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

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    Author
    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 A
    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
    Kälviäinen, 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
    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
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    Date
    2021-09-05
    Journal
    Neuropathology and Applied Neurobiology
    Publisher
    Wiley-Blackwell
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1111/nan.12758
    Abstract
    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.
    Rights/Terms
    © 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
    Keyword
    MRI
    cortical thinning
    gene expression
    post mortem
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17744
    ae974a485f413a2113503eed53cd6c53
    10.1111/nan.12758
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