How tobacco use disorder affects gray matter aberrance: The mediating effect of glymphatic system function

The glymphatic system (GS) represents a newly identified biological pathway, but its possible involvement in the pathophysiology of tobacco use disorder (TUD) remains unclear. We aimed to assess the GS function in TUD individuals and to establish the connections among GS, brain structure and clinical features of disease.

We recruited 149 male subjects, including 92 TUD individuals and 57 controls, then obtained their 3D-T1 weighted image scans, diffusion tensor image scans and clinical scales. Diffusion tensor imaging along the perivascular space (DTI-ALPS) index was calculated to evaluate glymphatic function changes between the groups. Gray matter (GM) regions associated with the DTI-ALPS index were identified by voxel-based morphometry analysis (VBM). Finally, the relationships between DTI-ALPS index, GM and smoking behaviors were assessed through a mediation model.

Compared to control group, TUD group displayed notably lower DTI-ALPS index in the whole brain and both bilateral hemispheres, which displayed negatively correlations with the severity of disease. The GMV alterations in left thalamus and right inferior temporal gyrus were positively correlated with the mean DTI-ALPS index. Moreover, the DTI-ALPS index partially mediated the relationship between GMV alterations and pack-year in TUD.

The current study revealed abnormalities of DTI-ALPS index in TUD and identified that abnormal GS function in TUD individuals could be the potential mechanism underlying the effects of tobacco exposure on GMV changes. These findings provided further evidence for understanding the pathogenesis of TUD and suggested GS function could serve as a new target for clinical therapeutic strategies.