms to alternative models. We found that the symptomatology is equally well accounted for using all factor analytic models as yet presented in the literature; the DSM-IV, we found, provides as good a fit to data as other models. Fourthly, we examined the neurofunctional correlates of PTSD symptoms and whether a treatment-induced (serotonin reuptake inhibitor - SSRI) reduction of PTSD symptoms is associated with altered rCBF during symptom provocation. Our results indicate that PTSD symptoms correlates with areas involved in memory, emotion, attention, and motor control and that SSRI treatment normalizes provocation-induced rCBF in these areas.

New biomarkers are needed to improve knowledge about pathophysiology, in order to provide earlier correct diagnosis and to follow disease progression of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). The aim of this thesis was to find new biomarkers for these diseases. First, increased serum levels and unchanged levels in postmortal spinal cord of vascular endothelial growth factor (VEGF) were demonstrated. VEGF was not detected in cerebrospinal fluid (CSF) in ALS. Second, increased levels of fibroblast growth factor 2 were found in the CSF and serum of ALS patients. Both studies used enzyme-linked immunoassays. Third, a proteomics method for CSF analysis was explored, based on tryptic digestion and subsequent separation and detection of the peptides by on-line liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry. ALS-specific patterns were observed. Four out of five samples were correctly assigned, but no single protein biomarker could be identified. Fourth, [11C](L)-deprenyl-D2 (DED) positron emission tomography (PET) demonstrated increased retention in the pons and white matter in ALS. DED binds to monoamino oxidase B, which in the brain is primarily located in astrocytes. Thus evidence was provided that astrocytosis may be detected in vivo in ALS. Fifth, normal [11C]-PIB binding in five nondemented patients with PD was reported, in contrast to previous findings of increased retention in Alzheimer's disease reflecting amyloid aggregation. Finally, the combined use of fluorodeoxyglucose and L-[β 11C]-DOPA PET for the differential diagnosis of parkinsonian syndromes was evaluated. PET provided support for the clinical diagnosis in 62 out of 75 patients, and served to exclude suspected diagnoses in another five patients.

The pathological process behind abdominal aortic aneurysm (AAA) formation is poorly understood and difficult to study. The aim of the thesis was to study the pathophysiology of AAA formation with positron emission tomography (PET) technology, a molecular imaging technique, allowing in vivo studies of pathophysiological changes. In study I 18F-FDG, a glucose analogue, was tested. It had previously been reported as a useful tracer studying inflammation in AAAs. These studies included, however, foremost large, symptomatic, and inflammatory AAAs. In the present study on five small and seven large asymptomatic AAAs, no increase in 18F-FDG uptake could be revealed in vivo. In study II 11C-PK11195, a macrophage tracer, and 11C-D-deprenyl, an unspecific inflammatory tracer, previously never tested on asymptomatic AAAs, were tested in vivo on five and 10 AAA-patients respectively, without signs of increased levels of inflammatory activity in the aorta. In study III several tracers were screened in vitro through autoradiography on AAA tissue. [18F]fluciclatide, targeting the integrin αVβ3 receptor upregulated in angiogenesis, was the only tracer with an increased uptake. In study IV [18F]fluciclatide-autoradiography was performed on AAA tissue from five patients and non-aneurysmal aortic tissue obtained from five age and sex matched organ donors. The study showed a 56% increased specific uptake in AAA, although not significant (P=0.136). Immunohistochemical revealed inflammatory cell foci in close relation to the vessels. In conclusion, PET has potential to elucidate the pathophysiology of AAA formation. For the large group of small asymptomatic AAAs, 18F-FDG is not suitable, as the chronic inflammation in asymptomatic AAA is not sufficiently metabolically active. Furthermore, 11C-PK11195 and 11C-D-deprenyl were unable to show the chronic inflammation seen in asymptomatic AAA. The interesting finding with uptake of [18F]fluciclatide showed that angiogenesis may be imaged in large asymptomatic AAAs in vitro, through the integrin αVβ3 receptor. Thus, it is likely that future studies of the role of angiogenesis in AAA formation in vivo, in small AAAs, could use this target site. The development of an integrin αVβ3 receptor tracer, preferably with higher affinity, is in progress for further in vitro and in vivo studies.

Die Positronen-Emissions-Tomographie (PET) bei der Schwerionentherapie ist eine wichtige Methode zur Qualitätskontrolle in der Tumortherapie mit Kohlenstoffionen. Die vorliegende Arbeit beschreibt die Verbesserungen des PET-Verfahrens, wodurch sich in der Folge präzisere Aussagen zur Dosisapplikation treffen lassen. Aufbauend auf den Grundlagen (Kap. 2) werden die Neuentwicklungen in den drei darauf folgenden Abschnitten (Modellierung des Abbildungsprozesses bei der PET, Streukorrektur für PET bei der Schwerionentherapie, Verarbeitung der rekonstruierten PET-Daten) beschrieben. Die PET-Methode bei der Schwerionentherapie basiert auf dem Vergleich zwischen den gemessenen und vorausberechneten Aktivitätsverteilungen. Die verwendeten Modelle in der Simulation (Erzeugung der Positronenemitter, deren Ausbreitung, der Transport und der Nachweis der Annihilationsquanten) sollten so präzise wie möglich sein, damit ein aussagekräftiger Vergleich möglich wird. Die Genauigkeit der Beschreibung der physikalischen Prozesse wurde verbessert und zeiteffiziente Algorithmen angewendet, die zu einer erheblichen Verkürzung der Rechenzeit führen. Die erwarteten bzw. die gemessenen räumlichen Radioaktivitätsverteilungen werden mit einem iterativen Verfahren rekonstruiert [Lau99]. Die gemessenen Daten müssen hinsichtlich der im Messobjekt auftretenden Comptonstreuung der Annihilationsphotonen korrigiert werden. Es wird ein geeignetes Verfahren zur Streukorrektur für die Therapieüberwachung vorgeschlagen und dessen Realisierung beschrieben. Zur Einschätzung der Güte der Behandlung wird die gemessene und die simulierte Aktivitätsverteilung verglichen. Dazu wurde im Rahmen der vorliegenden Arbeit eine Software entwickelt, das die rekonstruierten PET-Daten visualisiert und die anatomischen Informationen des Röntgentomogramms mit einbezieht. Nur durch dieses Auswerteverfahren war es möglich, Fehler im physikalischen Strahlmodell aufzudecken und somit die Bestrahlungsplanung zu verbessern.