Imaging of Dopamine and Serotonin Transporters. Pre-clinical Studies with Radiotracers for Positron Emission Tomography

The action of the neurotransmitters dopamine (DA) and serotonin (5-HT) at synapses is terminated by their rapid reuptake into presynaptic nerve endings via plasma membrane dopamine (DAT) and serotonin (SERT) transporters. Alterations in the function of these transporters have been suggested as a feature of several neurological and neuropsychiatric diseases, such as Parkinson’s disease (PD), depression, and anxiety. A suitable clinical method for studying these transporters non-invasively in vivo is positron emission tomography (PET) utilizing radiopharmaceuticals (tracers) labelled with short-lived positron-emitting radionuclides. The aim of this study was to evaluate in rats two novel radiotracers, [¹⁸F]beta -CFT-FP and ¹⁸FFMe-McN, for imaging DAT and SERT, respectively, using in vitro, ex vivo and in vivo methods. Substituting an N-methyl in [¹⁸F]beta-CFT, a well known DAT tracer, with a ¹⁸Ffluoropropyl group significantly changed the properties of the tracer. [¹⁸F]beta- CFT showed slow kinetics and metabolism, and a high specific uptake in the striatum, whereas [¹⁸F]beta-CFT-FP showed fast kinetics and metabolism, and a moderate specific uptake in the striatum. [¹⁸F]betaCFT-FP was selective for DAT; but [¹⁸F]beta-CFT also bound to the noradrenaline transporter. [¹⁸F]beta-CFT-FP may be a suitable PET tracer for imaging the striatal DAT sites, but a tracer with a higher affinity is needed for imaging extrastriatal DAT sites. In rats, ¹⁸FFMe-McN showed high target-to-non-target ratios, specificity and selectivity for SERT, but slow kinetics. However, ¹⁸FFMe-McN reveals potential for imaging SERT, at least in pre-clinical studies. In addition, the sensitivities of [¹⁸F]beta CFT and [¹⁸ F]FDOPA (a precursor of DA) for detecting mild nigrostriatal hypofunction were compared in an animal model of PD. The uptake of [¹⁸F]FDOPA was significantly affected by compensatory effects in dopaminergic cells, whereas [¹⁸F]beta-CFT was more sensitive and therefore more suitable for PET studies of mild dopaminergic symptoms. In conclusion, both novel tracers, [¹⁸F]-CFT-FP and ¹⁸FFMe-McN, have potential, but are not optimal PET tracers for DAT and SERT imaging in rats, respectively. [¹⁸F]beta-CFT is superior to [18F]FDOPA for imaging mild nigral lesions in rat brains.

Mild Cognitive Impairment and Early Detection of Alzheimer`s Disease. A Positron Emission Tomography Study

Alzheimer`s disease (AD) is characterised neuropathologically by the presence of extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss. The pathological changes in AD are believed to start even decades before clinical symptoms are detectable. AD gradually affects episodic memory, cognition, behaviour and the ability to perform everyday activities. Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia disorders, especially AD. The predictive accuracy of the current and commonly used MCI criteria devide this disorder into amnestic (aMCI) and non-amnestic (naMCI) MCI. It seems that many individuals with aMCI tend to convert to AD. However many MCI individuals will remain stable and some may even recover. At present, the principal drugs for the treatment of AD provide only symptomatic and palliative benefits. Safe and effective mechanism-based therapies are needed for this devastating neurodegenerative disease of later life. In conjunction with the development of new therapeutic drugs, tools for early detection of AD would be important. In future one of the challenges will be to detect at an early stage these MCI individuals who will convert to AD. Methods which can predict which MCI subjects will convert to AD will be much more important if the new drug candidates prove to have disease-arresting or even disease–slowing effects. These types of drugs are likely to have the best efficacy if administered in the early or even in the presymptomatic phase of the disease when the synaptic and neuronal loss has not become too widespread. There is no clinical method to determine with certainly which MCI individuals will progress to AD. However there are several methods which have been suggested as predictors of conversion to AD, e.g. increased [11C] PIB uptake, hippocampal atrophy in MRI, low CSF A beta 42 level, high CSF tau-protein level, apolipoprotein E (APOE) ε4 allele and impairment in episodic memory and executive functions. In the present study subjects with MCI appear to have significantly higher [¹¹C] PIB uptake vs healthy elderly in several brain areas including frontal cortex, the posterior cingulate, the parietal and lateral temporal cortices, putamen and caudate. Also results from this PET study indicate that over time, MCI subjects who display increased [¹¹C] PIB uptake appear to be significantly more likely to convert to AD than MCI subjects with negative [¹¹C] PIB retention. Also hippocampal atrophy seems to increase in MCI individuals clearly during the conversion to AD. In this study [¹¹C] PIB uptake increases early and changes relatively little during the AD process whereas there is progressive hippocampal atrophy during the disease. In addition to increased [¹¹C] PIB retention and hippocampal atrophy, the status of APOE ε4 allele might contribute to the conversion from MCI to AD.

