Correlation of 18F-sodium fluoride uptake and radiodensity in extraosseous metastases of medullary thyroid carcinoma

ABSTRACT Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, it can also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT) and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastases of MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

Brain glucose metabolism and gray matter volume in retired professional soccer players: a cross-sectional [18F]FDG-PET/MRI study.

BACKGROUND: Professional soccer athletes are exposed to repetitive head impacts and are at risk of developing chronic traumatic encephalopathy. OBJECTIVE: To evaluate regional brain glucose metabolism (rBGM) and gray matter (GM) volume in retired soccer players (RSPs). METHODS: Male RSPs and age and sex-matched controls prospectively enrolled between 2017 and 2019 underwent neurological and neuropsychological evaluations, brain MRI and [18F]FDG-PET in a 3.0-Tesla PET/MRI scanner. Visual analysis was performed by a blinded neuroradiologist and a blinded nuclear physician. Regional brain glucose metabolism and GM volume were assessed using SPM8 software. Groups were compared using appropriate statistical tests available at SPM8 and R. RESULTS: Nineteen RSPs (median [IQR]: 62 [50-64.5] years old) and 20 controls (60 [48-73] years old) were included. Retired soccer players performed worse on mini-mental state examination, digit span, clock drawing, phonemic and semantic verbal fluency tests, and had reduced rBGM in the left temporal pole (pFDR = 0.008) and the anterior left middle temporal gyrus (pFDR = 0.043). Semantic verbal fluency correlated with rBGM in the right hippocampus, left temporal pole, and posterior left middle temporal gyrus (p ≤ 0.042). Gray matter volume reduction was observed in similar anatomic regions but was less extensive and did not survive correction for multiple comparisons (pFDR ≥ 0.085). Individual [18F]FDG-PET visual analysis revealed seven RSPs with overt hypometabolism in the medial and lateral temporal lobes, frontal lobes, and temporoparietal regions. Retired soccer players had a higher prevalence of septum pellucidum abnormalities on MRI. CONCLUSION: Retired soccer players had reduced rBGM and GM volume in the temporal lobes and septum pellucidum abnormalities, findings possibly related to repetitive head impacts.

ANTECEDENTES: Jogadores profissionais de futebol estão expostos a impactos cranianos repetitivos e ao risco de desenvolver encefalopatia traumática crônica. OBJETIVO: Avaliar o metabolismo glicolítico cerebral regional (MGCr) e o volume de substância cinzenta (vSC) em jogadores de futebol aposentados (JFAs). MéTODOS: Jogadores de futebol aposentados masculinos e controles pareados por idade e sexo foram incluídos prospectivamente entre 2017 e 2019. Foram realizadas avaliações neurológica e neuropsicológica, ressonância magnética (RM) e [18F]FDG-PET cerebrais (3.0-Tesla PET/RM). As imagens foram analisadas visualmente por um neurorradiologista e um médico nuclear cegos ao grupo de cada participante. O metabolismo glicolítico cerebral regional e o vSC foram avaliados através do programa SPM8. Os grupos foram comparados através de testes estatísticos apropriados disponíveis em SPM8 e R, de acordo com a distribuição e o tipo dos dados. RESULTADOS: Dezenove JFAs (mediana [IIQ]: 62 [50­64.5] anos) e 20 controles (60 [48­73] anos) foram incluídos. Os JFAs tiveram pior desempenho no mini-exame do estado mental e nos testes de dígitos, desenho do relógio, fluência verbal e fluência semântica e apresentaram MGCr significativamente reduzido no polo temporal e no giro temporal médio anterior esquerdos. Fluência semântica (animais) apresentou correlação positiva com MGCr no hipocampo direito, no polo temporal esquerdo e no aspecto posterior do giro temporal médio esquerdo. Menor vSC foi observado nas mesmas regiões, porém este achado não sobreviveu à correção para comparações múltiplas. Análise individual do [18F]FDG-PET cerebral revelou sete JFAs com claro hipometabolismo nas faces medial e lateral dos lobos temporais, nos lobos frontais e nas regiões temporoparietais. Os JFAs apresentaram ainda maior prevalência de anormalidades do septo pelúcido. CONCLUSãO: Os JFAs apresentam MGCr e vSC reduzidos nos lobos temporais, além de anormalidades do septo pelúcido, achados possivelmente relacionados a impactos cranianos repetitivos.

