115 results on '"Janine Doorduin"'
Search Results
2. Prenatal infection and adolescent social adversity affect microglia, synaptic density, and behavior in male rats
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Cyprien G.J. Guerrin, Kavya Prasad, Daniel A. Vazquez-Matias, Jing Zheng, Maria Franquesa-Mullerat, Lara Barazzuol, Janine Doorduin, and Erik F.J. de Vries
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Maternal immune activation ,Social adversity ,Microglia ,Synaptic density ,Synaptophysin ,Neurodevelopmental disorders ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Maternal infection during pregnancy and childhood social trauma have been associated with neurodevelopmental and affective disorders, such as schizophrenia, autism spectrum disorders, bipolar disorder and depression. These disorders are characterized by changes in microglial cells, which play a notable role in synaptic pruning, and synaptic deficits. Here, we investigated the effect of prenatal infection and social adversity during adolescence – either alone or in combination – on behavior, microglia, and synaptic density. Male offspring of pregnant rats injected with poly I:C, mimicking prenatal infection, were exposed to repeated social defeat during adolescence. We found that maternal infection during pregnancy prevented the reduction in social behavior and increase in anxiety induced by social adversity during adolescence. Furthermore, maternal infection and social adversity, alone or in combination, induced hyperlocomotion in adulthood. Longitudinal in vivo imaging with [11C]PBR28 positron emission tomography revealed that prenatal infection alone and social adversity during adolescence alone induced a transient increase in translocator protein TSPO density, an indicator of glial reactivity, whereas their combination induced a long-lasting increase that remained until adulthood. Furthermore, only the combination of prenatal infection and social adversity during adolescence induced an increase in microglial cell density in the frontal cortex. Prenatal infection increased proinflammatory cytokine IL-1β protein levels in hippocampus and social adversity reduced anti-inflammatory cytokine IL-10 protein levels in hippocampus during adulthood. This reduction in IL-10 was prevented if rats were previously exposed to prenatal infection. Adult offspring exposed to prenatal infection or adolescent social adversity had a higher synaptic density in the frontal cortex, but not hippocampus, as evaluated by synaptophysin density. Interestingly, such an increase in synaptic density was not observed in rats exposed to the combination of prenatal infection and social adversity, perhaps due to the long-lasting increase in microglial density, which may lead to an increase in microglial synaptic pruning. These findings suggest that changes in microglia activity and cytokine release induced by prenatal infection and social adversity during adolescence may be related to a reduced synaptic pruning, resulting in a higher synaptic density and behavioral changes in adulthood.
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- 2023
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3. Alzheimer’s disease pattern derived from relative cerebral flow as an alternative for the metabolic pattern using SSM/PCA
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Débora E. Peretti, David Vállez García, Remco J. Renken, Fransje E. Reesink, Janine Doorduin, Bauke M. de Jong, Peter P. De Deyn, Rudi A. J. O. Dierckx, and Ronald Boellaard
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Alzheimer’s disease ,Disease pattern ,Relative cerebral blood flow ,SSM/PCA ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background 2-Deoxy-2-[18F]fluoroglucose (FDG) PET is an important tool for the identification of Alzheimer’s disease (AD) patients through the characteristic neurodegeneration pattern that these patients present. Regional cerebral blood flow (rCBF) images derived from dynamic 11C-labelled Pittsburgh Compound B (PIB) have been shown to present a similar pattern as FDG. Moreover, multivariate analysis techniques, such as scaled subprofile modelling using principal component analysis (SSM/PCA), can be used to generate disease-specific patterns (DP) that may aid in the classification of subjects. Therefore, the aim of this study was to compare rCBF AD-DPs with FDG AD-DP and their respective performances. Therefore, 52 subjects were included in this study. Fifteen AD and 16 healthy control subjects were used to generate four AD-DP: one based on relative cerebral trace blood (R 1), two based on time-weighted average of initial frame intervals (ePIB), and one based on FDG images. Furthermore, 21 subjects diagnosed with mild cognitive impairment were tested against these AD-DPs. Results In general, the rCBF and FDG AD-DPs were characterized by a reduction in cortical frontal, temporal, and parietal lobes. FDG and rCBF methods presented similar score distribution. Conclusion rCBF images may provide an alternative for FDG PET scans for the identification of AD patients through SSM/PCA.
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- 2022
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4. Social adversity during juvenile age but not adulthood increases susceptibility to an immune challenge later in life
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Cyprien G.J. Guerrin, Janine Doorduin, Kavya Prasad, Daniel A. Vazquez-Matias, Lara Barazzuol, and Erik F.J. de Vries
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Social stress ,Psychopathologies ,Microglia priming ,Dual hit model ,Adolescent social defeat ,LPS challenge ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Adverse experiences in early life can increase mental vulnerability to immune challenges experienced later in life, which may induce the development of stress-related psychopathologies. Here, we investigated whether the combined effect of both events is higher if the first adverse experience occurs when the brain is still in development. Therefore, male Wistar rats were exposed to repeated social defeat (RSD, first hit) during juvenile age or adulthood and to an immune challenge consisting of a single injection of lipopolysaccharide (LPS, second hit) in adulthood. Control animals were not exposed to RSD, but only to the LPS challenge. Translocator protein density, a marker for reactive microglia, microglia cell density and plasma corticosterone levels were measured using in vivo [11C]PBR28 positron emission tomography, iba1 immunostaining, and corticosterone ELISA, respectively. Anhedonia, social behavior and anxiety were measured with the sucrose preference, social interaction, and open field tests, respectively. Rats exposed to RSD during juvenile age exhibited enhanced anhedonia and social interaction dysfunction after an immune challenge in adulthood. This enhanced susceptibility was not observed in rats exposed to RSD during adulthood. In addition, exposure to RSD synergistically increased microglia cell density and glial reactivity to the LPS challenge. This increase in microglia cell density and reactivity to the LPS challenge was more pronounced in rats exposed to RSD during juvenile age than in adulthood. Exposure to RSD alone in juvenile age or adulthood induced similar short-term anhedonia, a long-lasting increase in plasma corticosterone and microglial activity, but no change in anxiety and social behavior. Our findings indicate that exposure to social stress during juvenile age, but not adulthood, primes the immune system and increases the sensitivity to an immune challenge experienced later in life. This suggests that juvenile social stress can have more deleterious effects in the long term than similar stress in adulthood.
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- 2023
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5. A single dose of ketamine cannot prevent protracted stress-induced anhedonia and neuroinflammation in rats
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Rodrigo Moraga-Amaro, Cyprien G. J. Guerrin, Luiza Reali Nazario, Bruno Lima Giacobbo, Rudi A. J. O. Dierckx, Jimmy Stehberg, Erik F. J. de Vries, and Janine Doorduin
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neuroinflammation ,major depressive disorder ,repeated social defeat ,ketamine ,positron emission tomography ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Worldwide, millions of people suffer from treatment-resistant depression. Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant effect even in treatment-resistant patients. A proposed mechanism for the antidepressant effect of ketamine is the reduction of neuroinflammation. To further explore this hypothesis, we investigated whether a single dose of ketamine can modulate protracted neuroinflammation in a repeated social defeat (RSD) stress rat model, which resembles features of depression. To this end, male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A combination of behavioral analyses and PET scans of the inflammatory marker TSPO in the brain were performed. Rats submitted to RSD showed anhedonia-like behavior in the sucrose preference test, decreased weight gain, and increased TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195 PET. Whole brain TSPO levels correlated with corticosterone levels in several brain regions of RSD exposed animals, but not in controls. Ketamine injection 1 day after RSD disrupted the correlation between TSPO levels and serum corticosterone levels, but had no effect on depressive-like symptoms, weight gain or the protracted RSD-induced increase in TSPO expression in male rats. These results suggest that ketamine does not exert its effect on the hypothalamic–pituitary–adrenal axis by modulation of neuroinflammation.
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- 2022
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6. Diagnostic performance of regional cerebral blood flow images derived from dynamic PIB scans in Alzheimer’s disease
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Débora E. Peretti, David Vállez García, Fransje E. Reesink, Janine Doorduin, Bauke M. de Jong, Peter P. De Deyn, Rudi A. J. O. Dierckx, and Ronald Boellaard
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Alzheimer’s disease ,PIB ,Relative cerebral blood flow ,PALZ ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background In clinical practice, visual assessment of glucose metabolism images is often used for the diagnosis of Alzheimer’s disease (AD) through 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) scans. However, visual assessment of the characteristic AD hypometabolic pattern relies on the expertise of the reader. Therefore, user-independent pipelines are preferred to evaluate the images and to classify the subjects. Moreover, glucose consumption is highly correlated with cerebral perfusion. Regional cerebral blood flow (rCBF) images can be derived from dynamic 11C-labelled Pittsburgh Compound B PET scans, which are also used for the assessment of the deposition of amyloid-β plaques on the brain, a fundamental characteristic of AD. The aim of this study was to explore whether these rCBF PIB images could be used for diagnostic purposes through the PMOD Alzheimer’s Discrimination Tool. Results Both tracer relative cerebral flow (R 1) and early PIB (ePIB) (20–130 s) uptake presented a good correlation when compared to FDG standardized uptake value ratio (SUVR), while ePIB (1–8 min) showed a worse correlation. All receiver operating characteristic curves exhibited a similar shape, with high area under the curve values, and no statistically significant differences were found between curves. However, R 1 and ePIB (1–8 min) had the highest sensitivity, while FDG SUVR had the highest specificity. Conclusion rCBF images were suggested to be a good surrogate for FDG scans for diagnostic purposes considering an adjusted threshold value.
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- 2019
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7. Feasibility of pharmacokinetic parametric PET images in scaled subprofile modelling using principal component analysis
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Débora E. Peretti, Remco J. Renken, Fransje E. Reesink, Bauke M. de Jong, Peter P. De Deyn, Rudi A.J.O. Dierckx, Janine Doorduin, Ronald Boellaard, and David Vállez García
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Alzheimer’s disease ,Disease pattern ,Pharmacokinetic modelling ,Pittsburgh compound B ,SSM/PCA ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Scaled subprofile model using principal component analysis (SSM/PCA) is a multivariate analysis technique used, mainly in [18F]-2-fluoro-2-deoxy-d-glucose (FDG) PET studies, for the generation of disease-specific metabolic patterns (DP) that may aid with the classification of subjects with neurological disorders, like Alzheimer’s disease (AD). The aim of this study was to explore the feasibility of using quantitative parametric images for this type of analysis, with dynamic [11C]-labelled Pittsburgh Compound B (PIB) PET data as an example. Therefore, 15 AD patients and 15 healthy control subjects were included in an SSM/PCA analysis to generate four AD-DPs using relative cerebral blood flow (R1), binding potential (BPND) and SUVR images derived from dynamic PIB and static FDG-PET studies. Furthermore, 49 new subjects with a variety of neurodegenerative cognitive disorders were tested against these DPs. The AD-DP was characterized by a reduction in the frontal, parietal, and temporal lobes voxel values for R1 and SUVR-FDG DPs; and by a general increase of values in cortical areas for BPND and SUVR-PIB DPs. In conclusion, the results suggest that the combination of parametric images derived from a single dynamic scan might be a good alternative for subject classification instead of using 2 independent PET studies.
