520 research outputs found
Clinical Imaging of Choroid Plexus in Health and in Brain Disorders: A Mini-Review
The choroid plexuses (ChPs) perform indispensable functions for the development, maintenance and functioning of the brain. Although they have gained considerable interest in the last years, their involvement in brain disorders is still largely unknown, notably because their deep location inside the brain hampers non-invasive investigations. Imaging tools have become instrumental to the diagnosis and pathophysiological study of neurological and neuropsychiatric diseases. This review summarizes the knowledge that has been gathered from the clinical imaging of ChPs in health and brain disorders not related to ChP pathologies. Results are discussed in the light of pre-clinical imaging studies. As seen in this review, to date, most clinical imaging studies of ChPs have used disease-free human subjects to demonstrate the value of different imaging biomarkers (ChP size, perfusion/permeability, glucose metabolism, inflammation), sometimes combined with the study of normal aging. Although very few studies have actually tested the value of ChP imaging biomarkers in patients with brain disorders, these pioneer studies identified ChP changes that are promising data for a better understanding and follow-up of diseases such as schizophrenia, epilepsy and Alzheimerâs disease. Imaging of immune cell trafficking at the ChPs has remained limited to pre-clinical studies so far but has the potential to be translated in patients for example using MRI coupled with the injection of iron oxide nanoparticles. Future investigations should aim at confirming and extending these findings and at developing translational molecular imaging tools for bridging the gap between basic molecular and cellular neuroscience and clinical research
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
Magnetic Resonance Imaging of cerebral phagocytic cells in mouse model of neuroinflammation
Lâaccident vasculaire cĂ©rĂ©bral ischĂ©mique (AVCi) est un enjeu majeur de santĂ© publique. Lâimagerie par rĂ©sonance magnĂ©tique (IRM) est de plus en plus utilisĂ©e pour la prise en charge en urgence des patients, afin de sĂ©lectionner les patients candidats aux thĂ©rapies de reperfusion, seul traitement approuvĂ© Ă ce jour. La dĂ©couverte de nouvelles thĂ©rapeutiques constitue donc un vĂ©ritable enjeu pour protĂ©ger le cerveau Ă la suite dâun AVCi. La piste des thĂ©rapeutiques anti-inflammatoires est particuliĂšrement intĂ©ressante. En effet, il a Ă©tĂ© dĂ©montrĂ© que dans lâAVCi, lâinflammation cĂ©rĂ©brale serait Ă lâorigine dâune aggravation de la lĂ©sion ischĂ©mique. Il est maintenant admis que les cellules du systĂšme monocluĂ©e phagocytaire ont un rĂŽle prĂ©dominant dans la cette rĂ©action inflammatoire, contribuant dans certains cas aux dommages tissulaires. Plus rĂ©cemment, il a Ă©galement Ă©tĂ© dĂ©montrĂ© que les plexus choroĂŻdes joueraient un rĂŽle important dans le recrutement de cellules immunitaires au niveau de la lĂ©sion ischĂ©mique. Pour amĂ©liorer la comprĂ©hension de lâimplication des cellules phagocytaires dans lâAVCi et dans les pathologies neuroinflammatoires en gĂ©nĂ©ral, lâimagerie in vivo est un outil translationnel prĂ©cieux. Au sein de notre Ă©quipe, la mĂ©thode non invasive dâIRM couplĂ©e Ă lâinjection intraveineuse de nanoparticules dâoxyde de fer, les USPIOs, a Ă©tĂ© mise au point. Cette technique permet dâimager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique, suite Ă leur internalisation des USPIOs. Dans ce contexte, ma thĂšse sâest articulĂ©e autour des deux axes suivants : 1) Evaluer le potentiel dâune nouvelle nanoparticule multimodale, la « NanoGd », pour imager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique. Un protocole expĂ©rimental prĂ©cis a Ă©tĂ© mis en place dans un modĂšle dâocclusion permanente de lâartĂšre cĂ©rĂ©brale moyenne chez la souris transgĂ©nique CX3CR1-GFP. LâoriginalitĂ© de notre Ă©tude repose sur le fait que ces souris ont Ă©tĂ© imagĂ©es in vivo avec des sessions dâIRM combinĂ©es Ă des sessions de microscopie biphotonique intravitale, nous permettant dâobtenir de prĂ©cieuses informations sur les origines biologiques des signaux visualisĂ©s avec lâIRM. Nos rĂ©sultats indiquent que lâimagerie multimodale de la NanoGd permettent dâimager in vivo les cellules phagocytaires Ă la suite dâun AVCi. 2) Evaluer le potentiel de notre technique dâIRM couplĂ©e Ă lâinjection intraveineuse