Vectorial-based analysis of dual-tracer PET imaging: A proof of concept.

BACKGROUND: The diagnosis of neurological diseases is complicated since they often share similar symptoms and occur in different severity levels. Imaging techniques such as PET molecular imaging are helpful for an early and accurate diagnosis and, staging allowing a noninvasive evaluation of the disease. The combination of two radioligands in the same patient could be valuable to achieve these diagnostic goals; nevertheless, the imaging data obtained with two radioligands is commonly interpreted independently. This novel approach to combine the PET data of two radiopharmaceuticals, separately acquired in the same subject, is to obtain new quantitative metrics. PET images of patients with Parkinson's disease (PD) and healthy controls (HC) were analyzed. Voxel-by-voxel uptake is compared by combining the imaging data. Dual-tracer PET imaging analysis was tested with [11C]DTBZ-[11C]Raclopride as proof of concept. RESULTS: The new proposed metric based on a resultant vector is capable of efficiently discriminating healthy controls from PD patients (p < 0.0001) allowing the detection of slight changes in patients undergoing therapeutic approaches. Significant differences were found between HC and PD patients for the evaluated radiotracers. CONCLUSIONS: The resultant vector appears to deliver useful information that could be helpful to evaluate PD patients under treatment and to improve differential diagnoses.

Semiquantitative analysis of cerebral [18F]FDG-PET uptake in pediatric patients.

BACKGROUND: Glycolytic metabolism in the brain of pediatric patients, imaged with [18F]  fluorodeoxyglucose-positron emission tomography (FDG-PET) is incompletely characterized. OBJECTIVE: The purpose of the current study was to characterize [18F]FDG-PET brain uptake in a large sample of pediatric patients with non-central nervous system diseases as an alternative to healthy subjects to evaluate changes at different pediatric ages. MATERIALS AND METHODS: Seven hundred ninety-five [18F]FDG-PET examinations from children < 18 years of age without central nervous system diseases were included. Each brain image was spatially normalized, and the standardized uptake value (SUV) was obtained. The SUV and the SUV relative to different pseudo-references were explored as a function of age. RESULTS: At all evaluated ages, the occipital lobe showed the highest [18F]FDG uptake (0.27 ± 0.04 SUV/year), while the parietal lobe and brainstem had the lowest uptake (0.17 ± 0.02 SUV/year, for both regions). An increase [18F]FDG uptake was found for all brain regions until 12 years old, while no significant uptake differences were found between ages 13 (SUV = 5.39) to 17 years old (SUV = 5.52) (P < 0.0001 for the whole brain). A sex dependence was found in the SUVmean for the whole brain during adolescence (SUV 5.04-5.25 for males, 5.68-5.74 for females, P = 0.0264). Asymmetries in [18F]FDG uptake were found in the temporal and central regions during infancy. CONCLUSIONS: Brain glycolytic metabolism of [18F]FDG, measured through the SUVmean, increased with age until early adolescence (< 13 years old), showing differences across brain regions. Age, sex, and brain region influence [18F]FDG uptake, with significant hemispheric asymmetries for temporal and central regions.

Characterization of metabolic activity induced by kainic acid in adult rat whole brain at the early stage: A 18FDG-PET study.

OBJECTIVE: Brain metabolic processes are not fully characterized in the kainic acid (KA)-induced Status Epilepticus (KASE). Thus, we evaluated the usefulness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as an experimental strategy to evaluate in vivo, in a non-invasive way, the glucose consumption in several brain regions, in a semi-quantitative study to compare and to correlate with data from electroencephalography and histology studies. METHODS: Sixteen male Wistar rats underwent FDG-PET scans at basal state and after KA injection. FDG-PET images were normalized to an MRI-based atlas and segmented to locate regions. Standardized uptake values (SUV) were obtained at several time points. EEGs and cell viability by histological analysis, were also evaluated. RESULTS: FDG-PET data showed changes in regions such as: amygdala, hippocampus, accumbens, entorhinal cortex, motor cortex and hypothalamus. Remarkably, hippocampal hypermetabolism was found (mean SUV = 2.66 ± 0.057) 2 h after KA administration, while hypometabolism at 24 h (mean SUV = 1.83 ± 0.056) vs basal values (mean SUV = 2.19 ± 0.057). EEG showed increased spectral power values 2 h post-KA administration. Hippocampal viable-cell counting 24 h after KA was decreased, while Fluoro-Jade B-positive cells were increased, as compared to control rats, coinciding with the hypometabolism detected in the same region by semi-quantitative FDG-PET at 24 h after KASE. CONCLUSIONS: PET is suitable to measure metabolic brain changes in the rat model of status epilepticus induced by KA (KASE) at the first 24 h, compared to that of EEG; PET data may also be sensitive to cell viability.

