Methodological advancements in data analysis and quantitative performance of positron emission tomography

Positron emission tomography (PET) is a medical imaging modality with which neurophysiological functions can be studied. After a radio-labeled molecule is injected intravenously, it is transported by the blood stream to the target of interest. The radioactive atom of the molecule decays, resulting in two gamma rays that the PET system detects. Based on this measurement, an image can be reconstructed displaying the distribution of the radioligand, which in turn provides useful information regarding the underlying physiology. This thesis focuses on methodological advancements in the quantification of PET data obtained from neurological studies. The work included in the thesis can be categorized into three sections. Section 1 comprises two studies (Study I and II) and focuses on the effect of the resolution of the PET system when quantifying the data. When using PET to study brain functions in for instance the brainstem, the structures of interest are small and therefore presumably affected by resolution. The results of study I showed that, using conventional methods for PET data analysis, the difference obtained between two PET systems with different resolution can be compensated for by applying algorithms that artificially compensate for resolution-induced image artifacts. This is an interesting finding as it enables data acquired in two different PET systems to be pooled into the same analysis, without introducing significant bias. In study II, we found that using a high resolution PET system, in combination with a noise suppression technique and a semiautomatic procedure to define regions of interests (ROIs), it is possible to accurately quantify radioligand binding in very small brain structures. The procedure allows for detailed mapping of the distribution of serotonin transporter in the brainstem, and may thus be used to help elucidate the role of the serotonin system in central nervous system disorders. Section 2 targets the definition of ROIs required for analysis of PET data. Conventionally, ROIs are defined manually by a neuranatomically trained expert on MR images acquired from the same subject. This procedure is time consuming and introduces a large amount of user interaction in the data analysis, making it prone to rater bias. In study III, it is shown that manual ROIs can reliably be replaced with automated versions provided by the software package FreeSurfer or the Automated Anatomical Labeling (AAL) template. These automated methods provide objective and reproducible analysis of PET data. In section 3, a new method to cluster the voxels of PET images is presented. This Pair-Wise Correlation (PWC) approach groups correlating voxels, either within or across subjects. The method is used for two different purposes. First, in study IV, the PWC method isolates the signal corresponding to arterial blood in the images. This image-derived blood signal provides the possibility to quantify PET data without measuring the radioactivity level in arterial blood, which significantly reduces the invasiveness during a PET examination. Second, in study V, the PWC method identifies a disease-specific pattern of amyloid- plaque in patients with Alzheimer’s disease. The pattern can in turn separate a group of AD patients from control subjects, suggesting that the PWC method may aid for early and objective detection of brain amyloid. In conclusion, this thesis focused on validation and implementation of advanced tools for quantification of PET data. The results indicate that the methods included in this thesis provide improved quantification of PET data and can be used in clinical PET studies

Early cold stress responses in post-meiotic anthers from tolerant and sensitive rice cultivars

Background: Rice grain production is susceptible to a changing environment that imposes both biotic and abiotic stress conditions. Cold episodes are becoming more frequent in the last years and directly affect rice yield in areas with a temperate climate. Rice is particularly susceptible to cold stress during the reproductive phase, especially in anthers during post-meiotic stages which, in turn, affect pollen production. However, a number of rice cultivars with a certain degree of tolerance to cold have been described, which may represent a good breeding resource for improvement of susceptible commercial varieties. Plants experiencing cold stress activate a molecular response in order to reprogram many metabolic pathways to face these hostile conditions. Results: Here we performed RNA-seq analysis using cold-stressed post-meiotic anther samples from a cold-tolerant, Erythroceros Hokkaido (ERY), and a cold-susceptible commercial cultivar Sant’Andrea (S.AND). Both cultivars displayed an early common molecular response to cold, although the changes in expression levels are much more drastic in the tolerant one. Comparing our datasets, obtained after one-night cold stress, with other similar genome-wide studies showed very few common deregulated genes, suggesting that molecular responses in coldstressed anthers strongly depend on conditions and the duration of the cold treatments. Cold-tolerant ERY exhibits specific molecular responses related to ethylene metabolism, which appears to be activated after cold stress. On the other hand, S.AND cold-treated plants showed a general downregulation of photosystem I and II genes, supporting a role of photosynthesis and chloroplasts in cold responses in anthers, which has remained elusive. Conclusions: Our study revealed that a number of ethylene-related transcription factors, as putative master regulators of cold responses, were upregulated in ERY providing promising candidates to confer tolerance to susceptible cultivars. Our results also suggest that the photosynthesis machinery might be a good target to improve cold tolerance in anthers. In summary, our study provides valuable candidates for further analysis and molecular breeding for cold-tolerant rice cultivars.Fil: Gonzalez Schain, Nahuel Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Roig Villanova, Irma. Università degli Studi di Milano; ItaliaFil: Kater, Martin M.. Università degli Studi di Milano; Itali

The missionary role of mainstream Christianity: Towards a narrative paradigm for social integration of minorities in pluralistic post-apartheid South Africa

This article attempts to add to the existing approaches of practical theology and specifically to the missionary approaches of mainline churches towards immigrants. This is an attempt to enhance the mission amongst immigrants by critically engaging with the two approaches, namely: mainstream and margins and pillarization. Notwithstanding the important contributions that these two approaches make to tolerance, integration and cohesion of differences I seek to point out some serious limitations of the two approaches. These limitations include social coercion, co-option, relativism and loss of identity. Considering these limitations a third approach, the narrative approach, takes serious community, tradition and symbol for more effective mission amongst immigrants by mainline churches. Social cohesion, a more realistic reality and integrated communities are some of the consequences of this approach when doing missionary activities amongst immigrants.DHE

Measuring endogenous changes in serotonergic neurotransmission with [11C]Cimbi-36 positron emission tomography in humans

Abstract Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HT2AR) agonist radioligand [11C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [11C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HT1AR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [11C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HT2AR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [11C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HT2AR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI

Turning round the telescope. Centre-right parties and immigration and integration policy in Europe

This is an Author's Original Manuscript of 'Turning round the telescope. Centre-right parties and immigration and integration policy in Europe', whose final and definitive form, the Version of Record, has been published in the Journal of European Public Policy 15(3):315-330, 2008 [copyright Taylor & Francis], available online at: http://www.tandfonline.com/doi.org/10.1080/13501760701847341

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Abstract Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia

Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</p

Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</p

Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</p

Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</p