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Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer's disease or Parkinson's disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge. [ABSTRACT FROM AUTHOR]

Purpose: Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model. Methods: This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed. Results and conclusions: Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods. [ABSTRACT FROM AUTHOR]

Introduction: Knowledge of the repeatability of quantitative parameters derived from [18F]FDG PET images is essential to define the group size and allow correct interpretation. Here we tested repeatability and accuracy of different [18F]FDG absolute and relative quantification parameters in a standardized preclinical setup in nonhuman primates (NHP). Material and methods: Repeated brain [18F]FDG scans were performed in 6 healthy NHP under controlled experimental factors likely to account for variability. Regional cerebral metabolic rate of glucose (CMRglu) was calculated using a Patlak plot with blood input function Semi-quantitative approaches measuring standard uptake values (SUV, SUV×glycemia and SUVR (SUV Ratio) using the pons or cerebellum as a reference region) were considered. Test-retest variability of all quantification parameters were compared in different brain regions in terms of absolute variability and intra-and-inter-subject variabilities. In an independent [18F]FDG PET experiment, robustness of these parameters was evaluated in 4 naive NHP. Results: Experimental conditions (injected dose, body weight, animal temperature) were the same at both imaging sessions (p >0.4). No significant difference in the [18F]FDG quantification parameters was found between test and retest sessions. Absolute variability of CMRglu, SUV, SUV×glycemia and normalized SUV ranged from 25 to 43%, 16 to 21%, 23 to 28%, and 7 to 14%, respectively. Intra-subject variability largely explained the absolute variability of all quantitative parameters. They were all significantly correlated to each other and they were all robust. Arterial and venous glycemia were highly correlated (r = 0.9691; p<0.0001). Conclusion: [18F]FDG test-retest studies in NHP protocols need to be conducted under well-standardized experimental conditions to assess and select the most reliable and reproducible quantification approach. Furthermore, the choice of the quantification parameter has to account for the transversal or follow-up study design. If pons and cerebellum regions are not affected, non-invasive SUVR is the most favorable approach for both designs. [ABSTRACT FROM AUTHOR]

The 18 kDa translocator protein (TSPO) is the main molecular target to image neuroinflammation by positron emission tomography (PET). However, TSPO-PET quantification is complex and none of the kinetic modelling approaches has been validated using a voxel-by-voxel comparison of TSPO-PET data with the actual TSPO levels of expression. Here, we present a single case study of binary classification of in vivo PET data to evaluate the statistical performance of different TSPO-PET quantification methods. To that end, we induced a localized and adjustable increase of TSPO levels in a non-human primate brain through a viral-vector strategy. We then performed a voxel-wise comparison of the different TSPO-PET quantification approaches providing parametric [18F]-DPA-714 PET images, with co-registered in vitro three-dimensional TSPO immunohistochemistry (3D-IHC) data. A data matrix was extracted from each brain hemisphere, containing the TSPO-IHC and TSPO-PET data for each voxel position. Each voxel was then classified as false or true, positive or negative after comparison of the TSPO-PET measure to the reference 3D-IHC method. Finally, receiver operating characteristic curves (ROC) were calculated for each TSPO-PET quantification method. Our results show that standard uptake value ratios using cerebellum as a reference region (SUVCBL) has the most optimal ROC score amongst all non-invasive approaches. [ABSTRACT FROM AUTHOR]

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [11C]PBR28, [18F]DPA714 and [11C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [11C]-R-PK11195 data from six healthy subjects. Then, we compared the [11C]-R-PK11195 vascular binding estimates with previously published values for [18F]DPA714 and [11C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [11C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering. [ABSTRACT FROM AUTHOR]

There is a great need for a non-invasive methodology enabling the quantification of translocator protein overexpression in PET clinical imaging. [18F]DPA-714 has emerged as a promising translocator protein radiotracer as it is fluorinated, highly specific and returned reliable quantification using arterial input function. Cerebellum gray matter was proposed as reference region for simplified quantification; however, this method cannot be used when inflammation involves cerebellum. Here we adapted and validated a supervised clustering (supervised clustering algorithm (SCA)) for [18F]DPA-714 analysis. Fourteen healthy subjects genotyped for translocator protein underwent an [18F]DPA-714 PET, including 10 with metabolite-corrected arterial input function and three for a test–retest assessment. Two-tissue compartmental modelling provided BPND AIF estimates that were compared to either BPND LoganSCA or BPND LoganCRB generated by Logan analysis (using supervised clustering algorithm extracted reference region or cerebellum gray matter). The supervised clustering algorithm successfully extracted a pseudo-reference region with similar reliability using classes that were defined using either all subjects, or separated into HAB and MAB subjects. BPND AIF, BPND LoganSCA and BPND LoganCRB were highly correlated (ICC of 0.91 ± 0.05) but BPND LoganSCA were ∼26% higher and less variable than BPND LoganCRB. Reproducibility was good with 5% variability in the test–retest study. The clustering technique for [18F]DPA-714 provides a simple, robust and reproducible technique that can be used for all neurological diseases. [ABSTRACT FROM AUTHOR]

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Astrocytes and microgha become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPOradioligands,[18F]DPA-714[W,iV-diethyl-2-(2-(4-(2-[18F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[l, 5-a]pyrimidin-3-yl)acetamide] and [ 11C]SSR180575 (7-cHoro-N,N-dimethyl-5-[ 11ClmethyU-oxo-S-phenyl-3,5-dmydro-4H-pyridazinoKS-è]indole-l-acetamide), show eda significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [iV-methyl-Af-(l-methylpropyl)-l-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was over expressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microgha. [ABSTRACT FROM AUTHOR]