Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study

Abstract

In the brain, microglia continuously scan the surrounding extracellular space in order to respond to damage or infection by becoming activated and participating in neuroinflammation. When activated, microglia increase the expression of translocator protein (TSPO) 18 kDa, thereby making the TSPO expression a marker for neuroinflammation. We used the radiotracer [C]DAA1106 (a ligand for TSPO) and positron emission tomography (PET) to determine the effect of smoking on availability of this marker for neuroinflammation. Forty-five participants (30 smokers and 15 non-smokers) completed the study and had usable data. Participants underwent a dynamic PET scanning session with bolus injection of [C]DAA1106 (with smokers in the satiated state) and blood draws during PET scanning to determine TSPO affinity genotype and plasma nicotine levels. Whole-brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (smoker vs non-smoker) and genotype as factors, thereby controlling for genotype. Smokers and non-smokers differed in whole-brain SUVs (P=0.006) owing to smokers having 16.8% lower values than non-smokers. The groups did not differ in injected radiotracer dose or body weight, which were used to calculate SUV. An inverse association was found between whole-brain SUV and reported cigarettes per day (P<0.05), but no significant relationship was found for plasma nicotine. Thus, smokers have less [C]DAA1106 binding globally than non-smokers, indicating less microglial activation. Study findings are consistent with much prior research demonstrating that smokers have impaired inflammatory functioning compared with non-smokers and that constituents of tobacco smoke other than nicotine affect inflammatory processes.

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…Conversely, there is evidence for lower levels of neuroimmune markers in long-term (>1 year) tobacco smoking compared to controls [105, 106]. Also, in vivo human neuroimaging data indicate long-term tobacco smokers exhibit lower gray matter volume compared to nonsmokers, perhaps indicative of cell loss [111, 112].…”

“…In a [ 11 C]DAA1106 PET study, TSPO availability was measured in 30 daily tobacco smokers versus 15 age-matched nonsmokers [106]. Smokers smoked to satiety (2–3 cigarettes; preferred brand) 30 min prior to the 90-min PET scan.…”

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

“…Specific binding of DAA1106 correlates with the presence of activated microglia identified by immunohistochemistry in situ (Venneti et al 2008) and immunohistochemistry combined with autoradiography in brain tissue (Venneti et al 2007). [ 11 C]DAA1106 was chosen for use here because of these favorable properties and previous experience by our group with this radiotracer (Brody et al 2017; Brody et al 2014). …”

“…Our group recently used [ 11 C]DAA1106 with PET scanning to compare smokers who had smoked to satiety (∼15 min prior to scanning) with non-smoking controls (Brody et al 2017). The groups differed in whole brain standardized uptake values (SUVs) for the radiotracer, with smokers having 16.8% lower values than non-smokers (and lower mean SUVs in menthol than non-menthol cigarette smokers).…”

“…In order to study smokers in a state with potentially significant differences from non-smoking controls, overnight (>12 h) abstinence from smoking was chosen as the time point of interest because nicotine would be expected to be recently eliminated from the body at that time (plasma half-life of ~2 h (Benowitz et al 2009)) and withdrawal symptoms (e.g., urge to smoke and anxiety/irritability) would be expected to be elevated (Schuh and Stitzer 1995; Ward et al 2001). As in our prior study (Brody et al 2017), we hypothesized that smoker versus non-smoker effects would occur globally, based on prior research demonstrating that cigarette smoke is rapidly absorbed (Hukkanen et al 2005) and results in saturation (or near saturation) of nicotinic acetylcholine receptors throughout the brain (Brody et al 2009a; Brody et al 2011; Brody et al 2006a; Esterlis et al 2010). We also sought to examine the effect of menthol, because menthol smoking is common (~1/3 of U.S. smokers) (SAMHSA 2009), menthol smokers have more trouble quitting in standard treatment programs than non-menthol cigarette smokers (Gandhi et al 2009; Okuyemi et al 2007; Pletcher et al 2006), menthol smoking has been found to lead to elevated serum nicotine/cotinine and exhaled carbon monoxide levels (Williams et al 2007) (though not all studies agree on this point (Heck 2009; Werley et al 2007)), and menthol smokers had lower mean [ 11 C]DAA1106 SUVs than non-menthol smokers in our prior study of smokers in satiety (Brody et al 2017).…”