RESUMEN
Early-life stress involved in the programming of stress-related illnesses can have a toxic influence on the functioning of the nigrostriatal motor system during aging. We examined the effects of perinatal stress (PRS) on the neurochemical, electrophysiological, histological, neuroimaging, and behavioral correlates of striatal motor function in adult (4 months of age) and old (21 months of age) male rats. Adult PRS offspring rats showed reduced dopamine (DA) release in the striatum associated with reductions in tyrosine hydroxylase-positive (TH+) cells and DA transporter (DAT) levels, with no loss of striatal dopaminergic terminals as assessed by positron emission tomography analysis with fluorine-18-l-dihydroxyphenylalanine. Striatal levels of DA and its metabolites were increased in PRS rats. In contrast, D2 DA receptor signaling was reduced and A2A adenosine receptor signaling was increased in the striatum of adult PRS rats. This indicated enhanced activity of the indirect pathway of the basal ganglia motor circuit. Adult PRS rats also showed poorer performance in the grip strength test and motor learning tasks. The aged PRS rats also showed a persistent reduction in striatal DA release and defective motor skills in the pasta matrix and ladder rung walking tests. In addition, the old rats showed large increases in the levels of SNAP-25 and synaptophysin, which are synaptic vesicle-related proteins in the striatum, and in the PRS group only, reductions in Syntaxin-1 and Rab3a protein levels were observed. Our findings indicated that the age-dependent threshold for motor dysfunction was lowered in PRS rats. This area of research is underdeveloped, and our study suggests that early-life stress can contribute to an increased understanding of how aging diseases are programmed in early-life.
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PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.
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Neoplasias Hepáticas , Tumores Neuroendocrinos , Compuestos Organometálicos , Fosfatasa Alcalina , Humanos , Neoplasias Hepáticas/radioterapia , Tumores Neuroendocrinos/radioterapia , Octreótido/efectos adversos , Compuestos Organometálicos/uso terapéutico , Resultado del TratamientoRESUMEN
Cerebral microbleeds (CMBs) could contribute to cognitive impairment in the general population and in patients with dementia. We designed a study to (i) develop a murine model of CMBs, (ii) assess whether CMBs affect cognition in this model and (iii) assess whether this model is sensitive to pharmacological modulation. Male C57Bl6/J mice were stereotactically administered collagenase to induce cortical lesion analysed by MRI at 24 h. CMB-mice were assessed at six weeks post-lesion for cognitive performances (Barnes maze and Touchscreen automated paired-associated learning (PAL) task) and for cerebral metabolism (in vivo PET/CT with fluorodeoxyglucose (FDG)). CMB-model sensitivity to pharmacological modulation was assessed by administering atorvastatin (5 mg/kg/day) over the follow-up period. CMB mice were compared to naïve littermates. Collagenase at 0.8 µU/µl appeared suitable to induce reproducible and reliable CMBs. At six weeks, a decline in learning, spatial and visuospatial memory was significantly observed in CMB-mice. Brain metabolism was impaired in all cortex, striatum and the ipsilateral dentate gyrus. A significant improvement in cognition performances was depicted under atorvastatin. In this novel murine model of CMBs, we validated that CMBs lowered cognitive performances and affected regional metabolism. We also proved that this CMB-model is sensitive to pharmacological modulation.
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Hemorragia Cerebral , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Animales , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Hemorragia Cerebral/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/tratamiento farmacológico , Colagenasas , Masculino , Ratones , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc-amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.