Peptide VSAK maintains tissue glucose uptake and attenuates pro-inflammatory responses caused by LPS in an experimental model of the systemic inflammatory response syndrome: a PET study.

The present investigation using Positron Emission Tomography shows how peptide VSAK can reduce the detrimental effects produced by lipopolysaccharides in Dutch dwarf rabbits, used to develop the Systemic Inflammatory Response Syndrome (SIRS). Animals concomitantly treated with lipopolysaccharides (LPS) and peptide VSAK show important protection in the loss of radiolabeled-glucose uptake observed in diverse organs when animals are exclusively treated with LPS. Treatment with peptide VSAK prevented the onset of changes in serum levels of glucose and insulin associated with the establishment of SIRS and the insulin resistance-like syndrome. Treatment with peptide VSAK also allowed an important attenuation in the circulating levels of pro-inflammatory molecules in LPS-treated animals. As a whole, our data suggest that peptide VSAK might be considered as a candidate in the development of new therapeutic possibilities focused on mitigating the harmful effects produced by lipopolysaccharides during the course of SIRS.

Estado actual y perspectivas de la imagen molecular PET en México.

Positron-emission tomography (PET) is a medical diagnostic technique by means of which functional images are obtained by recording the spatio-temporal biodistribution of specific radiopharmaceuticals targeted at specific molecular objectives, which provides biochemical information at the molecular level. Early in the first decade of this 21st century, the Faculty of Medicine of the National Autonomous University of Mexico acquired the technology to implement this diagnostic technique in Mexico, thus becoming a pioneer in PET applications in the country and in Latin America. Almost two decades after its implementation in Mexico, PET has become an essential tool in medical clinics. This article describes the background, current state and perspectives of PET molecular imaging in Mexico, and the impact it has had on the management of patients with oncological, neurological and heart diseases.

La tomografía por emisión de positrones (PET) es una técnica de diagnóstico médico mediante la cual se obtienen imágenes funcionales a partir de registrar la biodistribución espacio-temporal de radiofármacos específicos dirigidos a blancos moleculares específicos, proveyendo información bioquímica a nivel molecular. A principios de la primera década de este siglo XXI, la Facultad de Medicina de la Universidad Nacional Autónoma de México implementó esta técnica de diagnóstico en México, convirtiéndose en pionera en aplicaciones PET en el país y Latinoamérica. Casi dos décadas después, la PET se ha convertido en una herramienta esencial en la clínica médica. En este artículo se describen los antecedentes, el estado actual, las perspectivas de la imagen molecular PET en México y el impacto que ha tenido en el manejo de pacientes con enfermedades oncológicas, neurológicas y cardiológicas.

Estado actual y perspectivas de la imagen molecular PET en México / Current status and perspectives of PET molecular imaging in Mexico

Resumen La tomografía por emisión de positrones (PET) es una técnica de diagnóstico médico mediante la cual se obtienen imágenes funcionales a partir de registrar la biodistribución espacio-temporal de radiofármacos específicos dirigidos a blancos moleculares específicos, proveyendo información bioquímica a nivel molecular. A principios de la primera década de este siglo XXI, la Facultad de Medicina de la Universidad Nacional Autónoma de México implementó esta técnica de diagnóstico en México, convirtiéndose en pionera en aplicaciones PET en el país y Latinoamérica. Casi dos décadas después, la PET se ha convertido en una herramienta esencial en la clínica médica. En este artículo se describen los antecedentes, el estado actual, las perspectivas de la imagen molecular PET en México y el impacto que ha tenido en el manejo de pacientes con enfermedades oncológicas, neurológicas y cardiológicas.

