@article{f166ef4bef9f4b07a3671e360500d548,
title = "A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies",
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.",
keywords = "cortical thinning, gene expression, MRI, post mortem",
author = "{ENIGMA-Epilepsy Working Group} and {EpiPGX Consortium} and Andre Altmann and Mina Ryten and {Di Nunzio}, Martina and Teresa Ravizza and Daniele Tolomeo and Reynolds, {Regina H.} and Alyma Somani and Marco Bacigaluppi and Valentina Iori and Edoardo Micotti and {Di Sapia}, Rossella and Milica Cerovic and Eleonora Palma and Gabriele Ruffolo and Bot{\'i}a, {Juan A.} and Julie Absil and Saud Alhusaini and Alvim, {Marina K.M.} and Pia Auvinen and Nuria Bargallo and Emanuele Bartolini and Benjamin Bender and Bergo, {Felipe P.G.} and Tauana Bernardes and Andrea Bernasconi and Neda Bernasconi and Bernhardt, {Boris C.} and Karen Blackmon and Barbara Braga and Caligiuri, {Maria Eugenia} and Anna Calvo and Chad Carlson and Carr, {Sarah J.A.} and Cavalleri, {Gianpiero L.} and Fernando Cendes and Jian Chen and Shuai Chen and Andrea Cherubini and Luis Concha and Philippe David and Norman Delanty and Chantal Depondt and Orrin Devinsky and Doherty, {Colin P.} and Martin Domin and Focke, {Niels K.} and Sonya Foley and Wendy Franca and Keller, {Simon S.} and Richardson, {Mark P.}",
note = "Funding Information: A. Altmann holds a Medical Research Council eMedLab Medical Bioinformatics Career Development Fellowship. This work was supported by the Medical Research Council (grant number MR/L016311/1). M.R. holds a Medical Research Council Clinician Scientist Fellowship (grant number MR/N008324/1). R.H.R. was supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration. The work was supported by grants from the European Union (7th Framework Programme [FP7 Ideas: European Research Council] Grants 279062, EpiPGX and 602102, EPITARGET). This work was partly undertaken at UCLH Biomedical Research Centre/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Epilepsy Society through the Katy Baggott Foundation supports the Epilepsy Brain and Tissue Bank at UCL, and Epilepsy Research UK (ERUK) supports the Corsellis Epilepsy brain collection. The work was also supported by the Epilepsy Society, UK (C.L., S.M.S.), Associazione Italiana Contro L'Epilessia (FIRE‐AICE) and Fondazione Antonio Carlo Monzino (A.V.) and National Institutes of Health (NIH) Grants R01 NS097719 (M.E.M.), U54 EB020403 (P.T.) and NIH/NINDS R01 NS065838 (C.R.M.). Publisher Copyright: {\textcopyright} 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = sep,
day = "5",
doi = "10.1111/nan.12758",
language = "English",
volume = "48",
journal = "Neuropathology and Applied Neurobiology",
issn = "0305-1846",
publisher = "Wiley-Blackwell",
number = "1",
}
