206 research outputs found
Erratum to: Assessing brain immune activation in psychiatric disorders:clinical and preclinical PET imaging studies of the 18-kDa translocator protein (vol 3, pg 449, 2015)
No full textThe article “Assessing brain immune activation in psychiatric disorders: clinical and preclinical PET imaging studies of the 18-kDa translocator protein”, written by Thalia F. van der Doef, Janine Doorduin, Bart N. M. van Berckel, and Simon Cervenka, was originally published Online First without open access. After publication in volume 3, issue 6, pages 449–460, the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed t
Immune dysfunction and childhood trauma in schizophrenia spectrum disorders
Get PDFSchizophrenia spectrum disorders (SSS) is a group of disorders in which patients suffer from various symptoms such as delusions and hallucinations, as well as cognitive symptoms, depressive symptoms and negative symptoms (such as social withdrawal behaviour and apathy). The cause and underlying mechanisms involved in SSS are not precisely known. One hypothesis is that dysfunction of the immune system of the brain plays a role in the onset or perpetuation of symptoms. Some studies suggest that antipsychotics may affect the immune system of the brain positively and that this mechanism contributes to their working mechanism. The first part of this thesis consists of animal studies in which the effects of antipsychotics on immune dysfunction in the brains of rats were investigated using positron emission tomography (PET) scans. We found no or small effects, but methodological limitations make it difficult to draw conclusions. The second part of the study investigated the association between childhood trauma, immune dysfunction and negative and depressive symptoms in SSS patients. We found that childhood trauma leads to more severe depressive and negative symptoms and that childhood sexual abuse is more common in women. Based on the studies conducted, necessary elements of follow-up research were identified. Existing PET tracers are not specific enough to investigate immune dysfunction of the brain. Therefore, research into new PET tracers is important. In addition, it is important to look at men and women with SSS separately, because of the male-female differences in SSS patients
PET methodology in rat models of Parkinson’s disease
Get PDFParkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide. The use of animal, especially rodent, models is of utmost importance to expand our understanding of the pathological features and treatments for the disease. Research in PD patients and rodent disease models has indicated that several neurotransmitter systems and inflammatory processes are involved in the brain of PD patients. A common method for the assessment of physiological processes in vivo is positron emission tomography (PET). Radiolabelled compounds specific for a certain biological process are administered to a subject and subsequently their distribution through the body, or brain is followed over time using a PET camera. The distribution and kinetics of the radiolabelled compound can be used to quantify the physiological process of interest using mathematical models.In this thesis, methodological aspects for the quantification of markers of the cholinergic neurotransmitter system using PET imaging were evaluated. The optimal quantification methods for the PET radiotracers [11C]-PMP, an acetylcholinesterase substrate, and [18F]-FEOBV, a ligand of the vesicular acetylcholine transporter, were determined in rats. Furthermore, the newly characterized as well as established radiotracers were applied to quantify changes in cholinergic activity, dopaminergic innervation, and neuroinflammation in rat models of PD. In the first study in a striatal 6-OHDA model of PD, no increase in cholinergic activity was found up to one month after the 6-OHDA injection. Additionally, no effect of exercise on cholinergic activity was seen. In the second study, a rat model carrying one of the most common genetic mutations in PD patients (LRRK2 p.G2019S) was subjected to a peripheral inflammatory trigger and followed over several months. Ten months after the inflammatory trigger no change in dopaminergic innervation but increased neuroinflammation in brain regions related to other neurotransmitters was found
Biological interactions in depression: Insights from preclinical studies