Brain glucose metabolism and gray matter volume in retired professional soccer players: a cross-sectional [18F]FDG-PET/MRI study / Metabolismo glicolítico cerebral e volume de substância cinzenta em jogadores de futebol profissionais aposentados: um estudo transversal de [18F]FDG-PET/RM

Abstract Background Professional soccer athletes are exposed to repetitive head impacts and are at risk of developing chronic traumatic encephalopathy. Objective To evaluate regional brain glucose metabolism (rBGM) and gray matter (GM) volume in retired soccer players (RSPs). Methods Male RSPs and age and sex-matched controls prospectively enrolled between 2017 and 2019 underwent neurological and neuropsychological evaluations, brain MRI and [18F]FDG-PET in a 3.0-Tesla PET/MRI scanner. Visual analysis was performed by a blinded neuroradiologist and a blinded nuclear physician. Regional brain glucose metabolism and GM volume were assessed using SPM8 software. Groups were compared using appropriate statistical tests available at SPM8 and R. Results Nineteen RSPs (median [IQR]: 62 [50-64.5] years old) and 20 controls (60 [48-73] years old) were included. Retired soccer players performed worse on mini-mental state examination, digit span, clock drawing, phonemic and semantic verbal fluency tests, and had reduced rBGM in the left temporal pole (pFDR = 0.008) and the anterior left middle temporal gyrus (pFDR = 0.043). Semantic verbal fluency correlated with rBGM in the right hippocampus, left temporal pole, and posterior left middle temporal gyrus (p ≤ 0.042). Cray matter volume reduction was observed in similar anatomic regions but was less extensive and did not survive correction for multiple comparisons (pFDR ≥ 0.085). Individual [18F]FDG-PET visual analysis revealed seven RSPs with overt hypometabolism in the medial and lateral temporal lobes, frontal lobes, and temporoparietal regions. Retired soccer players had a higher prevalence of septum pellucidum abnormalities on MRI. Conclusion Retired soccer players had reduced rBCM and CM volume in the temporal lobes and septum pellucidum abnormalities, findings possibly related to repetitive head impacts.

Resumo Antecedentes Jogadores profissionais de futebol estão expostos a impactos cranianos repetitivos e ao risco de desenvolver encefalopatia traumática crônica. Objetivo Avaliar o metabolismo glicolítico cerebral regional (MCCr) e o volume de substância cinzenta (vSC) em jogadores de futebol aposentados (JFAs). Métodos Jogadores de futebol aposentados masculinos e controles pareados por idade e sexo foram incluídos prospectivamente entre 2017 e 2019. Foram realizadas avaliações neurológica e neuropsicológica, ressonância magnética (RM) e [18F]FDG-PET cerebrais (3.0-Tesla PET/RM). As imagens foram analisadas visualmente por um neurorradiologista e um médico nuclear cegos ao grupo de cada participante. O metabolismo glicolítico cerebral regional e o vSC foram avaliados através do programa SPM8. Os grupos foram comparados através de testes estatísticos apropriados disponíveis em SPM8 e R, de acordo com a distribuição e o tipo dos dados. Resultados Dezenove JFAs (mediana [IIQ]: 62 [50-64.5] anos) e 20 controles (60 [48-73] anos) foram incluídos. Os JFAs tiveram pior desempenho no mini-exame do estado mental e nos testes de dígitos, desenho do relógio, fluência verbal e fluência semântica e apresentaram MCCr significativamente reduzido no polo temporal e no giro temporal médio anterior esquerdos. Fluência semântica (animais) apresentou correlação positiva com MCCr no hipocampo direito, no polo temporal esquerdo e no aspecto posterior do giro temporal médio esquerdo. Menor vSC foi observado nas mesmas regiões, porém este achado não sobreviveu à correção para comparações múltiplas. Análise individual do [18F]FDG-PET cerebral revelou sete JFAs com claro hipometabolismo nas faces medial e lateral dos lobos temporais, nos lobos frontais e nas regiões temporoparietais. Os JFAs apresentaram ainda maior prevalência de anormalidades do septo pelúcido. Conclusão Os JFAs apresentam MCCr e vSC reduzidos nos lobos temporais, além de anormalidades do septo pelúcido, achados possivelmente relacionados a impactos cranianos repetitivos.