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- 2021
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8. Intrastriatal gradient analyses of 18F-FDOPA PET scans for differentiation of Parkinsonian disorders
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Gilles N. Stormezand, Lumi T. Chaves, David Vállez García, Janine Doorduin, Bauke M. De Jong, Klaus L. Leenders, Berry P.H. Kremer, and Rudi A.J.O. Dierckx
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Aim: L -3,4-dihydroxy-6–18F-fluorophenylalanine (18F-DOPA PET may be used to distinguish subjects with Parkinsonism from those with symptoms not originating from impaired dopaminergic transmission. However, it is not routinely utilized to discriminate Idiopathic Parkinson's disease (IPD) from Atypical Parkinsonian Disorders (APD). We investigated the potential of FDOPA PET to discriminate between IPD and APD, with a focus on the anterior-to-posterior decline in het striatum, considered to be more specific for IPD. Materials and methods: 18F-DOPA PET data from a total of 58 subjects were retrospectively analyzed. 28 subjects had idiopathic Parkinson's disease (14 male, 14 female; age at scan 61 +- 11,5), 13 atypical Parkinsonian disease (7 male, 6 females; age at scan: 69,6 +- 6,4) and 17 were controls (6 male, 11 female; age at scan 65,3 +-8,6). Regional striatal-to-occipital ratio's (RSOR's) were calculated, as well as multiple in-line VOI's from the caudate nucleus to the posterior part of the putamen. The linearity of anteroposterior decline was determined by a linear regression fit and associated R squared values. ROC curves were calculated to assess the diagnostic performance of these measurements. Data contralateral to the clinically most affected side were used for analysis. Results: ROC curve analysis for differentiation between controls and Parkinsonism patients showed the highest AUC for the caudate nucleus-to-posterior putamen ratio (AUC = 0.930; p
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- 2020
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9. Optimization of the k2′ Parameter Estimation for the Pharmacokinetic Modeling of Dynamic PIB PET Scans Using SRTM2
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Débora E. Peretti, Fransje E. Reesink, Janine Doorduin, Bauke M. de Jong, Peter P. De Deyn, Rudi A. J. O. Dierckx, Ronald Boellaard, and David Vállez García
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Alzheimer's disease ,pharmacokinetic modeling ,Pittsburgh compound B ,SRTM ,SRTM2 ,Physics ,QC1-999 - Abstract
Background: This study explores different approaches to estimate the clearance rate of the reference tissue (k2′) parameter used for pharmacokinetic modeling, using the simplified reference tissue model 2 (SRMT2) and further explores the effect on the binding potential (BPND) of 11C-labeled Pittsburgh Compound B (PIB) PET scans.Methods: Thirty subjects underwent a dynamic PIB PET scan and were classified as PIB positive (+) or negative (–). Thirteen regions were defined from where to estimate k2′: the whole brain, eight anatomical region based on the Hammer's atlas, one region based on a SPM comparison between groups on a voxel level, and three regions using different BPNDSRTM thresholds.Results: The different approaches resulted in distinct k2′ estimations per subject. The median value of the estimated k2′ across all subjects in the whole brain was 0.057. In general, PIB+ subjects presented smaller k2′ estimates than this median, and PIB–, larger. Furthermore, only threshold and white matter methods resulted in non-significant differences between groups. Moreover, threshold approaches yielded the best correlation between BPNDSRTM and BPNDSRTM2 for both groups (R2 = 0.85 for PIB+, and R2 = 0.88 for PIB–). Lastly, a sensitivity analysis showed that overestimating k2′ values resulted in less biased BPNDSRTM2 estimates.Conclusion: Setting a threshold on BPNDSRTM might be the best method to estimate k2′ in voxel-based modeling approaches, while the use of a white matter region might be a better option for a volume of interest based analysis.
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- 2019
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10. Altered Regional Cerebral Blood Flow in Chronic Whiplash Associated Disorders
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David Vállez García, Janine Doorduin, Antoon T.M. Willemsen, Rudi A.J.O. Dierckx, and Andreas Otte
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Whiplash associated disorders ,Positron emission tomography ,Non-painful electrical stimulation ,Neuropsychological questionnaires ,Medicine ,Medicine (General) ,R5-920 - Abstract
There is increasing evidence of central hyperexcitability in chronic whiplash-associated disorders (cWAD). However, little is known about how an apparently simple cervical spine injury can induce changes in cerebral processes. The present study was designed (1) to validate previous results showing alterations of regional cerebral blood flow (rCBF) in cWAD, (2) to test if central hyperexcitability reflects changes in rCBF upon non-painful stimulation of the neck, and (3) to verify our hypothesis that the missing link in understanding the underlying pathophysiology could be the close interaction between the neck and midbrain structures. For this purpose, alterations of rCBF were explored in a case-control study using H215O positron emission tomography, where each group was exposed to four different conditions, including rest and different levels of non-painful electrical stimulation of the neck. rCBF was found to be elevated in patients with cWAD in the posterior cingulate and precuneus, and decreased in the superior temporal, parahippocampal, and inferior frontal gyri, the thalamus and the insular cortex when compared with rCBF in healthy controls. No differences in rCBF were observed between different levels of electrical stimulation. The alterations in regions directly involved with pain perception and interoceptive processing indicate that cWAD symptoms might be the consequence of a mismatch during the integration of information in brain regions involved in pain processing.
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- 2016
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11. Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats.
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Setayesh R Tasbihgou, Mina Netkova, Alain F Kalmar, Janine Doorduin, Michel M R F Struys, Regien G Schoemaker, and Anthony R Absalom
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Medicine ,Science - Abstract
In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9-11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage.
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- 2018
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12. Increased White Matter Inflammation in Aging- and Alzheimer’s Disease Brain
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Divya Raj, Zhuoran Yin, Marjolein Breur, Janine Doorduin, Inge R. Holtman, Marta Olah, Ietje J. Mantingh-Otter, Debby Van Dam, Peter P. De Deyn, Wilfred den Dunnen, Bart J. L. Eggen, Sandra Amor, and Erik Boddeke
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white matter ,microglia ,neuroinflammation ,aging ,Alzheimer’s disease ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer’s disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.
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- 2017
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13. Positron Emission Tomography studies with [11C]PBR28 in the Healthy Rodent Brain: Validating SUV as an Outcome Measure of Neuroinflammation.
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Miklós Tóth, Janine Doorduin, Jenny Häggkvist, Andrea Varrone, Nahid Amini, Christer Halldin, and Balázs Gulyás
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Medicine ,Science - Abstract
Molecular imaging of the 18 kD Translocator protein (TSPO) with positron emission tomography (PET) is of great value for studying neuroinflammation in rodents longitudinally. Quantification of the TSPO in rodents is, however, quite challenging. There is no suitable reference region and the use of plasma-derived input is not an option for longitudinal studies. The aim of this study was therefore to evaluate the use of the standardized uptake value (SUV) as an outcome measure for TSPO imaging in rodent brain PET studies, using [11C]PBR28. In the first part of the study, healthy male Wistar rats (n = 4) were used to determine the correlation between the distribution volume (VT, calculated with Logan graphical analysis) and the SUV. In the second part, healthy male Wistar rats (n = 4) and healthy male C57BL/6J mice (n = 4), were used to determine the test-retest variability of the SUV, with a 7-day interval between measurements. Dynamic PET scans of 63 minutes were acquired with a nanoScan PET/MRI and nanoScan PET/CT. An MRI scan was made for anatomical reference with each measurement. The whole brain VT of [11C]PBR28 in rats was 42.9 ± 1.7. A statistically significant correlation (r2 = 0.96; p < 0.01) was found between the VT and the SUV. The test-retest variability in 8 brain region ranged from 8 to 20% in rats and from 7 to 23% in mice. The interclass correlation coefficient (ICC) was acceptable to excellent for rats, but poor to acceptable for mice.The SUV of [11C]PBR28 showed a high correlation with VT as well as good test-retest variability. For future longitudinal small animal PET studies the SUV can thus be used to describe [11C]PBR28 uptake in healthy brain tissue. Based on the present observations, further studies are needed to explore the applicability of this approach in small animal disease models, with special regard to neuroinflammatory models.
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- 2015
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14. Correction: A Standardized Method for the Construction of Tracer Specific PET and SPECT Rat Brain Templates: Validation and Implementation of a Toolbox.
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David Vállez Garcia, Cindy Casteels, Adam J Schwarz, Rudi A J O Dierckx, Michel Koole, and Janine Doorduin
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Medicine ,Science - Published
- 2015
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15. A standardized method for the construction of tracer specific PET and SPECT rat brain templates: validation and implementation of a toolbox.
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David Vállez Garcia, Cindy Casteels, Adam J Schwarz, Rudi A J O Dierckx, Michel Koole, and Janine Doorduin
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Medicine ,Science - Abstract
High-resolution anatomical image data in preclinical brain PET and SPECT studies is often not available, and inter-modality spatial normalization to an MRI brain template is frequently performed. However, this procedure can be challenging for tracers where substantial anatomical structures present limited tracer uptake. Therefore, we constructed and validated strain- and tracer-specific rat brain templates in Paxinos space to allow intra-modal registration. PET [18F]FDG, [11C]flumazenil, [11C]MeDAS, [11C]PK11195 and [11C]raclopride, and SPECT [99mTc]HMPAO brain scans were acquired from healthy male rats. Tracer-specific templates were constructed by averaging the scans, and by spatial normalization to a widely used MRI-based template. The added value of tracer-specific templates was evaluated by quantification of the residual error between original and realigned voxels after random misalignments of the data set. Additionally, the impact of strain differences, disease uptake patterns (focal and diffuse lesion), and the effect of image and template size on the registration errors were explored. Mean registration errors were 0.70 ± 0.32 mm for [18F]FDG (n = 25), 0.23 ± 0.10mm for [11C]flumazenil (n = 13), 0.88 ± 0.20 mm for [11C]MeDAS (n = 15), 0.64 ± 0.28 mm for [11C]PK11195 (n = 19), 0.34 ± 0.15 mm for [11C]raclopride (n = 6), and 0.40 ± 0.13 mm for [99mTc]HMPAO (n = 15). These values were smallest with tracer-specific templates, when compared to the use of [18F]FDG as reference template (p
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- 2015
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16. An animal model of emotional blunting in schizophrenia.