Get PDFMajor depressive disorder (MDD) is considered a major global health burden, being the single largest contributor to global disability and suicides. Because of its complex multifactorial nature and the variety of symptoms observed in this disorder, still around 50% of MDD patients show no or incomplete response to pharmacological therapies. In this regard, studying the molecular interactions and risk factors of MDD is a key step to improve our knowledge of the etiology and the differences in the treatment response between patients. This thesis aimed to investigate the contribution of several underlying biological processes on the development of depressive behavior in animal models, such as steroidal hormone and monoamine signaling and neuroinflammation. We found that PET imaging is a useful tool to study the effects of sex hormones in the brain in a menopausal animal model, but that chronic stress was not a strong risk factor for developing depressive symptoms in this model. In addition, we showed in a stress model of depression that repeated social defeat induced neuroinflammation, but that this effect was not counteracted by the fast antidepressant ketamine or caffeine. In this animal model, we also showed that social stress caused delayed changes in dopaminergic and serotonergic transmission when depressive symptoms had already resolved. Finally, we observed that antidepressant therapy during pregnancy had a detrimental effect on cognition in the offspring. In conclusion, this thesis provides insight in different interactions between systems and risk factors, contributing to the general knowledge of MDD
Quantification methods for brain imaging with novel and repurposed PET tracers
Get PDFThe number of people suffering from brain disorders is annually increasing. Knowledge about the molecular processes in the healthy and diseased brain is essential for a better understanding of disease conditions, treatment selection, and drug development. Positron emission tomography (PET) is a noninvasive imaging technique that can be used to acquire information about processes that are essential for normal brain functioning, but are altered in neurodegenerative diseases. Quantitative information about specific targets inside the brain, such as the density, activity, or occupancy of particular enzymes, transporters, or receptors, can be obtained by pharmacokinetic modeling of PET data. In the present study, we assessed quantification methods for brain imaging with novel and repurposed PET tracers. A PET tracer for inflammation in the brain, called [11C]SC-560, was evaluated, but overexpression of the inflammatory marker COX-1, could not be detected in the inflamed rat brain. Thus, more efforts to find an appropriate tracer are required. Next, we determined the optimal method for quantification of histamine H3 receptors in the rat brain, using PET and the radiotracer [11C]GSK-189254. Blockade of these receptors may improve cognition in patients with dementia. [11C]GSK-189254 PET and [11C]raclopride PET were subsequently used to measure the dose-dependent occupancy of histamine H3 and dopamine D2 receptors in the brain of living rats by the investigational drug AG-0029. D2 receptors play an important role in motor control. Since AG-0029 blocks histamine H3 receptors and stimulates dopamine D2 receptors, AG-0029 is a candidate drug for treatment of Parkinson disease. Finally, we evaluated the feasibility of quantifying the expression of estrogen receptors in the brains of post-menopausal women with [18F]FES PET. We were able to detect estrogen receptors in brain regions with a high density of the receptor (i.e., the pituitary). The methods described in this study may be used to enhance knowledge about the brain, the treatment of brain diseases and the development of novel drugs
PET imaging of brain sex steroid hormone receptors and the role of estrogen in depression
Get PDFAndrogens and estrogens are steroid hormones that are involved in several neurodegenerative and psychiatric disorders. Decreased levels of steroid hormones are associated with e.g. decreased cognition, anxiety and depression. Androgens and estrogens exert their biological effects through their corresponding receptors. To better understand the role of androgen and estrogen receptors in the brain, it would be advantageous to be able to quantify the expression of these receptors in living subjects. Positron emission tomography (PET) is a non-invasive imaging technique that may allow quantification of steroid receptors in the brain. [18F]FDHT and [18F]FES are validated PET tracers for imaging of androgen and estrogen receptors in respectively prostate and breast cancer. In this thesis, [18F]FDHT and [18F]FES were evaluated as PET tracers for imaging of androgen and estrogen receptors in the brain of male and female rats. However, [18F]FDHT PET proved unsuitable for imaging of brain androgen receptors, whereas [18F]FES PET was only able to visualize estrogen receptors in brain regions with high receptor density like pituitary and hypothalamus. Next, the effect of estrogen replacement and stress on brain activity ([18F]FDG PET) and behavior (forced swim test, open-field test) was evaluated in ovariectomized rats with reduced levels of circulating estrogens. Ovariectomized rats can be considered as a model for post-menopausal women. Immediate treatment with estrogens could prevent a reduction in metabolism in fear processing brain regions and the depressive-like behavior induced by ovariectomy. Exposure to additional stress did not aggravate the effect of estrogen depletion on depressive-like behavior and brain metabolism