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Antioxidantes/metabolismo , Resistencia a Antineoplásicos , Glucosa/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanoma/metabolismo , Melanoma/patología , Factor 2 Relacionado con NF-E2/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Glutamatos/biosíntesis , Glutatión/biosíntesis , Humanos , Ratones SCID , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Ácido Pirúvico/metabolismoRESUMEN
Empirical evidence currently supports the idea that neurovascular dysfunction is involved in the neurodegenerative process of Alzheimer's disease (AD). In fact, epidemiological studies report that i) vascular risk factors are directly associated with an increased incidence of AD and ii) vascular lesions are frequently co-existent with AD. The neurovascular unit is a key control system for oxygen and nutrients exchange between neurons and microvessels so the integrity of this system is essential for neuronal activity and cell survival. This suggests that hypoxia arising from various vascular injuries may participate in the pathogenesis of AD and aggravate cognitive deficit. Moreover, hypoxia appears to have a direct effect on cognitive functions, in particular memory, by inducing a transient or definitive dysfunction of synaptic transmission. The interplay of hypoxic phenomenon and the development of AD-related pathologies support the use of hypoxia as a challenge model to assess symptomatic (i.e. cognitive enhancers) AD-treatment. Such challenge should be characterized and validated with current symptomatic drugs based on different mechanisms of action before being offered as alternative models for testing new drugs. To date, symptomatic treatments of AD including anticholinesterasic- (donepezil, rivastigmine and galantamine) and antiglutamatergic- (memantine) drugs target various neurotransmission impairments occurring at different stages of the disease. The first aim of the present review is to provide an overview of the methods used to achieve experimental hypoxia in rodents and to characterize the cognitive alterations induced by each method. The second objective is to summarize the main results from studies that have tested the effect of acetylcholinesterase inhibitors on hypoxiainduced cognitive impairment. Overall, the literature research yielded only a small number of studies investigating the effect of hypoxia on cognition in rodents and the different models described sometime differ substantially in terms of timing, severity and nature of cognitive impairment. Chronic exposure to intermittent normobaric or continuous hypobaric hypoxia induced persistent spatial reference and working memory alterations. In contrast, acute hypoxia exposure was shown to induce more transient associative and spatial memory impairments. Treatment with acetylcholinesterase inhibitors was shown to improve hypoxia-induced memory impairment in various hypoxia protocols.
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Trastornos del Conocimiento/etiología , Cognición , Hipoxia Encefálica/complicaciones , Hipoxia Encefálica/psicología , Animales , Inhibidores de la Colinesterasa/farmacología , Cognición/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Humanos , Hipoxia Encefálica/tratamiento farmacológico , Hipoxia Encefálica/fisiopatologíaRESUMEN
Pharmacological therapies currently marketed for Alzheimer's disease (AD) are only symptomatic and show limited effects in terms of clinical benefit. Thus, the development of new symptomatic drugs remains essential. However the dramatic increase in costs associated with drug development together with the poor number of emerging drugs highlights how crucial it is to accelerate the findings aiming to bringing new drugs to market. In this respect, optimization of the development process by integrating, at early stage, reliable biomarkers able to predict clinical benefit in phase III clinical trials may help. The improvement of certain techniques such as imaging and electrophysiological methods has led to a more accurate assessment of the brain's physiological impact of pharmacological treatments used to alleviate symptoms in AD patients. This review aims to gather the main findings from clinical studies where the effect of anti-dementia drugs were assessed in healthy volunteers and AD patients through one or several such biomarkers (electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)). Overall, evidence presented in this review suggests that various biomarkers associated with key impairments observed in AD were sensitive to acetylcholinesterase inhibitors (AChE-I) medication and memantine with a good correlation with enhancement of cognitive performance. In most of the reviewed studies, only one kind of biomarker was used. Among these, deficits in quantitative EEG profile, P300 latency, and regional brain activity measured by either functional MRI (fMRI) during face encoding and working memory task or by PET/SPECT have been shown to be reversed by anti-dementia drugs. It is therefore suggested that a single biomarker approach would be limited and not be sufficiently predictive to extensively assess the potential of a new symptomatic drug. Hence, it appears that a combination approach with the use of a panel of biomarkers rather than a single biomarker may be more appropriate to establish a good correlation between the disease and therapeutic intervention.
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Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Descubrimiento de Drogas , HumanosRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-ß (Aß) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced Aß cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal fluid of AD patients. The goal of the present study was to assess if LPS-induced neuroinflammation and Aß production could be altered by genetic PKR down regulation. The results show that, in the hippocampus of LPS-injected wild type mice, neuroinflammation, cytokine release and Aß production are significantly increased and not in LPS-treated PKR knock-out mice. In addition BACE1 and activated STAT3 levels, a putative transcriptional regulator of BACE1, were not found increased in the brain of PKR knock-out mice as observed in wild type mice. Using PET imaging, the decrease of hippocampal metabolism induced by systemic LPS was not observed in LPS-treated PKR knock-out mice. Altogether, these findings demonstrate that PKR plays a major role in brain changes induced by LPS and could be a valid target to modulate neuroinflammation and Aß production.
