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PET imaging shows no changes in TSPO brain density after IFN-? immune challenge in healthy human volunteers.

ABSTRACT: Depression is associated with peripheral inflammation, but its link with brain microglial activity remains unclear. In seven healthy males, we used repeated translocator protein-Positron Emission Tomography (TSPO-PET) dynamic scans with [¹¹C]PBR28 to image brain microglial activation before and 24?h after the immune challenge interferon (IFN)-?. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-? administration decreased [¹¹C]PBR28 PET tissue volume of distribution (Vt) across the brain (-20?±?4%; t₆?=?4.1, p?=?0.01), but after correction for radioligand free-plasma fraction there were no longer any changes (+23?±?31%; t?=?0.1, p?=?0.91). IFN-? increased serum IL-6 (1826?±?513%, t₆?=?-7.5, p?6?=?-3.6, p?=?0.01), IL-10 (328?±?48%, t₆?=?-12.8, p?6?=?-7.0, p?6?=?-7.5, p?6?=?-3.5, p?=?0.013), and C-reactive protein (1320?±?459%, t₆?=?-7.2, p?11C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.

SUBMITTER: Nettis MA

PROVIDER: S-EPMC7063038 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers.

Nettis M A MA Veronese M M Nikkheslat N N Mariani N N Lombardo G G Sforzini L L Enache D D Harrison N A NA Turkheimer F E FE Mondelli V V Pariante C M CM

Translational psychiatry 20200309 1

Depression is associated with peripheral inflammation, but its link with brain microglial activity remains unclear. In seven healthy males, we used repeated translocator protein-Positron Emission Tomography (TSPO-PET) dynamic scans with [<sup>11</sup>C]PBR28 to image brain microglial activation before and 24 h after the immune challenge interferon (IFN)-α. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-α a ...[more]

PMID: 32152285

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Project description:To date, ¹¹C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands (¹?F-PBR111, ¹¹C-PBR28, ¹¹C-DPA713) and ¹¹C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within-subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data. The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BP(ND)]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between-subject performance was characterised in terms of the number of subjects required to distinguish between different populations. The results indicated that the within-subject variability for ¹?F-PBR111, ¹¹C-PBR28 and ¹¹C-DPA713 (0.9% to 2.2%) was significantly lower than ¹¹C-(R)-PK11195 (16% to 36%) for HABs and MABs in both normal and diseased states. For between-subject studies, sample sizes required to detect 50% differences in TSPO density with the 2nd generation tracers are approximately half that required with ¹¹C-(R)-PK11195 when binding class information is known a priori. As binding class can be identified using a simple genetic test or from peripheral blood assays, the combination of binding class information with 2nd generation TSPO imaging data should provide superior tools to investigate inflammatory processes in humans in vivo.

Project description:PurposeThe aim of this study was to investigate the use of spectral analysis (SA) for voxel-wise analysis of TSPO PET imaging studies. TSPO PET quantification is methodologically complicated by the heterogeneity of TSPO expression and its cell-dependent modulation during neuroinflammatory response. Compartmental models to account for this complexity exist, but they are unreliable at the high noise typical of voxel data. On the contrary, SA is noise-robust for parametric mapping and provides useful information about tracer kinetics with a free compartmental structure.ProceduresSA impulse response function (IRF) calculated at 90 min after tracer injection was used as main parameter of interest in 3 independent PET imaging studies to investigate its sensitivity to (1) a TSPO genetic polymorphism (rs6971) known to affect tracer binding in a cross-sectional analysis of healthy controls scanned with [11C]PBR28 PET; (2) TSPO density with [11C]PBR28 in a competitive blocking study with a TSPO blocker, XBD173; and (3) the higher affinity of a second radiotracer for TSPO, by using data from a head-to-head comparison between [11C]PBR28 and [11C]ER176 scans.ResultsSA-IRF produced parametric maps of visually good quality. These were sensitive to TSPO genotype (mean relative difference between high- and mixed-affinity binders = 25 %) and TSPO availability (mean signal displacement after 90 mg oral administration of XBD173 = 39 %). Regional averages of voxel-wise IRF estimates were strongly associated with regional total distribution volume (VT) estimated with a 2-tissue compartmental model with vascular compartment (Pearson's r = 0.86 ± 0.11) but less strongly with standard 2TCM-VT (Pearson's r = 0.76 ± 0.32). Finally, SA-IRF estimates for [11C]ER176 were significantly higher than [11C]PBR28 ones, consistent with the higher amount of specific binding of the former tracer.ConclusionsSA-IRF can be used for voxel-wise quantification of TSPO PET data because it generates high-quality parametric maps, it is sensitive to TSPO availability and genotype, and it accounts for the complexity of TSPO tracer kinetics with no additional assumptions.

Dataset Information

PET imaging shows no changes in TSPO brain density after IFN-? immune challenge in healthy human volunteers.

Publications

PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers.

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