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A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis

Authors
  • Nutma, Erik1
  • Stephenson, Jodie A1, 2
  • Gorter, Rianne P1
  • de Bruin, Joy1
  • Boucherie, Deirdre M1
  • Donat, Cornelius K3
  • Breur, Marjolein1
  • van der Valk, Paul1
  • Matthews, Paul M3, 4
  • Owen, David R3
  • Amor, Sandra1, 2
  • 1 Department of Pathology, Amsterdam UMC
  • 2 Centre for Neuroscience and Trauma, Blizard Institute
  • 3 Department of Brain Sciences, Imperial College London
  • 4 UK Dementia Research Institute, Imperial College London
Type
Published Article
Journal
Brain
Publisher
Oxford University Press
Publication Date
Oct 03, 2019
Volume
142
Issue
11
Pages
3440–3455
Identifiers
DOI: 10.1093/brain/awz287
PMID: 31578541
PMCID: PMC6821167
Source
PubMed Central
Keywords
License
Unknown

Abstract

The 18 kDa 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 pathogenic microglia, although quantitative neuropathological data to support this interpretation have 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 HLA-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 subtypes 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-PBR28 was 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 emphasize 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 characterization of TSPO expression for the interpretation of TSPO PET in other neurodegenerative disorders.

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