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A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis

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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