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2. Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Is There a Relevant Experimental Model? A Systematic Review of Preclinical Literature

Author

Suzanne Goursaud, Sara Martinez de Lizarrondo, François Grolleau, Audrey Chagnot, Véronique Agin, Eric Maubert, Maxime Gauberti, Denis Vivien, Carine Ali, and Clément Gakuba

Subjects
delayed cerebral ischemia, experimental models, subarachnoid hemorrhage, vasospasm, systematic review, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Delayed cerebral ischemia (DCI) is one of the main prognosis factors for disability after aneurysmal subarachnoid hemorrhage (SAH). The lack of a consensual definition for DCI had limited investigation and care in human until 2010, when a multidisciplinary research expert group proposed to define DCI as the occurrence of cerebral infarction (identified on imaging or histology) associated with clinical deterioration. We performed a systematic review to assess whether preclinical models of SAH meet this definition, focusing on the combination of noninvasive imaging and neurological deficits. To this aim, we searched in PUBMED database and included all rodent SAH models that considered cerebral ischemia and/or neurological outcome and/or vasospasm. Seventy-eight publications were included. Eight different methods were performed to induce SAH, with blood injection in the cisterna magna being the most widely used (n = 39, 50%). Vasospasm was the most investigated SAH-related complication (n = 52, 67%) compared to cerebral ischemia (n = 30, 38%), which was never investigated with imaging. Neurological deficits were also explored (n = 19, 24%). This systematic review shows that no preclinical SAH model meets the 2010 clinical definition of DCI, highlighting the inconsistencies between preclinical and clinical standards. In order to enhance research and favor translation to humans, pertinent SAH animal models reproducing DCI are urgently needed.

Published
2021
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3. Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Author

Alice Gilbert, Xabier Elorza-Vidal, Armelle Rancillac, Audrey Chagnot, Mervé Yetim, Vincent Hingot, Thomas Deffieux, Anne-Cécile Boulay, Rodrigo Alvear-Perez, Salvatore Cisternino, Sabrina Martin, Sonia Taïb, Aontoinette Gelot, Virginie Mignon, Maryline Favier, Isabelle Brunet, Xavier Declèves, Mickael Tanter, Raul Estevez, Denis Vivien, Bruno Saubaméa, and Martine Cohen-Salmon

Subjects
MLC, MLC1, gliovascular unit, astrocytes, development, Medicine, Science, Biology (General), QH301-705.5
Abstract

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare type of leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes. Perivascular astrocytic processes along with blood vessels form the gliovascular unit. It was not previously known how MLC1 influences the physiology of the gliovascular unit. Here, using the Mlc1 knock-out mouse model of MLC, we demonstrated that MLC1 controls the postnatal development and organization of perivascular astrocytic processes, vascular smooth muscle cell contractility, neurovascular coupling, and intraparenchymal interstitial fluid clearance. Our data suggest that MLC is a developmental disorder of the gliovascular unit, and perivascular astrocytic processes and vascular smooth muscle cell maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

Published
2021
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4. In mice and humans, brain microvascular contractility matures postnatally

Author

Leila Slaoui, Alice Gilbert, Armelle Rancillac, Barbara Delaunay-Piednoir, Audrey Chagnot, Quentin Gerard, Gaëlle Letort, Philippe Mailly, Noémie Robil, Antoinette Gelot, Mathilde Lefebvre, Maryline Favier, Karine Dias, Laurent Jourdren, Laetitia Federici, Sylvain Auvity, Salvatore Cisternino, Denis Vivien, Martine Cohen-Salmon, Anne-Cécile Boulay, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenoSplice [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), Plateforme Histologie, Immunomarquage et Microdissection laser [Institut Cochin] (HistIM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Cohen-Salmon, Martine, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Université Paris Descartes - Paris 5 (UPD5)

Subjects
[SDV] Life Sciences [q-bio], Postnatal development, Histology, General Neuroscience, [SDV]Life Sciences [q-bio], Vascular smooth muscle cell, microvessel contractility, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Cerebral blood flow, Brain microvessels Postnatal development Vascular smooth muscle cell microvessel contractility Cerebral blood flow, Brain microvessels
Abstract

International audience; Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific orpreferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF), with heterogenous developmental trajectories within cortical regions. Samples of human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.