dâUSPIOs comme outil pour imager in vivo lâimplication des plexus choroĂŻdes dans des phĂ©nomĂšnes inflammatoires prĂ©coces. Pour cela, nous avons travaillĂ© avec un modĂšle murin de neuroinflammation induite par injection intrapĂ©ritonĂ©ale de lipopolysaccharide. La prĂ©sence des USPIOs au niveau des plexus choroĂŻdes a Ă©tĂ© quantifiĂ©e sur les images IRM Ă lâaide dâun systĂšme de scoring multi-opĂ©rateurs, et comparĂ©e entre le groupe de souris LPS et le groupe contrĂŽle. Nous avons montrĂ© que lâIRM couplĂ©e Ă lâinjection iv dâUSPIOs permettait de mettre en Ă©vidence in vivo les phĂ©nomĂšnes inflammatoires Ă lâintĂ©rieur des plexus choroĂŻdes. Cette Ă©tude sur lâimagerie in vivo de lâinflammation dans les plexus choroĂŻdes fait suite Ă la rĂ©daction dâune revue sur lâimagerie clinique des plexus choroĂŻdes en conditions physiologiques et pathologiques. Nous avons montrĂ© que les plexus choroĂŻdes sont impliquĂ©s de nombreuses maniĂšres dans le maintien de lâhomĂ©ostasie cĂ©rĂ©brale, et que bien quâil sâagisse dâun domaine en pleine expansion, lâimagerie clinique de ces structures est encore largement insuffisante. Ce travail de thĂšse a donc permis de mettre au point et de valider deux approches dâimagerie in vivo pour lâĂ©tude de lâinflammation cĂ©rĂ©brale, dans lâAVCi et les pathologies avec une composante neuroinflammatoire, et lâutilisation de ces mĂ©thodes dans des modĂšles souris de neuroinflammation a dâores et dĂ©jĂ permis dâamĂ©liorer la comprĂ©hension des mĂ©canismes inflammatoires dans ces pathologiesStroke is a major public health issue. Magnetic resonance imaging (MRI) is increasingly used for the emergency management of these patients, during the interruption of blood flow to better select patients who are candidates for reperfusion therapies, the only treatment approved to date. The discovery of new therapeutics is therefore a real challenge to protect the brain following a stroke. Among the different lines of research, anti-inflammatory therapeutics are particularly interesting. Indeed, cerebral ischemia causes an inflammatory reaction and it has been shown that the runaway of this reaction would cause an aggravation of the cerebral lesions. Although the establishment of this inflammatory reaction is still to be characterized more precisely, significant progress has been made in this area. It is now recognized that cells of the phagocytic monoclonal system play a predominant role in the establishment and maintenance of this inflammatory response, contributing in some cases to tissue damage. More recently, it has also been shown that choroid plexuses play an important role in the recruitment of immune cells to the level of ischemic injury, including circulating monocytes/macrophages. To improve our understanding of phagocytic cells involvement in ischemic stroke and neuroinflammatory pathologies in general, in vivo imaging is a promising translational tool. In our team, the non-invasive MRI method coupled with the intravenous injection of iron oxide nanoparticles, the USPIOs, has been developed and validated through pre-clinical and clinical studies. This technique enables to image the phagocytic cells present at the level of the ischemic lesion, following their internalization of the USPIOs.In this context, my thesis was articulated around the following two axes:1) Evaluate the potential of a new multimodal nanoparticle composed with gadolinium fluoride, the "NanoGd", to image phagocytic cells present in the ischemic lesion. A precise experimental protocol was implemented in a model of permanent occlusion of the middle cerebral artery in CX3CR1-GFP transgenic mouse. The originality of our study rests on the fact that these mice were imaged in vivo with MRI sessions back-to-back with intravital two-photon microscopy sessions, allowing us to obtain valuable information on the biological origins of the signals visualized with the MRI. Our results indicate that multimodal imaging of NanoGd can be used to image phagocytic cells in vivo following ischemic stroke. 