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A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis
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A-quantitative-neuropathological-assessment-of-translocator.pdf | Published version | 2.02 MB | Adobe PDF | View/Open |
Title: | A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis |
Authors: | Nutma, E Stephenson, JA Gorter, RP De Bruin, J Boucherie, DM Donat, CK Breur, M Van der Valk, P Matthews, P Owen, D Amor, S |
Item Type: | Journal Article |
Abstract: | The 18kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely-considered to reflect activated pathogenicmicroglia, although quantitative neuropathological data to support this interpretation has not been available. With the increasing interest in the role of chronic microglial activation in multiple sclerosis, characterising the cellular neuropathology associated with TSPO expression is of clear importance for understanding the cellular and pathological processes on which TSPO PET imaging is reporting.Here we have studied the cellular expression of TSPO and specific binding of two TSPO targeting radioligands ([3H]PK11195 and [3H]PBR28) in tissue sections from 42 multiple sclerosis cases and 12 age-matched controls. Markers of homeostatic and reactive microglia, astrocytes, and lymphocytes were used to investigate the phenotypes of cells expressing TSPO. There was an approximate 20-fold increase in cells double positive for TSPO and human leukocyte antigen -DR in active lesions and in the rim of chronic active lesion, relative to normal appearing white matter. TSPO was uniformly expressed across myeloid cells irrespective of their phenotype, rather than being preferentially associated with pro-inflammatory microglia or macrophages. TSPO+astrocytes were increased up to 7-fold compared to normal appearing white matter across all lesion sub-types and accounted for 25% of the TSPO+ cells in these lesions. To relate TSPO protein expression to ligand binding, specific binding of the TSPO ligands [3H]PK11195 and [3H]PBR28was determined in the same lesions. TSPO radioligand binding was increased up to seven times for [3H]PBR28 and up to two times for [3H]PK11195 in active lesions and the centre of chronic active lesions and a strong correlation was found between the radioligand binding signal for both tracers and the number of TSPO+ cells across all of the tissues examined.In summary, in multiple sclerosis, TSPO expression arises from microglia of different phenotypes, rather than being restricted to microglia which express classical pro-inflammatory markers. While the majority of cells expressing TSPO in active lesions or chronic active rims are microglia/macrophages, our findings also emphasise the significant contribution of activated astrocytes, as well as smaller contributions from endothelial cells. These observations establish a quantitative framework for interpretation of TSPO in multiple sclerosis and highlight the need for neuropathological characterisation of TSPO expression for the interpretation of TSPO PET in other neurodegenerative disorders. |
Issue Date: | 1-Nov-2019 |
Date of Acceptance: | 25-Jul-2019 |
URI: | http://hdl.handle.net/10044/1/72546 |
DOI: | 10.1093/brain/awz287 |
ISSN: | 1460-2156 |
Publisher: | Oxford University Press (OUP) |
Start Page: | 3440 |
End Page: | 3455 |
Journal / Book Title: | Brain |
Volume: | 142 |
Issue: | 11 |
Copyright Statement: | © (2019) The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
Sponsor/Funder: | Medical Research Council (MRC) Medical Research Council (MRC) Alzheimer's Society |
Funder's Grant Number: | MR/N008219/1 MR/N026934/1 440 (AS-CTF-18-006) |
Keywords: | Science & Technology Life Sciences & Biomedicine Clinical Neurology Neurosciences Neurosciences & Neurology translocator protein multiple sclerosis microglia astrocytes positron emission tomography PERIPHERAL BENZODIAZEPINE-RECEPTOR POSITRON-EMISSION-TOMOGRAPHY IN-VIVO DETECTION MICROGLIAL ACTIVATION 18 KDA ALZHEIMERS-DISEASE BINDING-SITES GLIAL RESPONSES MOUSE MODELS TSPO LIGAND astrocytes microglia multiple sclerosis positron emission tomography translocator protein Acetamides Aged Aged, 80 and over Astrocytes Autopsy Female Genotype Homeostasis Humans Isoquinolines Lymphocytes Male Microglia Middle Aged Multiple Sclerosis Positron-Emission Tomography Pyridines Radiopharmaceuticals Receptors, GABA Astrocytes Microglia Lymphocytes Humans Multiple Sclerosis Acetamides Pyridines Isoquinolines Receptors, GABA Radiopharmaceuticals Positron-Emission Tomography Autopsy Homeostasis Genotype Aged Aged, 80 and over Middle Aged Female Male 11 Medical and Health Sciences 17 Psychology and Cognitive Sciences Neurology & Neurosurgery |
Publication Status: | Published |
Online Publication Date: | 2019-10-03 |
Appears in Collections: | Faculty of Medicine Department of Brain Sciences |