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Some scientific discoveries are well known only to a core group of researchers working on technical subjects. Nevertheless, they open new research directions, allow existing knowledge to be viewed in entirely new and useful ways, or provide a way to make something that was hard or impossible to make before. Carbon-11 methyl triflate ([11C]MeOTf) is one such advance, facilitating the synthesis of many carbon-11 radio tracers and broadening the range of applications of carbon-11 radiochemistry. The year 2022 marked the 30th anniversary of the original paper in Applied Radiation and Isotopes introducing a simple synthesis of [11C]MeOTf from carbon-11 methyl iodide ([11C]MeI) and it also marked the end of the fruitful career and life of the researcher who developed it, Douglas Jewett. It seems fitting to say a few words on how it came to be and how it has helped advance carbon-11 radiochemistry.
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BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-ß (Aß) pathology. OBJECTIVE: To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aß and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aß, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD). METHODS: Patients (nâ=â21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aß and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aß, total tau, and Pτ181 were measured by ELISA from the ventricular (nâ=â15) and the lumbar (nâ=â9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1). RESULTS: [11C]PIB uptake in the right frontal cortex (ρ=â0.60, pâ<â0.01) and the combined neocortical [11C]PIB uptake score (ρ=â0.61, pâ<â0.01) were associated with a higher Aß load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aß (ρ=â-0.58, pâ=â0.03). CONCLUSIONS: The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aß pathology in the patients with iNPH might also warrant treatment with current AD drugs.
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Radioisótopos de Carbono/farmacología , Lóbulo Frontal , Hidrocéfalo Normotenso , Tomografía de Emisión de Positrones/métodos , Anciano , Biopsia/métodos , Femenino , Finlandia , Estudios de Seguimiento , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Humanos , Hidrocéfalo Normotenso/diagnóstico , Hidrocéfalo Normotenso/metabolismo , Hidrocéfalo Normotenso/patología , Hidrocéfalo Normotenso/psicología , Masculino , Pruebas de Estado Mental y Demencia , Reproducibilidad de los Resultados , Presión Ventricular , Derivación Ventriculoperitoneal/métodos , Proteínas tau/metabolismoRESUMEN
OBJECTIVE: To investigate quantitative positron emission tomography (PET) findings and to study whether the cholinergic function differs between respondents to cholinergic medication versus nonrespondents. SETTING: Outpatient clinic and university PET imaging center. PARTICIPANTS: We studied 17 subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication. DESIGN: Cholinergic function was assessed with [methyl-C] N-methylpiperidyl-4-acetate-PET (C-MP4A-PET), which reflects the activity of the acetylcholinesterase (AChE) enzyme. The subjects were PET scanned twice: without medication and after a 4-week treatment with rivastigmine 1.5 mg twice a day. MEASURES: Regional cerebral AChE activity was measured with PET. RESULTS: At baseline Statistical Parametric Mapping analyses showed significantly lower AChE activity in respondents bilaterally in the frontal cortex as compared with nonrespondents. Region of interest (ROI) analysis revealed that the difference was most pronounced in the lateral frontal cortex (-9.4%, P = .034) and anterior cingulate (-6.0%, P = .049). After rivastigmine treatment, AChE activity was notably lower throughout the cortex in both respondents and nonrespondents, without significant differences between them. CONCLUSION: Our study suggests that frontal cholinergic dysfunction is associated with the clinical response to cholinergic stimulation in patients with traumatic brain injury.
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Acetilcolinesterasa/metabolismo , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/enzimología , Inhibidores de la Colinesterasa/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Rivastigmina/uso terapéutico , Adulto , Lesiones Traumáticas del Encéfalo/psicología , Enfermedad Crónica , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/enzimología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de PositronesRESUMEN
Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [125I]5-Iodo-2'-deoxyuridine (125I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining 125I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and 125I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and 125I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy.
