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.
Highlights
Microglial cells are the resident macrophages of the central nervous system (CNS) that play different roles in both physiological and pathological conditions, by maintaining brain parenchyma integrity and involving in a wide range of neurodegenerative diseases
translocator protein-18 kDa (TSPO) Positron Emission Tomography (PET) tracers have been investigated in various preclinical and clinical studies and we have reported major advances provided by the development of new tracers (Table 1)
New PET biomarkers reflecting some specific functions of activated microglia conjugated with a multiplex strategy combining several modalities may solve clinicians’ concerns about characterizing the role of activated microglia over the progression of CNS disorders
Summary
Microglial cells are the resident macrophages of the central nervous system (CNS) that play different roles in both physiological and pathological conditions, by maintaining brain parenchyma integrity and involving in a wide range of neurodegenerative diseases. The brain homeostasis is achieved in part though the ability of microglia to regulate inflammation, such as cytotoxicity, repair and regeneration [3] In parallel to their well-known immune-modulatory functions, microglia are highly dynamic cells which contribute to the synaptic remodelling/plasticity as well as synaptogenesis, synaptic transmission and pruning [4]. Based on peripheral monocytes/macrophages, the reactive phenotype of microglial cells is dichotomized into “classical activation” or M1, pro-inflammatory and “alternative activation” or M2, anti-inflammatory reactions. According to this concept, microglia phenotypes are defined by triggering responses to cytokines and microbial agents. Microglia polarization/action is a process highly context-dependent [12] (nature of activating stimulus; e.g., PAMPS and/or DAMPS) which is integrated in a time-dependent fashion (acute versus chronic injury) [6]
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