Published
2022
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5. Preventing the Long-term Effects of General Anesthesia on the Developing Brain: How Translational Research can Contribute

Author

Carine Ali, Souhayl Dahmani, Gilles Orliaguet, Jean-Luc Hanouz, Clément Gakuba, Jean-Louis Gérard, Denis Vivien, Audrey Chagnot, Nicolas Poirel, Jean-Philippe Salaün, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de psychologie du développement et de l'éducation de l'enfant (LaPsyDÉ - UMR 8240), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Hôpital Robert Debré Paris, Hôpital Robert Debré, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte (URP_7323), Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, medicine.medical_specialty, Brain development, business.industry, General Neuroscience, Public health, Brain, Translational research, Anesthesia, General, 3. Good health, Translational Research, Biomedical, Food and drug administration, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Anesthesia, Pediatric surgery, medicine, Humans, Neurotoxicity Syndromes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Child, business, 030217 neurology & neurosurgery, Anesthetics
Abstract

International audience; In 2017, the Food and Drug Administration published a safety recommendation to limit the exposure to general anesthesia as much as possible below the age of three. Indeed, several preclinical and clinical studies have questioned the possible toxicity of general anesthesia on the developing brain. Since then, recent clinical studies tried to mitigate this alarming issue. What is true, what is false? Contrary to some perceptions, the debate is not over yet. Only stronger translational research will allow scientists to provide concrete answers to this public health issue. In this review, we will provide and discuss the more recent data in this field, including the point of view of preclinical researchers, neuropsychologists and pediatric anesthesiologists. Through translational research, preclinical researchers have more than ever a role to play to better understand and identify long-term effects of general anesthesia for pediatric surgery on brain development in order to minimize it.

Published
2021
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6. In mice and humans, brain microvascular contractility matures postnatally Brain microvessel post-natal maturation

Author

Leila Slaoui, Alice Gilbert, Armelle Rancillac, Audrey Chagnot, Laetitia Federici, Quentin Gerard, Antoinette Gelot, Mathilde Becmeur-Lefebvre, Maryline Favier, Noémie Robil, Gaëlle Letort, Karine Dias, Laurent Jourdren, Philippe Mailly, Sylvain Auvity, Salvatore Cisternino, Denis Vivien, Martine Cohen-Salmon, and Anne-Cécile Boulay

Abstract

Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific or -preferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF). Samples of human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.

Published
2022
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8. Author response: Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

Author

Sonia Taïb, Mickael Tanter, Mervé Yetim, Denis Vivien, Xavier Declèves, Alice Gilbert, Vincent Hingot, Bruno Saubaméa, Martine Cohen-Salmon, Armelle Rancillac, Salvatore Cisternino, Audrey Chagnot, Xabier Elorza-Vidal, Raúl Estévez, Isabelle Brunet, Rodrigo Alvear-Perez, Aontoinette Gelot, Maryline Favier, Virginie Mignon, Sabrina Martin, Thomas Deffieux, and Anne-Cécile Boulay

Subjects
Developmental disorder, Pathology, medicine.medical_specialty, Megalencephalic leukoencephalopathy with subcortical cysts, business.industry, medicine, medicine.disease, business
Published
2021
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9. Magnetic Resonance Imaging of Blood–Brain Barrier permeability in Dementia

Author

Axel Montagne, Audrey Chagnot, and Samuel Barnes

Subjects
medicine.diagnostic_test, business.industry, General Neuroscience, Contrast Media, Magnetic resonance imaging, Context (language use), medicine.disease, Blood–brain barrier, Magnetic Resonance Imaging, Permeability, Article, medicine.anatomical_structure, Neuroimaging, Alzheimer Disease, Blood-Brain Barrier, Cerebral Small Vessel Diseases, medicine, Dementia, Humans, Blood brain barrier permeability, Small vessel, skin and connective tissue diseases, business, Neuroscience
Abstract

Alzheimer's disease (AD) and cerebral small vessel disease (cSVD) are the two main causes of dementia with blood-brain barrier (BBB) breakdown being a common contributor. Recent advances in neuroimaging techniques offer new possibilities to understand how the brain functions in health and disease. This includes methods such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) which allows the detection of subtle regional changes in the BBB integrity. The purpose of this work is to provide a review on the recent DCE-MRI findings of subtle BBB leakage focusing on cSVD and AD, including both clinical and pre-clinical studies. Despite being widely used and well-established, we also highlight some of the DCE-MRI challenges and pitfalls faced in the context of dementia inherent to the subtle nature of BBB impairment.

Published
2021
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