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Antineoplásicos/administración & dosificación , Glioblastoma/radioterapia , Xenoinjertos , Idoxuridina/administración & dosificación , Radioterapia/métodos , Animales , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Modelos Animales de Enfermedad , Quimioterapia Combinada , Metotrexato/administración & dosificación , Ratas Desnudas , Análisis de Supervivencia , Temozolomida , Resultado del TratamientoRESUMEN
The serotonin 5-HT1A receptor is a putative drug development target in disorders with cognitive and in particular memory deficits. However, previous human positron emission tomography (PET) studies on 5-HT1A receptor binding and memory functions have yielded discrepant results. We explored the association between verbal memory and 5-HT1A receptor binding in 24 healthy subjects (14 male, 10 female, aged 18-41 years). The cognitive tests included the Wechsler Memory Scale-Revised (WMS-R), Wechsler Adult Intelligence Scale-Revised (WAIS-R) and Wisconsin Card Sorting Test (WCST). 5-HT1A receptor binding was measured with PET and the radioligand [carbonyl-(11)C]WAY-100635, which was quantified with the gold standard method based on kinetic modeling using arterial blood samples. We found that global 5-HT1A receptor binding was positively correlated with measures of verbal memory, such that subjects who had higher receptor binding tended to have better verbal memory than subjects who had lower receptor binding. Regional analyses suggested significant correlations in multiple neocortical brain regions and the raphe nuclei. We did not find significant correlations between 5-HT1A receptor binding and executive functions as measured with WCST. We conclude that neocortical as well as raphe 5-HT1A receptors are involved in verbal memory function in man.
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Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Memoria/fisiología , Piperazinas/farmacología , Piperazinas/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Receptor de Serotonina 5-HT1A/metabolismo , Adolescente , Adulto , Mapeo Encefálico , Radioisótopos de Carbono/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Aprendizaje Verbal/fisiología , Adulto JovenRESUMEN
INTRODUCTION: NS9531, NS9762 and NS6417 are nitroquinolinyl-diazabicyclo-alkane derivatives that have been developed as inhibitors of serotonin reuptake transporters (SERT) by NeuroSearch A/S. METHODS: IC50 was measured on the up-take of serotonin, dopamine and noradrenaline in synaptosomes prepared from selected rat brain regions. For the pre-clinical evaluation in pigs, [(11)C]NS9531, [(11)C]NS9762 and [(11)C]NS6417 were prepared by N-methylation using [(11)C]methyl iodide. These syntheses were later on optimized regarding: 1) choice of labelled precursor; 2) HPLC purification conditions; and 3) formulation using SPE columns. The synthesis protocols were then fully automated on a GE FXc Pro. Preclinical evaluation was performed by PET studies in landrace pigs before and after treatment with citalopram. RESULTS: IC50 measurements showed that all three compounds have low nanomolar affinity for SERT, and micromolar affinity for DAT and NET. The radiochemical yield (r.y.) of all three ligands from [(11)C]methyl iodide was higher than 30%. From [(11)C]methyl triflate, the r.y. of [(11)C]NS9531 and [(11)C]NS9762 were higher than 80% whereas the r.y. of [(11)C]NS6417 was 65%. Residual precursor amounts in final products could be significantly reduced by the use of [(11)C]methyl triflate, <0.2 µg compared with <10 µg, calculated for a 300 MBq injection at 20 minutes EOS. The optimized conditions gave 2.5-4.5 GBq of products with a specific radioactivity of 20-70 MBq/nmol, residual acetonitrile 15-30 ppm, and pH 6.5-7.1. All three compounds showed a rapid and comparable high pig brain uptake of about 3%, producing PET images of good contrast, and uptake was reduced after pre-administration with citalopram. CONCLUSION: The three (11)C labelled PET tracers could be prepared in medium to high yield and high purity. IC50 measurements showed that the three NS compounds were highly selective, high affinity SERT inhibitors. PET studies in pig showed high brain uptake that could be blocked by citalopram pre-treatment.
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Radioisótopos de Carbono , Mesilatos/química , Nitroquinolinas/química , Nitroquinolinas/síntesis química , Radiofármacos/química , Radiofármacos/síntesis química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Técnicas de Química Sintética , Química Farmacéutica , Femenino , Hidrocarburos Yodados/química , Marcaje Isotópico , Tomografía de Emisión de Positrones , Control de Calidad , Trazadores Radiactivos , Ratas , PorcinosRESUMEN
The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.
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Amiloide/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Anciano , Compuestos de Anilina/metabolismo , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Tiazoles/metabolismoRESUMEN
Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy subjects is unclear. We measured brain serotonin 5-HT1A receptor in 34 healthy subjects in vivo using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635. Binding potential (BPP) was determined using the golden standard of kinetic compartmental modeling using arterial blood samples and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may be a trait-like phenomenon and partly explained by higher neuroticism in patients with affective disorders. The link between personality traits and 5-HT1A receptors should be studied in patients with major depression.