Abstract Positron-emission tomography (PET) is a medical diagnostic technique by means of which functional images are obtained by recording the spatio-temporal biodistribution of specific radiopharmaceuticals targeted at specific molecular objectives, which provides biochemical information at the molecular level. Early in the first decade of this 21st century, the Faculty of Medicine of the National Autonomous University of Mexico acquired the technology to implement this diagnostic technique in Mexico, thus becoming a pioneer in PET applications in the country and in Latin America. Almost two decades after its implementation in Mexico, PET has become an essential tool in medical clinics. This article describes the background, current state and perspectives of PET molecular imaging in Mexico, and the impact it has had on the management of patients with oncological, neurological and heart diseases.

Reference tissue models in the assessment of 11 C-DTBZ binding to the VMAT2 in rat striatum: A test-retest reproducibility study.

Dopaminergic PET imaging is a useful tool to assess the dopaminergic integrity and to follow-up longitudinal studies. The aim of this study was to evaluate the reliability and reproducibility of different reference tissue-based methods to determine the non-displaceable binding potential (BPND ) as a quantitative measure of 11 C-DTBZ binding to the VMAT2 in rat striatum using cerebellum as reference region. Eight healthy Wistar rats underwent two microPET scans at the age of 12 (test) and 20 weeks (retest). BPND was determined using the simplified reference tissue model, Logan reference tissue model, and multilinear reference tissue models (MRTMo and MRTM2). Additionally, a striatal-to-cerebellar-ratio (SCR) analysis was performed. The reproducibility between the two scans was assessed using the interclass correlation coefficients (ICC) and the variability index. Repeatability indices showed acceptable ICC = 0.66 (SCR) to excellent ICC = 0.98 (MRTM2) reliability for this study and a variability ranging from 12.26% (SCR) to 3.28% (MRTM2). To the best of our knowledge, this is the first report on longitudinal studies for 11 C-DTBZ in rats using reference tissue methods. Excellent intersubject and intrasubject reproducibility was obtained with the multilinear reference MRTM2, suggesting this as the best method to compare longitudinal studies, whereas the SCR method had poor reliability. Logan method, however, is a method simple to compute that shows accurate reproducibility with a reasonable level of inter- and intra-subject variability allowing crossover studies to follow-up the uptake of 11 C-DTBZ in rat striatum.

Investigación preclínica por microPET en la UNAM / Pre-clinical research at UNAM using microPET

La tomografía por emisión de positrones (PET) es una técnica de imágenes de medicina nuclear ya establecida en México, fundamental en el diagnóstico y seguimiento clínico de enfermedades oncológicas, neurológicas y cardiológicas. Esta modalidad de imagenología molecular está basada en la administración de cantidades muy pequeñas de fármacos marcados con emisores de positrones y en la subsecuente detección de radiación con el fin de obtener imágenes tomográficas que reflejan la distribución del radiofármaco en el paciente. El desarrollo de nuevos radiofármacos para PET requiere de un método para verificar que éstos siguen las rutas metabólicas de interés, que su vida media biológica es suficiente para la realización de un estudio, que no tienen efectos adversos y que es viable para estudios en pacientes. El desarrollo de equipos de microtomografía por emisión de positrones (microPET), dedicados a estudiar animales de laboratorio, ha permitido realizar estas pruebas antes de su aplicación clínica. Además, el microPET es una herramienta de gran utilidad en la investigación preclínica de diversas enfermedades, en el desarrollo de tratamientos innovadores que permite el seguimiento no invasivo en modelos animales. En la Unidad PET/CT-Ciclotrón de la Facultad de Medicina de la UNAM, se cuenta desde hace unos años con un equipo microPET para investigación. En este trabajo se muestran algunos resultados de los estudios que se realizan con mayor frecuencia con el microPET utilizando los radiofármacos de mayor uso en el medio clínico y se muestra la utilidad que puede tener en diversos proyectos de investigación.