2) Evaluate the potential of USPIO-enhanced MRI as a tool to image in vivo the involvement of choroid plexuses in early inflammatory phenomena. For this, we worked with a mouse model of neuroinflammation induced by intraperitoneal injection of lipopolysaccharide. The presence of USPIOs at the level of the choroid plexuses was quantified on the MRI images using a multi-operator scoring system and compared between the LPS mouse group and the control group. We have shown with our study that the MRI coupled with the iv injection of USPIOs allowed to highlight in vivo the inflammatory phenomena inside the choroid plexuses. This study on in vivo imaging of inflammation in choroid plexuses followed the writing of a review about the clinical imaging of choroid plexuses in physiological and pathological conditions. In this study, we have shown that choroid plexuses are involved in many ways in maintaining cerebral homeostasis, and that although this is a rapidly expanding field, the clinical imaging of these structures is still largely insufficient. This work has allowed to develop and validate two in vivo imaging approaches for the study of brain inflammation, in stroke and pathologies with a neuroinflammatory component, and the use of these methods in mouse models of neuroinflammation has already made it possible to improve the understanding of inflammatory mechanisms in these pathologie
Imagerie par Résonance Magnétique des cellules phagocytaires cérébrales dans des modÚles murins de neuroinflammation
Stroke is a major public health issue. Magnetic resonance imaging (MRI) is increasingly used for the emergency management of these patients, during the interruption of blood flow to better select patients who are candidates for reperfusion therapies, the only treatment approved to date. The discovery of new therapeutics is therefore a real challenge to protect the brain following a stroke. Among the different lines of research, anti-inflammatory therapeutics are particularly interesting. Indeed, cerebral ischemia causes an inflammatory reaction and it has been shown that the runaway of this reaction would cause an aggravation of the cerebral lesions. Although the establishment of this inflammatory reaction is still to be characterized more precisely, significant progress has been made in this area. It is now recognized that cells of the phagocytic monoclonal system play a predominant role in the establishment and maintenance of this inflammatory response, contributing in some cases to tissue damage. More recently, it has also been shown that choroid plexuses play an important role in the recruitment of immune cells to the level of ischemic injury, including circulating monocytes/macrophages. To improve our understanding of phagocytic cells involvement in ischemic stroke and neuroinflammatory pathologies in general, in vivo imaging is a promising translational tool. In our team, the non-invasive MRI method coupled with the intravenous injection of iron oxide nanoparticles, the USPIOs, has been developed and validated through pre-clinical and clinical studies. This technique enables to image the phagocytic cells present at the level of the ischemic lesion, following their internalization of the USPIOs.In this context, my thesis was articulated around the following two axes:1) Evaluate the potential of a new multimodal nanoparticle composed with gadolinium fluoride, the "NanoGd", to image phagocytic cells present in the ischemic lesion. A precise experimental protocol was implemented in a model of permanent occlusion of the middle cerebral artery in CX3CR1-GFP transgenic mouse. The originality of our study rests on the fact that these mice were imaged in vivo with MRI sessions back-to-back with intravital two-photon microscopy sessions, allowing us to obtain valuable information on the biological origins of the signals visualized with the MRI. Our results indicate that multimodal imaging of NanoGd can be used to image phagocytic cells in vivo following ischemic stroke. 2) Evaluate the potential of USPIO-enhanced MRI as a tool to image in vivo the involvement of choroid plexuses in early inflammatory phenomena. For this, we worked with a mouse model of neuroinflammation induced by intraperitoneal injection of lipopolysaccharide. The presence of USPIOs at the level of the choroid plexuses was quantified on the MRI images using a multi-operator scoring system and compared between the LPS mouse group and the control group. We have shown with our study that the MRI coupled with the iv injection of USPIOs allowed to highlight in vivo the inflammatory phenomena inside the choroid plexuses. This study on in vivo imaging of inflammation in choroid plexuses followed the writing of a review about the clinical imaging of choroid plexuses in physiological and pathological conditions. In this study, we have shown that choroid plexuses are involved in many ways