A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

Autor: Altmann A; Centre for Medical Image Computing, University College London, London, UK., Ryten M; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., Di Nunzio M; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Ravizza T; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Tolomeo D; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Reynolds RH; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., Somani A; Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK., Bacigaluppi M; Department of Neurology, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan, Italy., Iori V; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Micotti E; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Di Sapia R; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Cerovic M; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Palma E; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy., Ruffolo G; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy., Botía JA; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain., Absil J; Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium., Alhusaini S; Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Neurology Department, Yale University School of Medicine, New Haven, CT, USA., Alvim MKM; Department of Neurology, University of Campinas, Campinas, Brazil., Auvinen P; Epilepsy Center, Department of Neurology, Kuopio University, Kuopio, Finland.; Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland., Bargallo N; Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain.; Centre de Diagnostic Per la Imatge (CDIC), Hospital Clinic, Barcelona, Spain., Bartolini E; Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy.; Neurology Unit, USL Centro Toscana, Nuovo Ospedale Santo Stefano, Prato, Italy., Bender B; Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany., Bergo FPG; Department of Neurology, University of Campinas, Campinas, Brazil., Bernardes T; Department of Neurology, University of Campinas, Campinas, Brazil., Bernasconi A; Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada., Bernasconi N; Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada., Bernhardt BC; Multimodal Imaging and Connectome Analysis Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada., Blackmon K; Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA., Braga B; Department of Neurology, University of Campinas, Campinas, Brazil., Caligiuri ME; Neuroscience Research Center, Department of Medical and Surgical Sciences, University 'Magna Graecia' of Catanzaro, Catanzaro, Italy., Calvo A; Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain., Carlson C; Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, New York, USA.; Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Carr SJA; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Cavalleri GL; Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.; FutureNeuro Research Centre, RCSI, Dublin, Ireland., Cendes F; Department of Neurology, University of Campinas, Campinas, Brazil., Chen J; Department of Computer Science and Engineering, The Ohio State University, Columbus, Ohio, USA., Chen S; Cognitive Science Department, Xiamen University, Xiamen, China.; Fujian Key Laboratory of the Brain-like Intelligent Systems, Xiamen, China., Cherubini A; Neuroscience Research Center, Department of Medical and Surgical Sciences, University 'Magna Graecia' of Catanzaro, Catanzaro, Italy., Concha L; Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico., David P; Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium., Delanty N; Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.; FutureNeuro Research Centre, RCSI, Dublin, Ireland.; Division of Neurology, Beaumont Hospital, Dublin 9, Ireland., Depondt C; Department of Neurology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium., Devinsky O; Department of Neurology, Langone School of Medicine, New York University, New York, NY, USA., Doherty CP; FutureNeuro Research Centre, RCSI, Dublin, Ireland.; School of Medicine, Trinity College Dublin, Dublin, Ireland., Domin M; Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany., Focke NK; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Department of Clinical Neurophysiology, University Medicine Göttingen, Göttingen, Germany., Foley S; The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK., Franca W; Department of Neurology, University of Campinas, Campinas, Brazil., Gambardella A; Neuroscience Research Center, Department of Medical and Surgical Sciences, University 'Magna Graecia' of Catanzaro, Catanzaro, Italy.; Institute of Neurology, University 'Magna Graecia', Catanzaro, Italy., Guerrini R; Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy., Hamandi K; The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK., Hibar DP; Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA., Isaev D; Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA., Jackson GD; The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia., Jahanshad N; Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA., Kälviäinen R; Epilepsy Center, Department of Neurology, Kuopio University, Kuopio, Finland.; Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland., Keller SS; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK., Kochunov P; Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA., Kotikalapudi R; Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany.; Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Kowalczyk MA; The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia., Kuzniecky R; Department of Neurology, Zucker Hofstra School of Medicine, New York, New York, USA., Kwan P; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia., Labate A; Neuroscience Research Center, Department of Medical and Surgical Sciences, University 'Magna Graecia' of Catanzaro, Catanzaro, Italy.; Institute of Neurology, University 'Magna Graecia', Catanzaro, Italy., Langner S; Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany., Lenge M; Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy., Liu M; Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada., Martin P; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Mascalchi M; 'Mario Serio' Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy., Meletti S; Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy., Morita-Sherman ME; Department of Neurology, University of Campinas, Campinas, Brazil.; Cleveland Clinic Neurological Institute, Cleveland, USA., O'Brien TJ; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.; The Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia., Pariente JC; Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain., Richardson MP; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.; Department of Neurology, King's College Hospital, London, UK., Rodriguez-Cruces R; Multimodal Imaging and Connectome Analysis Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.; Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico., Rummel C; Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland., Saavalainen T; Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.; Medical Imaging Unit, Central Finland Central Hospital, Jyväskylä, Finland., Semmelroch MK; The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia., Severino M; Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genoa, Italy., Striano P; Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Thesen T; Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, New York, USA., Thomas RH; Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK., Tondelli M; Cleveland Clinic Neurological Institute, Cleveland, USA., Tortora D; Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genoa, Italy., Vaudano AE; Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy., Vivash L; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.; Melbourne Brain Centre, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia., von Podewils F; Department of Neurology, University Medicine Greifswald, Greifswald, Germany., Wagner J; Department of Neurology, University of Ulm and Universitäts- and Rehabilitationskliniken Ulm, Ulm, Germany., Weber B; Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany., Wiest R; Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland., Yasuda CL; Department of Neurology, University of Campinas, Campinas, Brazil., Zhang G; Department of Computer Science and Electrical Engineering, University of Maryland, Baltimore County, Baltimore, Maryland, USA., Zhang J; Cognitive Science Department, Xiamen University, Xiamen, China.; Fujian Key Laboratory of the Brain-like Intelligent Systems, Xiamen, China., Leu C; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK., Avbersek A; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA., Thom M; Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK.; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK., Whelan CD; Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.; Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA., Thompson P; Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA., McDonald CR; Multimodal Imaging Laboratory, University of California San Diego, San Diego, California, USA.; Department of Psychiatry, University of California San Diego, San Diego, California, USA., Vezzani A; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Sisodiya SM; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.; Chalfont Centre for Epilepsy, Bucks, UK.
Jazyk: angličtina
Zdroj: Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2022 Feb; Vol. 48 (1), pp. e12758. Date of Electronic Publication: 2021 Sep 05.
DOI: 10.1111/nan.12758
Abstrakt: Aims: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis.
Methods: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy.
Results: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia.
Conclusions: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
(© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
Databáze: MEDLINE
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