Cholinergic system adaptations are associated with cognitive function in people recently abstinent from smoking: a (-)-[18F]flubatine PET study

Abstract

The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β₂-subunit containing nicotinic acetylcholine receptor (β₂*-nAChR) partial agonist radioligand (-)-[¹⁸F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[¹⁸F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (V_T) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[¹⁸F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[¹⁸F]flubatine V_T, consistent with increased cortical acetylcholine levels reducing the number of β₂*-nAChR sites available for (-)-[¹⁸F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[¹⁸F]flubatine V_T was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.

Fig. 1. Physostigmine-induced percent change in β₂*-nAChR availability in people who never smoked cigarettes and people who recently stopped smoking cigarettes.

In the frontal cortex, physostigmine significantly decreases estimates of β₂*-nAChR availability ((-)-[¹⁸F]flubatine V_T) in people who never smoked cigarettes (light circles) (p_uncorr < 0.001) and ‘trend’-level decreases estimates in people who recently stopped smoking cigarettes (dark squares) (p_uncorr = 0.068). Physostigmine significantly decreases estimates of β₂*-nAChR availability in the occipital, parietal, and temporal cortices of people who never smoked cigarettes (p_corr-values<0.05), and in the occipital and parietal cortices of people who recently stopped smoking cigarettes (p_corr-values<0.05). The magnitude of physostigmine-induced percent change in β₂*-nAChR availability is not significantly different between groups in any regions. Mean V_T (bars) and group mean values of physostigmine-induced percent change in β₂*-nAChR availability (percentages) are presented. n: sample size.

Fig. 2. Executive function and physostigmine-induced percent change in β₂*-nAChR availability in people who recently stopped smoking cigarettes.

People who recently stopped smoking cigarettes (‘AS,’ or ‘abstinent smokers,’ dark squares) do not significantly differ from people who never smoked cigarettes (‘NS,’ light circles) in number of errors made on the ‘Groton Maze Learning’ executive function task (NS: 49 ± 15 errors; AS: 48 ± 21 errors; p_corr = 0.90) (left panel). Higher number of errors made (i.e., worse executive function) is associated with higher physostigmine-induced percent change in (-)-[¹⁸F]flubatine V_T (%ΔV_T) estimates (i.e., higher magnitude increase in acetylcholine levels) in the frontal cortex of people who recently stopped smoking (r = 0.73, p_corr = 0.009) (right panel). Plots include task-completing individuals who received physostigmine. The plots are generated with distributions, sample sizes, and statistical analyses which exclude one statistical outlier who recently stopped smoking, included as a hollow marker for transparency. n: sample size. Horizontal bars (left panel): group mean task performance speed. r: Pearson correlation coefficient. Significance: *p < 0.05.

Fig. 3. Working memory and β₂*-nAChR availability in low-cotinine people who recently stopped smoking cigarettes.

Low-cotinine people who recently stopped smoking cigarettes (‘AS,’ or ‘abstinent smokers,’ dark squares) do not significantly differ from people who never smoked cigarettes (‘NS,’ light circles) in performance speed on the ‘One-Back’ working memory task (NS: 2.9 ± 0.1 log₁₀ ms; AS: 2.9 ± 0.1 log₁₀ ms; p = 0.49) (left panel). Slower task performance (i.e., worse working memory) is associated with higher (-)-[¹⁸F]flubatine V_T estimates (i.e., higher β₂*-nAChR availability) in the frontal cortex of low-cotinine people who recently stopped smoking (r = 0.59, p_uncorr = 0.045), without correction for multiple cognitive tasks (right panel). This relationship becomes statistically non-significant after correction for multiple cognitive tasks (p_corr = 0.14). n: sample size. Horizontal bars (left panel): group mean task performance speed. r: Pearson correlation coefficient. Significance: *p < 0.05.