TY - JOUR
T1 - PET imaging shows no changes in TSPO brain density after IFN-α immune challenge 4 in healthy human volunteers
AU - Nettis, Maria Antonietta
AU - Veronese, Mattia
AU - Nikkheslat, Naghmeh
AU - Lombardo, Giulia
AU - Mariani, Nicole
AU - Sforzini, Luca
AU - Enache, Daniela
AU - Harrison, Neil A.
AU - Turkheimer, Federico
AU - Mondelli, Valeria
AU - Pariante, Carmine
PY - 2020/3/9
Y1 - 2020/3/9
N2 - 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 hours 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<0.001), IL-7 (39±12%, t6=-3.6, p=0.01), IL-10 (328±48%, t6=-12.8, p<0.001) and IFN- (272±64%, t6=-7.0, p<0.001) at 4-6 hours, and increased serum TNF- (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 hours. IFN- induced temporary mood changes and sickness symptoms after 4-6 hours, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p0.04). 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.
AB - 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 hours 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<0.001), IL-7 (39±12%, t6=-3.6, p=0.01), IL-10 (328±48%, t6=-12.8, p<0.001) and IFN- (272±64%, t6=-7.0, p<0.001) at 4-6 hours, and increased serum TNF- (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 hours. IFN- induced temporary mood changes and sickness symptoms after 4-6 hours, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p0.04). 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.
M3 - Article
SN - 2158-3188
JO - Translational psychiatry
JF - Translational psychiatry
ER -
