RESUMO
The purpose of this study is to assess the diagnostic performance of diffusion kurtosis imaging (DKI) for in vivo molecular profiling of human glioma. Normalized mean kurtosis (MKn) and mean diffusivity (MDn) metrics from DKI were assessed in 50 patients with histopathologically confirmed glioma. The results were compared in regard to the WHO-based histological findings and molecular characteristics leading to integrated diagnosis (Haarlem Consensus): isocitrate-dehydrogenase (IDH1/2) mutation status, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression, chromosome 1p/19q loss of heterozygosity (LOH), and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. MKn was significantly lower in tumors with IDH1/2 mutation (0.43 ± 0.09) and ATRX loss of expression (0.41 ± 0.11) than in those with IDH1/2 wild type (0.57 ± 0.09, p < 0.001) and ATRX maintained expression (0.51 ± 0.10, p = 0.004), respectively. Regarding the integrated molecular diagnosis, MKn was significantly higher in primary glioblastoma (0.57 ± 0.10) than in astrocytoma (0.39 ± 0.11, p < 0.001) and oligodendroglioma (0.47 ± 0.05, p = 0.003). MK may be used to provide insight into the human glioma molecular profile regarding IDH1/2 mutation status and ATRX expression. Considering the diagnostic and prognostic significance of these molecular markers, MK appears to be a promising in vivo biomarker for glioma. The diagnostic performance of MK seems to fit more with the integrated molecular approach than the conventional histological findings of the current WHO 2007 classification.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Imagem de Difusão por Ressonância Magnética/métodos , Glioma/diagnóstico por imagem , Glioma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Estudos Retrospectivos , Estatísticas não Paramétricas , Adulto Jovem , Talassemia alfa/genéticaRESUMO
This article contains raw and processed data related to research published by Vega et al. (2022). This complementary dataset provides further insight into the experimental validation of a single common carotid artery occlusion (CCAO) model upon pretreatment with pertussis toxin (PTX). We present data showing the extent of different PTX concentrations on neurological severity measured by Bederson score following CCAO. In addition, data indicate a protective effect of isoflurane on cerebral infarction and neurological deficits, as well as the consequences of PTX pretreatment on reperfusion after occlusion using time-of-flight magnetic resonance angiography. With these data, we aim to provide detailed experimental settings of this newly described model.
RESUMO
Pertussis toxin (PTX) is a potent virulence factor in patients suffering from whooping cough, but in its detoxified version, it is applied for vaccination. It is thought to contribute to the pathology of the disease including various CNS malfunctions. Based on its enzymatic activity, PTX disrupts GPCR-dependent signaling by modifying the α-subunit of heterotrimeric Gi/o-proteins. It is also extensively used as a research tool to study neuronal functions in vivo and in vitro. However, data demonstrating the penetration of PTX from the blood into the brain are missing. Here, we examined the Gαi/o-modifying activity of PTX in murine brains after its parenteral application. Ex vivo biodistribution analysis of [124I]-PTX displayed poor distribution to the brain while relatively high concentrations were visible in the pancreas. PTX affected CNS and endocrine functions of the pancreas as shown by open-field and glucose tolerance tests, respectively. However, while pancreatic islet Gαi/o-proteins were modified, their neuronal counterparts in brain tissue were resistant towards PTX as indicated by different autoradiographic and immunoblot SDS-PAGE analyses. In contrast, PTX easily modified brain Gαi/o-proteins ex vivo. An attempt to increase BBB permeability by application of hypertonic mannitol did not show PTX activity on neuronal G proteins. Consistent with these findings, in vivo MRI analysis did not point to an increased blood-brain barrier (BBB) permeability following PTX treatment. Our data demonstrate that the CNS is protected from PTX. Thus, we hypothesize that the BBB hinders PTX to penetrate into the CNS and to deliver its enzymatic activity to brain Gαi/o-proteins. KEY MESSAGES: i.p. applied PTX is poorly retained in the brain while reaches high concentration in the pancreas. Pancreatic islet Gαi/o- but not cerebral Gαi/o-proteins are modified by i.p. administered PTX. Gαi/o-proteins from isolated cerebral cell membranes were easily modified by PTX ex vivo. CNS is protected from i.p. administered PTX. PTX does not permeabilize the BBB.
Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Injeções/métodos , Neuroproteção , Toxina Pertussis/administração & dosagem , Toxina Pertussis/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Membrana Celular/metabolismo , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/deficiência , Radioisótopos do Iodo , Ilhotas Pancreáticas/diagnóstico por imagem , Ilhotas Pancreáticas/metabolismo , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Distribuição TecidualRESUMO
Positron emission tomography (PET) is a non-invasive imaging technology employed to describe metabolic, physiological, and biochemical processes in vivo. These include receptor availability, metabolic changes, neurotransmitter release, and alterations of gene expression in the brain. Since the introduction of dedicated small-animal PET systems along with the development of many novel PET imaging probes, the number of PET studies using rats and mice in basic biomedical research tremendously increased over the last decade. This article reviews challenges and advances of quantitative rodent brain imaging to make the readers aware of its physical limitations, as well as to inspire them for its potential applications in preclinical research. In the first section, we briefly discuss the limitations of small-animal PET systems in terms of spatial resolution and sensitivity and point to possible improvements in detector development. In addition, different acquisition and post-processing methods used in rodent PET studies are summarized. We further discuss factors influencing the test-retest variability in small-animal PET studies, e.g., different receptor quantification methodologies which have been mainly translated from human to rodent receptor studies to determine the binding potential and changes of receptor availability and radioligand affinity. We further review different kinetic modeling approaches to obtain quantitative binding data in rodents and PET studies focusing on the quantification of endogenous neurotransmitter release using pharmacological interventions. While several studies have focused on the dopamine system due to the availability of several PET tracers which are sensitive to dopamine release, other neurotransmitter systems have become more and more into focus and are described in this review, as well. We further provide an overview of latest genome engineering technologies, including the CRISPR/Cas9 and DREADD systems that may advance our understanding of brain disorders and function and how imaging has been successfully applied to animal models of human brain disorders. Finally, we review the strengths and opportunities of simultaneous PET/magnetic resonance imaging systems to study drug-receptor interactions and challenges for the translation of PET results from bench to bedside.