99mTc-HYNIC/Cy7-Fab(Bevacizumab): su empleo como agente de imagen en mieloma múltiple / 99mTc-HYNIC/Cy7-Fab(Bevacizumab): its use as an imaging agent in Multiple Myeloma / 99mTc-HYNIC/Cy7-Fab (Bevacizumab): seu uso como agente de imagem em mieloma múltiplo

Introducción: el mieloma múltiple es un trastorno hematológico maligno y el segundo cáncer de la sangre más frecuente. El proceso de la angiogénesis tumoral es fundamental para el crecimiento y metástasis de muchos tipos de tumores, incluido en mieloma múltiple. Se sabe que la sobreexpresión del factor de crecimiento endothelial vascular se encuentra asociado a un mal pronóstico en esta patología, representando un blanco clave para la terapia anti-angiogénica en mieloma múltiple. El anticuerpo monoclonal Bevacizumab es capaz de unirse con gran afinidad al factor de crecimiento endothelial vascular bloqueando su acción. Objetivo: evaluar el Fab(Bevacizumab) marcado con 99mTc o Cy7 como potenciales agentes de imagen moleculares de la expresión de factor de crecimiento endothelial vascular en mieloma múltiple. Material y métodos: la expresión de factor de crecimiento endothelial vascular fue analizada mediante citometría de flujo en la línea celular huaman de mieloma múltiple, la MM1S. Fab(Bevacizumab) fue producido mediante digestión de Bevacizumab con papaína, conjugado a NHS-HYNIC-Tfa y radiomarcado con 99mTc. Se realizaron estudios de biodistribución y de tomografía computarizada por emisión del fotón simple. A su vez, Fab(Bevacizumab) fue marcado con Cy7 para obtener imágenes de fluorescencia in vivo hasta 96 horas. Resultados: el análisis por citometría de flujo en la línea celular MM1S reveló que la expresión de factor de crecimiento endothelial vascular es predominantemente intracelular. Los estudios de biodistribución y SPECT/CT del complejo 99mTc-HYNIC-Fab(Bevacizumab) mostraron una rápida eliminación sanguínea y una significativa captación a nivel renal y tumoral. Las imágenes por fluorescencia empleando Cy7-Fab(Bevacizumab) permitieron la visualización tumoral hasta 96 h p.i. Conclusiones: logramos visualizar la expresión de factor de crecimiento endothelial vascular in vivo en mieloma múltiple mediante el empleo del fragmento Fab del anticuerpo anti-VEGF (Bevacizumab) marcado con 99mTc y Cy7. Estos nuevos agentes de imagen molecular podrían ser empleados potencialmente en el ámbito clínico para la estadificación y el seguimiento de pacientes con mieloma múltiple, mediante la visualización radioactiva in vivo de la expresión de factor de crecimiento endothelial vascular en todo el cuerpo. La imagen óptica de estos trazadores mejoraría el muestreo tumoral y podría guiar la extirpación quirúrgica.

