PET imaging shows no changes in TSPO brain density after IFN-α 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 [ 11 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 administration decreased [ 11 C]PBR28 PET tissue volume of distribution (Vt) across the brain (−20 ± 4%; t 6 = 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%, t 6 = −7.5, p < 0.001), IL-7 (39 ± 12%, t 6 = −3.6, p = 0.01), IL-10 (328 ± 48%, t 6 = −12.8, p < 0.001), and IFN-γ (272 ± 64%, t 6 = −7.0, p < 0.001) at 4-6 h, and increased serum TNF-α (49 ± 7.6%, t 6 = −7.5, p < 0.001), IL-8 (39 ± 12%, t 6 = −3.5, p = 0.013), and C-reactive protein (1320 ± 459%, t 6 = −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 [ 11 C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial

“…It is therefore possible that minocycline could exert its antidepressant properties through a more direct effect on CNS inflammation, preceding that on peripheral inflammation. So far, a correlation between neuroinflammatory processes and peripheral inflammatory biomarkers has not been found in patients with MDD [9,50], suggesting possibly the presence of complex and not linear interaction between central and peripheral inflammation, with potentially different timings and dynamics involved in development and regression of central and peripheral inflammatory processes.…”

A modest increase in 11C-PK11195-PET TSPO binding in depression is not associated with serum C-reactive protein or body mass index

“…One study showed that injection of Escherichia coli lipopolysaccharide significantly increased measures of brain TSPO (51). Another showed that immune challenge with interferon alpha exhibited no change in brain TSPO (52) and both studies showed no link between peripheral inflammation, measured by serum CRP, and brain TSPO (51, 52).…”

Sick for science: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression

“…However, these findings need to be interpreted with caution, as results of TSPO PET studies in neuroinflammatory conditions or states have shown inconsistent results [77], challenging the general assumption that altered TSPO expression or binding unequivocally mirrors neuroinflammation [78,79]. In line with this, no changes in TSPO binding were found after IFN-α immune challenge in healthy human volunteers [80], or in patients with rheumatoid arthritis [81], or severe seasonal allergy [82].…”