Compton scattering tomography for agricultural measurements

This paper presents a new approach in tomographic instrumentation for agriculture based on Compton scattering, which allows for the simultaneous measurements of density and moisture of soil samples. Compton tomography is a technique that can be used to obtain a spatial map of electronic density of samples. Quantitative results can be obtained by using a reconstruction algorithm that takes into account the absorption of incident and scattered radiation. Results show a coefficient of linear correlation better than 0.81, when comparison is made between soil density measurements based on this method and direct transmission tomography. For soil water contents, a coefficient of linear correlation better than 0.79 was found when compared with measurements obtained by time domain reflectrometry (TDR). In addition, a set of Compton scatter images are presented to illustrate the efficacy of this imaging technique, which makes possible improved spatial variability analysis of pre-established planes.

In vivo imaging of vascular adhesion protein 1 - preclinical studies with positron emission tomography

The golden standard in nuclear medicine imaging of inflammation is the use of radiolabeled leukocytes. Although their diagnostic accuracy is good, the preparation of the leukocytes is both laborious and potentially hazardous for laboratory personnel. Molecules involved in leukocyte migration could serve as targets for the development of inflammation imaging agents. An excellent target would be a molecule that is absent or expressed at low level in normal tissues, but is induced or up-regulated at the site of inflammation. Vascular adhesion protein-1 (VAP-1) is a very promising target for in vivo imaging, since it is translocated to the endothelial cell surface when inflammation occurs. VAP-1 functions as an endothelial adhesion molecule that participates in leukocyte recruitment to inflamed tissues. Besides being an adhesion molecule, VAP-1 also has enzymatic activity. In this thesis, the targeting of VAP-1 was studied by using Gallium-68 (68Ga) labeled peptides and an Iodine-124 (124I) labeled antibody. The peptides were designed based on molecular modelling and phage display library searches. The new imaging agents were preclinically tested in vitro, as well as in vivo in animal models. The most promising imaging agent appeared to be a peptide belonging to the VAP-1 leukocyte ligand, Siglec-9 peptide. The 68Ga-labeled Siglec-9 peptide was able to detect VAP-1 positive vasculature in rodent models of sterile skin inflammation and melanoma by positron emission tomography. In addition to peptides, the 124I-labeled antibody showed VAP-1 specific binding both in vitro and in vivo. However, the estimated human radiation dose was rather high, and thus further preclinical studies in disease models are needed to clarify the value of this imaging agent. Detection of VAP-1 on endothelium was demonstrated in these studies and this imaging approach could be used in the diagnosis of inflammatory conditions as well as melanoma. These studies provide a proof-of-concept for PET imaging of VAP-1 and further studies are warranted.

Application of x-ray computed tomography in the evaluation of soil porosity in soil management systems

The study aimed to evaluate a methodology to quantify the porosity of the soil using computed tomography in areas under no-tillage, conventional tillage and native forest. Three soil management systems were selected for the study: forest, conventional tillage and no-tillage. In each soil management system, undisturbed soil samples were collected in the surface layer (0.0 to 0.10 m). The tomographic images were obtained using a X-ray microtomography. After obtaining the images, they were processed, and a methodology was evaluated for image conversion into numerical values. The statistical method which provided the greatest accuracy was the percentile method. The methodology used to analyze the tomographic image allowed quantifying the porosity of the soil under different soil management. The method enabled the characterization of soil porosity in a non-evasive and non-destructive way.