The two sides of the coin of psychosocial stress: Evaluation by positron emission tomography
Get PDFDepressieve stoornissen behoren tot de meest belastende aandoeningen voor de samenleving vanwege de hoge gezondheidszorgkosten, productiviteitsverlies, hoge invaliditeitsgraad en zelfmoord. Wereldwijd leiden ongeveer 350 miljoen mensen aan depressieve stoornissen; de levenslange prevalentie is 15-20%. Ondanks aanzienlijke inspanningen, zijn de mechanismen die ten grondslag liggen aan depressie nog onbekend. Een recente hypothese suggereert dat ontstekingsprocessen in de hersenen mogelijk betrokken zijn bij depressie. Stress is een belangrijke risicofactor voor het ontwikkelen van een depressie. Onderzoek naar de biologische processen die gerelateerd zijn aan stress en onstekingsprocessen in de hersenen zou kunnen helpen om de ziekte beter te begrijpen. In de huidige studie vonden wij dat activering van het stress systeem in het goed-gevalideerde “social defeat” diermodel ontstekingsprocessen in de hersenen en depressieve symptomen kan veroorzaken. We hebben in dit diermodel ook laten zien dat een stressvolle gebeurtenis op jonge leeftijd en significant effect heeft op het individuele gedrag en de ontstekingsreacties in de hersenen na een herhaling van de stressvolle situatie op latere leeftijd. Daarnaast hebben we gevonden in “social defeat” diermodel dat het winnen van agressieve confrontaties veranderingen veroorzaakt van receptoren in het brein die betrokken zijn bij het plezier/beloningsysteem. Dit suggereert dat er een verslavend effect ontstaat dat leidt tot geweld en agressie. In onze studies werd positron emissie tomografie (PET), een niet-invasieve functionele beeldvormende techniek, gebruikt om potentiële processen die ten grondslag liggen aan depressie en agressie te onderzoeken. Aangezien dezelfde methodologie ook in mensen kan worden toegepast, heeft PET de potentie om belangrijke informatie te verschaffen over veranderingen in het brein van depressieve en agressieve patiënten en aldus een bijdrage te leveren aan toekomstige gepersonaliseerde diagnose en therapie voor patiënten
Biologische risicofactoren (2): virussen
No full textNog niet zo heel lang geleden kregen patiënten in Nederland de diagnose schizofrenie te weinig en vaak ook te laat, waardoor gespecialiseerde behandeling veelal uitbleef. Gelukkig zijn diagnostiek en behandeling van patiënten met schizofrenie de laatste 25 jaar beduidend verbeterd. Men realiseerde zich dat het vanuit wetenschappelijk oogpunt essentieel was ook het begin van schizofrenie te bestuderen. Zo konden patiënten die nog nooit of weinig behandeling hadden gehad prospectief gevolgd worden om de etiologie en het beloop in kaart te brengen. Er kwamen in Nederland verschillende gespecialiseerde afdelingen voor patiënten met een eerste psychose, eerst in de academische ziekenhuizen en niet veel later ook in grote ggz-instellingen. Als het gaat om wetenschappelijk onderzoek naar ontstaan, beloop en behandeling van schizofrenie, wordt in Nederland steeds meer en intensiever samengewerkt.Desalniettemin blijft de discussie over schizofrenie levendig. Is schizofrenie één ziekte? Is het wel een ziekte? Welke nieuwe wetenschappelijke technieken moeten worden gebruikt om de oorzaken te ontrafelen? Moet de diagnose wel worden gesteld zo aan het begin van de ziekte? Wat heeft het geven van een diagnose schizofrenie voor effect op het beloop? Moet de naam ‘schizofrenie’ niet worden veranderd om het stigma te bestrijden? Wat is de beste behandeling en wat moet je doen in welke fase van de ziekte? Moeten we niet meer aan preventie doen en hoe kunnen we mensen met een hoog risico identificeren? Moeten we schizofrenie gaan stageren, zoals dat bij somatische aandoeningen als kanker wordt gedaan? En last but not least, wat vinden de patiënt en diens familie, en hoe kan in gezamenlijkheid de behandeling worden verbeterd? Handboek schizofrenie gaat onder meer in op deze vragen.<br/
Pre-clinical investigation of brain mechanisms associated with Parkinson’s disease: the impact of diet
