The role of serotonergic and dopaminergic mechanisms and their interaction in Levodopa-induced dyskinesias

Long–term levodopa treatment in Parkinson’s disease (PD) is commonly associated with troublesome levodopa–induced dyskinesias (LIDs). Striatal serotonergic terminals amid the degenerating dopaminergic ones are proposed to play an important role in LIDs by taking up exogenous levodopa and releasing dopamine in an unregulated fashion. However, to date, the underlying mechanisms of LIDs are not fully understood. By using single photon emission computed tomography (SPECT) with 123I–Ioflupane and positron emission tomography (PET) with 11C–DASB and 11C–PE2I, the clinical studies conducted for this thesis aimed (a) to estimate the role of striatal dopamine transporter (DAT) availability in early PD as a prognostic marker for LIDs, (b) to explore whether striatal DAT availability changes over time are related to the appearance of LIDs, (c) to estimate the role of striatal serotonin-to-dopamine transporter (SERT–to–DAT) binding ratios to LIDs, and (d) to look for a relation between the changes in striatal SERT, DAT and SERT–to–DAT binding ratios over time and the appearance of LIDs. The main findings are as follows: (a) in early PD, striatal DAT availability alone does not predict the appearance of future LIDs, (b) at later stages, the occurrence of LIDs may be dependent on the magnitude of DAT decline in the putamen, (c) the SERT–to–DAT binding ratio in the putamen is increased in PD patients as compared to controls, and within PD, it is higher in patients with LIDs as compared to nondyskinetic patients, (d) as PD continues to progress, putaminal serotonergic terminals remain relatively unchanged in comparison to the dopaminergic ones and the aforementioned imbalance (as reflected by the binding ratio) increases over time. These findings provide fundamental insight in the pathophysiology of LIDs and have direct implications for further research towards novel therapeutics in PD dyskinesia.Open Acces

Mining imaging and clinical data with machine learning approaches for the diagnosis and early detection of Parkinson\u27s disease

Parkinson\u27s disease (PD) is a common, progressive, and currently incurable neurodegenerative movement disorder. The diagnosis of PD is challenging, especially in the differential diagnosis of parkinsonism and in early PD detection. Due to the advantages of machine learning such as learning complex data patterns and making inferences for individuals, machine-learning techniques have been increasingly applied to the diagnosis of PD, and have shown some promising results. Machine-learning-based imaging applications have made it possible to help differentiate parkinsonism and detect PD at early stages automatically in a number of neuroimaging studies. Comparative studies have shown that machine-learning-based SPECT image analysis applications in PD have outperformed conventional semi-quantitative analysis in detecting PD-associated dopaminergic degeneration, performed comparably well as experts\u27 visual inspection, and helped improve PD diagnostic accuracy of radiologists. Using combined multi-modal (imaging and clinical) data in these applications may further enhance PD diagnosis and early detection. To integrate machine-learning-based diagnostic applications into clinical systems, further validation and optimization of these applications are needed to make them accurate and reliable. It is anticipated that machine-learning techniques will further help improve differential diagnosis of parkinsonism and early detection of PD, which may reduce the error rate of PD diagnosis and help detect PD at pre-motor stage to make it possible for early treatments (e.g., neuroprotective treatment) to slow down PD progression, prevent severe motor symptoms from emerging, and relieve patients from suffering

SPECT imaging and Automatic Classification Methods in Movement Disorders

This work investigates neuroimaging as applied to movement disorders by the use of radionuclide imaging techniques. There are two focuses in this work: 1) The optimisation of the SPECT imaging process including acquisition and image reconstruction. 2) The development and optimisation of automated analysis techniques The first part has included practical measurements of camera performance using a range of phantoms. Filtered back projection and iterative methods of image reconstruction were compared and optimised. Compensation methods for attenuation and scatter are assessed. Iterative methods are shown to improve image quality over filtered back projection for a range of image quality indexes. Quantitative improvements are shown when attenuation and scatter compensation techniques are applied, but at the expense of increased noise. The clinical acquisition and processing procedures were adjusted accordingly. A large database of clinical studies was used to compare commercially available DaTSCAN quantification software programs. A novel automatic analysis technique was then developed by combining Principal Component Analysis (PCA) and machine learning techniques (including Support Vector Machines, and Naive Bayes). The accuracy of the various classification methods under different conditions is investigated and discussed. The thesis concludes that the described method can allow automatic classification of clinical images with equal or greater accuracy to that of commercially available systems

Clinical correlates and advanced processing of the dopamine transporter spect - applications in parkinsonism.