in maintaining cerebral homeostasis, and that although this is a rapidly expanding field, the clinical imaging of these structures is still largely insufficient. This work has allowed to develop and validate two in vivo imaging approaches for the study of brain inflammation, in stroke and pathologies with a neuroinflammatory component, and the use of these methods in mouse models of neuroinflammation has already made it possible to improve the understanding of inflammatory mechanisms in these pathologiesLâaccident vasculaire cĂ©rĂ©bral ischĂ©mique (AVCi) est un enjeu majeur de santĂ© publique. Lâimagerie par rĂ©sonance magnĂ©tique (IRM) est de plus en plus utilisĂ©e pour la prise en charge en urgence des patients, afin de sĂ©lectionner les patients candidats aux thĂ©rapies de reperfusion, seul traitement approuvĂ© Ă ce jour. La dĂ©couverte de nouvelles thĂ©rapeutiques constitue donc un vĂ©ritable enjeu pour protĂ©ger le cerveau Ă la suite dâun AVCi. La piste des thĂ©rapeutiques anti-inflammatoires est particuliĂšrement intĂ©ressante. En effet, il a Ă©tĂ© dĂ©montrĂ© que dans lâAVCi, lâinflammation cĂ©rĂ©brale serait Ă lâorigine dâune aggravation de la lĂ©sion ischĂ©mique. Il est maintenant admis que les cellules du systĂšme monocluĂ©e phagocytaire ont un rĂŽle prĂ©dominant dans la cette rĂ©action inflammatoire, contribuant dans certains cas aux dommages tissulaires. Plus rĂ©cemment, il a Ă©galement Ă©tĂ© dĂ©montrĂ© que les plexus choroĂŻdes joueraient un rĂŽle important dans le recrutement de cellules immunitaires au niveau de la lĂ©sion ischĂ©mique. Pour amĂ©liorer la comprĂ©hension de lâimplication des cellules phagocytaires dans lâAVCi et dans les pathologies neuroinflammatoires en gĂ©nĂ©ral, lâimagerie in vivo est un outil translationnel prĂ©cieux. Au sein de notre Ă©quipe, la mĂ©thode non invasive dâIRM couplĂ©e Ă lâinjection intraveineuse de nanoparticules dâoxyde de fer, les USPIOs, a Ă©tĂ© mise au point. Cette technique permet dâimager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique, suite Ă leur internalisation des USPIOs. Dans ce contexte, ma thĂšse sâest articulĂ©e autour des deux axes suivants : 1)Evaluer le potentiel dâune nouvelle nanoparticule multimodale, la « NanoGd », pour imager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique. Un protocole expĂ©rimental prĂ©cis a Ă©tĂ© mis en place dans un modĂšle dâocclusion permanente de lâartĂšre cĂ©rĂ©brale moyenne chez la souris transgĂ©nique CX3CR1-GFP. LâoriginalitĂ© de notre Ă©tude repose sur le fait que ces souris ont Ă©tĂ© imagĂ©es in vivo avec des sessions dâIRM combinĂ©es Ă des sessions de microscopie biphotonique intravitale, nous permettant dâobtenir de prĂ©cieuses informations sur les origines biologiques des signaux visualisĂ©s avec lâIRM. Nos rĂ©sultats indiquent que lâimagerie multimodale de la NanoGd permettent dâimager in vivo les cellules phagocytaires Ă la suite dâun AVCi. 2)Evaluer le potentiel de notre technique dâIRM couplĂ©e Ă lâinjection intraveineuse dâUSPIOs comme outil pour imager in vivo lâimplication des plexus choroĂŻdes dans des phĂ©nomĂšnes inflammatoires prĂ©coces. Pour cela, nous avons travaillĂ© avec un modĂšle murin de neuroinflammation induite par injection intrapĂ©ritonĂ©ale de lipopolysaccharide. La prĂ©sence des USPIOs au niveau des plexus choroĂŻdes a Ă©tĂ© quantifiĂ©e sur les images IRM Ă lâaide dâun systĂšme de scoring multi-opĂ©rateurs, et comparĂ©e entre le groupe de souris LPS et le groupe contrĂŽle. Nous avons montrĂ© que lâIRM couplĂ©e Ă lâinjection iv dâUSPIOs permettait de mettre en Ă©vidence in vivo les phĂ©nomĂšnes inflammatoires Ă lâintĂ©rieur des plexus choroĂŻdes. Cette Ă©tude sur lâimagerie in vivo de lâinflammation dans les plexus choroĂŻdes fait suite Ă la rĂ©daction dâune revue sur lâimagerie clinique des plexus choroĂŻdes en conditions physiologiques et pathologiques. Nous avons montrĂ© que les plexus choroĂŻdes sont impliquĂ©s de nombreuses maniĂšres dans le maintien de lâhomĂ©ostasie cĂ©rĂ©brale, et que bien quâil sâagisse dâun domaine en pleine expansion, lâimagerie clinique de ces structures est encore largement insuffisante. Ce travail de thĂšse a donc permis de mettre au point et de valider deux approches dâimagerie in vivo pour lâĂ©tude de lâinflammation cĂ©rĂ©brale, dans lâAVCi et les pathologies avec une composante neuroinflammatoire, et lâutilisation de ces mĂ©thodes dans des modĂšles souris de neuroinflammation a dâores et dĂ©jĂ permis dâamĂ©liorer la comprĂ©hension des mĂ©canismes inflammatoires dans ces pathologie