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Péptidos beta-Amiloides/metabolismo , Regulación de la Expresión Génica , Inflamación/genética , Inflamación/metabolismo , eIF-2 Quinasa/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Regulación hacia Abajo , Activación Enzimática , Hipocampo/metabolismo , Hipocampo/patología , Inflamación/diagnóstico , Inflamación/patología , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/efectos adversos , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Microglía/inmunología , Microglía/metabolismo , Fosforilación , Tomografía de Emisión de Positrones , Factor de Transcripción STAT3/metabolismo , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/metabolismoRESUMEN
Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. A number of studies show the major role of the vascular effect in the tumor eradication by PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting neuropilin-1 (NRP-1) peptide and encapsulated photosensitizer and magnetic resonance imaging (MRI) contrast agents, have been designed. Nanoplatforms confer photosensitivity to cells and demonstrate a molecular affinity to NRP-1. Intravenous injection into rats bearing intracranial glioma exhibited a dynamic contrast-enhanced MRI for angiogenic endothelial cells lining the neovessels mainly located in the peripheral tumor. By using MRI completed by NRP-1 protein expression of the tumor and brain adjacent to tumor tissues, we checked the selectivity of the nanoparticles. This study represents the first in vivo proof of concept of closed-head iPDT guided by real-time MRI using targeted ultrasmall nanoplatforms. From the clinical editor: The authors constructed tumor vascular peptide targeting multifunctional silica-based nanoparticles, with encapsulated gadolinium oxide as MRI contrast agent and chlorin as a photosensitizer, as a proof of concept novel treatment for glioblastoma in an animal model.
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Neoplasias Encefálicas , Glioma , Angiografía por Resonancia Magnética , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes , Animales , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Femenino , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Humanos , Nanopartículas/química , Nanopartículas/uso terapéutico , Neuropilina-1/química , Neuropilina-1/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Radiografía , Ratas , Ratas DesnudasRESUMEN
AIMS: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. RESULTS: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. INNOVATION: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. CONCLUSIONS: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.
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Quelantes del Hierro/uso terapéutico , Hierro/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Piridonas/uso terapéutico , Animales , Línea Celular , Terapia Combinada , Deferiprona , Modelos Animales de Enfermedad , Método Doble Ciego , Humanos , Quelantes del Hierro/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proyectos Piloto , Piridonas/administración & dosificación , Piridonas/farmacologíaRESUMEN
Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([(18)F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [(18)F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides 'real-time' results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this 'coclinical' trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.
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Antineoplásicos/farmacología , Indoles/farmacología , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Sulfonamidas/farmacología , Adulto , Animales , Antineoplásicos/efectos adversos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fluorodesoxiglucosa F18 , Humanos , Indoles/efectos adversos , Melanoma/enzimología , Melanoma/genética , Melanoma/secundario , Ratones SCID , Imagen Multimodal , Mutación , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Radiofármacos , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Sulfonamidas/efectos adversos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Carga Tumoral/efectos de los fármacos , Vemurafenib , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The use of classic antipsychotic drugs is limited by the occurrence of extrapyramidal motor symptoms, which are caused by dopamine (DA) receptor blockade in the neostriatum. We examined the impact of early-life stress on haloperidol-induced catalepsy using the rat model of prenatal restraint stress (PRS). Adult "PRS rats," i.e., the offspring of mothers exposed to restraint stress during pregnancy, were resistant to catalepsy induced by haloperidol (0.5-5 mg/kg i.p.) or raclopride (2 mg/kg s.c.). Resistance to catalepsy in PRS rats did not depend on reductions in blood or striatal levels, as compared with unstressed control rats. PRS rats also showed a greater behavioral response to the DA receptor agonist, apomorphine, suggesting that PRS causes enduring neuroplastic changes in the basal ganglia motor circuit. To examine the activity of this circuit, we performed a stereological counting of c-Fos(+) neurons in the external and internal globus pallidus, subthalamic nucleus, and ventral motor thalamic nuclei. Remarkably, the number of c-Fos(+) neurons in ventral motor thalamic nuclei was higher in PRS rats than in unstressed controls, both under basal conditions and in response to single or repeated injections with haloperidol. Ventral motor thalamic nuclei contain exclusively excitatory projection neurons that convey the basal ganglia motor programming to the cerebral cortex. Hence, an increased activity of ventral motor thalamic nuclei nicely explains the refractoriness of PRS rats to haloperidol-induced catalepsy. Our data raise the interesting possibility that early-life stress is protective against extrapyramidal motor effects of antipsychotic drugs in the adult life.