La visualización del transportador de dopamina (DAT) a través del SPECT con [123I]FP-CIT es una prueba de imagen ampliamente usada en el diagnóstico de la enfermedad de Parkinson (EP) y otros trastornos del movimiento que cursan con síntomas parkinsonianos. Dicha imagen permite visualizar y cuantificar los niveles de DAT en el estriado y sus regiones putamen y caudado, y es por tanto una herramienta útil para evaluar in-vivo el estado de las terminales presinápticos dopaminérgicos de la vía nigroestriada. En la práctica clínica es comúnmente utilizado para la diferenciación de parkinsonismos neurodegenerativos con afectación presináptica y otros trastornos del movimiento con síntomas similares pero sin afectación presináptica como el temblor esencial. En la imagen se suele observar un patrón de degeneración postero-anterior que se corresponde con la progresión de síntomas en la EP debido a la afectación progresiva de los circuitos de los ganglios basales. De hecho, numerosos estudios han mostrado que la falta de DAT en el putamen y caudado se correlacionan con síntomas motores y cognitivos, respectivamente. Sin embargo, a pesar de su uso extendido, su uso clínico dado los métodos de evaluación actuales se limita a determinar la presencia o no de degeneración nigroestriada. En esta tesis se plantea como hipótesis que el uso de métodos de procesamiento y evaluación más sofisticados, utilizando técnicas de procesamiento de imágenes y de reconocimiento de patrones a nivel de vóxel, podría potenciar el desarrollo de nuevas aplicaciones clínicas; incluyendo la evaluación de síntomas y el diagnóstico diferencial entre parkinsonismos. Para ello, hemos caracterizado clínicamente y recogido imágenes de SPECT de cientos de pacientes con EP y otros parkinsonismos, persiguiendo dos objetivos globales: i) investigar ciertos conceptos actuales sobre los síntomas motores y cognitivos en la EP; y ii) desarrollar nuevos métodos de procesamiento y evaluación que permitan extender el rango actual de aplicaciones clínicas de dicha prueba. Se presentan un total de 5 publicaciones agrupadas en dos temáticas, una para cada objetivo global. En la primera temática, se engloban dos trabajos con títulos: 1) Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype, Plos One 2017 Mar 30;12(3):e0174644; y 2) Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease, Plos One 2017 Apr 11;12(4):e0175560. En el trabajo 1 se investigaron las diferencias entre los niveles de ácido úrico y dopamina estriatal en los subtipos motores de EP: tremorígeno, intermedio, y con trastorno de la marcha e inestabilidad postural. Estudiamos 75 pacientes con EP de larga evolución y encontramos que aquellos que presentaron un predominio de temblor al inicio y mantuvieron este fenotípo clinico durante el curso de la enfermedad, tuvieron niveles de ácido úrico y dopamina estriatal mayores que aquellos que desarrollaron trastorno de la marcha e inestabilidad postural. Además, los niveles de ácido úrico y de dopamina estriatal se correlacionaron. Como conclusión, especulamos que niveles bajos de este antioxidante natural (el ácido úrico) puede reducer los niveles de neuroprotección y por tanto influenciar el perfil y curso de fenotipo motor en la EP. En el trabajo 2 se investigó la contribución de los principales factores genéticos descritos en la literatura en los síndromes duales de deterioro cognitivo en la EP (fronto-estriatal que conlleva un alto riesgo de síndrome disejecutivo – causado por falta de dopamina – y posterior-cortical que conlleva un alto riesgo de demencia). Evaluamos la imagen, el estado cognitivo y el genotipo de 298 pacientes con EP. Como resultado, observamos que el alelo APOE2, los polimorfismos SNCA rs356219 y COMT Val158Met, y las variantes patogénicas en GBA se asociaron con los niveles de denervación dopaminérgica estriatal, mientras que el alelo APOE4 y de nuevo las variaciones patogénicas en GBA se asociaron con el desarrollo de demencia (sugiriendo un doble rol del gen GBA). No encontramos ninguna relación del haplotipo MAPT H1 en ninguno de los síndromes. Concluimos que la dicotomía de los síndromes duales puede estar conducida por una dicotomía en estos factores genéticos. En la segunda temática, se presentan otros 3 trabajos más centrados en el desarrollo de metodología, titulados: 3) Machine learning models for the differential diagnosis of vascular parkinsonism and Parkinson's disease using [123I]FP-CIT SPECT, European Journal of Nuclear Medicine and Molecular Imaging, 2015 Jan;42(1):112-9; 4) A