Quantum Tomography with Phase Space Measurements

This thesis addresses the use of covariant phase space observables in quantum tomography. Necessary and sufficient conditions for the informational completeness of covariant phase space observables are proved, and some state reconstruction formulae are derived. Different measurement schemes for measuring phase space observables are considered. Special emphasis is given to the quantum optical eight-port homodyne detection scheme and, in particular, on the effect of non-unit detector efficiencies on the measured observable. It is shown that the informational completeness of the observable does not depend on the efficiencies. As a related problem, the possibility of reconstructing the position and momentum distributions from the marginal statistics of a phase space observable is considered. It is shown that informational completeness for the phase space observable is neither necessary nor sufficient for this procedure. Two methods for determining the distributions from the marginal statistics are presented. Finally, two alternative methods for determining the state are considered. Some of their shortcomings when compared to the phase space method are discussed.

Jejunum and ileum blunt trauma: what has changed with the implementation of multislice computed tomography?

OBJECTIVE: to evaluate the impact of the new technology of multidetector computed tomography (MDCT) in improving the accuracy and early diagnosis of BSBI.METHODS: patients with blunt small bowel injuries (BSBI) grade> I were identified retrospectively and their CT scans reviewed by an experienced radiologist. Clinical and tomographic findings were analyzed and patients grouped as "pre-MDCT" and "post-MDCT", according to the time of implementation of a 64-slice MDCT.RESULTS: of the 26 patients with BSBI 16 had CT scans. Motor vehicle collision (62.5%) was the most frequent mechanism of injury. In the pre-MDCT period, five of the 13 patients (38.5%) had abdominal CT, and in the post-MDCT, 11 of 13 patients (84.6%) had the exam. During pre-MDCT, all CT scans were abnormal with findings of pneumoperitoneum (60%), free fluid (40%) and bowel wall enhancement (20%). In the post-MDCT group, all exams but one were abnormal and the most frequent findings were free fluid (90.9%), bowel wall enhancement (72.7%), and pneumoperitoneum (54.5%). However, the rate of delayed laparotomy did not change. The mortality rate in both groups were similar, with 20% during pre-MDCT and 18.2% during post-MDCT.CONCLUSION: the use of MDCT in abdominal trauma in our service has increased the sensibility of the diagnosis, but has had no impact on outcome so far.

Evaluation of the use of tomography in penetrating neck trauma

ABSTRACTObjective:the study has the intention of evaluate the accuracy of computed tomography for the diagnosis of cervical lesions on penetrating neck trauma and also identify the most frequent mechanisms of trauma. Most injured structures, determine the age range and the most prevalent sex.Methods: observational descriptive retrospective study executed by the systematic retrospective review of medical records of all patients victims of penetrating neck trauma that went through surgery and CT scans, admitted into Hospital do Trabalhador, between January 2009 and December 2013.Results:the final sample was of 30 patients, 96.7% of the male sex, the median age was of 28 years old. Most patients suffered injuries by gun (56.7%) and 33,3% suffered stab wounds. The most stricken area of the neck was Zone II (77.8%) and the left side (55.2%). Regarding the structures injured, the CT showed 6.7% lesions on airways but the surgery showed 40% of damaged, with a value of p=0.002. As to damages of the esophagus and pharynx the CT detected 10% of lesions, while surgery found 30% of lesions, therefore with a significant value of p=0.013. As for the analysis the CT showed reliable. As for the analysis of vascular damage, the CT showed to be, in most cases, reliable to the findings during the surgical act.Conclusion:besides the great use of CT for the diagnosis of penetrating neck injuries we can say that this is an exam with low accuracy for the diagnosis of lesions of aerodigestive tract, therefore it is important a clinical correlation for a good diagnosis.as for the vascular lesions and of other structures, the CT had high sensibility and specificity, thus a good exam to be used in overall.