Imagerie par Résonance Magnétique des cellules phagocytaires cérébrales dans des modÚles murins de neuroinflammation
Stroke is a major public health issue. Magnetic resonance imaging (MRI) is increasingly used for the emergency management of these patients, during the interruption of blood flow to better select patients who are candidates for reperfusion therapies, the only treatment approved to date. The discovery of new therapeutics is therefore a real challenge to protect the brain following a stroke. Among the different lines of research, anti-inflammatory therapeutics are particularly interesting. Indeed, cerebral ischemia causes an inflammatory reaction and it has been shown that the runaway of this reaction would cause an aggravation of the cerebral lesions. Although the establishment of this inflammatory reaction is still to be characterized more precisely, significant progress has been made in this area. It is now recognized that cells of the phagocytic monoclonal system play a predominant role in the establishment and maintenance of this inflammatory response, contributing in some cases to tissue damage. More recently, it has also been shown that choroid plexuses play an important role in the recruitment of immune cells to the level of ischemic injury, including circulating monocytes/macrophages. To improve our understanding of phagocytic cells involvement in ischemic stroke and neuroinflammatory pathologies in general, in vivo imaging is a promising translational tool. In our team, the non-invasive MRI method coupled with the intravenous injection of iron oxide nanoparticles, the USPIOs, has been developed and validated through pre-clinical and clinical studies. This technique enables to image the phagocytic cells present at the level of the ischemic lesion, following their internalization of the USPIOs.In this context, my thesis was articulated around the following two axes:1) Evaluate the potential of a new multimodal nanoparticle composed with gadolinium fluoride, the "NanoGd", to image phagocytic cells present in the ischemic lesion. A precise experimental protocol was implemented in a model of permanent occlusion of the middle cerebral artery in CX3CR1-GFP transgenic mouse. The originality of our study rests on the fact that these mice were imaged in vivo with MRI sessions back-to-back with intravital two-photon microscopy sessions, allowing us to obtain valuable information on the biological origins of the signals visualized with the MRI. Our results indicate that multimodal imaging of NanoGd can be used to image phagocytic cells in vivo following ischemic stroke. 2) Evaluate the potential of USPIO-enhanced MRI as a tool to image in vivo the involvement of choroid plexuses in early inflammatory phenomena. For this, we worked with a mouse model of neuroinflammation induced by intraperitoneal injection of lipopolysaccharide. The presence of USPIOs at the level of the choroid plexuses was quantified on the MRI images using a multi-operator scoring system and compared between the LPS mouse group and the control group. We have shown with our study that the MRI coupled with the iv injection of USPIOs allowed to highlight in vivo the inflammatory phenomena inside the choroid plexuses. This study on in vivo imaging of inflammation in choroid plexuses followed the writing of a review about the clinical imaging of choroid plexuses in physiological and pathological conditions. In this study, we have shown that choroid plexuses are involved in many ways in maintaining cerebral homeostasis, and that although this is a rapidly expanding field, the clinical imaging of these structures is still largely insufficient. This work has allowed to develop and validate two in vivo imaging approaches for the study of brain inflammation, in stroke and pathologies with a neuroinflammatory component, and the use of these methods in mouse models of neuroinflammation has already made it possible to improve the understanding of inflammatory mechanisms in these pathologiesLâaccident vasculaire cĂ©rĂ©bral ischĂ©mique (AVCi) est un enjeu majeur de santĂ© publique. Lâimagerie par rĂ©sonance magnĂ©tique (IRM) est de plus en plus utilisĂ©e pour la prise en charge en urgence des patients, afin de sĂ©lectionner les patients candidats aux thĂ©rapies de reperfusion, seul traitement approuvĂ© Ă ce jour. La dĂ©couverte de nouvelles thĂ©rapeutiques constitue donc un vĂ©ritable