Bayesian spatial model for neuroimaging using multiscale functional parcellations, En revisión en la revista euroimage; y un último trabajo que está en elaboración y cuyos resultados preliminares fueron presentados recientemente: 5) Probabilistic intensity normalization of PET/SPECT images via Variational mixture of Gamma distributions, 30th Neural Information and Processing Systems Conference, November 2016, Barcelona, Spain. En el trabajo 3 se desarrollaron algoritmos usando imágenes de SPECT para distinguir un parkinsonismo secundario – el parkinsonismo vascular (PV) – de la EP. Observamos que una simple regresión logística – incluyendo los valores medios de captación estriatales, junto con el sexo, la edad, y los años de evolución – diferenció ambas entidades con un 90% de exactitud. De manera similar, encontramos que el uso de algoritmos objetivos y automáticos usando técnicas de machine learning basadas en vóxeles también discriminaron ambas entidades con un 90% de exactitud. Concluimos que el diagnóstico diferencial de ambas enfermedades puede ser asistido por algoritmos automáticos basados en imagen. En el trabajo 4 se desarrolló una nueva metodología, más allá del método estándar basado en vóxeles, para realizar inferencias en neuroimagen funcional. Se desarrolló un modelo multivariado espacial que permitió modelar imágenes de SPECT de sujetos sanos de manera muy eficiente con un número de parámetros muy inferior al número de vóxeles. Dicho modelo consiste en una superposición lineal de funciones base utilizando subparcelaciones multi-escala del estriado, éstas obtenidas tras procesar imágenes de resonancia magnética funcional. También demostramos la utilidad de nuestro modelo para desarrollar aplicaciones clínicas mediante la construcción de clasificadores para diferenciar la EP de controles sanos y un parkinsonismo atípico: la parálisis supranuclear progresiva. Esta nueva metodología ofrece ventajas sin precedentes para el análisis de neuroimagen con respecto al clásico modelo lineal general univariado basado en vóxel, incluyendo: i) mayor interpretabilidad de las señales cerebrales; ii) modelos parsimoniosos y por tanto incremento del poder estadístico; y iii) modelado de la correlación espacial entre regiones y a distintos niveles de granuralidad en neuroimagen funcional. Además, desarrollamos metodología bayesiana para detectar de manera automática (y cuantificar la incertidumbre) las regiones cerebrales que estén relacionadas con ciertas variables fenotípicas. En el trabajo 5 se desarrolló un método para armonizar la intensidad de las imágenes de SPECT producidas por distintos fabricantes (y calibración) de cámaras Gamma. El método se basa en modelar el histograma de la imagen con un modelo mixto de distribuciones Gamma. Se utilizó la función de densidad acumulada de la distribución Gamma que modela la región específica de captación para reparametrizar la imagen con valores de vóxel entre 0 y 1. Observamos que dicha normalización mejoró sustancialmente (hasta un 10%) el diagnóstico de EP cuando los algoritmos se desarrollaron usando imágenes de distintas cámaras y/o calibraciones. Dicha normalización puede suponer un paso clave en pre-procesado de estas imágenes de cara a la realización de estudios multicéntricos y el desarrollo de aplicaciones clínicas generalizables. Como conclusión es importante resaltar la relevancia de los trabajos. En los trabajos 1 y 2 hemos aportado resultados con biomarcadores de valor pronóstico en la progresión de la EP. En los trabajos 3, 4 y 5, hemos aportado una nueva metodología, muy superior a la existente, de procesamiento y evaluación de esta prueba de imagen. La metodología desarrollada en el trabajo 4 permite explorar regiones cerebrales a un de nivel de complejidad espacial y granularidad sin precedentes. Por ello, nuestro modelo podría captar las diferencias entre las imágenes de pacientes con distintas patologías y/o entre síntomas específicos residir en patrones espaciales sutiles y complejos. De hecho, en los trabajos 3 y 4 aportamos resultados excelentes en la diferenciación de la EP con otros síndromes parkinsonianos. Además, el trabajo 5 tiene el potencial de constituirse en el campo como un paso fundamental de pre-procesado, especialmente en estudios ulticéntricos y estudios que pretendan desarrollar aplicaciones clínicas generalizables, independientemente de la cámara Gamma y el centro donde se realice la prueba. Es importante señalar además que los métodos desarrollados se podrían igualmente aplicar para procesar y