Get PDFTentativas estão sendo feitas para encontrar uma cura ou pelo menos um tratamento melhor que possa retardar a progressão da doença de Parkinson (DP), mas, recentemente, nenhuma intervenção foi descoberta. Uma melhor compreensão dos mecanismos básicos que estão por trás dessa doença é de grande importância para o desenvolvimento de novos medicamentos. Fatores do estilo de vida, como a dieta, podem influenciar diversos mecanismos biológicos envolvidos na DP, como o sistema purinérgico, o sistema dopaminérgico, a neuroinflamação e a microbiota. Nesta tese, esses fatores serão explorados em diferentes modelos animais. No Capítulo 2, a interação dos receptores de adenosina com os receptores dopaminérgicos e o papel potencial dos ligantes do receptor de adenosina no tratamento da DP são revisados. Neste capítulo, a relação potencial da adenosina com o estilo de vida e o diabetes também é discutida. No Capítulo 3, investigamos a interação de receptores purinérgicos e dopaminérgicos em um modelo de DP em peixe-zebra. Após injeção intra-encefálica de 6-OHDA, o peixe-zebra apresentou alterações comportamentais e ligeiro efeito no sistema dopaminérgico. No Capítulo 4, investigamos a viabilidade da imagem PET in vivo em peixes-zebra adultos saudáveis e em um modelo de inflamação do peixe-zebra. Este estudo demonstrou que a imagem PET in vivo com 18F-FDG e 18F-NaF em peixes-zebra vivos é viável e diferenças na captação podem ser vistas em um modelo de inflamação. No Capítulo 5, analisamos o impacto de uma dieta de cafeteria no sistema de recompensa em ratos. Nosso estudo sugere que os receptores D2 desempenham um papel na obesidade e no consumo de uma dieta de cafeteria, mas nenhuma alteração após o desafio foi observada. Para elucidar a influência de uma dieta rica em gordura (HFD) na progressão da DP, investigamos o efeito de uma HFD sobre a disponibilidade de receptores D2 e parâmetros comportamentais em ratos, no Capítulo 6. A HFD agravou o dano no modelo de DP, sugerindo um papel prejudicial do HFD no início ou na progressão da DP. No Capítulo 7, sugerimos que o impacto documentado da HFD na neuroinflamação pode ser mediado pela microbiota intestinal no modelo de DP utilizando 6-OHDA em ratos e este é independente da inflamação periférica. O conhecimento dos mecanismos básicos subjacentes à DP e sua relação com as mudanças no estilo de vida pode ajudar os cientistas a entender melhor os fatores que desencadeiam o aparecimento da doença e no desenvolvimento de novos tratamentos e ferramentas de diagnóstico. Esses estudos podem ajudar a revelar a interação entre comportamento, microbiota, resposta dopaminérgica e purinérgica e inflamação no intestino e no cérebro.Attempts are being made to find a cure or at least a better treatment that can slow down the progression of Parkinson’s disease, but recently, no intervention has been discovered. A better understanding of the basic mechanisms that underlie this disease is of great importance for the development of new drugs. Lifestyle factors, such diet, can influence different biological mechanisms involved in PD, such as the purinergic system, the dopaminergic system, neuroinflammation and microbiota. In this thesis, these factors will be explored in different animal models. In Chapter 2, the interaction of adenosine receptors with dopaminergic receptors and the potential role of adenosine receptor ligands in the treatment of PD are reviewed. In this chapter, the potential relation of adenosine with lifestyle and diabetes is discussed as well. In Chapter 3, we investigated the interaction of purinergic and dopaminergic receptors in a zebrafish model of PD. After intra-encephalic injection of 6-OHDA, zebrafish presented behavioral changes and slight effect on the dopaminergic system. In Chapter 4, we investigated the feasibility of in vivo PET imaging in living healthy adult zebrafish and in a zebrafish model of inflammation. This study demonstrated that in vivo PET imaging with 18F-FDG and 18F-NaF in living zebrafish is feasible and differences in uptake can be seen in a model of inflammation. In Chapter 5, we analyzed the impact of a cafeteria diet on the reward system in rats. Our study suggests that D2 receptors play a role in obesity and consumption of a cafeteria diet, but no alterations after challenge was observed. To elucidate the influence of a high fat diet (HFD) on PD progression, we investigated the effect of a HFD on the availability of D2 receptors and behavioral parameters in rats, in Chapter 6. The HFD aggravated the damage in the PD model, suggesting a detrimental role of the HFD on the onset or progression of PD. In Chapter 7, we suggest that the documented impact of HFD on neuroinflammation may be mediated by the gut microbiome in the 6-OHDA rat model of PD and it is independent of peripheral inflammation. The knowledge of the basic mechanisms underlying PD and their relationship with changes in lifestyle can help scientists to better understand the factors that trigger the onset of the disease and aid the development of new treatments and diagnostic tools. These studies can help reveal of the interaction between behavior, microbiota, dopaminergic and purinergic response, and inflammation in the gut and the brain
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