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Charmaine Y Pietersen, Fokko J Bosker, Janine Doorduin, Minke E Jongsma, Folkert Postema, Joseph V Haas, Michael P Johnson, Tineke Koch, Tony Vladusich, and Johan A den Boer
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Medicine ,Science - Abstract
Schizophrenia is often associated with emotional blunting--the diminished ability to respond to emotionally salient stimuli--particularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed.
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- 2007
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17. Antiviral treatment in schizophrenia: a randomized pilot PET study on the effects of valaciclovir on neuroinflammation
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Iris Jonker, Janine Doorduin, Henderikus Knegtering, Erna van't Hag, Rudi A. Dierckx, Erik F. J. de Vries, Robert A. Schoevers, and Hans C. Klein
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Psychiatry and Mental health ,Applied Psychology - Abstract
Abstract Background Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. Methods We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition. Results Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31–40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found. Conclusion We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research.
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- 2023
18. Immune Activation in Pregnant Rats Affects Brain Glucose Consumption, Anxiety-like Behaviour and Recognition Memory in their Male Offspring
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Cyprien G. J. Guerrin, Alexandre Shoji, Janine Doorduin, Erik F. J. de Vries, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Male ,Memory Disorders ,Cancer Research ,Behavior, Animal ,Brain ,Anxiety ,Rats ,Disease Models, Animal ,Poly I-C ,Glucose ,Receptors, GABA ,Oncology ,Pregnancy ,Fluorodeoxyglucose F18 ,Prenatal Exposure Delayed Effects ,Humans ,Animals ,Female ,Radiology, Nuclear Medicine and imaging - Abstract
Purpose Prenatal infection during pregnancy is a risk factor for schizophrenia, as well as for other developmental psychiatric disorders, such as autism and bipolar disorder. Schizophrenia patients were reported to have altered brain metabolism and neuroinflammation. However, the link between prenatal infection, altered brain inflammation and metabolism, and schizophrenia remains unclear. In this project, we aimed to evaluate whether there are changes in brain glucose consumption and microglia activation in the offspring of pregnant rats exposed to maternal immune activation (MIA), and if so, whether these changes occur before or after the initiation of schizophrenia-like behaviour. Procedures Pregnant rats were treated with the viral mimic polyinosinic-polycytidylic acid (MIA group) or saline (control group) on gestational day 15. Static PET scans of the male offspring were acquired on postnatal day (PND) 21, 60, and 90, using [11C]-PK11195 and deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) as tracers to measure TSPO expression in activated microglia and brain glucose consumption, respectively. On PND60 and PND90, anxiety-like behaviour, recognition memory, and sensorimotor gating were measured using the open field test (OFT), novel object recognition test (NOR), and prepulse inhibition test (PPI). Results [18F]-FDG PET demonstrated that MIA offspring displayed higher brain glucose consumption in the whole brain after weaning (p = 0.017), and in the frontal cortex during late adolescence (p = 0.001) and adulthood (p = 0.037) than control rats. [11C]-PK11195 PET did not reveal any changes in TSPO expression in MIA offspring. Prenatal infection induced age-related behavioural alterations. Adolescent MIA offspring displayed a more anxious state in the OFT than controls (p = 0.042). Adult MIA offspring showed recognition memory deficits in the NOR (p = 0.003). Our study did not show any PPI deficits. Conclusions Our results suggest that prenatal immune activation changed neurodevelopment, resulting in increased brain glucose consumption, but not in microglia activation. The increased brain glucose consumption in the frontal cortex of MIA offspring remained until adulthood and was associated with increased anxiety-like behaviour during adolescence and recognition memory deficits in adulthood.
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- 2022
19. Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia.
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Xiaoyun Zhou, Janine Doorduin, Philip H. Elsinga, Rudi A. J. O. Dierckx, Erik F. J. de Vries, and Cindy Casteels
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- 2017
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20. Pharmacokinetic Modeling of [11C]GSK-189254, PET Tracer Targeting H3 Receptors, in Rat Brain
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Nafiseh Ghazanfari, Aren van Waarde, Janine Doorduin, Jürgen W. A. Sijbesma, Maria Kominia, Martin Koelewijn, Khaled Attia, Antoon T. M. Willemsen, Ton J. Visser, André Heeres, Rudi A. J. O. Dierckx, Erik F. J. de Vries, Philip H. Elsinga, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Molecular Neuroscience and Ageing Research (MOLAR), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
Drug Discovery ,Pharmaceutical Science ,Molecular Medicine - Abstract
The histamine H3 receptor has been considered as a target for the treatment of various central nervous system diseases. Positron emission tomography (PET) studies with the radiolabeled potent and selective histamine H3 receptor antagonist [11C]GSK-189254 in rodents could be used to examine the mechanisms of action of novel therapeutic drugs or to assess changes of regional H3 receptor density in animal models of neurodegenerative disease. [11C]GSK-189254 was intravenously administered to healthy Wistar rats (n = 10), and a 60 min dynamic PET scan was carried out. Arterial blood samples were obtained during the scan to generate a metabolite-corrected plasma input function. PET data were analyzed using a one-tissue compartment model (1T2k), irreversible (2T3k) or reversible two-tissue compartment models (2T4k), graphical analysis (Logan and Patlak), reference tissue models (SRTM and SRTM2), and standard uptake values (SUVs). The Akaike information criterion and the standard error of the estimated parameters were used to select the most optimal quantification method. This study demonstrated that the 2T4k model with a fixed blood volume fraction and Logan graphical analysis can best describe the kinetics of [11C]GSK-189254 in the rat brain. SUV40-60 and the reference tissue-based measurements DVR(2T4k), BPND(SRTM), and SUV ratio could also be used as a simplified method to estimate H3 receptor availability in case blood sampling is not feasible.
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- 2022
21. The dual hit hypothesis of schizophrenia
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Janine Doorduin, Cyprien G J Guerrin, Erik F. J. de Vries, and Iris E. C. Sommer
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business.industry ,Dopamine ,Maternal Deprivation ,Cognitive Neuroscience ,Dopaminergic ,food and beverages ,Bioinformatics ,medicine.disease ,Affect (psychology) ,Substance abuse ,Disease Models, Animal ,Behavioral Neuroscience ,Neuropsychology and Physiological Psychology ,Schizophrenia ,medicine ,Genetic predisposition ,Animals ,Humans ,Animal studies ,Social isolation ,medicine.symptom ,Risk factor ,business - Abstract
Schizophrenia is a heterogeneous psychiatric disorder, which can severely impact social and professional functioning. Epidemiological and clinical studies show that schizophrenia has a multifactorial aetiology comprising genetic and environmental risk factors. Although several risk factors have been identified, it is still not clear how they result in schizophrenia. This knowledge gap, however, can be investigated in animal studies. In this review, we summarise animal studies regarding molecular and cellular mechanisms through which genetic and environmental factors may affect brain development, ultimately causing schizophrenia. Preclinical studies suggest that early environmental risk factors can affect the immune, GABAergic, glutamatergic, or dopaminergic system and thus increase the susceptibility to another risk factor later in life. A second insult, like social isolation, stress, or drug abuse, can further disrupt these systems and the interactions between them, leading to behavioural abnormalities. Surprisingly, first insults like maternal infection and early maternal separation can also have protective effects. Single gene mutations associated with schizophrenia did not have a major impact on the susceptibility to subsequent environmental hits.
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- 2021
22. Is cyclooxygenase‐1 involved in neuroinflammation?
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Rudi Dierckx, Aren van Waarde, Erik F. J. de Vries, Janine Doorduin, and Nafiseh Ghazanfari
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Lipopolysaccharides ,Chemokine ,Postmortem studies ,Inflammation ,Dinoprostone ,neuroinflammation ,prostaglandins ,Cellular and Molecular Neuroscience ,PET TRACER ,PARKINSONS-DISEASE ,T-LYMPHOCYTES ,Downregulation and upregulation ,In vivo ,Animals ,Humans ,Medicine ,Prostaglandin E2 ,IN-VIVO ,Neuroinflammation ,biology ,Microglia ,COX-1 ,ACTIVATED MICROGLIA ,business.industry ,CENTRAL-NERVOUS-SYSTEM ,PHOSPHOLIPASE-C ,cyclooxygenase ,ALZHEIMERS-DISEASE ,medicine.anatomical_structure ,GENERAL-METHOD ,Cyclooxygenase 2 ,Neuroinflammatory Diseases ,Cyclooxygenase 1 ,biology.protein ,Cancer research ,COX-2 INHIBITORS ,medicine.symptom ,business ,medicine.drug - Abstract
Purpose Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX-2 subtype has been associated with inflammation, whereas the constitutively expressed COX-1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX-1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX-1. Methods Five databases were used to retrieve relevant studies that addressed COX-1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX-1 isoform under such conditions. Results Reviewed literature generally indicated that the overexpression of COX-1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX-1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX-1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX-1 in patients with Alzheimer's disease. Conclusion Taken together, studies in cultured cells and living rodents suggest that COX-1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX-1-expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX-1 in neuroinflammation in the living human brain is still largely lacking.