evaluar otro tipo de imágenes de medicina nuclear y/u otras regiones cerebrales. Es por ello que esperamos que este trabajo tenga un gran impacto en general en la evaluación de este tipo de imágenes y en el desarrollo de algoritmos que den soporte a la decisiones clínicas en trastornos del movimiento y potencialmente en otras enfermedades.The imaging of the dopamine transporter (DAT) with [123I]FP-CIT SPECT is a routinely used assessment in the diagnostic pipeline of Parkinson’s disease (PD) and other movement disorders that present with parkinsonian symptoms. In this scan, the levels of striatal DAT can be visualized and quantified, also at the region-of-interest (ROI) level in putamen and caudate, and therefore it constitutes an useful tool to assess in-vivo the state of the dopaminergic presynaptic terminals in the nigrostriatal pathway. In routine clinical practice it is especially utilized for the differential diagnlosis of presynaptic neurodegenerative disorders like PD and other non-presynaptic movement disorders like essential tremor. Also, numerous research studies have shown that striatal DAT deficits quantitatively correlate with motor and cognitive impairment in PD. Indeed, it can be seen in the image a posterior-to-anterior pattern of degeneration that well corresponds with disease progression due to the progressive lost of dopaminergic input into the motor and associative loops between the basal ganglia and the cortex. However, despite its known utility and widespread availability, its use with current assessment methods in real clinical practice is limited to determining the presence of nigrostriatal degeneration at a single-subject level in a binary fashion. We hypothesized in this thesis that an enhanced processing and assessment of this scan with modern image processing and pattern recognition techniques may help to boost its use in the clinic with new and more accurate applications, including symptom risk assessment and differential diagnosis with other parkinsonisms. We collected DAT scans of several hundreds of well-clinicallyphenotyped patients with PD and other parkinsonims, envisaging two main global objectives: i) to investigate some trending hypotheses and concepts about the motor and cognitive impairment in PD; and ii) to develop new processing and evaluation strategies with computational techniques to shed light into new clinical applications. A total of 5 publications are herein presented and grouped in two themes, one for each global objective. In the first theme, two works are presented, entitled: 1) Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype, Plos One 2017 Mar 30;12(3):e0174644; and 2) Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease, Plos One 2017 Apr 11;12(4):e0175560. In work 1 we investigated the differences in uric acid and striatal DAT in PD motor subtypes: tremor-dominant, intermediate, or postural instability and gait disorder (PIGD). We studied 75 PD patients of long-term evolution and found that those who presented with a tremor onset and maintained predominance of tremor, or, to a lesser extent, evolved to an intermediate phenotype, had higher levels of uric acid and striatal DAT binding than those who developed a IGD phenotype. We also found that uric acid and striatal DAT levels were highly correlated. We speculate that low levels of this natural antioxidant may lead to a lesser degree of neuroprotection and could therefore influence the motor phenotype and course. In work 2 we investigated the contribution to the dual syndromes of cognitive impairment in PD (frontostriatal dopamine-mediated and posterior cortical leading to dementia) of the main genetic risk factors decribed in the literature. We evaluated the scans, the cognitive status, and the genotypes of 298 PD patients and found that APOE2 allele, SNCA rs356219 and COMT Val158Met polymorphisms, and deleterious variants in GBA influenced striatal dopaminergic depletion, and that APOE4 allele and deleterious variants in GBA influenced dementia, thus suggesting a doubleedged role for GBA. We did not found any role of MAPT H1 haplotype. We conclude that the dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors. In the second theme, we present three other works with more focus on methodology, entitled: 3) Machine learning models for the differential diagnosis of vascular parkinsonism and Parkinson's disease using [123I]FP-CIT SPECT, European Journal of Nuclear Medicine and Molecular Imaging, 2015 Jan;42(1):112-9; 4) A Bayesian spatial model for neuroimaging