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Catalepsia/inducido químicamente , Haloperidol/farmacología , Estrés Fisiológico/fisiología , Animales , Antipsicóticos/farmacología , Apomorfina/farmacología , Catalepsia/sangre , Catecolaminas/sangre , Catecolaminas/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Agonistas de Dopamina/farmacología , Femenino , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Haloperidol/sangre , Masculino , Exposición Materna , Relaciones Materno-Fetales/efectos de los fármacos , Embarazo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Racloprida/farmacología , Ratas , Receptores Dopaminérgicos/metabolismo , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/metabolismo , Núcleos Talámicos Ventrales/efectos de los fármacos , Núcleos Talámicos Ventrales/metabolismoRESUMEN
Theory of mind reasoning-the ability to understand someone else's mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone else's mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimer's disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone else's mental perspective requires two distinct processes: inferring someone else's belief and inhibiting one's own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimer's disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimer's disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimer's disease had a predominant deficit in inferring someone else's belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting one's own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone else's beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimer's disease and patients with behavioural variant frontotemporal dementia.
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Enfermedad de Alzheimer/fisiopatología , Demencia Frontotemporal/fisiopatología , Teoría de la Mente/fisiología , Anciano , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
INTRODUCTION: [(18)F]FP-TZTP is an M2 muscarinic subtype selective receptor-binding radiotracer used in vivo to image human and nonhuman primate brain following both bolus injection and infusion. In order to carry out repeated studies in rodents, the techniques developed for primates must be transferred to rodents with the same precision. This includes obtaining a metabolite-corrected input function. METHODS: We compared bolus injection with constant infusion in rats that were awake or under isoflurane anesthesia. Brain-plasma and brain-blood distribution ratios were calculated by dividing brain (18)F concentrations, determined in vivo by positron emission tomography imaging with the Advanced Technology Laboratory Animal Scanner, ex vivo by direct counting in excised brain tissue or by quantitative autoradiography by the plasma or whole blood concentrations that had been corrected for metabolite contents. RESULTS: Blood volume constraints prevented adequate blood sampling to define a precise input function after bolus injection, thus preventing full kinetic analysis. Constant infusion, however, required fewer blood samples to define the input function, allowing calculation of distribution ratios, but complete equilibrium between plasma and tissue had not yet been reached after 120 min. CONCLUSION: Our results showed that the blood clearance and metabolism were too rapid to obtain a reproducible input function after bolus injection. The equilibrium distribution ratios did not lead to precise biochemical parameters, but the constant infusion was more suitable in that distribution ratios between tissue and plasma were statistically more precise. Constant infusion is the better approach for studying [(18)F]FP-TZTP by small animal imaging.
