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      Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

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          Abstract

          In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease’s stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia’s role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.

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          The relation between inflammation and neurodegeneration in multiple sclerosis brains

          Josa M. Frischer, Stephan Bramow, Assunta Dal-Bianco … (2009)
          Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.
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            Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.

            Roberta Magliozzi, Owain W Howell, Abhilash Vora … (2007)
            Intrathecal antibody production is a hallmark of multiple sclerosis and humoral immunity is thought to play an important role in the inflammatory response and development of demyelinated lesions. The presence of lymphoid follicle-like structures in the cerebral meninges of some multiple sclerosis patients indicates that B-cell maturation can be sustained locally within the CNS and contribute to the establishment of a compartmentalized humoral immune response. In this study we examined the distribution of ectopic B-cell follicles in multiple sclerosis cases with primary and secondary progressive clinical courses to determine their association with clinical and neuropathological features. A detailed immunohistochemical and morphometric analysis was performed on post-mortem brain tissue samples from 29 secondary progressive (SP) and 7 primary progressive (PP) multiple sclerosis cases. B-cell follicles were detected in the meninges entering the cerebral sulci of 41.4% of the SPMS cases, but not in PPMS cases. The SPMS cases with follicles significantly differed from those without with respect to a younger age at multiple sclerosis onset, irreversible disability and death and more pronounced demyelination, microglia activation and loss of neurites in the cerebral cortex. Cortical demyelination in these SPMS cases was also more severe than in PPMS cases. Notably, all meningeal B-cell follicles were found adjacent to large subpial cortical lesions, suggesting that soluble factors diffusing from these structures have a pathogenic role. These data support an immunopathogenetic mechanism whereby B-cell follicles developing in the multiple sclerosis meninges exacerbate the detrimental effects of humoral immunity with a subsequent major impact on the integrity of the cortical structures.
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              Global burden of depressive disorders in the year 2000.

              T Ustün, J Ayuso-Mateos, S Chatterji … (2004)
              The initial Global Burden of Disease study found that depression was the fourth leading cause of disease burden, accounting for 3.7% of total disability adjusted life years (DALYs) in the world in 1990. To present the new estimates of depression burden for the year 2000. DALYs for depressive disorders in each world region were calculated, based on new estimates of mortality, prevalence, incidence, average age at onset, duration and disability severity. Depression is the fourth leading cause of disease burden, accounting for 4.4% of total DALYs in the year 2000, and it causes the largest amount of non-fatal burden, accounting for almost 12% of all total years lived with disability worldwide. These data on the burden of depression worldwide represent a major public health problem that affects patients and society.
              Article 0 comments Cited 327 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Styliani-Anna E. Tsirka: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 07 April 2017
                Publication date Collection: April 2017
                Volume: 18
                Issue: 4
                Electronic Location Identifier: 785
                Affiliations
                [1 ]CHRU Tours, 2 Boulevard Tonnellé, 37044 Tours, France; berenger.largeau@ 123456etu.univ-tours.fr (B.L.); maria.ribeiro@ 123456univ-tours.fr (M.J.S.R.); denis.guilloteau@ 123456univ-tours.fr (D.G.); nicolas.arlicot@ 123456univ-tours.fr (N.A.)
                [2 ]Institut National de la Santé et de la Recherche Médicale U930, 10 Boulevard Tonnellé, 37032 Tours, France; claire.tronel@ 123456univ-tours.fr
                Author notes
                [* ]Correspondence: ac.dupont@ 123456chu-tours.fr ; Tel.: +33-(0)2-47-47-97-07
                Article
                Publisher ID: ijms-18-00785
                DOI: 10.3390/ijms18040785
                PMC ID: 5412369
                PubMed ID: 28387722
                SO-VID: 306c090a-b810-4f7d-a109-f79f3ba193a3
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 31 January 2017
                Date accepted : 04 April 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: microglial activation,neuroinflammation,pet,radiopharmaceutical,tspo,neurodegenerative diseases,psychiatric disorders
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: microglial activation, neuroinflammation, pet, radiopharmaceutical, tspo, neurodegenerative diseases, psychiatric disorders

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