Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/27230
Title: A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.
Austin Authors: Altmann, Andre;Ryten, Mina;Di Nunzio, Martina;Ravizza, Teresa;Tolomeo, Daniele;Reynolds, Regina H;Somani, Alyma;Bacigaluppi, Marco;Iori, Valentina;Micotti, Edoardo;Di Sapia, Rossella;Cerovic, Milica;Palma, Eleonora;Ruffolo, Gabriele;Botía, Juan A;Absil, Julie;Alhusaini, Saud;Alvim, Marina K M;Auvinen, Pia;Bargallo, Nuria;Bartolini, Emanuele;Bender, Benjamin;Bergo, Felipe P G;Bernardes, Tauana;Bernasconi, Andrea;Bernasconi, Neda;Bernhardt, Boris C;Blackmon, Karen;Braga, Barbara;Caligiuri, Maria Eugenia;Calvo, Anna;Carlson, Chad;Carr, Sarah J;Cavalleri, Gianpiero L;Cendes, Fernando;Chen, Jian;Chen, Shuai;Cherubini, Andrea;Concha, Luis;David, Philippe;Delanty, Norman;Depondt, Chantal;Devinsky, Orrin;Doherty, Colin P;Domin, Martin;Focke, Niels K;Foley, Sonya;Franca, Wendy;Gambardella, Antonio;Guerrini, Renzo;Hamandi, Khalid;Hibar, Derrek P;Isaev, Dmitry;Jackson, Graeme D ;Jahanshad, Neda;Kalviainen, Reetta;Keller, Simon S;Kochunov, Peter;Kotikalapudi, Raviteja;Kowalczyk, Magdalena A;Kuzniecky, Ruben;Kwan, Patrick;Labate, Angelo;Langner, Soenke;Lenge, Matteo;Liu, Min;Martin, Pascal;Mascalchi, Mario;Meletti, Stefano;Morita-Sherman, Marcia E;O'Brien, Terence J;Pariente, Jose C;Richardson, Mark P;Rodriguez-Cruces, Raul;Rummel, Christian;Saavalainen, Taavi;Semmelroch, Mira K H G ;Severino, Mariasavina;Striano, Pasquale;Thesen, Thomas;Thomas, Rhys H;Tondelli, Manuela;Tortora, Domenico;Vaudano, Anna Elisabetta;Vivash, Lucy;von Podewils, Felix;Wagner, Jan;Weber, Bernd;Wiest, Roland;Yasuda, Clarissa L;Zhang, Guohao;Zhang, Junsong;Leu, Costin;Avbersek, Andreja;Thom, Maria;Whelan, Christopher D;Thompson, Paul;McDonald, Carrie R;Vezzani, Annamaria;Sisodiya, Sanjay M
Affiliation: Chalfont Centre for Epilepsy, Bucks, UK..
Centre for Medical Image Computing, University College London, London, UK..
Department of Neurology, Royal Melbourne Hospital, Parkville, Australia
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
FutureNeuro Research Centre, RCSI, Dublin, Ireland..
Department of Computer Science and Engineering, The Ohio State University, USA
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK..
Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK
Department of Computer Science and Electrical Engineering, University of Maryland, Baltimore County, USA
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy..
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Department of Neurology, King's College Hospital, London, UK..
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..
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada..
Epilepsy Center, Department of Neurology, Kuopio University, Kuopio, Finland
Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland..
Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain
Centre de Diagnostic Per la Imatge (CDIC), Hospital Clinic, Barcelona, Spain..
Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Italy
IRCCS Stella Maris Foundation, Pisa, Italy..
Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada
Multimodal Imaging and Connectome Analysis Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada..
Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, USA
Department of Physiology, Neuroscience and Behavioral Science, St. George's University, Grenada, West Indies..
FutureNeuro Research Centre, RCSI, Dublin, Ireland
Division of Neurology, Beaumont Hospital, Dublin 9, Ireland..
Neurology Department, St. James's Hospital, Dublin 8, Ireland..
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..
Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Catanzaro, Italy
Institute of Neurology, University ' "Magna Graecia", Catanzaro, Italy..
Institute of Psychological Medicine and Clinical Neurosciences, Cardiff, UK
Department of Neurology, University Hospital of Wales, Cardiff, UK..
Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany..
Neuroradiology Unit, Children's Hospital A. Meyer, Florence, Italy
"Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy..
The Florey Institute of Neuroscience and Mental Health
Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia
Department of Medicine, University of Melbourne, Parkville, VIC, Australia
Melbourne Brain Centre, Department of Medicine, University of Melbourne, Parkville, VIC, Australia
Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Maryland, USA
Department of Neurology, Zucker Hofstra School of Medicine, New York, NY, USA
Multimodal Imaging Laboratory, University of California San Diego, San Diego, California, USA
Department of Psychiatry, University of California San Diego, San Diego, California, USA
Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland
Central Finland Central Hospital, Medical Imaging Unit, Jyväskylä, Finland..
Department of Epileptology, University Hospital Bonn, Bonn, Germany
Department of Neurocognition/Imaging, Life & Brain Research Centre, Bonn, Germany..
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
Cognitive Science Department, Xiamen University, Xiamen, China
Fujian Key Laboratory of the Brain-like Intelligent Systems, China..
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK..
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy..
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK..
Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK..
Department of Neurology, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan, Italy..
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy..
Department of Physiology and Pharmacology, University of Rome, Sapienza..
Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium..
Department of Neurology, University of Campinas, Campinas, Brazil..
Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany..
Department of Neurology, University of Campinas, Campinas, Brazil..
Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada..
Department of Neurology, University of Campinas, Campinas, Brazil..
Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Catanzaro, Italy..
Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain..
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK..
Department of Neurology, University of Campinas, Campinas, Brazil..
Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Catanzaro, Italy..
Instituto de Neurobiología, Universidad Nacional Autónoma de México. Querétaro, Querétaro, México..
Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium..
Department of Neurology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium..
Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany..
Cardiff University Brain Research Imaging Centre, School of Psychology, Wales, UK..
Department of Neurology, University of Campinas, Campinas, Brazil..
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, UK..
Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany..
Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Italy..
Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada..
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany..
Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy..
Department of Neurology, University of Campinas, Campinas, Brazil..
Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain..
Instituto de Neurobiología, Universidad Nacional Autónoma de México. Querétaro, Querétaro, México..
Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland..
Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genova, Italy..
Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy..
Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy..
Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genova, Italy..
Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy..
Department of Neurology, University Medicine Greifswald, Greifswald, Germany..
Department of Neurology, University of Ulm and Universitäts- and Rehabilitationskliniken Ulm, Germany..
Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland..
Department of Neurology, University of Campinas, Campinas, Brazil..
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK..
Issue Date: Feb-2022
Date: 2021
Publication information: Neuropathology and applied neurobiology 2022; 48(1): e12758
Abstract: 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. 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. 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. 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/27230
DOI: 10.1111/nan.12758
ORCID: 0000-0002-9265-2393
0000-0001-7481-5198
0000-0002-3205-4631
0000-0003-4730-5322
0000-0001-7712-2629
Journal: Neuropathology and Applied Neurobiology
PubMed URL: 34388852
Type: Journal Article
Subjects: MRI
cortical thinning
gene expression
post mortem
Appears in Collections:Journal articles

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