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Trastornos de Ansiedad/metabolismo , Encéfalo/metabolismo , Personalidad/fisiología , Receptor de Serotonina 5-HT1A/metabolismo , Adulto , Trastornos de Ansiedad/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Masculino , Neuroticismo , Piperazinas/farmacología , Tomografía de Emisión de Positrones/métodos , Piridinas/farmacología , Antagonistas de la Serotonina/farmacología , Adulto JovenRESUMEN
Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [(11)C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [(11)C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40-50 minutes) and intervention (60-85 minutes) revealed an average 12.6% decrease in [(11)C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST (r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus (r=-0.87, P=0.003) and putamen (r=-0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.
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Dopamina/metabolismo , Etanol/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Estriado Ventral/efectos de los fármacos , Estriado Ventral/metabolismo , Antagonistas de Dopamina/administración & dosificación , Humanos , Procesamiento de Imagen Asistido por Computador , Infusiones Intravenosas , Masculino , Racloprida/administración & dosificación , Radioisótopos/administración & dosificación , Estriado Ventral/diagnóstico por imagen , Adulto JovenRESUMEN
UNLABELLED: We report the development of a PET tracer for α2C adrenoceptor imaging and its preliminary preclinical evaluation. α2C adrenoceptors in the human brain may be involved in various neuropsychiatric disorders, such as depression, schizophrenia, and neurodegenerative diseases. PET tracers are needed for imaging of this receptor system in vivo. METHODS: High-specific-activity (11)C-ORM-13070 (1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-4-(3-(11)C-methoxymethylpyridin-2-yl)-piperazine) was synthesized by (11)C-methylation of O-desmethyl-ORM-13070 with (11)C-methyl triflate, which was prepared from cyclotron-produced (11)C-methane via (11)C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography. The specificity of (11)C-ORM-13070 binding to α2 adrenoceptors was demonstrated in rats pretreated with atipamezole, an α2 adrenoceptor antagonist. The α2C adrenoceptor selectivity of the tracer was determined by comparing tracer binding in wild-type and α2A- and α2AC adrenoceptor knockout (KO) mice. (11)C-ORM-13070 and its radioactive metabolites in rat plasma and brain tissue were analyzed with radio-high-performance liquid chromatography and mass spectroscopy. Human radiation dose estimates were extrapolated from rat biodistribution data. RESULTS: The radiochemical yield, calculated from initial cyclotron-produced (11)C-methane, was 9.6% ± 2.7% (decay-corrected to end of bombardment). The specific activity of the product was 640 ± 390 GBq/µmol (decay-corrected to end of synthesis). The radiochemical purity exceeded 99% in all syntheses. The highest levels of tracer binding were observed in the striatum and olfactory tubercle of rats and control and α2A KO mice-that is, in the brain regions known to contain the highest densities of α2C adrenoceptors. In rats pretreated with atipamezole and in α2AC KO mice, (11)C tracer binding in the striatum and olfactory tubercle was low, similar to that of the frontal cortex and thalamus, regions with low densities of α2C adrenoceptors. Two radioactive metabolites were found in rat plasma, but only one of them was found in the brain; their identity was not revealed. The estimated effective radiation dose was comparable with the average exposure level in PET studies with (11)C tracers. CONCLUSION: An efficient method for the radiosynthesis of (11)C-ORM-13070 was developed. (11)C-ORM-13070 emerged as a potential novel radiotracer for in vivo imaging of brain α2C adrenoceptors.
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Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Dioxanos/síntesis química , Piperazinas/síntesis química , Tomografía de Emisión de Positrones/métodos , Receptores Adrenérgicos alfa 2/metabolismo , Animales , Dioxanos/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Piperazinas/metabolismo , Trazadores Radiactivos , Radioquímica , Ratas , Especificidad por Sustrato , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND/OBJECTIVE: Our aim was to elucidate factors that contribute to amyloid-ß (Aß) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors. METHODS: We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11C-PIB, in 64 cognitively healthy subjects (54-89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM). RESULTS: The effects of age (p < 0.001), APOE ε4 carrier status (p = 0.003), and gender (p = 0.001) on composite cortical 11C-PIB uptake were all significant. The effect of educational level was non-significant (p = 0.37). No significant interactions were found between any of the factors. Cortical 11C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49 ± 0.34 versus 1.29 ± 0.26) and males had higher uptake than females (1.49 ± 0.39 versus 1.29 ± 0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11C-PIB uptake in the frontal cortex. CONCLUSIONS: Age and APOE ε4 genotype were associated with higher 11C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11C-PIB uptake than women. Possible gender differences in Aß accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted.
