Effect of overnight smoking abstinence on a marker for microglial activation: a [11C]DAA1106 positron emission tomography study

Abstract

Rationale Microglia are the main immune cells in the central nervous system and participate in neuroinflammation. When activated, microglia express increased levels of the translocator protein 18 kDa (TSPO), thereby making TSPO availability a marker for neuroinflammation. Using positron emission tomography (PET) scanning, our group recently demonstrated that smokers in the satiated state had 16.8% less binding of the radiotracer [11C]DAA1106 (a radioligand for TSPO) in the brain than non-smokers. Objectives We sought to determine the effect of overnight smoking abstinence on [11C]DAA1106 binding in the brain. Methods Forty participants (22 smokers and 18 non-smokers) completed the study (at one of two sites) and had usable data, which included images from a dynamic [11C]DAA1106 PET scanning session (with smokers having been abstinent for 17.9±2.3 h) and a blood sample for TSPO genotyping. Whole brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (overnight abstinent smoker vs. non-smoker), site, and TSPO genotype as factors, thereby controlling for site and genotype. Results Overnight abstinent smokers had lower whole brain SUVs (by 15.5% and 17.0% for the two study sites) than non-smokers (ANCOVA, P=0.004). The groups did not significantly differ in injected radiotracer dose or body weight, which were used to calculate SUV. Conclusions These results in overnight abstinent smokers are similar to those in satiated smokers, indicating that chronic cigarette smoking leads to global impairment of microglial activation which persists into early abstinence. Other explanations for study results, such as smoking leading to reduced numbers of microglia or smokers having more rapid metabolism of the radiotracer than non-smokers, are also possible.

Tobacco Smoking in People Is Not Associated with Altered 18-kDa Translocator Protein Levels: A PET Study

“…Therefore, the neuroimmune effects of tobacco smoking are likely subtler than chronic activation of the brain's immune system. The present finding is not consistent with previous TSPO PET imaging reports that tobacco smokers exhibited lower brain SUV levels at early times post-injection (20-40 min) compared with nonsmokers (22,23). Considering that our study exhibits sufficient power to detect medium effect sizes, underlying methodological issues likely explain the seemingly conflicting results.…”

“…Based on preclinical research demonstrating that tobacco smoke exposure increased neuroimmune markers (20,21), we hypothesized that tobacco smokers would have higher TSPO levels compared to nonsmokers. Interestingly, two previous studies reported significantly lower brain concentrations of a TSPOspecific radioligand in the brains of tobacco smokers compared to nonsmokers (22,23). A major limitation of these reports was the outcome measure of normalized radioligand concentrations in brain (standardized uptake value; SUV).…”

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F‐18]FEPPA

“…However, results of a PET study showed no association with cocaine use on brain TSPO binding (using a second‐generation tracer) in the human 33 . Brody et al 37–38 have reported cigarette smoking linked to a modest reduction in TSPO expression and therefore might be a confounding factor, as most MA users of our study used tobacco; however, this finding was not recently replicated by Hillmer et al 39 who employed, unlike Brody, arterial sampling to determine total distribution volume. Furthermore, we found no significant difference using an ANCOVA between brain TSPO binding in the small MA smoking (n = 8) and nonsmoking groups (n = 3) and no significant correlation between [F‐18]FEPPA binding and number of cigarettes typically used.…”

“…However, results of a PET study showed no association with cocaine use on brain TSPO binding (using a secondgeneration tracer) in the human. 33 Brody et al 37,38 40 ; in our small sampled study, we do not find difference between MA users who used cannabis vs those who did not.…”

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

“…Due to the above-mentioned limitations of [ 11 C] 1 , development of novel radioligands with greater binding specificity and higher brain uptake was pursued. More than 50 novel PET tracers for TSPO have been reported, including [ 11 C]PBR28 [ 11 C]DAA1106 [ 11 C]DPA713 [ 11 C]vinpocetine [ 11 C]DAC [ 18 F]PBR06 [ 18 F]DPA-714 [ 18 F]PBR111 [ 18 F]FEPPA, and others 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ( Fig. 2 ).…”