Introduction: Multiple myeloma is a hematologic malignancy and the second most common blood cancer. The process of tumor angiogenesis is central to the growth and metastasis of many types of tumors, including multiple myeloma. Overexpression of vascular endothelial growth factor is known to be associated with poor prognosis in this pathology, representing a key target for anti-angiogenic therapy in multiple myeloma. The monoclonal antibody Bevacizumab is able to bind with high affinity to vascular endothelial growth factor blocking its action. Objective: to evaluate 99mTc- or Cy7-labeled Fab(Bevacizumab) as potential molecular imaging agents of vascular endothelial growth factor expression in multiple myeloma. Methods: Vascular endothelial growth factor expression was analyzed by flow cytometry in the multiple myeloma huaman cell line, MM1S. Fab(Bevacizumab) was produced by digestion of Bevacizumab with papain, conjugated to NHS-HYNIC-Tfa and radiolabeled with 99mTc. Biodistribution and single photon emission computed tomography studies were performed. In turn, Fab(Bevacizumab) was labeled with Cy7 to obtain in vivo fluorescence images up to 96 hours. Results: Flow cytometry analysis in the MM1S cell line revealed that vascular endothelial growth factor expression is predominantly intracellular. Biodistribution and SPECT/CT studies of the 99mTc-HYNIC-Fab(Bevacizumab) complex showed rapid blood clearance and significant renal and tumor uptake. Fluorescence imaging using Cy7-Fab(Bevacizumab) allowed tumor visualization up to 96 h p.i. Conclusions: we were able to visualize vascular endothelial growth factor expression in vivo in multiple myeloma using the Fab fragment of the anti-VEGF antibody (Bevacizumab) labeled with 99mTc and Cy7. These new molecular imaging agents could potentially be employed in the clinical setting for staging and monitoring of patients with multiple myeloma by in vivo radioactive visualization of vascular endothelial growth factor expression throughout the body. Optical imaging of these tracers would improve tumor sampling and could guide surgical excision.

Introdução: O mieloma múltiplo é uma malignidade hematológica e o segundo câncer de sangue mais comum. O processo de angiogênese tumoral é fundamental para o crescimento e a metástase de muitos tipos de tumores, incluindo o mieloma múltiplo. Sabe-se que a superexpressão do fator de crescimento endotelial vascular está associada a um prognóstico ruim no mieloma múltiplo, representando um alvo importante para a terapia antiangiogênica no mieloma múltiplo. O anticorpo monoclonal Bevacizumab é capaz de se ligar com alta afinidade ao fator de crescimento endotelial vascular e bloquear sua ação. Objetivo: avaliar o Fab(Bevacizumab) marcado com 99mTc ou Cy7 como possíveis agentes de imagem molecular da expressão do fator de crescimento endotelial vascular no mieloma múltiplo. Métodos: A expressão do fator de crescimento endotelial vascular foi analisada por citometria de fluxo na linha celular de mieloma múltiplo MM1S. O Fab(Bevacizumab) foi produzido pela digestão do Bevacizumab com papaína, conjugado com NHS-HYNIC-Tfa e radiomarcado com 99mTc. Foram realizados estudos de biodistribuição e tomografia computadorizada por emissão de fóton único. Por sua vez, o Fab(Bevacizumab) foi marcado com Cy7 para geração de imagens de fluorescência in vivo por até 96 horas. Resultados: A análise de citometria de fluxo na linha celular MM1S revelou que a expressão do fator de crescimento endotelial vascular é predominantemente intracelular. Os estudos de biodistribuição e SPECT/CT do complexo 99mTc-HYNIC-Fab(Bevacizumab) mostraram uma rápida depuração sanguínea e uma captação renal e tumoral significativa. A imagem de fluorescência usando Cy7-Fab(Bevacizumab) permitiu a visualização do tumor até 96 horas p.i. Conclusões: Conseguimos visualizar a expressão do fator de crescimento endotelial vascular in vivo no mieloma múltiplo usando o fragmento Fab do anticorpo anti-VEGF (Bevacizumab) marcado com 99mTc e Cy7. Esses novos agentes de imagem molecular poderiam ser usados no cenário clínico para o estadiamento e o monitoramento de pacientes com mieloma múltiplo, visualizando radioativamente a expressão do fator de crescimento endotelial vascular in vivo em todo o corpo. A geração de imagens ópticas desses traçadores melhoraria a amostragem do tumor e poderia orientar a excisão cirúrgica.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease.

OBJECTIVE: Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer's disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer's disease. METHODS: We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer's disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping. RESULTS: We found that the probable Alzheimer's disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration. CONCLUSIONS: Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease

Objective: Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer's disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer's disease. Methods: We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer's disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping. Results: We found that the probable Alzheimer's disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration. Conclusions: Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Comparison of different quantification methods for 18F-fluorodeoxyglucose-positron emission tomography studies in rat brains.