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Encéfalo/metabolismo , Radioisótopos de Flúor/farmacocinética , Piridinas/farmacocinética , Cintigrafía/métodos , Tiazoles/farmacocinética , Acetilcolina/metabolismo , Anestésicos por Inhalación/efectos adversos , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor/administración & dosificación , Isoflurano/efectos adversos , Masculino , Tomografía de Emisión de Positrones , Piridinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M2/metabolismo , Tiazoles/administración & dosificación , Distribución TisularRESUMEN
PURPOSE: Stroking the whiskers of a rat is known to increase cerebral blood flow and glucose utilization in the somatosensory cortex. We sought to determine whether this activation could be detected with small animal PET and 2-[F]fluoro-2-deoxyglucose ([F]FDG). METHODS: Awake rats were coinjected with [F]FDG and [C]deoxyglucose ([C]DG), and during the uptake of the tracers, five, 10, or 15 whiskers on one side of the face were continuously stimulated. At the end of uptake, the animal was killed and imaged with the Advanced Technology Laboratory Animal Scanner small animal PET scanner. Carbon-14 autoradiography was then performed on brain sections obtained from each animal, and increases in tracer uptake in the somatosensory cortex were compared with those determined with PET. RESULTS: Both methods showed increases in [F]FDG and [C]DG uptake in the somatosensory cortex in response to the stimulation of as few as five whiskers. However, the magnitude of activation determined from the PET images was less than that from autoradiography due to the lower spatial resolution of the PET scanner. CONCLUSION: Advanced Technology Laboratory Animal Scanner small animal PET imaging with [F]FDG can be used to assess neuronal functional activity in vivo.
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Radioisótopos de Carbono , Desoxiglucosa , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones/métodos , Corteza Somatosensorial/diagnóstico por imagen , Corteza Somatosensorial/metabolismo , Vibrisas/fisiología , Animales , Autorradiografía/métodos , Glucemia/análisis , Glucemia/metabolismo , Masculino , Radiofármacos , RatasRESUMEN
Alzheimer's disease is nowadays the leading cause of dementia. It affects more than a third of people over 85 years old. The gold standard diagnostic proof is currently based upon pathology examination. It seems rather crucial to find methodologies that make an early and accurate in vivo diagnosis so as to offer the patient the most suitable treatment. We hereby go over several available neuro-imaging techniques used in nuclear medicine that increase the diagnostic accuracy of Alzheimer's disease.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/psicología , Amiloidosis/diagnóstico por imagen , Amiloidosis/epidemiología , Amiloidosis/fisiopatología , Amiloidosis/psicología , Encéfalo/irrigación sanguínea , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Estudios Transversales , Diagnóstico Diferencial , Dominancia Cerebral/fisiología , Dopamina/metabolismo , Metabolismo Energético/fisiología , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/epidemiología , Demencia Frontotemporal/fisiopatología , Demencia Frontotemporal/psicología , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/epidemiología , Enfermedad por Cuerpos de Lewy/fisiopatología , Enfermedad por Cuerpos de Lewy/psicología , Flujo Sanguíneo Regional/fisiologíaRESUMEN
BACKGROUND: We used the Monte Carlo code "CELLDOSE" to assess the dose received by specific target cells from electron emissions in a complex environment. (131)I in a simulated thyroid was used as a model. METHODS: Thyroid follicles were represented by 170 microm diameter spherical units made of a lumen of 150 microm diameter containing colloidal matter and a peripheral layer of 10 microm thick thyroid cells. Neighbouring follicles are 4 microm apart. (131)I was assumed to be homogeneously distributed in the lumen and absent in cells. We firstly assessed electron dose distribution in a single follicle. Then, we expanded the simulation by progressively adding neighbouring layers of follicles, so to reassess the electron dose to this single follicle implemented with the contribution of the added layers. RESULTS: Electron dose gradient around a point source showed that the (131)I electron dose is close to zero after 2,100 microm. Therefore, we studied all contributions to the central follicle deriving from follicles within 12 orders of neighbourhood (15,624 follicles surrounding the central follicle). The dose to colloid of the single follicle was twice as high as the dose to thyroid cells. Even when all neighbours were taken into account, the dose in the central follicle remained heterogeneous. For a 1-Gy average dose to tissue, the dose to colloidal matter was 1.168 Gy, the dose to thyroid cells was 0.982 Gy, and the dose to the inter-follicular tissue was 0.895 Gy. Analysis of the different contributions to thyroid cell dose showed that 17.3% of the dose derived from the colloidal matter of their own follicle, while the remaining 82.7% was delivered by the surrounding follicles. On the basis of these data, it is shown that when different follicles contain different concentrations of (131)I, the impact in terms of cell dose heterogeneity can be important. CONCLUSION: By means of (131)I in the thyroid as a theoretical model, we showed how a Monte Carlo code can be used to map electron dose deposit and build up the dose to target cells in a complex multi-source environment. This approach can be of considerable interest for comparing different radiopharmaceuticals as therapy agents in oncology.