enjeu pour protĂ©ger le cerveau Ă la suite dâun AVCi. La piste des thĂ©rapeutiques anti-inflammatoires est particuliĂšrement intĂ©ressante. En effet, il a Ă©tĂ© dĂ©montrĂ© que dans lâAVCi, lâinflammation cĂ©rĂ©brale serait Ă lâorigine dâune aggravation de la lĂ©sion ischĂ©mique. Il est maintenant admis que les cellules du systĂšme monocluĂ©e phagocytaire ont un rĂŽle prĂ©dominant dans la cette rĂ©action inflammatoire, contribuant dans certains cas aux dommages tissulaires. Plus rĂ©cemment, il a Ă©galement Ă©tĂ© dĂ©montrĂ© que les plexus choroĂŻdes joueraient un rĂŽle important dans le recrutement de cellules immunitaires au niveau de la lĂ©sion ischĂ©mique. Pour amĂ©liorer la comprĂ©hension de lâimplication des cellules phagocytaires dans lâAVCi et dans les pathologies neuroinflammatoires en gĂ©nĂ©ral, lâimagerie in vivo est un outil translationnel prĂ©cieux. Au sein de notre Ă©quipe, la mĂ©thode non invasive dâIRM couplĂ©e Ă lâinjection intraveineuse de nanoparticules dâoxyde de fer, les USPIOs, a Ă©tĂ© mise au point. Cette technique permet dâimager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique, suite Ă leur internalisation des USPIOs. Dans ce contexte, ma thĂšse sâest articulĂ©e autour des deux axes suivants : 1)Evaluer le potentiel dâune nouvelle nanoparticule multimodale, la « NanoGd », pour imager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique. Un protocole expĂ©rimental prĂ©cis a Ă©tĂ© mis en place dans un modĂšle dâocclusion permanente de lâartĂšre cĂ©rĂ©brale moyenne chez la souris transgĂ©nique CX3CR1-GFP. LâoriginalitĂ© de notre Ă©tude repose sur le fait que ces souris ont Ă©tĂ© imagĂ©es in vivo avec des sessions dâIRM combinĂ©es Ă des sessions de microscopie biphotonique intravitale, nous permettant dâobtenir de prĂ©cieuses informations sur les origines biologiques des signaux visualisĂ©s avec lâIRM. Nos rĂ©sultats indiquent que lâimagerie multimodale de la NanoGd permettent dâimager in vivo les cellules phagocytaires Ă la suite dâun AVCi. 2)Evaluer le potentiel de notre technique dâIRM couplĂ©e Ă lâinjection intraveineuse dâUSPIOs comme outil pour imager in vivo lâimplication des plexus choroĂŻdes dans des phĂ©nomĂšnes inflammatoires prĂ©coces. Pour cela, nous avons travaillĂ© avec un modĂšle murin de neuroinflammation induite par injection intrapĂ©ritonĂ©ale de lipopolysaccharide. La prĂ©sence des USPIOs au niveau des plexus choroĂŻdes a Ă©tĂ© quantifiĂ©e sur les images IRM Ă lâaide dâun systĂšme de scoring multi-opĂ©rateurs, et comparĂ©e entre le groupe de souris LPS et le groupe contrĂŽle. Nous avons montrĂ© que lâIRM couplĂ©e Ă lâinjection iv dâUSPIOs permettait de mettre en Ă©vidence in vivo les phĂ©nomĂšnes inflammatoires Ă lâintĂ©rieur des plexus choroĂŻdes. Cette Ă©tude sur lâimagerie in vivo de lâinflammation dans les plexus choroĂŻdes fait suite Ă la rĂ©daction dâune revue sur lâimagerie clinique des plexus choroĂŻdes en conditions physiologiques et pathologiques. Nous avons montrĂ© que les plexus choroĂŻdes sont impliquĂ©s de nombreuses maniĂšres dans le maintien de lâhomĂ©ostasie cĂ©rĂ©brale, et que bien quâil sâagisse dâun domaine en pleine expansion, lâimagerie clinique de ces structures est encore largement insuffisante. Ce travail de thĂšse a donc permis de mettre au point et de valider deux approches dâimagerie in vivo pour lâĂ©tude de lâinflammation cĂ©rĂ©brale, dans lâAVCi et les pathologies avec une composante neuroinflammatoire, et lâutilisation de ces mĂ©thodes dans des modĂšles souris de neuroinflammation a dâores et dĂ©jĂ permis dâamĂ©liorer la comprĂ©hension des mĂ©canismes inflammatoires dans ces pathologie
Imagerie par Résonance Magnétique des cellules phagocytaires cérébrales dans des modÚles murins de neuroinflammation
Stroke is a major public health issue. Magnetic resonance imaging (MRI) is increasingly used for the emergency management of these patients, during the interruption of blood flow to better select patients who are candidates for reperfusion therapies, the only treatment approved to date. The discovery of new therapeutics is therefore a real challenge to protect the brain following a stroke. Among the different lines of research, anti-inflammatory therapeutics are particularly interesting. Indeed, cerebral ischemia causes an inflammatory reaction and it has been shown that the runaway of this reaction would cause an aggravation of the cerebral lesions. Although the establishment of this inflammatory reaction is still to be characterized