OBJECTIVES: This study aimed to evaluate several methods to estimate glucose consumption in the male Wister rat brain as measured by PET. METHODS: Fourteen male Wistar normoglycemic rats were studied. The input function consisted of seventeen blood samples drawn manually from the femoral artery. Glucose uptake values were calculated using the input function resulting from the arterial blood samples and the tissue time-activity curve derived from the PET images. The estimated glucose consumption rate (Ki) based on the 2-tissue compartment model (2TCM) served as the standard for comparisons with the values calculated by the Patlak analysis and with the fractional uptake rate (FUR), standardized uptake value (SUV) and glucose corrected SUV (SUVglu). RESULTS: No significant difference between the standard Ki and the Patlak Ki was observed. The standard Ki was also found to have strong correlations and concordance with the Ki value estimated by the Patlak analysis. The FUR method presented an excellent correlation with the Ki value obtained by the 2TCM/Patlak analyses, in contrast to the SUV or SUVglu. CONCLUSIONS: From a methodological point of view, the present findings confirm the theoretical limitations of the cerebral SUV and SUVglu as a substitute for Ki in the estimation of glucose consumption in the brain. Our data suggest that the FUR is the surrogate to Ki.

Effects of ketamine/xylazine and isoflurane on rat brain glucose metabolism measured by 18 F-fluorodeoxyglucose-positron emission tomography.

The aim of the present study was to investigate changes in glucose metabolism in male Wistar rats induced by the anesthetics isoflurane and ketamine combined with xylazine via 18 F-fluorodeoxyglucose-positron emission tomography. We analyzed the differential effects of the anesthetics on 18 F-fluorodeoxyglucose uptake and pharmacokinetics in 33 rats using quantification methods: (a) the standardized uptake value, (b) voxel-based analyses, and (c) kinetic analysis. Both anesthetics reduced glucose uptake in the entire brain. The voxel-based analyses detected smaller uptake reductions in the bilateral primary somatosensory system cortex and part of the limbic system in the ketamine-xylazine (KX) group and in the vestibular nucleus in the isoflurane group. Through kinetic analysis, we found that the volume of distribution and the membrane transport rate K1 were reduced in the KX group. Through various methods of 18 F-fluorodeoxyglucose-positron emission tomography quantification, the present study found that anesthesia with the ketamine-xylazine combination induced a global reduction of glucose metabolism compared with isoflurane; this reduction of metabolism was relatively lower in the primary somatosensory cortex and part of the limbic system. The volume of distribution of 18 F-fluorodeoxyglucose and its Glut1-mediated transport across the brain membranes (K1 ) were decreased in the KX group.

Comparison of different quantification methods for 18F-fluorodeoxyglucose-positron emission tomography studies in rat brains

OBJECTIVES: This study aimed to evaluate several methods to estimate glucose consumption in the male Wister rat brain as measured by PET. METHODS: Fourteen male Wistar normoglycemic rats were studied. The input function consisted of seventeen blood samples drawn manually from the femoral artery. Glucose uptake values were calculated using the input function resulting from the arterial blood samples and the tissue time-activity curve derived from the PET images. The estimated glucose consumption rate (Ki) based on the 2-tissue compartment model (2TCM) served as the standard for comparisons with the values calculated by the Patlak analysis and with the fractional uptake rate (FUR), standardized uptake value (SUV) and glucose corrected SUV (SUVglu). RESULTS: No significant difference between the standard Ki and the Patlak Ki was observed. The standard Ki was also found to have strong correlations and concordance with the Ki value estimated by the Patlak analysis. The FUR method presented an excellent correlation with the Ki value obtained by the 2TCM/Patlak analyses, in contrast to the SUV or SUVglu. CONCLUSIONS: From a methodological point of view, the present findings confirm the theoretical limitations of the cerebral SUV and SUVglu as a substitute for Ki in the estimation of glucose consumption in the brain. Our data suggest that the FUR is the surrogate to Ki.

Synthesis of hydrophilic HYNIC-[1,2,4,5]tetrazine conjugates and their use in antibody pretargeting with 99mTc.

Pretargeted imaging, based on the highly reactive process between [1,2,4,5]tetrazines with trans-cyclooctene (TCO), appears as an attractive strategy to overcome disadvantages associated with traditional radioimmunoconjugates. To be successful, the radiolabeled component should react in vivo with the conjugated antibody and the non reactive excess clear fast from the organism. Herein, we explore the in vivo effects of hydrophilic linker incorporation into [1,2,4,5]tetrazine systems bearing a 6-hydrazinonicotinyl (HYNIC) moiety for technetium-99m coordination. Incorporation of a polypeptide chain containing hydrophilic aminoacids, resulted in a derivative with renal clearance. Pretargeted bevacizumab imaging was used as proof of concept.

