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)-α. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-α 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-α increased serum IL-6 (1826 ± 513%, t6 = −7.5, p < 0.001), IL-7 (39 ± 12%, t6 = −3.6, p = 0.01), IL-10 (328 ± 48%, t6 = −12.8, p < 0.001), and IFN-γ (272 ± 64%, t6 = −7.0, p < 0.001) at 4–6 h, and increased serum TNF-α (49 ± 7.6%, t6 = −7.5, p < 0.001), IL-8 (39 ± 12%, t6 = −3.5, p = 0.013), and C-reactive protein (1320 ± 459%, t6 = −7.2, p < 0.001) at 24 h. IFN-α induced temporary mood changes and sickness symptoms after 4–6 h, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p ≤ 0.04). No association was found between changes in peripheral inflammation and changes in PET or mood measures. Our work suggests that brain TSPO-PET signal is highly dependent of inflammation-induced changes in ligand binding to plasma proteins. This limits its usefulness as a sensitive marker of neuroinflammation and consequently, data interpretation. Thus, our results can be interpreted as showing either that [11C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.
Highlights
Microglial activation has been proposed as the core neuroinflammatory process in psychiatric disorders
Measured [11C]PBR28 positron emission tomography (PET) uptake is influenced by inflammation-induced changes in the free-plasma fraction of the radioligand, and there are no IFN-α effects once adjusted for this The administration of IFN-α led to a generalized reduction of [11C]PBR28 PET uptake across the entire brain in all subjects but one (Fig. 2a, lower part)
Arterial whole blood (Cb) and plasma (Cp) [11C]PBR28 radioactivity were significantly affected by IFN-α administration, compared to baseline conditions, with a pattern indicating a reduction in the ligand available to bind to translocator protein (TSPO) in the brain
Summary
Microglial activation has been proposed as the core neuroinflammatory process in psychiatric disorders. Radioligands targeting translocator protein (TSPO), a protein located on outer mitochondrial membranes in microglia, as TSPO appears to be overexpressed when microglial cells are activated during neuroinflammation[5]. Despite some negative results[6], the majority of TSPOPET studies in patients with depression have reported increased TSPO binding compared with healthy controls[7,8,9,10,11], suggesting increased microglial activation in these patients. These studies propose that the inflammatory response in depression involves the Nettis et al Translational Psychiatry (2020)10:89
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