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Envejecimiento/fisiología , Amiloide/metabolismo , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Caracteres Sexuales , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Compuestos de Anilina , Apolipoproteína E4/genética , Benzotiazoles , Estudios Transversales , Escolaridad , Femenino , Genotipo , Técnicas de Genotipaje , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Radiofármacos , TiazolesRESUMEN
The human striatum has structural and functional subdivisions, both dorsoventrally and rostrocaudally. To date, the gradients of dopamine D2/3 receptor binding in the human striatum have not been measured with positron emission tomography (PET). Seven healthy male subjects aged 24.5 ± 3.5 years were scanned with brain-dedicated high-resolution research tomography (HRRT, Siemens Medical Solutions, Knoxville, TN, USA) and [(11)C]raclopride. Coronally defined regions of interest (ROIs) of the caudate nucleus, putamen and ventral striatum (VST) were sampled plane-by-plane, 1.5mm apart, on spatially normalized binding potential (BPND) images. Regional [(11)C]raclopride BPND values were calculated using the simplified reference tissue model (SRTM) from a total of 25 coronal planes. An increasing rostrocaudal gradient of the D2/3 receptor binding was detected in the putamen, which is consistent with the known distribution of D2/3 dopamine receptors. In the caudate nucleus, there was an initial increase in the BPND values in the most anterior planes, suggesting that the highest D2/3 receptor binding occurred in the head; however, there was an overall descending gradient. A declining trend was also observed in the VST. The novelty of this study lies in the presentation, for the first time, of the D2/3 receptor binding gradients in each striatal subregion in the brains of living healthy humans. The high spatial resolution provided by HRRT enables frequent sampling of BPND along the longitudinal extent of striatum; this method is superior to the sectioning used in previous post mortem studies. Regarding the functional organization of the striatum, our findings can inform future investigations of normal neurophysiology as well as efforts to differentiate neuropsychiatric disorders affecting the brain dopamine (DA) system. Furthermore, the average distribution of D2/3 receptor binding revealed in this study could serve as a basis for a database that includes distributions of various DA markers as a function of healthy aging.
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Mapeo Encefálico/métodos , Cuerpo Estriado/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Racloprida , Radiofármacos , Adulto JovenRESUMEN
BACKGROUND: Using positron emission tomography (PET), we compared two tracers, [11C]metomidate ([11C]MTO) and [11C]acetate ([11C]ACE), for the characterization of hepatic tumors. METHODS: Thirty-three patients underwent PET with [11C]MTO and [11C]ACE and magnetic resonance imaging (MRI). Based on the histology of the tumor biopsy, 14 patients had hepatocellular carcinoma (HCC), 9 patients had focal nodular hyperplasia (FNH), and 10 patients had other types of hepatic tumors. Tumor uptake was evaluated by calculating the maximum and mean standardized uptake value and tumor-to-liver ratio. RESULTS: Altogether, 120 hepatic lesions (59 HCC, 18 FNH, 30 metastases of different primaries, 9 adenomas, and 4 regenerating nodules of liver cirrhosis) were detected by MRI. The overall tumor detection rate was slightly higher for [11C]MTO (39%) than for [11C]ACE (33%). [11C]ACE was more sensitive for HCC detection (50% versus 43%, respectively), whereas [11C]MTO was more sensitive for FNH detection (78% versus 44%, respectively). In HCC patients, the tumor grade correlated with [11C]ACE, but not with [11C]MTO. All of the patients with liver metastases, from various primary tumors (n = 10), were negative for both tracers. CONCLUSIONS: Due to low sensitivity, [11C]MTO and [11C]ACE PET have only limited value in diagnosing hepatic tumors.
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This study examines the relationship between fibrillar beta-amyloid (Aß) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aß deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aß increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.
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Enfermedad de Alzheimer/complicaciones , Amiloide/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Trastornos del Conocimiento , Tomografía de Emisión de Positrones , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina , Mapeo Encefálico , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Sensibilidad y Especificidad , TiazolesRESUMEN
PURPOSE: Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies. METHODS: In this study 238 [(11)C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [(11)C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 ± 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 ± 8 years) and 51 healthy controls (mean age 67.4 ± 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 ± 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype. RESULTS: [(11)C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [(11)C]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [(11)C]PIB retention was observed in MCI ApoE ε4 carriers compared to non-ApoE ε4 carriers (p < 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted. CONCLUSION: This study demonstrated the robustness of [(11)C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.