Positron emission tomography (PET) is a nuclear medicine imaging technique well established in Mexico, essential for the clinical diagnosis and follow-up of oncological, neurological and cardiac pathologies. This molecular imaging modality is based on the administration of small amounts of drugs labeled with a positron emitting radionuclides and the subsequent radiation detection to obtain tomographic images which reflect the distribution of the radiopharmaceutical in the patient. The development of new radiopharmaceuticals for PET requires a method to verify that they follow the expected metabolic pathways, that they have a long-enough biological half-life for imaging studies, that they have no side effects and that it is viable for use in patients. The development of positron emission microtomography (microPET) systems to be used in small laboratory animale has allowed researchers to perform these tests on radiopharmaceuticals before being used in the clinic. In addition, microPET is a useful tool in preclinical research of different diseases in the development of innovating non-invasive treatments allowing to follow up animal models. At the PET/CT-Ciclotron Unit, Facultad de Medicina, UNAM, a microPET system has been available in the last few years for research purposes. In this work, examples of frequent imaging studies performed with the microPET and in-the-clinic commonly-used radiopharmaceuticals, as well the use it may have in different research projects are shown here.

[Cardiac metabolism and perfusion evaluation in a rat model using 18F- FDG, 1-11C-acetate, 13NH3 and micro-positron emission tomography (microPET)]. / Modelo de evaluación de metabolismo y perfusión en el miocardio de rata mediante 18FFDG, 1-11C- acetato, 13N-amoniaco y micro-tomografía por emisión de positrones (micro PET).

OBJECTIVE: To standardize an acquisition protocol for the study of myocardial glucolitic and oxidative metabolism and perfusion in a rat model. METHODS: Studies were carried out with the three main radiopharmaceuticals used to assess heart function:[18F]-FDG for glucolitic metabolism; [1-11C]-acetate for oxidative metabolism and [13N]-NH3for myocardial perfusion.[18F]-FDG -Five Wistar adult male rats were studied in three different protocols: non-fasting group, fasting group,8 h before the study with water provided ad libitum, and a fasting group by the same time receiving an oral 50%-glucose solution. Thirty-minute scans were performed with a microPET Focus 120, 30 and 60 min after the administration of 370 - 555 MBq 18F-FDG. [1-11C]-Acetate -Eight rats were studied. Four static and four dynamic 30 min acquisitions after a 370 - 555 MBq of [1-11C]-acetate caudal vein administration.[13N]-NH3-Ten static studies were acquired 15 min post-administration of 370- 555 MBq of 13NH3 isofluorane anesthesia. Comparative and visual analyses wy performer by two experts in the field. A semi-quantitative analysis was performa using 3D reconstructions and ROI selections with AMIDE software. RESULTS: The best images were those obtained from the non-fasting group, especially those taken at 60 min after the [18F]-FDG administration. High quality myocardial, static images were obtained with [1-11C]-acetate, and the dynamic adquisitions allowed the identification of myocardial perfusion. The 13NH3images showed a homogeneous distribution of the radiotracer in different segments of the short, long and horizontal axes in the left ventricle. CONCLUSIONS: It is possible to standardize the microPET acquisition protocols for the three main radiopharmaceuticals to evaluate the heart function in a rat model. It is feasible to establish a valid protocol for measuring glucolitic and oxidative myocardial metabolism and perfusion for gene, drug or surgical therapy assessment.

Modelo de evaluación de metabolismo y perfusión en el miocardio de rata mediante 18F-FDG, 1-11C-acetato, 13N-amoniaco y micro-tomografía por emisión de positrones (micro PET) / Cardiac metabolism and perfusion evaluation in a rat model using 18F-FDG,1- 11C-acetate, 13NH3 and micro-positron emission tomography (microPET)