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- 2021
23. Cerebral adenosine A1 receptors are upregulated in rodent encephalitis.
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Soumen Paul, Shivashankar Khanapur, Wytske Boersma, Jurgen W. A. Sijbesma, Kiichi Ishiwata, Philip H. Elsinga, Peter Meerlo, Janine Doorduin, Rudi A. Dierckx, and Aren van Waarde
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- 2014
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24. Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D
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Nafiseh, Ghazanfari, Aren, van Waarde, Janine, Doorduin, Jürgen W A, Sijbesma, Maria, Kominia, Martin, Koelewijn, Khaled, Attia, David, Vállez-García, Antoon T M, Willemsen, André, Heeres, Rudi A J O, Dierckx, Ton J, Visser, Erik F J, de Vries, and Philip H, Elsinga
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Male ,Mammals ,Receptors, Dopamine D2 ,Dopamine ,Receptors, Dopamine D3 ,Brain ,Ligands ,Rats ,Pharmaceutical Preparations ,Raclopride ,Positron-Emission Tomography ,Animals ,Rats, Wistar ,Histamine - Published
- 2022
25. Pharmacokinetic Modeling of [
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Nafiseh, Ghazanfari, Aren, van Waarde, Janine, Doorduin, Jürgen W A, Sijbesma, Maria, Kominia, Martin, Koelewijn, Khaled, Attia, Antoon T M, Willemsen, Ton J, Visser, André, Heeres, Rudi A J O, Dierckx, Erik F J, de Vries, and Philip H, Elsinga
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Niacinamide ,Positron-Emission Tomography ,Animals ,Brain ,Neurodegenerative Diseases ,Benzazepines ,Radiopharmaceuticals ,Rats, Wistar ,Carrier Proteins ,Histamine ,Rats - Abstract
The histamine H
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- 2022
26. The Acute and Early Effects of Whole-Brain Irradiation on Glial Activation, Brain Metabolism, and Behavior
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Andrea Parente, Janine Doorduin, Magdalini Ioannou, Erik F. J. de Vries, Peter van Luijk, Aren van Waarde, Rudi Dierckx, Johannes A. Langendijk, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Molecular Neuroscience and Ageing Research (MOLAR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
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Male ,Cancer Research ,Cerebellum ,Brain irradiation ,PET imaging ,Striatum ,Somatosensory system ,0302 clinical medicine ,RAT MODEL ,Carbon Radioisotopes ,IN-VIVO ,Microglia activation ,medicine.diagnostic_test ,Behavior, Animal ,LONG-TERM SURVIVORS ,Brain ,CRANIAL IRRADIATION ,medicine.anatomical_structure ,Oncology ,Hypothalamus ,Positron emission tomography ,030220 oncology & carcinogenesis ,CEREBRAL GLUCOSE-METABOLISM ,Neuroglia ,Motor cortex ,Research Article ,medicine.medical_specialty ,Brain imaging ,NEUROINFLAMMATION ,Brain metabolism ,MICROGLIA ,03 medical and health sciences ,Fluorodeoxyglucose F18 ,Internal medicine ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Rats, Wistar ,Neuroinflammation ,Behavior ,business.industry ,TRANSPLANTATION ,Body Weight ,Isoquinolines ,COGNITIVE IMPAIRMENT ,Transplantation ,Endocrinology ,Positron-Emission Tomography ,RADIATION ,business ,030217 neurology & neurosurgery - Abstract
Purpose Radiotherapy is a frequently applied treatment modality for brain tumors. Concomitant irradiation of normal brain tissue can induce various physiological responses. The aim of this study was to investigate whether acute and early-delayed effects of brain irradiation on glial activation and brain metabolism can be detected with positron emission tomography (PET) and whether these effects are correlated with behavioral changes. Procedures Rats underwent 0-, 10-, or 25-Gy whole-brain irradiation. At 3 and 31 days post irradiation, 1-(2-chlorophenyl)-N-[11C]methyl-(1-methylpropyl)-3-isoquinoline carboxamide ([11C]PK11195) and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET scans were acquired to detect changes in glial activation (neuroinflammation) and glucose metabolism, respectively. The open-field test (OFT) was performed on days 6 and 27 to assess behavioral changes. Results Twenty-five-gray-irradiated rats showed higher [11C]PK11195 uptake in most brain regions than controls on day 3 (striatum, hypothalamus, accumbens, septum p p 11C]PK11195 uptake than controls and 10-Gy-irradiated group (p 11C]PK11195 uptake in individual brain regions of 25-Gy treated rats remained stable or slightly increased between days 3 and 31. In contrast, a significant reduction (p 18F]FDG uptake on day 3 (p 18F]FDG uptake decreased between days 3 and 31 in all groups; no significant differences between groups were observed anymore on day 31, except for increased uptake in the hypothalamus in the 10-Gy group. The OFT did not show any significant differences between groups. Conclusions Non-invasive PET imaging indicated that brain irradiation induces neuroinflammation and a metabolic flare, without causing acute or early-delayed behavioral changes.
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- 2020
27. Modeling of [F-18]FEOBV Pharmacokinetics in Rat Brain
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Erik F. J. de Vries, Rudi Dierckx, Anna Schildt, Antoon T.M. Willemsen, Jurgen W. A. Sijbesma, Vesna Sossi, Rodrigo Moraga-Amaro, Bruno Lima-Giacobbo, Janine Doorduin, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Molecular Neuroscience and Ageing Research (MOLAR), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
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Cancer Research ,Positron emission tomography ,Kinetic modeling ,Coefficient of variation ,TERMINALS ,Standardized uptake value ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,GRAPHICAL EVALUATION ,0302 clinical medicine ,Nuclear magnetic resonance ,Cognition ,Pharmacokinetics ,Vesicular acetylcholine transporter ,medicine ,Radioligand ,Radiology, Nuclear Medicine and imaging ,VESICULAR ACETYLCHOLINE TRANSPORTER ,TRANSFER CONSTANTS ,NEURONS ,Volume of distribution ,medicine.diagnostic_test ,Chemistry ,Neurotransmitters ,ISOFLURANE ,Animal studies ,PET ,Oncology ,RADIOTRACER ,Blood sampling - Abstract
Purpose: [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated the quantification of [18F]FEOBV in rats in control conditions and after partial saturation of VAChT using plasma and reference tissue input models and test-retest reliability. Procedure: Ninety-minute dynamic [18F]FEOBV PET scans with arterial blood sampling were performed in control rats and rats pretreated with 10 μg/kg FEOBV. Kinetic analyses were performed using one- (1TCM) and two-tissue compartmental models (2TCM), Logan and Patlak graphical analyses with metabolite-corrected plasma input, reference tissue Patlak with cerebellum as reference tissue, standard uptake value (SUV) and SUV ratio (SUVR) using 60- or 90-min acquisition. To assess test-retest reliability, two dynamic [18F]FEOBV scans were performed 1 week apart. Results: The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate Ki showed a lower coefficient of variation (COV, 14–24 %) than the volume of distribution VT (16–108 %). Patlak graphical analysis showed a good fit to the data for both acquisition times with a COV (12–27 %) comparable to the irreversible 2TCM. For 60 min, Logan analysis performed comparably to both irreversible models (COV 14–32 %) but showed lower sensitivity to VAChT saturation. Partial saturation of VAChT did not affect model selection when using plasma input. However, poor correlations were found between irreversible 2TCM and SUV and SUVR in partially saturated VAChT states. Test-retest reliability and intraclass correlation for SUV were good. Conclusion: [18F]FEOBV is best modeled using the irreversible 2TCM or Patlak graphical analysis. SUV should only be used if blood sampling is not possible.
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- 2020
28. Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats
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Anna Schildt, Erik F. J. de Vries, Elke Bromberg, Bruno Lima Giacobbo, Janine Doorduin, Luiza Reali Nazario, Rodrigo Moraga-Amaro, Rudi Dierckx, Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
- Subjects
Male ,medicine.medical_specialty ,Monoamine Oxidase Inhibitors ,PET imaging ,Hippocampus ,Major depressive disorder ,Open field ,Social defeat ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Harmine ,Neuroinflammation ,Internal medicine ,medicine ,Animals ,Chronic stress ,Rats, Wistar ,030304 developmental biology ,Original Investigation ,Pharmacology ,Social stress ,0303 health sciences ,Behavior ,business.industry ,Depression ,Brain-Derived Neurotrophic Factor ,Anhedonia ,Brain ,Antidepressive Agents ,Rats ,Endocrinology ,Treatment Outcome ,chemistry ,Exploratory Behavior ,Antidepressant ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Stress, Psychological - Abstract
Introduction Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. Aim The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. Material and methods Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [11C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. Results RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. Discussion Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.
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- 2020
29. Effect of dopamine D2 receptor antagonists on [18F]-FEOBV binding
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Aren van Waarde, Jurgen W. A. Sijbesma, Antoon T. M. Willemsen, Erik F. J. de Vries, Vesna Sossi, Janine Doorduin, Anna Schildt, Rodrigo Moraga-Amaro, Bruno Lima Giacobbo, Rudi Dierckx, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Molecular Neuroscience and Ageing Research (MOLAR), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
- Subjects
Male ,Fluorine Radioisotopes ,positron emission tomography ,Vesicular Acetylcholine Transport Proteins ,Pharmaceutical Science ,02 engineering and technology ,Striatum ,030226 pharmacology & pharmacy ,0302 clinical medicine ,Piperidines ,Cerebellum ,Drug Discovery ,Haloperidol ,Receptor ,σ receptor ,Raclopride ,Chemistry ,vesicular acetylcholine transporter ,Dopaminergic ,Parkinson Disease ,021001 nanoscience & nanotechnology ,Receptor antagonist ,Dopamine D2 Receptor Antagonists ,Molecular Medicine ,0210 nano-technology ,Protein Binding ,medicine.drug ,medicine.medical_specialty ,medicine.drug_class ,Article ,03 medical and health sciences ,Dopamine receptor D2 ,Internal medicine ,medicine ,Animals ,Receptors, sigma ,Rats, Wistar ,kinetic modeling ,Corpus Striatum ,D2 receptor ,Rats ,animal studies ,Kinetics ,Endocrinology ,Positron-Emission Tomography ,Parkinson’s disease ,Cholinergic ,Radiopharmaceuticals - Abstract
The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased Ki in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower Ki than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.
- Published
- 2020
30. No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [11C]-PK11195
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Ruud P. H. Raijmakers, Mihai G. Netea, Megan E. Roerink, Jos W. M. van der Meer, Stephan P. Keijmel, Janine Doorduin, Chantal P. Bleeker-Rovers, Leo A. B. Joosten, Hans C. Klein, Hans Knoop, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Medical Psychology, and APH - Mental Health
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Q fever ,Article ,Young Adult ,Receptors, GABA ,Internal medicine ,Translocator protein ,medicine ,Chronic fatigue syndrome ,Humans ,Fatigue ,Neuroinflammation ,Fatigue Syndrome, Chronic ,biology ,business.industry ,Brain ,11c pk11195 ,Middle Aged ,Isoquinolines ,medicine.disease ,Amides ,Pathophysiology ,Substance abuse ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Neurology ,Positron-Emission Tomography ,Neuroinflammatory Diseases ,biology.protein ,Population study ,Female ,Neurology (clinical) ,Q Fever ,business - Abstract
Background and ObjectivesThe pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide ([11C]-PK11195).MethodsThe study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [11C]-PK11195 PET scan, and the [11C]-PK11195 binding potential (BPND) was calculated.ResultsNo statistically significant differences in BPND were found for patients with CFS or patients with QFS compared with HSs. BPND of [11C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS.DiscussionIn contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS.Trial Registration InformationEudraCT number 2014-004448-37.