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Electrones , Método de Montecarlo , Dosis de Radiación , Glándula Tiroides/citología , Glándula Tiroides/efectos de la radiación , Radioisótopos de Yodo , Modelos BiológicosRESUMEN
UNLABELLED: Rapid-onset dystonia-parkinsonism (RDP) is a rare, autosomal-dominantly inherited syndrome characterized by abrupt onset, over hours to days, of dystonic and parkinsonian symptoms. To date, RDP has been described in a small number of families, and in only four sporadic cases. METHODS: We here report a new sporadic case of RDP who has a novel de novo mutation in the ATP1A3 gene. Striatal dopamine transporters have been assessed quantitatively using [123I]-FP-CIT SPECT. A volume of interest (VOI) was drawn within the occipital cortex to obtain non-specific activity and specific to non-specific binding ratios (BR) were calculated. A single template of predefined VOI 3D-drawn on right and left caudate nucleus and putamen was applied to the spatially normalized BR images. BR values were compared to those obtained from an age-matched control group and from a group of patients suffering from Parkinson's disease (Hoehn and Yahr score 2 or 3). A [99mTc]-HMPAO cerebral blood flow study was also performed. RESULTS: In the control group, BR values (mean+/-Standard Deviation) were 3.5+/-0.4 for the left striatum and 3.3+/-0.3 for the right one. RDP patient's values were 3 and 2.7, respectively. In the Parkinson group, values were 1.6+/-0.3 and 1.7+/-0.4, respectively. [99mTc]-HMPAO scan showed homogeneous cortical and sub-cortical perfusion. CONCLUSION: Quantification of striatal [123I]-FP-CIT uptake in a new sporadic case of RDP with a novel mutation in the ATP1A3 gene showed values just within the range of normality. [99mTc]-HMPAO scan was normal.
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Distonía/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Exametazima de Tecnecio Tc 99m , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Distonía/complicaciones , Distonía/genética , Humanos , Radioisótopos de Yodo , Masculino , Mutación , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Prostate adenocarcinoma is generally characterized by slow progression although some phenotypes have a more aggressive behavior with tendency to local invasion and distant metastases, mainly to bones. Better specific care could be provided to the aggressive phenotype-group of patients if pre-surgical identification were available. MATERIAL AND METHODS: Correlations between pre-surgical levels of 6 blood molecules and pathological tumour staging, post-surgical Gleason score and disease-free survival have been observed. Plasma and sera from 162 men affected by prostate adenocarcinoma were analysed with ELISA to assess levels of neovascularization-related molecule (VEGF), endothelial cell adhesion molecule (VCAM), extracellular matrix destruction-related molecules (MMP-2, MMP-9), and tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2). RESULTS: The median values of serum determinations were for VEGF 279 pg/ml, VCAM 633 ng/ml, MMP-2 206 ng/ml and MMP-9 614 ng/ml. Plasma medians (ng/ml) were 94 for TIMP-1 and 90 for TIMP-2. Patients with VCAM values > 633 ng/ml had a worse disease-free survival than patients with values <633 ng/ml with an adjusted Hazard Ratio of 2.1, significant (95% confidence interval 0.8-5.6). Patients with levels of MMP-2 < 206 ng/ml showed an increased risk of progression (adjusted HR 1.7; 95% C.I. 0.6-4.8). CONCLUSIONS: Levels of VCAM and MMP-2 should be checked in patients with prostate adenocarcinoma, because distant spread is more likely to occur in patients with high levels of VCAM and low levels of MMP-2. The scientific community should further investigate impact on prognosis of VCAM and MMP-2.