using multiscale functional parcellations, Under Review in Neuroimage; and a last piece of work that it is in preparation for submission and that I have adapted for this thesis from 5) Probabilistic intensity normalization of PET/SPECT images via Variational mixture of Gamma distributions, 30th Neural Information and Processing Systems Conference, November 2016, Barcelona, Spain. In work 3 we developed analytical models using DAT SPECT data to discriminate vascular parkinsonism (VP) from PD. We collected scans from 80 VP and 164 PD and found that a simple logistic regression using the quantification of the striatal subregions putamen and caudate together with age, sex and disease duration discriminated both entities with over 90% accuracy. Also, we found that the use of more automated and rater-independent machine learning algorithms such as support vector machines with the voxel-wise data of the striatum also gives discrimination accuracy over 90%. We conclude that the differential diagnosis of both diseases can be aided by automated image-based algorithms. In work 4 we developed a new anaylsis framework to perform inferences with functional neuroimaging data. We developed a multivariate spatial model by which an imaged brain region can be efficiently represented in low dimensions with a linear superposition of basis functions. To demonstrate, we accurately modeled DATSCAN images from healthy subjects with a linear combination of multi-resolutional striatum parcellations derived from functional MRI experiments. We also demonstrate the utility of our model to develop clinical application by constructing accurate classifiers to differentiate PD from normal controls and patients with an atypical parkinsonism: the progressive supranuclear palsy. This approach offers unprecedent benefits with respect to classical univariate voxel methods, including: i) greater biological interpretability of the detected brain signals ii) parsimonity in the models and hence gain in statistical power; and iii) multi-range modeling of the spatial dependencies in brain images. Furthermore, we provide a bayesian analysis framework to automatically identifying brain subregions/subnetworks that are meaningful for particular phenotypic variables. In work 5 we developed a voxel-based intensity normalization method for DAT SPECT images aiming at overcoming the liminations of the current ROI-based normalization standard, namely ROI delineation dependence and intensity values dependence on Gamma camera. We found that the intensity histogram of a DAT SPECT image can be modeled as a mixture model of Gamma distributions. The cumulative distribution function (CDF) of the fitted Gamma distributions can be used to re-cast the voxel intensity values into a new normalized feature space between 0 and 1. We found that this re-parametrization equalized intensity across cameras and drastically improved the accuracy of PD diagnosis (up to 10%) when images from different cameras were pooled. Importantly, our method may constitute a key pre-processing step for group-level and multi-center studies. As a final remark, it is important to stress the relevance of the work. In the works 1 and 2, we have provided new insights on biomarkers that have prognostic value in the progression of PD. In the works 3, 4 and 5, which set the grounds of a new powerful approach to process and evaluate these images. The machine learning framework developed in work 4) allows to exploring brain regions at a unprecedent level of spatial complexity and granurality. Thus, challenging tasks such as the differential diagnosis between different parkinsonian disorders or the identification of fine-grained regions/networks responsible for specific parkinsonian symptoms can be tackled with the proposed approach. In fact, we obtained excellent results in works 3 and 4 in the differentiation of PD from other parkinsonian syndromes. Also, the work 5 may constitute a fundamental pre-processing step, especially in multi-center studies and studies aiming at developing generalizable clinical applications, regardless of the Gamma camera manufacturer and site where the scan is made. It is important to note that, besides DATSCAN, these methods could be also applied to other nuclearmedicine images and/or brain regions. We hope that this work will have an impact in the assessment of this type of images and in the development of algorithms supporting clinical decisions in movement disorders and potentially in other diseases as well.Premio Extraordinario de Doctorado U