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- 2022
31. Imaging of neuroinflammation due to repetitive head injury in currently active kickboxers
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Gilles N. Stormezand, Janine Doorduin, Sandra E. Rakers, Jacoba M. Spikman, Joukje van der Naalt, David Vállez García, Anouk van der Hoorn, Chris W. J. van der Weijden, Berry P. H. Kremer, Remco J. Renken, Rudi A. J. O. Dierckx, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Clinical Neuropsychology, Movement Disorder (MD), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Perceptual and Cognitive Neuroscience (PCN), and Radiology and nuclear medicine
- Subjects
Repetitive head injury ,TSPO PET ,Kickboxers ,Brain ,TRAIL ,Neurodegenerative Diseases ,General Medicine ,BRAIN-INJURY ,CHRONIC TRAUMATIC ENCEPHALOPATHY ,ACTIVATION ,MOVEMENT ,PET ,Diffusion Tensor Imaging ,Neuroinflammation ,Receptors, GABA ,Positron-Emission Tomography ,Athletic Injuries ,Neuroinflammatory Diseases ,Craniocerebral Trauma ,Humans ,Radiology, Nuclear Medicine and imaging ,BOXERS ,TSPO ,Martial Arts ,FOOTBALL LEAGUE PLAYERS - Abstract
Purpose Chronic traumatic encephalopathy refers to a neurodegenerative disease resulting from repetitive head injury of participants in contact sports. Similar to other neurodegenerative diseases, neuroinflammation is thought to play a role in the onset and progression of the disease. Limited knowledge is available regarding the neuroinflammatory consequences of repetitive head injury in currently active contact sports athletes. PET imaging of the 18-kDa translocator protein (TSPO) allows quantification of microglial activation in vivo, a marker of neuroinflammation. Methods Eleven rank A kickboxers and 11 age-matched controls underwent TSPO PET using [11C]-PK11195, anatomical MRI, diffusion tensor imaging, and neuropsychological testing. Relevant imaging parameters were derived and correlated with the outcomes of the neuropsychological testing. Results On a group level, no statistically significant differences were detected in non-displaceable binding potential (BPND) using PET. Individually, 3 kickboxers showed increased BPNDs in widespread regions of the brain without a correlation with other modalities. Increased FA was observed in the superior corona radiata bilaterally. DTI parameters in other regions did not differ between groups. Conclusion Despite negative results on a group level, individual results suggest that neuroinflammation may be present as a consequence of repetitive head injury in active kickboxers. Future studies using a longitudinal design may determine whether the observed TSPO upregulation is related to the future development of neuropsychiatric symptoms.
- Published
- 2021
32. Human in vivo neuroimaging to detect reprogramming of the cerebral immune response following repeated systemic inflammation
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Matthijs Kox, Mark Rijpkema, Annemieke M. Peters van Ton, Gerben M. Franssen, Niklas Bruse, Peter Pickkers, Jan Booij, Wilson F. Abdo, Guus P. Leijte, Janine Doorduin, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Radiology and Nuclear Medicine, ANS - Brain Imaging, and ANS - Compulsivity, Impulsivity & Attention
- Subjects
0301 basic medicine ,Male ,Cerebral immunotolerance ,Lipopolysaccharide ,medicine.medical_treatment ,Immunology ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Neuroimaging ,Systemic inflammation ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Immune tolerance ,03 medical and health sciences ,Behavioral Neuroscience ,chemistry.chemical_compound ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Immune system ,Receptors, GABA ,Neuroinflammation ,Receptors ,medicine ,Translocator protein ,Humans ,TSPO neuroimaging ,Inflammation ,Innate immunity ,Innate immune system ,biology ,Endocrine and Autonomic Systems ,business.industry ,Immunity ,Brain ,Inflammation/immunology ,Brain/diagnostic imaging ,030104 developmental biology ,Cytokine ,chemistry ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Positron-Emission Tomography ,biology.protein ,Receptors, GABA/metabolism ,medicine.symptom ,GABA/metabolism ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,030217 neurology & neurosurgery - Abstract
Despite increasing evidence that immune training within the brain may affect the clinical course of neuropsychiatric diseases, data on cerebral immune tolerance are scarce. This study in healthy volunteers examined the trajectory of the immune response systemically and within the brain following repeated lipopolysaccharide (LPS) challenges. Five young males underwent experimental human endotoxemia (intravenous administration of 2 ng/kg LPS) twice with a 7-day interval. The systemic immune response was assessed by measuring plasma cytokine levels. Four positron emission tomography (PET) examinations, using the translocator protein (TSPO) ligand 18F-DPA-714, were performed in each participant, to assess brain immune cell activation prior to and 5 hours after both LPS challenges. The first LPS challenge caused a profound systemic inflammatory response and resulted in a 53% [95%CI 36-71%] increase in global cerebral 18F-DPA-714 binding (p < 0.0001). Six days after the first challenge, 18F-DPA-714 binding had returned to baseline levels (p = 0.399). While the second LPS challenge resulted in a less pronounced systemic inflammatory response (i.e. 77 ± 14% decrease in IL-6 compared to the first challenge), cerebral inflammation was not attenuated, but decreased below baseline, illustrated by a diffuse reduction of cerebral 18F-DPA-714 binding (-38% [95%CI -47 to -28%], p < 0.0001). Our findings constitute evidence for in vivo immunological reprogramming in the brain following a second inflammatory insult in healthy volunteers, which could represent a neuroprotective mechanism. These results pave the way for further studies on immunotolerance in the brain in patients with systemic inflammation-induced cerebral dysfunction.
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- 2021
33. No evidence for decreased D2/3 receptor availability and frontal hypoperfusion in subjects with compulsive pornography use
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David Vállez García, Jan Booij, Rudi Dierckx, Janine Doorduin, Robert A. Schoevers, Lumi T. Chaves, Fokko Nienhuis, Berry Kremer, Gilles N. Stormezand, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Radiology and Nuclear Medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and Radiology and nuclear medicine
- Subjects
Male ,medicine.medical_specialty ,DISORDERS ,media_common.quotation_subject ,Neuroscience (miscellaneous) ,Striatum ,PREFRONTAL CORTEX ,Audiology ,Impulsivity ,03 medical and health sciences ,0302 clinical medicine ,DEPENDENCE ,BINDING ,MINI ,Erotica ,Sensation seeking ,Pornography ,Medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Prefrontal cortex ,IN-VIVO ,media_common ,D-3 RECEPTOR ,business.industry ,Receptors, Dopamine D2 ,Addiction ,Dopaminergic ,Cerebral blood flow ,Dopaminergic imaging ,Corpus Striatum ,030227 psychiatry ,Psychiatry and Mental health ,SEVERITY ,PET ,STRIATAL DOPAMINE RELEASE ,Raclopride ,Positron-Emission Tomography ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Pornographic addiction - Abstract
Pornographic addiction refers to an addiction model associated with compulsive and repeated use of pornographic material. Whether the use of pornography may indeed become addictive remains a matter of debate. The current study investigated whether compulsive pornography use (CPU) is accompanied by reduced D2/3 receptor availability in the striatum and frontal hypofunctionality. Male subjects between 18 and 50 years of age with and without CPU were recruited using online and newspaper advertisements. Questionnaires were used to the assess the severity of compulsive pornography use (CIUS) and symptoms of depression, impulsivity and sensation seeking. Dopaminergic imaging was performed using [11C]-raclopride PET. Striatal binding potentials (BPND) and regional frontal cerebral influx values (R1) of [11C]-raclopride were calculated. Arterial Spin Labeling (ASL) MRI was performed to assess regional cerebral blood flow. No group differences between striatal BPND's of [11C]-raclopride in subjects with (n = 15) and without (n = 10) CPU were detected. In CPU subjects, no correlation was found between the CIUS score and striatal BPND's. Cerebral R1 values in frontal brain regions and cerebral blood flow measurements did not differ between groups. The current study fails to provide imaging support for sharing similar neurobiological alterations as previously has been reported in other addictive modalities.
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- 2021
34. F-18-sodium fluoride positron emission tomography assessed microcalcifications in culprit and non-culprit human carotid plaques
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M. H. de Borst, Robert A. Pol, Clark J. Zeebregts, J.L. Hillebrands, Pieter Willem Kamphuisen, S A de Boer, Melanie Reijrink, Douwe J. Mulder, Hendrikus H. Boersma, Janine Doorduin, Riemer H. J. A. Slart, Hilde Hop, Biomedical Photonic Imaging, Cardiovascular Centre (CVC), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Man, Biomaterials and Microbes (MBM), Translational Immunology Groningen (TRIGR), Molecular Neuroscience and Ageing Research (MOLAR), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
- Subjects
inorganic chemicals ,Volume of interest ,PET/CT imaging ,FEASIBILITY ,PET/CT ,IMPACT ,medicine.medical_treatment ,PROGRESSION ,030204 cardiovascular system & hematology ,Culprit ,CALCIUM ,030218 nuclear medicine & medical imaging ,Calcification ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,VASCULAR CALCIFICATION ,Sodium fluoride ,F-18-sodium fluoride (F-18-NaF) ,medicine ,Radiology, Nuclear Medicine and imaging ,Carotid artery stenosis ,Stage (cooking) ,Endarterectomy ,PET-CT ,medicine.diagnostic_test ,business.industry ,ENDARTERECTOMY ,technology, industry, and agriculture ,18F-sodium fluoride (18F-NaF) ,Vulnerable atherosclerotic plaque ,F-sodium fluoride (F-NaF) ,medicine.disease ,body regions ,chemistry ,Positron emission tomography ,MARKER ,DENSITY ,Original Article ,ATHEROSCLEROTIC PLAQUE ,Cardiology and Cardiovascular Medicine ,Nuclear medicine ,business - Abstract
Background 18F-NaF positron emission tomography (PET) targets microcalcifications. We compared in vitro microPET assessed 18F-NaF uptake between culprit and non-culprit human carotid plaques. Furthermore, we compared 18F-NaF uptake with calcification visualized on microcomputed tomography (microCT). Methods Carotid plaques from stroke patients undergoing surgery were incubated in 18F-NaF and scanned using a microPET and a microCT scan. The average PET assessed 18F-NaF uptake was expressed as percentage of the incubation dose per gram (%Inc/g). 18F-NaF PET volume of interest (VOI) was compared with CT calcification VOI. Results 23 carotid plaques (17 culprit, 6 non-culprit) were included. The average 18F-NaF uptake in culprit carotid plaques was comparable with the uptake in non-culprit carotid plaques (median 2.32 %Inc/g [IQR 1.98 to 2.81] vs. median 2.35 %Inc/g [IQR 1.77 to 3.00], P = 0.916). Only a median of 10% (IQR 4 to 25) of CT calcification VOI showed increased 18F-NaF uptake, while merely a median of 35% (IQR 6 to 42) of 18F-NaF PET VOI showed calcification on CT. Conclusions 18F-NaF PET represents a different stage in the calcification process than CT. We observed a similar PET assessed 18F-NaF uptake and pattern in culprit and non-culprit plaques of high-risk patients, indicating that this method may be of more value in early atherosclerotic stenosis development. Electronic supplementary material The online version of this article (10.1007/s12350-018-1325-5) contains supplementary material, which is available to authorized users.