more precisely, significant progress has been made in this area. It is now recognized that cells of the phagocytic monoclonal system play a predominant role in the establishment and maintenance of this inflammatory response, contributing in some cases to tissue damage. More recently, it has also been shown that choroid plexuses play an important role in the recruitment of immune cells to the level of ischemic injury, including circulating monocytes/macrophages. To improve our understanding of phagocytic cells involvement in ischemic stroke and neuroinflammatory pathologies in general, in vivo imaging is a promising translational tool. In our team, the non-invasive MRI method coupled with the intravenous injection of iron oxide nanoparticles, the USPIOs, has been developed and validated through pre-clinical and clinical studies. This technique enables to image the phagocytic cells present at the level of the ischemic lesion, following their internalization of the USPIOs.In this context, my thesis was articulated around the following two axes:1) Evaluate the potential of a new multimodal nanoparticle composed with gadolinium fluoride, the "NanoGd", to image phagocytic cells present in the ischemic lesion. A precise experimental protocol was implemented in a model of permanent occlusion of the middle cerebral artery in CX3CR1-GFP transgenic mouse. The originality of our study rests on the fact that these mice were imaged in vivo with MRI sessions back-to-back with intravital two-photon microscopy sessions, allowing us to obtain valuable information on the biological origins of the signals visualized with the MRI. Our results indicate that multimodal imaging of NanoGd can be used to image phagocytic cells in vivo following ischemic stroke. 2) Evaluate the potential of USPIO-enhanced MRI as a tool to image in vivo the involvement of choroid plexuses in early inflammatory phenomena. For this, we worked with a mouse model of neuroinflammation induced by intraperitoneal injection of lipopolysaccharide. The presence of USPIOs at the level of the choroid plexuses was quantified on the MRI images using a multi-operator scoring system and compared between the LPS mouse group and the control group. We have shown with our study that the MRI coupled with the iv injection of USPIOs allowed to highlight in vivo the inflammatory phenomena inside the choroid plexuses. This study on in vivo imaging of inflammation in choroid plexuses followed the writing of a review about the clinical imaging of choroid plexuses in physiological and pathological conditions. In this study, we have shown that choroid plexuses are involved in many ways in maintaining cerebral homeostasis, and that although this is a rapidly expanding field, the clinical imaging of these structures is still largely insufficient. This work has allowed to develop and validate two in vivo imaging approaches for the study of brain inflammation, in stroke and pathologies with a neuroinflammatory component, and the use of these methods in mouse models of neuroinflammation has already made it possible to improve the understanding of inflammatory mechanisms in these pathologiesLâaccident vasculaire cĂ©rĂ©bral ischĂ©mique (AVCi) est un enjeu majeur de santĂ© publique. Lâimagerie par rĂ©sonance magnĂ©tique (IRM) est de plus en plus utilisĂ©e pour la prise en charge en urgence des patients, afin de sĂ©lectionner les patients candidats aux thĂ©rapies de reperfusion, seul traitement approuvĂ© Ă ce jour. La dĂ©couverte de nouvelles thĂ©rapeutiques constitue donc un vĂ©ritable enjeu pour protĂ©ger le cerveau Ă la suite dâun AVCi. La piste des thĂ©rapeutiques anti-inflammatoires est particuliĂšrement intĂ©ressante. En effet, il a Ă©tĂ© dĂ©montrĂ© que dans lâAVCi, lâinflammation cĂ©rĂ©brale serait Ă lâorigine dâune aggravation de la lĂ©sion ischĂ©mique. Il est maintenant admis que les cellules du systĂšme monocluĂ©e phagocytaire ont un rĂŽle prĂ©dominant dans la cette rĂ©action inflammatoire, contribuant dans certains cas aux dommages tissulaires. Plus rĂ©cemment, il a Ă©galement Ă©tĂ© dĂ©montrĂ© que les plexus choroĂŻdes joueraient un rĂŽle important dans le recrutement de cellules immunitaires au niveau de la lĂ©sion ischĂ©mique. Pour amĂ©liorer la comprĂ©hension de lâimplication des cellules phagocytaires dans lâAVCi et dans les pathologies neuroinflammatoires en gĂ©nĂ©ral, lâimagerie in vivo est un outil translationnel prĂ©cieux. Au sein de notre Ă©quipe, la mĂ©thode non