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Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide/análisis , Tomografía de Emisión de Positrones , Anciano , Compuestos de Anilina , Apolipoproteínas E/análisis , Encéfalo/diagnóstico por imagen , Química Encefálica , Estudios de Casos y Controles , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos , TiazolesRESUMEN
BACKGROUND/AIMS: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI. METHODS: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images. RESULTS: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function. CONCLUSION: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.
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Amiloide/metabolismo , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/psicología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Compuestos de Anilina , Núcleo Caudado/diagnóstico por imagen , Cognición/fisiología , Trastornos del Conocimiento/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Psicometría , Radiofármacos , Lóbulo Temporal/diagnóstico por imagen , TiazolesRESUMEN
Previous PET studies in healthy humans have shown that brain µ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain µ-opioid receptor binding at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured µ-opioid receptor binding potential (BP(ND)) with µ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects. Later, we recruited these subjects to participate in a separate psychophysical testing session to measure cold pressor pain threshold, cold pressor pain tolerance and tactile sensitivity with von Frey monofilaments. We used both voxel-by-voxel and region-of-interest image analyses to examine the potential associations between µ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal µ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal µ-opioid receptor density is involved in setting individual pain threshold.
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Frío , Cuerpo Estriado/metabolismo , Dolor/fisiopatología , Receptores Opioides mu/metabolismo , Adulto , Radioisótopos de Carbono , Cuerpo Estriado/diagnóstico por imagen , Fentanilo/análogos & derivados , Fentanilo/metabolismo , Humanos , Masculino , Umbral del Dolor , Tomografía de Emisión de Positrones , Radiofármacos/metabolismo , Receptores Opioides mu/agonistas , Valores de Referencia , TactoRESUMEN
Harm Avoidance is a temperament trait that associates with sensitivity to aversive and non-rewarding stimuli, higher anticipated threat and negative emotions during stress as well as a higher risk for affective disorders. The neurobiological correlates of interindividual differences in Harm Avoidance are largely unknown. We hypothesized that variability in Harm Avoidance trait would be explained by differences in the activity of µ-opioid system as the opioid system is known to regulate affective states and stress sensitivity. Brain µ-opioid receptor availability was measured in 22 healthy subjects using positron emission tomography and [(11)C]carfentanil, a selective µ-opioid receptor agonist. The subjects were selected from a large Finish population-based cohort (N=2075) on the basis of their pre-existing Temperament and Character Scores. Subjects scoring consistently in the upper (10) and lower (12) quartiles for the Harm Avoidance trait were studied. High Harm Avoidance score associated with high µ-opioid receptor availability (i.e. lower endogenous µ-opioid drive) in anterior cingulate cortex, ventromedial and dorsolateral prefrontal cortices and anterior insular cortex. These associations were driven by two subscales of Harm Avoidance; Shyness with Strangers and Fatigability and Asthenia. In conclusion, higher Harm Avoidance score in healthy subjects is associated with higher µ-opioid availability in regions involved in the regulation of anxiety as well as in the control of emotions, affective component of pain and interoceptive awareness. The results have relevance in the research of vulnerability factors for affective disorders.
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Analgésicos Opioides , Fentanilo/análogos & derivados , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiología , Radiofármacos , Receptores Opioides mu/fisiología , Temperamento/fisiología , Adulto , Envejecimiento/fisiología , Ansiedad/fisiopatología , Mapeo Encefálico , Radioisótopos de Carbono , Miedo/fisiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Receptores Opioides mu/agonistas , Caracteres Sexuales , Transmisión Sináptica/fisiologíaRESUMEN
INTRODUCTION: The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. AIMS: To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy ((1)H-MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with (18)F-fluorodeoxyglucose and (11)C-palmitate. (1)H-MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. RESULTS: Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P = NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P ≤ 0.01). TMZ halved total and triglyceride-derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 µmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 µmol/min, respectively; P ≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10(2), NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10(2), P = 0.036). CONCLUSIONS: In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA-derived energy for mechanical work. TMZ reduced the oxidation of triglyceride-derived myocardial FAs improving myocardial efficiency.