- Published
- 2019
35. Brain-Derived Neurotrophic Factor in Brain Disorders
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Elke Bromberg, Janine Doorduin, Erik F. J. de Vries, Hans C. Klein, Bruno Lima Giacobbo, and Rudi Dierckx
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0301 basic medicine ,Aging ,medicine.medical_specialty ,Neurology ,Neuroscience (miscellaneous) ,Inflammation ,Models, Biological ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Neuroinflammation ,Neurotrophic factors ,Neurotoxicity ,medicine ,Animals ,Humans ,Neurotransmitter ,Brain-derived neurotrophic factor ,Brain Diseases ,biology ,business.industry ,Brain-Derived Neurotrophic Factor ,Brain ,medicine.disease ,030104 developmental biology ,chemistry ,nervous system ,biology.protein ,medicine.symptom ,business ,Neuroscience ,Neurological disorders ,030217 neurology & neurosurgery ,Neurotrophin - Abstract
Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.
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- 2019
36. Correction to
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Gilles N. Stormezand, Janine Doorduin, Sandra E. Rakers, Jacoba M. Spikman, Joukje van der Naalt, David Vállez García, Anouk van der Hoorn, Chris W. J. van der Weijden, Berry P. H. Kremer, Remco J. Renken, and Rudi A. J. O. Dierckx
- Subjects
Radiology, Nuclear Medicine and imaging ,General Medicine - Published
- 2022
37. No signs of neuroinflammation in women with chronic fatigue syndrome or Q fever fatigue syndrome using the TSPO ligand [11C]-PK11195
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Ruud Raijmakers, Megan E. Roerink, Stephan P. Keijmel, Leo A.B. Joosten, Mihai G. Netea, Jos W.M. van der Meer, Hans Knoop, Hans C. Klein, Chantal P. Bleeker-Rovers, and Janine Doorduin
- Abstract
Background The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study we investigated neuroinflammation in female CFS and QFS patients compared with healthy women, using Positron Emission Tomography (PET) with the TSPO ligand [11C]-PK11195. Methods The study population consisted of CFS patients (n = 9), QFS patients (n = 10), and healthy controls (n = 9). All subjects were women, matched for age (± 5 years) and neighbourhood, between 18 and 59 years of age, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last six months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview (MINI). All subjects underwent a [11C]-PK11195 PET scan and the [11C]-PK11195 binding potential (BPND) was calculated. Results No statistically significant differences in BPND were found for CFS patients or QFS patients when compared to healthy controls. BPND of [11C]-PK11195 positively correlated with symptom severity scores in QFS patients, but a negative correlation was found in CFS patients. Conclusions In contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing CFS or QFS patients to healthy neighbourhood controls. In this small series we were unable to find signs of neuroinflammation in patients with CFS and QFS. Trial registration EudraCT number: 2014-004448-37
- Published
- 2021
38. Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study
- Author
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Erik F. J. de Vries, Rudi Dierckx, Elisa Scandiuzzi Maciel, Janine Doorduin, Andrea Parente, Johannes A. Langendijk, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Male ,Pathology ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Spatial Behavior ,Brain tissue ,Carbohydrate metabolism ,Radiation Dosage ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Myelin ,0302 clinical medicine ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Longitudinal Studies ,Rats, Wistar ,Cognitive impairment ,Myelin Sheath ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,fungi ,Body Weight ,food and beverages ,Treatment options ,Brain ,Rats ,Radiation therapy ,medicine.anatomical_structure ,Glucose ,Positron emission tomography ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Whole brain radiation therapy ,business - Abstract
Purpose: Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation. Materials and methods: Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, 18F-fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-11C-methyl-4,4′-diaminostilbene (11C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes. Results: Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with 18F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced 18F-FDG uptake on day 94. 11C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, 11C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and 11C-MeDAS uptake was observed in irradiated rats. Conclusions: Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats.
- Published
- 2020
39. Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress
- Author
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M. A. Khayum, Janine Doorduin, E. F. J. de Vries, Rodrigo Moraga-Amaro, Michel Koole, J.A. den Boer, Rudi Dierckx, Bauke Buwalda, Buwalda lab, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
HOMEOSTASIS ,Endocrinology, Diabetes and Metabolism ,Hippocampus ,0302 clinical medicine ,Endocrinology ,Chronic mild stress ,ESTRADIOL ,education.field_of_study ,Behavior, Animal ,CMS ,Depression ,WOMEN ,Brain ,Menopause ,Psychiatry and Mental health ,Hypothalamus ,Female ,medicine.medical_specialty ,MENOPAUSE ,Positron emission tomography ,SEX-DIFFERENCES ,medicine.drug_class ,Ovariectomy ,Population ,Carbohydrate metabolism ,Brain metabolism ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,MODULATION ,Rats, Wistar ,education ,Biological Psychiatry ,Estrogen depletion ,Endocrine and Autonomic Systems ,business.industry ,PERIMENOPAUSAL DEPRESSION ,KETAMINE ,medicine.disease ,030227 psychiatry ,Rats ,MODEL ,Disease Models, Animal ,Estrogen ,business ,030217 neurology & neurosurgery ,Homeostasis ,Stress, Psychological ,Behavioural despair test - Abstract
The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS. ispartof: Psychoneuroendocrinology vol:115 pages:104610- ispartof: location:England status: published
- Published
- 2020
40. Modeling of [
- Author
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Anna, Schildt, Erik F J, de Vries, Antoon T M, Willemsen, Rodrigo, Moraga-Amaro, Bruno, Lima-Giacobbo, Jürgen W A, Sijbesma, Vesna, Sossi, Rudi A J O, Dierckx, and Janine, Doorduin
- Subjects
Male ,Fluorine Radioisotopes ,Vesicular Acetylcholine Transport Proteins ,Brain ,Reproducibility of Results ,Ligands ,Models, Biological ,Rats ,Kinetics ,Piperidines ,Species Specificity ,Positron-Emission Tomography ,Animals ,Humans ,Tissue Distribution ,Radiopharmaceuticals ,Rats, Wistar - Abstract
[Ninety-minute dynamic [The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate K[
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- 2020
41. Intrastriatal gradient analyses of 18F-FDOPA PET scans for differentiation of Parkinsonian disorders
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David Vállez García, Rudi Dierckx, Gilles N. Stormezand, Klaus L. Leenders, Lumi T. Chaves, Bauke M. de Jong, Berry Kremer, Janine Doorduin, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Molecular Neuroscience and Ageing Research (MOLAR), Movement Disorder (MD), and Radiology and nuclear medicine
- Subjects
MULTIPLE SYSTEM ATROPHY ,Male ,Parkinson's disease ,Caudate nucleus ,Striatum ,CLINICAL-DIAGNOSIS ,lcsh:RC346-429 ,DISEASE ,0302 clinical medicine ,Putamen ,Parkinsonism ,05 social sciences ,Dopaminergic ,Regular Article ,Parkinson Disease ,Middle Aged ,Dihydroxyphenylalanine ,Neurology ,lcsh:R858-859.7 ,Female ,Cognitive Neuroscience ,Neuroimaging ,lcsh:Computer applications to medicine. Medical informatics ,050105 experimental psychology ,Diagnosis, Differential ,03 medical and health sciences ,18f fdopa ,Parkinsonian Disorders ,medicine ,Humans ,0501 psychology and cognitive sciences ,Radiology, Nuclear Medicine and imaging ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Retrospective Studies ,Receiver operating characteristic ,business.industry ,medicine.disease ,Atypical Parkinsonism ,Corpus Striatum ,nervous system diseases ,FDOPA ,PET ,nervous system ,Positron-Emission Tomography ,Neurology (clinical) ,Caudate Nucleus ,Nuclear medicine ,business ,030217 neurology & neurosurgery - Abstract
Highlights • FDOPA PET allows quantification of presynaptic dopaminergic functioning in vivo. • Subregional analysis within the striatum provides additional diagnostic value for differentiation within Parkinsonian disorders. • Depletion of F-DOPA uptake in both patients with idiopathic Parkinson's disease and patients with atypical Parkinsonism preferentially affects the posterior part of the putamen. • A more linear decrease of FDOPA uptake from the head of the caudate nucleus to the posterior putamen is present in patients with IPD than in APD., Aim L -3,4-dihydroxy-6–18F-fluorophenylalanine (18F-DOPA PET may be used to distinguish subjects with Parkinsonism from those with symptoms not originating from impaired dopaminergic transmission. However, it is not routinely utilized to discriminate Idiopathic Parkinson's disease (IPD) from Atypical Parkinsonian Disorders (APD). We investigated the potential of FDOPA PET to discriminate between IPD and APD, with a focus on the anterior-to-posterior decline in het striatum, considered to be more specific for IPD. Materials and methods 18F-DOPA PET data from a total of 58 subjects were retrospectively analyzed. 28 subjects had idiopathic Parkinson's disease (14 male, 14 female; age at scan 61 +- 11,5), 13 atypical Parkinsonian disease (7 male, 6 females; age at scan: 69,6 +- 6,4) and 17 were controls (6 male, 11 female; age at scan 65,3 +-8,6). Regional striatal-to-occipital ratio's (RSOR's) were calculated, as well as multiple in-line VOI's from the caudate nucleus to the posterior part of the putamen. The linearity of anteroposterior decline was determined by a linear regression fit and associated R squared values. ROC curves were calculated to assess the diagnostic performance of these measurements. Data contralateral to the clinically most affected side were used for analysis. Results ROC curve analysis for differentiation between controls and Parkinsonism patients showed the highest AUC for the caudate nucleus-to-posterior putamen ratio (AUC = 0.930; p
- Published
- 2020
42. Test-Retest Stability of Cerebral 2-Deoxy-2-[18F]Fluoro-D-Glucose ([18F]FDG) Positron Emission Tomography (PET) in Male and Female Rats
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David Vállez García, Aren van Waarde, Rudi Dierckx, Hendrikus H. Boersma, Janine Doorduin, Juergen W. A. Sijbesma, Riemer H. J. A. Slart, Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Cardiovascular Centre (CVC), Translational Immunology Groningen (TRIGR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Radiology and nuclear medicine