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/sangre , Metaloproteinasa 2 de la Matriz/sangre , Neoplasias de la Próstata/metabolismo , Molécula 1 de Adhesión Celular Vascular/sangre , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Supervivencia sin Enfermedad , Ensayo de Inmunoadsorción Enzimática , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Metaloproteinasa 9 de la Matriz/sangre , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Fenotipo , Proyectos Piloto , Modelos de Riesgos Proporcionales , Prostatectomía , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Medición de Riesgo , Factores de Tiempo , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidor Tisular de Metaloproteinasa-2/sangre , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: Focal metastasis may be treated with radiofrequency ablation (RFA), a low invasive method yet limited by the lack of direct evidence of radicality of treatment. We, hereby, aimed at assessing the role of positron emission tomography-computed tomography (PET/CT) with fluoride radiolabeled deoxy-glucose ([(18)F]FDG) in RFA treatment success evaluation and early diagnosis of local relapse of liver metastasis after RFA procedure. METHODS: RFA was performed in nine patients on 12 liver metastasis, serially imaged through [(18)F]FDG-PET/CT and multidetector CT (MDCT) at 1, 3, 6, and 9 months after treatment. Eight lesions were also scanned with [(18)F]FDG-PET/CT at 1 week after treatment. Imaging analyses were performed on 47 [(18)F]FDG-PET/CT and 51 MDCT. Imaging reading outcomes were compared to each other and to biopsy tissue results when available. RESULTS: In one case, [(18)F]FDG-PET/CT revealed radiotracer uptake at RFA site a week after procedure. Negative concordant outcome was obtained on eight lesions at 1 month after RFA, on eight cases at 3 months, on four at 6 months, and on two cases at 9 months. Extra-liver (peritoneal) disease was detected in one case by both [(18)F]FDG-PET/CT and MDCT. In seven cases, [(18)F]FDG-PET/CT revealed the presence of local recurrence earlier than MDCT. In no cases did MDCT detect local relapse earlier than [(18)F]FDG-PET/CT. CONCLUSION: [(18)F]FDG-PET/CT may detect RFA treatment failure as well as local relapse after RFA earlier than MDCT.
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Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundario , Técnicas de Ablación , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundario , Carcinoma Ductal de Mama/cirugía , Neoplasias del Colon , Femenino , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirugía , Masculino , Tomografía de Emisión de Positrones , Terapia por Radiofrecuencia , Radiofármacos , Neoplasias del Recto , Tomografía Computarizada por Rayos XRESUMEN
RATIONALE: Thymic masses may represent an unsolved diagnostic problem which often require surgical procedures for an accurate staging. A non-invasive way to determine the nature of thymic lesions would help identify the patients which are true candidates for surgery. Our retrospective study aims to assess multidetector computed tomography and 2-[(18)F]fluoro-2-deoxyglucose positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) capacity to distinguish benign from malignant thymic lesions. METHODS: Helical multidetector CT (MDCT) and [(18)F]FDG-PET/CT of twenty consecutive patients presenting with a thymic mass at our Institute were retrospectively analyzed. MDCT scans were focused on morphologic features and invasiveness characteristics. Qualitative and semi-quantitative analyses by maximum standardized uptake value corrected for body weight (SUVbw max) were performed on [(18)F]FDG-PET/CT. In all cases, readers were blinded to pathology findings. Both imaging techniques were correlated to final pathology. Student's t-test was performed on SUVbw max stratified for thymic epithelial tumors. RESULTS: In the group of benign lesions MDCT correctly identified well-defined margins of masses in 8 out of 8 patients whereas [(18)F]FDG-PET/CT was negative in 7 out of 8 patients. Among malignant lesions MDCT revealed mediastinum fat or infiltration of adjacent organs in 10/12 patients. On the other hand [(18)F]FDG-PET/CT showed increased radiotracer uptake in 12/12 patients. CONCLUSIONS: MDCT and [(18)F]FDG-PET/CT alone are not able to differentiate the nature of thymic lesions. However, they are two non-invasive complementary techniques which can be used to differentiate benign from high-risk malignant thymic lesions. These findings should be taken into account before surgery is performed as a diagnostic procedure.