Objetivos: Estandarizar un protocolo de adquisición para el estudio del metabolismo glucolítico, oxidativo y de perfusión miocárdicos en un modelo de rata. Métodos: Se realizaron estudios con los tres principales radiotrazadores usados para evaluar la función cardiaca: 18F-FDG para evaluar el metabolismo glucolítico en tres protocolos distintos; 1-11C-acetato para el metabolismo oxidativo y 13NH3 para la perfusión cardiaca. (18F-FDG)- cinco ratas Wistar macho en tres diferentes protocolos: con acceso a libre demanda de comida y agua; con ayuno de ocho horas y con ayuno de ocho horas más carga oral de glucosa al 50%. Se adquirieron imágenes del área torácica durante 30 minutos mediante microPET; 30 y 60 minutos post-administración de 370 - 555 MBq de 18F-FDG vía IP. (1-11C-acetato)- Se estudiaron ocho ratas. Cuatro estudios estáticos de 30 minutos y cuatro adquisiciones dinámicas de 30 minutos tras administración de 370 - 555 MBq de1-11C-acetato por vena caudal.(13NH3)- 10 estudios estáticos de 15 minutos después de una dosis IV de 370 - 555 MBq de 13NH3, bajo anestesia inhalada con isofluorano a 1.5% a 2%. Se realizó análisis comparativo y cualitativo de todas las imágenes obtenidas por dos médicos especialistas en el área y un análisis semi-cuantitativo mediante reconstrucciones 3D y selección de ROIs con el programa AMIDE en el caso de 18F-FDG. Resultados: Se determinó que las mejores imágenes para fines de evaluación metabólica del miocardio fueron las correspondientes a los 60 minutos post-administración de la 18F-FDG del protocolo sin ayuno. Se visualizó sin problemas el miocardio de rata de las imágenes estáticas con 1-11C-acetato, y mediante adquisición dinámica, se pudo apreciar la perfusión miocárdica. Las imágenes con 13NH3 permitieron observar una distribución homogénea del radiotrazador en los diferentes segmentos del ventrículo izquierdo en el eje corto, eje largo vertical y eje largo horizontal. Conclusiones: Se logró la estandarización de protocolos de adquisición de imágenes de los tres principales radiotrazadores utilizados para el estudio del metabolismo y perfusión cardiacos, en un modelo animal. Es factible establecer un protocolo válido para la valoración de perfusión, metabolismo glucolítico y oxidativo miocárdicos, con el fin de utilizarlo como punto de referencia para la evaluación de terapias génica, farmacológica o quirúrgica a nivel experimental.

Objective: To standardize an acquisition protocol for the study of myocardial glucolitic and oxidative metabolism and perfusion in a rat model. Methods: Studies were carried out with the three main radiopharmaceuticals used to assess heart function:[18F]-FDG for glucolitic metabolism; [1-11C]-acetate for oxidative metabolism and [13N]-NH3for myocardial perfusion.[18F]-FDG -Five Wistar adult male rats were studied in three different protocols: non-fasting group, fasting group,8 h before the study with water provided ad libitum, and a fasting group by the same time receiving an oral 50%-glucose solution. Thirty-minute scans were performed with a microPET Focus 120, 30 and 60 min after the administration of 370-555 MBq 18F-FDG. [1-11C]-Acetate -Eight rats were studied. Four static and four dynamic 30 min acquisitions after a 370-555 MBq of [1-11C]-acetate caudal vein administration.[13N]-NH3-Ten static studies were acquired 15 min post-administration of 370555 MBqof13NH3, under 1.5-2% isofluorane anesthesia. Comparative and visual analyses were performed by two experts in the field. A semi-quantitative analysis was performed using 3D reconstructions and ROI selections with AMIDE software. Results: The best images were those obtained from the non-fasting group, especially those taken at 60 min after the [18F]-FDG administration. High quality myocardial, static images were obtained with [1-11C]-acetate, and the dynamic acquisitions allowed the identification of myocardial perfusion. The 13NH3images showed a homogeneous distribution of the radiotracer in different segments of the short, long and horizontal axes in the left ventricle. Conclusions: It is possible to standardize the microPET acquisition protocols for the three main radiopharmaceuticals to evaluate the heart function in a rat model. It is feasible to establish a valid protocol for measuring glucolitic and oxidative myocardial metabolism and perfusion for gene, drug or surgical therapy assessment.