Prevalence of alterations in chest computerized tomography in patients with head and neck cancer

Objective: to assess the prevalence of abnormalities found by computed tomography (CT) of the chest in patients with squamous cell carcinoma of the head and neck. Methods: we retrospectively analyzed chest CT exams of 209 patients with squamous cell carcinoma of the head and neck. The CT findings were stratified as inflammatory / infectious, parenchymal, nodular uncharacteristic and nodular metastatic / tumoral Results: alterations were diagnosed in 66.6% of patients. Of these, 25.3% represented emphysema; 18.8%, uncharacteristic micronodules; 12.9%, metastases; 11.9%, thoracic lymph node enlargements; and in 6.6% we detected active pulmonary tuberculosis or its sequelae, pneumonia or inflammatory / infectious signs and pleural thickening or effusion. Conclusion: the prevalence of exams with alterations and the considerable rate of detected metastases indicate that chest CT should be required for diagnostic and / or staging in cases of head and neck cancer.

Imaging of Tumour Microenvironment for the Planning of Oncological Therapies Using Positron Emission Tomography

Tumour cells differ from normal tissue cells in several important ways. These differences, like for example changed energy metabolism, result in altered microenvironment of malignant tumours. Non-invasive imaging of tumour microenvironment has been at the centre of intense research recently due to the important role that this changed environement plays in the development of malignant tumours and due to the role it plays in the treatment of these tumours. In this respect, perhaps the most important characteristics of the tumour microenvironment from this point of view are the lack of oxygen or hypoxia and changes in blood flow (BF). The purpose of this thesis was to investigate the processes of energy metabolism, BF and oxygenation in head and neck cancer and pancreatic tumours and to explore the possibilities of improving the methods for their quantification using positron emission tomography (PET). To this end [18F]EF5, a new PET tracer for detection of tumour hypoxia was investigated. Favourable uptake properties of the tracer were observed. In addition, it was established that the uptake of this tracer does not correlate with the uptake of existing tracers for the imaging of energy metabolism and BF, so the information about the presence of tissue hypoxia cannot therefore be obtained using tracers such as [18F]FDG or [15O]H2O. These results were complemented by the results of the follow-up study in which it was shown that the uptake of [18F]EF5 in head and neck tumours prior to treatment is also associated with the overall survival of the patients, indicating that tumour hypoxia is a negative prognostic factor and might be associated with therapeutic resistance. The influences of energy metabolism and BF on the survival of patients with pancreatic cancer were investigated in the second study. The results indicate that the best predictor of survival of patients with pancreatic cancer is the relationship between energy metabolism and BF. These results suggest that the cells with high metabolic activity in a hypoperfused tissue have the most aggressive phenotype.

Computed tomography image of the mediastinal and axillary lymph nodes in clinically sound Rottweilers

Trough computed tomography (CT), it is possible to evaluate lymph nodes in detail and to detect changes in these structures earlier than with radiographs and ultrasound. Lack of information in the veterinary literature directed the focus of this report to normal aspects of the axillary and mediastinal lymph nodes of adult dogs on CT imaging. A CT scan of 15 normal adult male and female Rottweilers was done. To define them as clinically sound, anamnesis, physical examination, complete blood count, renal and hepatic biochemistry, ECG, and thoracic radiographs were performed. After the intravenous injection of hydrosoluble ionic iodine contrast medium contiguous 10mm in thickness thoracic transverse images were obtained with an axial scanner. In the obtained images mediastinal and axillary lymph nodes were sought and when found measured in their smallest diameter and their attenuation was compared to musculature. Mean and standard deviation of: age, weight, body length and the smallest diameter of the axillary and mediastinal lymph nodes were determined. Mean and standard deviation of parameters: age 3.87±2.03 years, weight 41.13±5.12, and body length 89.61±2.63cm. Axillary lymph nodes were seen in 60% of the animals, mean of the smallest diameter was 3.58mm with a standard deviation of 2.02 and a minimum value of 1mm and a maximum value of 7mm. From 13 observed lymph nodes 61.53% were hypopodense when compared with musculature, and 30.77% were isodense. Mediastinal lymph nodes were identified in 73.33% of the dogs; mean measure of the smallest diameter was 4.71mm with a standard deviation of 2.61mm and a minimum value of 1mm, and a maximum value of 8mm. From 14 observed lymph nodes 85.71% were isodense when compared with musculature and 14.28% were hypodense. The results show that it is possible to visualize axillary and mediastinal lymph nodes in adult clinically sound Rottweilers with CT using a slice thickness and interval of 10mm. The smallest diameter of the axillary and mediastinal lymph nodes not surpassed 7mm and 8mm respectively. Their attenuations were equal or smaller than that of musculature in the post contrast scan.