- Subjects
Cancer Research ,medicine.medical_specialty ,SEX-DIFFERENCES ,Population ,Regional cerebral metabolic rate of glucose ,FDG-Positron Emission Tomography ,Patlak plot ,030218 nuclear medicine & medical imaging ,GRAPHICAL EVALUATION ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Blood plasma ,Heart rate ,Gender differences ,Medicine ,Radiology, Nuclear Medicine and imaging ,Test-retest stability ,education ,IN-VIVO ,Estrous cycle ,GENDER-DIFFERENCES ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,GLUCOSE METABOLIC-RATES ,Estrogens ,BRAIN TRANSFER CONSTANTS ,SMALL-ANIMAL PET ,Endocrinology ,Oncology ,Isoflurane ,Positron emission tomography ,business ,Small animal imaging ,medicine.drug - Abstract
Purpose: An important issue in rodent imaging is the question whether a mixed population of male and female animals can be used rather than animals of a single sex. For this reason, the present study examined the test-retest stability of positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in male rats and female rats at different phases of the estrous cycle. Procedures: Long–Evans rats (age 1 year) were divided into three groups: (1) males (n = 6), (2) females in metestrous (low estrogen levels, n = 9), and (3) females in proestrous (high estrogen levels, n = 7). Two standard [18F]FDG scans with rapid arterial blood sampling were made at an interval of 10 days in subjects anesthetized with isoflurane and oxygen. Body temperature, heart rate, and blood oxygenation were continuously monitored. Regional cerebral metabolic rates of glucose were calculated using a Patlak plot with plasma radioactivity as input function. Results: Regional metabolic rate of glucose (rCMRglucose) in male and female rats, or [18F]FDG uptake in females at proestrous and metestrous, was not significantly different, but females showed significantly higher standardized uptake values (SUVs) and Patlak flux than males, particularly in the initial scan. The relative difference between the scans and the test-retest variability (TRV) were greater in females than in males. Intra-class correlation coefficients (ICCs) of rCMRglucose, SUV, normalized SUV, and glucose flux were good to excellent in males but poor to moderate in females. Conclusions: Based on these data for [18F]FDG, the mixing of sexes in imaging studies of the rodent brain will result in an impaired test-retest stability of PET data and a need for larger group sizes to maintain statistical power in group comparisons. The observed differences between males and females do not indicate any specific gender difference in cerebral metabolism but are related to different levels of non-radioactive glucose in blood plasma during isoflurane anesthesia.
- Published
- 2018
43. PET Imaging with S-[C-11]Methyl-L-Cysteine and L-[Methyl-C-11]Methionine in Rat Models of Glioma, Glioma Radiotherapy, and Neuroinflammation
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Alexandre Shoji, Erik F. J. de Vries, R. Zijlma, Andrea Parente, Rudi Dierckx, Janine Doorduin, Aren van Waarde, Bram Maas, Daniele de Paula Faria, Johannes A. Langendijk, Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
- Subjects
Cancer Research ,medicine.medical_specialty ,Pathology ,Positron emission tomography ,Lipopolysaccharide ,medicine.medical_treatment ,Striatum ,01 natural sciences ,Brain tumors ,Lesion ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,TUMOR ,Internal medicine ,Glioma ,medicine ,Radiology, Nuclear Medicine and imaging ,Saline ,Neuroinflammation ,Inflammation ,Methionine ,medicine.diagnostic_test ,business.industry ,Brain ,medicine.disease ,3. Good health ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Endocrinology ,Oncology ,chemistry ,Amino acids ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Small animal imaging - Abstract
PURPOSE: S-[(11)C]-methyl-L-cysteine ([(11)C]MCYS) has been claimed to offer higher tumor selectivity than L-[methyl- (11)C]methionine ([(11)C]MET). We examined this claim in animal models.PROCEDURES: Rats with implanted untreated (n = 10) or irradiated (n = 7, 1 × 25 Gy, on day 8) orthotopic gliomas were scanned after 6, 9, and 12 days, using positron emission tomography. Rats with striatal injections of saline (n = 9) or bacterial lipopolysaccharide (n = 9) were scanned after 3 days.RESULTS: Uptake of the two tracers in untreated gliomas was similar. [(11)C]MCYS was not accumulated in salivary glands, nasal epithelium, and healing wounds, in contrast to [(11)C]MET, but showed 40 % higher accumulation in the healthy brain. Both tracers showed a reduced tumor uptake 4 days after irradiation and minor accumulation in inflamed striatum. [(11)C]MCYS indicated higher lesion volumes than [(11)C]MET (untreated tumor + 47 %; irradiated tumor up to + 500 %; LPS-inflamed striatum + 240 %).CONCLUSIONS: [(11)C]MCYS was less accumulated in some non-tumor tissues than [(11)C]MET, but showed lower tumor-to-brain contrast.
- Published
- 2018
44. Therapeutic effects of dietary intervention on neuroinflammation and brain metabolism in a rat model of photothrombotic stroke
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Rudi Dierckx, Hans C. Klein, Ulrich L. M. Eisel, Janine Doorduin, J Martin Verkuyl, Erik F. J. de Vries, Cindy Casteels, Ewelina Kurtys, Laus M. Broersen, Caroline Cristiano Real, Eisel lab, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
0301 basic medicine ,Male ,PET imaging ,Pharmacology ,Somatosensory system ,neuroinflammation ,Brain Ischemia ,Rats, Sprague-Dawley ,Random Allocation ,0302 clinical medicine ,Pharmacology (medical) ,Gliosis ,Stroke ,RISK ,Brain ,RECOVERY ,3. Good health ,Astrogliosis ,Psychiatry and Mental health ,medicine.anatomical_structure ,nutrition ,ACID ,INSTITUTE ,Original Article ,medicine.symptom ,Astrocyte ,photothrombotic stroke ,Ischemia ,Brain damage ,Motor Activity ,MECHANISMS ,Lesion ,03 medical and health sciences ,Physiology (medical) ,medicine ,Animals, Outbred Strains ,Animals ,Neuroinflammation ,Inflammation ,CEREBRAL-ISCHEMIA ,business.industry ,CYTOKINE PRODUCTION ,Original Articles ,medicine.disease ,PREVENTION ,PROTEIN SUPPLEMENTATION ,Disease Models, Animal ,030104 developmental biology ,Glucose ,Astrocytes ,business ,030217 neurology & neurosurgery - Abstract
INTRODUCTION: A possible target for stroke management is modulation of neuroinflammation. Evidence suggests that food components may exert anti-inflammatory properties and thus may reduce stroke-induced brain damage.AIM: To investigate the efficacy of a diet, containing anti-inflammatory ingredients, as treatment for focal ischemic brain damage induced by photothrombotic stroke in the somatosensory cortex of rats.RESULTS: Brain lesions were surrounded by strong astrogliosis on both day 7 and day 21 after stroke and were accompanied by a trend toward globally decreased glucose metabolism on day 7. The investigational diet applied 2 weeks before the ischemia did not affect astrocyte activation on day 7, but reduced it at day 21. The investigational diet applied immediately after the ischemia, increased astrocyte activation on day 7 and completely reversed this effect on day 21. Moreover, postischemic intervention increased glucose metabolism in somatosensory cortex ipsilateral to the lesion on day 7.CONCLUSION: This study reveals potentially beneficial effects of a diet containing elevated amounts of anti-inflammatory nutrients on the recovery from ischemic brain damage. Therefore, dietary intervention can be considered as an adjuvant therapy for recovery from this brain pathology.
- Published
- 2018
45. P.0455 Maternal immune activation reduced recognition memory and increased anxiety-like behaviour and brain metabolism in the rat offspring
- Author
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Erik De Vries, Cyprien Guerrin, and Janine Doorduin
- Subjects
Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2021
46. Repeated social defeat induces transient glial activation and brain hypometabolism: A positron emission tomography imaging study
- Author
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Luis Eduardo Juarez-Orozco, Paula Kopschina Feltes, Cristina M Moriguchi-Jeckel, Erik F. J. de Vries, Rudi Dierckx, Ewelina Kurtys, Janine Doorduin, Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
- Subjects
Male ,0301 basic medicine ,Time Factors ,STRESS ,BENZODIAZEPINE-RECEPTOR ,ANXIETY-LIKE BEHAVIOR ,neuroinflammation ,Social defeat ,chemistry.chemical_compound ,0302 clinical medicine ,Corticosterone ,OBJECT RECOGNITION ,ANIMAL-MODEL ,Depression (differential diagnoses) ,repeated social defeat ,Behavior, Animal ,medicine.diagnostic_test ,Brain ,Neurology ,Positron emission tomography ,depression ,Cardiology and Cardiovascular Medicine ,Neuroglia ,CORTEX ,medicine.medical_specialty ,Elevated plus maze ,positron emission tomography imaging ,RAT-BRAIN ,Brain metabolism ,03 medical and health sciences ,In vivo ,Internal medicine ,medicine ,Animals ,Rats, Long-Evans ,Rats, Wistar ,MEMORY IMPAIRMENT ,Neuroinflammation ,Inflammation ,business.industry ,ELEVATED PLUS-MAZE ,Original Articles ,MAJOR DEPRESSION ,Rats ,Cortex (botany) ,030104 developmental biology ,Endocrinology ,chemistry ,Positron-Emission Tomography ,Neurology (clinical) ,business ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Psychosocial stress is a risk factor for the development of depression. Recent evidence suggests that glial activation could contribute to the development of depressive-like behaviour. This study aimed to evaluate in vivo whether repeated social defeat (RSD) induces short- and long-term inflammatory and metabolic alterations in the brain through positron emission tomography (PET). Male Wistar rats ( n = 40) were exposed to RSD by dominant Long-Evans rats on five consecutive days. Behavioural and biochemical alterations were assessed at baseline, day 5/6 and day 24/25 after the RSD protocol. Glial activation (11C-PK11195 PET) and changes in brain metabolism (18F-FDG PET) were evaluated on day 6, 11 and 25 (short-term), and at 3 and 6 months (long-term). Defeated rats showed transient depressive- and anxiety-like behaviour, increased corticosterone and brain IL-1β levels, as well as glial activation and brain hypometabolism in the first month after RSD. During the third- and six-month follow-up, no between-group differences in any investigated parameter were found. Therefore, non-invasive PET imaging demonstrated that RSD induces transient glial activation and reduces brain glucose metabolism in rats. These imaging findings were associated with stress-induced behavioural changes and support the hypothesis that neuroinflammation could be a contributing factor in the development of depression.