Evaluation of GX1 and RGD-GX1 peptides as new radiotracers for angiogenesis evaluation in experimental glioma models.

Gliomas are the most common type among all central nervous system tumors. The aggressiveness of gliomas is correlated with the level of angiogenesis and is often associated with prognosis. The aim of this study is to evaluate the novel GX1 peptide and the heterodimer RGD-GX1 radiolabeled with technetium-99m, for angiogenesis detection in glioma models. Radiolabeling and radiochemical controls were assessed for both radioconjugates. In vitro binding studies in glioma tumor cells were performed, as well as biodistribution in SCID mice bearing tumor cells, in order to evaluate the biological behavior and tumor uptake of the radiocomplexes. Blocking and imaging studies were also conducted. MicroSPECT/CT images were acquired in animals with experimentally implanted intracranial tumor. Open field activity was performed to evaluate behavior, as well as perfusion and histology analysis. The radiochemical purity of both radiotracers was greater than 96 %. In vitro binding studies revealed rather similar binding profi le for each molecule. The highest binding was for RGD-GX1 peptide at 120 min in U87MG cells (1.14 ± 0.35 %). Tumor uptake was also favorable for RGD-GX1 peptide in U87MG cells, reaching 2.96 ± 0.70 % at 1 h p.i. with 47 % of blocking. Imaging studies also indicated better visualization for RGD-GX1 peptide in U87MG cells. Behavior evaluation pointed brain damage and histology studies confirmed actual tumor in the uptake site. The results with the angiogenesis seeking molecule (99m)Tc-HYNIC-E-[c(RGDfk)-c(GX1)] were successful, and better than with (99m)Tc-HYNIC-PEG4-c(GX1). Future studies targeting angiogenesis in other glioma and nonglioma tumor models are recommended.

Aging Effects on Whole-Brain Functional Connectivity in Adults Free of Cognitive and Psychiatric Disorders.

Aging is associated with decreased resting-state functional connectivity (RSFC) within the default mode network (DMN), but most functional imaging studies have restricted the analysis to specific brain regions or networks, a strategy not appropriate to describe system-wide changes. Moreover, few investigations have employed operational psychiatric interviewing procedures to select participants; this is an important limitation since mental disorders are prevalent and underdiagnosed and can be associated with RSFC abnormalities. In this study, resting-state fMRI was acquired from 59 adults free of cognitive and psychiatric disorders according to standardized criteria and based on extensive neuropsychological and clinical assessments. We tested for associations between age and whole-brain RSFC using Partial Least Squares, a multivariate technique. We found that normal aging is not only characterized by decreased RSFC within the DMN but also by ubiquitous increases in internetwork positive correlations and focal internetwork losses of anticorrelations (involving mainly connections between the DMN and the attentional networks). Our results reinforce the notion that the aging brain undergoes a dedifferentiation processes with loss of functional diversity. These findings advance the characterization of healthy aging effects on RSFC and highlight the importance of adopting a broad, system-wide perspective to analyze brain connectivity.

Gray matter volumes in patients with bipolar disorder and their first-degree relatives.

Bipolar disorder (BD) is highly heritable. First-degree relatives of BD patient have an increased risk to develop the disease. We investigated abnormalities in gray matter (GM) volumes in healthy first-degree relatives of BD patients to identify possible brain structural endophenotypes for the disorder. 3D T1-weighted magnetic resonance images were obtained from 25 DSM-IV BD type I patients, 23 unaffected relatives, and 27 healthy controls (HC). A voxel-based morphometry protocol was used to compare differences in GM volumes between groups. BD patients presented reduced GM volumes bilaterally in the thalamus compared with HC. Relatives presented no global or regional GM differences compared with HC. Our negative results do not support the role of GM volume abnormalities as endophenotypes for BD. Thalamic volume abnormalities may be associated the pathophysiology of the disease.