(I123)FP-CIT reporting: Machine Learning, Effectiveness and Clinical Integration

(I123)FP-CIT imaging is used for differential diagnosis of clinically uncertain Parkinsonian Syndromes. Conventional reporting relies on visual interpretation of images and analysis of semi-quantification results. However, this form of reporting is associated with variable diagnostic accuracy results. The first half of this thesis clarifies whether machine learning classification algorithms, used as computer aided diagnosis (CADx) tool, can offer improved performance. Candidate machine learning classification algorithms were developed and compared to a range of semi-quantitative methods, which showed the superiority of machine learning tools in terms of binary classification performance. The best of the machine learning algorithms, based on 5 principal components and a linear Support Vector Machine classifier, was then integrated into clinical software for a reporting exercise (pilot and main study). Results demonstrated that the CADx software had a consistently high standalone accuracy. In general, CADx caused reporters to give more consistent decisions and resulted in improved diagnostic accuracy when viewing images with unfamiliar appearances. However, although these results were undoubtedly impressive, it was also clear that a number of additional, significant hurdles remained, that needed to be overcome before widespread clinical adoption could be achieved. Consequently, the second half of this thesis focuses on addressing one particular aspect of the remaining translation gap for (I123)FP-CIT classification software, namely heterogeneity of the clinical environment. Introduction of new technology, such as machine learning, may require new metrics, which in this work were informed through novel methods (such as the use of innovative phantoms) and strategies, enabling sensitivity testing to be developed, applied and evaluated. The pathway to acceptance of novel and progressive technology in the clinic is a tortuous one, and this thesis emphasises the importance of many factors in addition to the core technology that need to be addressed if such tools are ever to achieve clinical adoption

Neuroimaging correlates of progressive cognitive decline and clinical symptoms in prodromal Lewy body disease. A multimodal imaging study

Ph. D. Thesis.Introduction There has been an interest in earlier diagnosis of cognitive impairment at the prodromal stage. Mild cognitive impairment (MCI) is a prodromal cognitive phenotype of dementia. Differentiating MCI with Lewy bodies (MCI-LB) and MCI due to AD (MCI-AD) using clinical features alone is challenging and biomarkers are likely to aid diagnosis. This thesis investigated whether cross-sectional structural magnetic resonance imaging (MRI) or repeat 123I-FP-CIT single photon emission tomography (SPECT) could be utilised to differentiate between MCI-LB and MCI-AD. Methods Prospective repeat 133I-FP-CIT SPECT study: 85 subjects were included in this analysis, consisting of; healthy controls (HC) (n=29), MCI-AD (n=19), possible MCI-LB (n=10), probable MCI-LB (n=27). All subjects underwent comprehensive clinical and neuropsychological assessment as well as repeat 123I-FP-CIT SPECT and baseline cardiac 123I-MIBG scintigraphy. Cross- sectional MRI study: 97 subjects were included in this analysis, consisting of; HC (n=31), MCIAD (n=32), probable MCI-LB (n=34). All subjects underwent comprehensive clinical and neuropsychological assessment as well as baseline 123I-FP-CIT SPECT, cardiac 123I-MIBG scintigraphy and structural magnetic resonance imaging. Results Progressive dopaminergic loss was detected in MCI-LB in excess of HC, with mean annual striatal decline of 6% in the MCI-LB cohorts. MCI-AD had no difference in longitudinal striatal uptake when compared to HC. Structural MRI data found: (1) grey matter volume loss in the frontal and temporal lobes in MCI-LB compared to HC, (2) bilateral cerebellar volume reduction in MCI-LB compared to iii MCI-AD, (3) no relative preservation of the medical temporal lobe in MCI-LB compared to MCI-AD, (4) no cortical thickness difference between MCI-LB and MCI-AD (5) thalamic volume loss and relative preservation of the amygdala in MCI-LB compared to MCI-AD. Conclusion Sequential 123I-FP-CIT SPECT imaging is a promising biomarker for identifying MCI-LB. Structural MRI showed no difference in cortical indexes but some differences in subcortical and cerebellar measures between MCI-LB and MCI-AD

12 Chapters on Nuclear Medicine

The development of nuclear medicine as a medical specialty has resulted in the large-scale application of its effective imaging methods in everyday practice as a primary method of diagnosis. The introduction of positron-emitting tracers (PET) has represented another fundamental leap forward in the ability of nuclear medicine to exert a profound impact on patient management, while the ability to produce radioisotopes of different elements initiated a variety of tracer studies in biology and medicine, facilitating enhanced interactions of nuclear medicine specialists and specialists in other disciplines. At present, nuclear medicine is an essential part of diagnosis of many diseases, particularly in cardiologic, nephrologic and oncologic applications and it is well-established in its therapeutic approaches, notably in the treatment of thyroid cancers. Data from official sources of different countries confirm that more than 10-15 percent of expenditures on clinical imaging studies are spent on nuclear medicine procedures