- Published
- 2017
47. Evaluation of exercise-induced modulation of glial activation and dopaminergic damage in a rat model of Parkinson’s disease using [11C]PBR28 and [18F]FDOPA PET
- Author
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Paula Kopschina Feltes, Erik F. J. de Vries, Caroline Cristiano Real, Janine Doorduin, Luiz R.G. Britto, Daniele de Paula Faria, David Vállez García, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Radiology and nuclear medicine
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,POSITRON EMISSION TOMOGRAPHY ,EXERCISE ,Striatum ,Open field ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Hippocampus (mythology) ,PARKINSON DISEASE ,Neuroinflammation ,Tyrosine hydroxylase ,business.industry ,Dopaminergic ,GLIAL ACTIVATION ,medicine.disease ,DOPAMINE SYNTHESIS ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Neurology ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Astrocyte - Abstract
Evidence suggests that exercise can modulate neuroinflammation and neuronal damage. We evaluated if such effects of exercise can be detected with positron emission tomography (PET) in a rat model of Parkinson’s disease (PD). Rats were unilaterally injected in the striatum with 6-hydroxydopamine (PD rats) or saline (controls) and either remained sedentary (SED) or were forced to exercise three times per week for 40 min (EX). Motor and cognitive functions were evaluated by the open field, novel object recognition, and cylinder tests. At baseline, day 10 and 30, glial activation and dopamine synthesis were assessed by [11C]PBR28 and [18F]FDOPA PET, respectively. PET data were confirmed by immunohistochemical analysis of microglial (Iba-1) / astrocyte (GFAP) activation and tyrosine hydroxylase (TH). [11C]PBR28 PET showed increased glial activation in striatum and hippocampus of PD rats at day 10, which had resolved at day 30. Exercise completely suppressed glial activation. Imaging results correlated well with post-mortem Iba-1 staining, but not with GFAP staining. [18F]FDOPA PET, TH staining and behavioral tests indicate that 6-OHDA caused damage to dopaminergic neurons, which was partially prevented by exercise. These results show that exercise can modulate toxin-induced glial activation and neuronal damage, which can be monitored noninvasively by PET.
- Published
- 2017
48. Prenatal fluoxetine impairs non-hippocampal but not hippocampal memory in adult male rat offspring
- Author
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Ursula Wyneken, Erik F. J. de Vries, Valentina Ugalde, Sergio Linsambarth, R. Moraga-Amaro, Francisca Peña, Janine Doorduin, Juan Pablo Donoso-Ramos, Estibaliz Ampuero, Jimmy Stehberg, Rodrigo Pacheco, Raul Díaz-Galarce, Molecular Neuroscience and Ageing Research (MOLAR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
RECEPTOR CHANNELS ,Male ,STRESS ,SEROTONIN REUPTAKE INHIBITORS ,In utero ,Morris water navigation task ,Hippocampus ,Anxiety ,Open field ,Pregnancy ,Temporal cortex ,REMOTE SPATIAL MEMORY ,Depression ,Learning Disabilities ,Memory impairment ,Hindlimb Suspension ,Prenatal Exposure Delayed Effects ,Antidepressive Agents, Second-Generation ,Female ,Remote memory ,medicine.drug ,medicine.medical_specialty ,PERINATAL FLUOXETINE ,Offspring ,Food Preferences ,Cellular and Molecular Neuroscience ,Fluoxetine ,Internal medicine ,medicine ,Retention deficit ,Animals ,EXPOSURE ,Maze Learning ,Pharmacology ,Memory Disorders ,business.industry ,Recognition, Psychology ,NR2B ,Tail suspension test ,Rats ,Endocrinology ,NMDA ,BEHAVIORAL OUTCOMES ,business ,Psychomotor Performance - Abstract
Fluoxetine is often prescribed to treat depression during pregnancy. Rodent studies have shown that fluoxetine exposure during early development can induce persistent changes in the emotional behavior of the offspring. However, the effects of prenatal fluoxetine on memory have not been elucidated. This study evaluates the memory of adult male offspring from rat dams orally administered with a clinically relevant dose of 0.7 mg/kg fluoxetine from 9 weeks before pregnancy to 1 week before delivery. Hippocampal-dependent (Morris Water Maze, MWM) and non-hippocampal-dependent (Novel Object Recognition, NOR) memory paradigms were assessed. Anxiety- and depressive-like symptoms were also evaluated using the Open Field Test, Tail Suspension Test and Sucrose Preference Test. Male rats exposed to fluoxetine during gestation displayed NOR memory impairments during adulthood, as well as increased anxiety- and depressive-like symptoms. In the MWM, the offspring of fluoxetine-treated dams did not show learning deficits. However, a retention impairment was found on remote memory, 15 days after the end of training. Molecular analyses showed increased expression of NMDA subunit NR2B, and a decrease in NR2A-to- NR2B ratio in the temporal cortex, but not in the hippocampus, suggesting changes in NMDA receptor composition. These results suggest that in utero exposure to fluoxetine induces detrimental effects on non-hippocampal memory and in remote retention of hippocampal-dependent memory, which is believed to be stored in the temporal cortex, possibly due to changes in cortical NMDA receptor subunit stoichiometry. The present results warrant the need for studies on potential remote memory deficits in human offspring exposed to fluoxetine in utero.
- Published
- 2021
49. Effect of Preventive and Curative Fingolimod Treatment Regimens on Microglia Activation and Disease Progression in a Rat Model of Multiple Sclerosis
- Author
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Daniele de Paula Faria, Erik F. J. de Vries, Rudi Dierckx, Janine Doorduin, David Vállez García, Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), and Radiology and nuclear medicine
- Subjects
0301 basic medicine ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Lymphocyte ,Immunology ,Neuroscience (miscellaneous) ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Neuroinflammation ,Fingolimod Hydrochloride ,medicine ,Animals ,Immunology and Allergy ,Experimental autoimmune encephalomyelitis ,Microglia ,business.industry ,Multiple sclerosis ,Fingolimod ,medicine.disease ,Rats ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Disease Progression ,Female ,Original Article ,Brainstem ,Positron-emission tomography ,business ,Immunosuppressive Agents ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Fingolimod was the first oral drug approved for multiple sclerosis treatment. Its principal mechanism of action is blocking of lymphocyte trafficking. In addition, recent studies have shown its capability to diminish microglia activation. The effect of preventive and curative fingolimod treatment on the time-course of neuroinflammation was investigated in the experimental autoimmune encephalomyelitis rat model for multiple sclerosis. Neuroinflammatory progression was followed in Dark Agouti female rats after immunization. Positron-Emission tomography (PET) imaging with (R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29 and 34 during normal disease progression, preventive and curative treatments with fingolimod (1 mg/kg/day). Additionally, bodyweight and clinical symptoms were determined. Preventive treatment diminished bodyweight loss and inhibited the appearance of neurological symptoms. In non-treated rats, PET showed that neuroinflammation peaked in the brainstem at day 19, whereas the imaging signal was decreased in cortical regions. Both preventive and curative treatment reduced neuroinflammation in the brainstem at day 19. Eight days after treatment withdrawal, neuroinflammation had flared-up, especially in cortical regions. Preventive treatment with fingolimod suppressed clinical symptoms and neuroinflammation in the brainstem. After treatment withdrawal, clinical symptoms reappeared together with neuroinflammation in cortical regions, suggesting a different pathway of disease progression. Electronic supplementary material The online version of this article (doi:10.1007/s11481-017-9741-x) contains supplementary material, which is available to authorized users.
- Published
- 2017
50. Novel approach to repeated arterial blood sampling in small animal PET
- Author
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David Vállez García, M. C. Houwertjes, Philip H. Elsinga, Xiaoyun Zhou, Jurgen W. A. Sijbesma, Chantal Kwizera, Rudi Dierckx, Riemer H. J. A. Slart, Janine Doorduin, Bram Maas, Peter Meerlo, Aren van Waarde, Molecular Neuroscience and Ageing Research (MOLAR), Meerlo lab, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Cardiovascular Centre (CVC), Translational Immunology Groningen (TRIGR), and Radiology and nuclear medicine
- Subjects
Male ,Cancer Research ,Positron emission tomography ,A(1) RECEPTORS ,PRESSURE ,Ligands ,RAT-BRAIN ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Adenosine A1 receptor ,0302 clinical medicine ,POSITRON-EMISSION-TOMOGRAPHY ,Catheterization procedure ,Small animal ,Test-retest reproducibility ,REPRODUCIBILITY ,BINDING ,Radioligand ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Rats, Wistar ,RADIOLIGAND ,Medicine(all) ,Blood Specimen Collection ,medicine.diagnostic_test ,business.industry ,Receptor, Adenosine A1 ,Body Weight ,Sampling (statistics) ,Reproducibility of Results ,Brain ,ADENOSINE ,Arterial blood sampling ,Oncology ,Positron-Emission Tomography ,Xanthines ,Nuclear medicine ,business ,030217 neurology & neurosurgery ,Blood sampling ,Research Article - Abstract
Purpose: Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial sampling on repeated occasions in the same animal. Procedures: Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [11C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (VT) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week. Results: Surgery was successful in 90 % of the cases, and discomfort was minor. The VT data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects. Conclusion: Repeated quantitative imaging with a high reproducibility is possible with this approach.
- Published
- 2016
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