invasive dâIRM couplĂ©e Ă lâinjection intraveineuse de nanoparticules dâoxyde de fer, les USPIOs, a Ă©tĂ© mise au point. Cette technique permet dâimager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique, suite Ă leur internalisation des USPIOs. Dans ce contexte, ma thĂšse sâest articulĂ©e autour des deux axes suivants : 1)Evaluer le potentiel dâune nouvelle nanoparticule multimodale, la « NanoGd », pour imager les cellules phagocytaires prĂ©sentes au niveau de la lĂ©sion ischĂ©mique. Un protocole expĂ©rimental prĂ©cis a Ă©tĂ© mis en place dans un modĂšle dâocclusion permanente de lâartĂšre cĂ©rĂ©brale moyenne chez la souris transgĂ©nique CX3CR1-GFP. LâoriginalitĂ© de notre Ă©tude repose sur le fait que ces souris ont Ă©tĂ© imagĂ©es in vivo avec des sessions dâIRM combinĂ©es Ă des sessions de microscopie biphotonique intravitale, nous permettant dâobtenir de prĂ©cieuses informations sur les origines biologiques des signaux visualisĂ©s avec lâIRM. Nos rĂ©sultats indiquent que lâimagerie multimodale de la NanoGd permettent dâimager in vivo les cellules phagocytaires Ă la suite dâun AVCi. 2)Evaluer le potentiel de notre technique dâIRM couplĂ©e Ă lâinjection intraveineuse dâUSPIOs comme outil pour imager in vivo lâimplication des plexus choroĂŻdes dans des phĂ©nomĂšnes inflammatoires prĂ©coces. Pour cela, nous avons travaillĂ© avec un modĂšle murin de neuroinflammation induite par injection intrapĂ©ritonĂ©ale de lipopolysaccharide. La prĂ©sence des USPIOs au niveau des plexus choroĂŻdes a Ă©tĂ© quantifiĂ©e sur les images IRM Ă lâaide dâun systĂšme de scoring multi-opĂ©rateurs, et comparĂ©e entre le groupe de souris LPS et le groupe contrĂŽle. Nous avons montrĂ© que lâIRM couplĂ©e Ă lâinjection iv dâUSPIOs permettait de mettre en Ă©vidence in vivo les phĂ©nomĂšnes inflammatoires Ă lâintĂ©rieur des plexus choroĂŻdes. Cette Ă©tude sur lâimagerie in vivo de lâinflammation dans les plexus choroĂŻdes fait suite Ă la rĂ©daction dâune revue sur lâimagerie clinique des plexus choroĂŻdes en conditions physiologiques et pathologiques. Nous avons montrĂ© que les plexus choroĂŻdes sont impliquĂ©s de nombreuses maniĂšres dans le maintien de lâhomĂ©ostasie cĂ©rĂ©brale, et que bien quâil sâagisse dâun domaine en pleine expansion, lâimagerie clinique de ces structures est encore largement insuffisante. Ce travail de thĂšse a donc permis de mettre au point et de valider deux approches dâimagerie in vivo pour lâĂ©tude de lâinflammation cĂ©rĂ©brale, dans lâAVCi et les pathologies avec une composante neuroinflammatoire, et lâutilisation de ces mĂ©thodes dans des modĂšles souris de neuroinflammation a dâores et dĂ©jĂ permis dâamĂ©liorer la comprĂ©hension des mĂ©canismes inflammatoires dans ces pathologie
L' ischémie rénale d'effort (à propos de trois cas)
POITIERS-BU MĂ©decine pharmacie (861942103) / SudocSudocFranceF
MRI coupled with clinically-applicable iron oxide nanoparticles reveals choroid plexus involvement in a murine model of neuroinflammation
International audienceChoroid plexus (ChPs) are involved in the early inflammatory response that occurs in many brain disorders. However, the activation of immune cells within the ChPs in response to neuroinflammation is still largely unexplored in-vivo. There is therefore a crucial need for developing imaging tool that would allow the non-invasive monitoring of ChP involvement in these diseases. Magnetic resonance imaging (MRI) coupled with superparamagnetic particles of iron oxide (SPIO) is a minimally invasive technique allowing to track phagocytic cells in inflammatory diseases. Our aim was to investigate the potential of ultrasmall SPIO (USPIO)-enhanced MRI to monitor ChP involvement in-vivo in a mouse model of neuroinflammation obtained by intraperitoneal administration of lipopolysaccharide. Using high resolution MRI, we identified marked USPIO-related signal drops in the ChPs of animals with neuroinflammation compared to controls. We confirmed these results quantitatively using a 4-points grading system. Ex-vivo analysis confirmed USPIO accumulation within the ChP stroma and their uptake by immune cells. We validated the translational potential of our approach using the clinically-applicable USPIO Ferumoxytol. MR imaging of USPIO accumulation within the ChPs may serve as an imaging biomarker to study ChP involvement in neuroinflammatory disorders that could be applied in a straightforward way in clinical practice
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