Neutron tomography using projection data obtained by Monte Carlo simulation for nondestructive evaluation

This work present the application of a computer package for generating of projection data for neutron computerized tomography, and in second part, discusses an application of neutron tomography, using the projection data obtained by Monte Carlo technique, for the detection and localization of light materials such as those containing hydrogen, concealed by heavy materials such as iron and lead. For tomographic reconstructions of the samples simulated use was made of only six equal projection angles distributed between 0º and 180º, with reconstruction making use of an algorithm (ARIEM), based on the principle of maximum entropy. With the neutron tomography it was possible to detect and locate polyethylene and water hidden by lead and iron (with 1cm-thick). Thus, it is demonstrated that thermal neutrons tomography is a viable test method which can provide important interior information about test components, so, extremely useful in routine industrial applications.

Differentiation of Metabolically Distinct Areas within Head and Neck Region using Dynamic 18F-FDG Positron Emission Tomography Imaging

Positron Emission Tomography (PET) using ¹⁸F-FDG is playing a vital role in the diagnosis and treatment planning of cancer. However, the most widely used radiotracer, ¹⁸F-FDG, is not specific for tumours and can also accumulate in inflammatory lesions as well as normal physiologically active tissues making diagnosis and treatment planning complicated for the physicians. Malignant, inflammatory and normal tissues are known to have different pathways for glucose metabolism which could possibly be evident from different characteristics of the time activity curves from a dynamic PET acquisition protocol. Therefore, we aimed to develop new image analysis methods, for PET scans of the head and neck region, which could differentiate between inflammation, tumour and normal tissues using this functional information within these radiotracer uptake areas. We developed different dynamic features from the time activity curves of voxels in these areas and compared them with the widely used static parameter, SUV, using Gaussian Mixture Model algorithm as well as K-means algorithm in order to assess their effectiveness in discriminating metabolically different areas. Moreover, we also correlated dynamic features with other clinical metrics obtained independently of PET imaging. The results show that some of the developed features can prove to be useful in differentiating tumour tissues from inflammatory regions and some dynamic features also provide positive correlations with clinical metrics. If these proposed methods are further explored then they can prove to be useful in reducing false positive tumour detections and developing real world applications for tumour diagnosis and contouring.

Use of single photon emission computed tomography and magnetic resonance to evaluate central nervous system involvement in patients with juvenile systemic lupus erythematosus

The objective of the present study was to identify the single photon emission computed tomography (SPECT) and magnetic resonance (MR) findings in juvenile systemic lupus erythematosus (JSLE) patients with CNS involvement and to try to correlate them with neurological clinical history data and neurological clinical examination. Nineteen patients with JSLE (16 girls and 3 boys, mean age at onset 9.2 years) were submitted to neurological examination, electroencephalography, cerebrospinal fluid analysis, SPECT and MR. All the evaluations were made separately within a period of 15 days. SPECT and MR findings were analyzed independently by two radiologists. Electroencephalography and cerebrospinal fluid analysis revealed no relevant alterations. Ten of 19 patients (53%) presented neurological abnormalities including present or past neurological clinical history (8/19, 42%), abnormal neurological clinical examination (5/19, 26%), and abnormal SPECT or MR (8/19, 42% and 3/19, 16%, respectively). The most common changes in SPECT were cerebral hypoperfusion and heterogeneous distribution of blood flow. The most common abnormalities in MR were leukomalacia and diffuse alterations of white matter. There was a correlation between SPECT and MR (P<0.05). We conclude that SPECT and MR are complementary and useful exams in the evaluation of neurological involvement of lupus.