The protective role of cigarette smoking against Parkinson's disease via moderation of the interaction between iron deposition in the nigrostriatal pathway and clinical symptoms.

Background: Although cigarette smoking is a risk factor for multiple disorders, it has long been thought to protect against Parkinson's disease (PD). Quantitative susceptibility mapping (QSM) is a novel magnetic resonance imaging (MRI)-based technique for assessing iron accumulation Methods: In this observational study, we enrolled 35 male PD patients and 47 male healthy controls (HCs) and divided them into four groups. We performed an enhanced T2 star-weighted angiography (ESWAN) MRI sequence to measure the iron content of the nuclei within the nigrostriatal pathway. With the age and total intracranial volume (TIV) controlled as covariates, we performed inter-group comparisons of QSM values and moderation analyses for PD patients using smoking status and the smoking index (SI), respectively, as moderator variables. Results: The 2-way multivariate analysis of covariance (MANCOVA) results showed higher QSM values in the left red nucleus (P=0.024) in PD patients compared with those in HCs, and in the bilateral globi pallidi [left/right (L/R): P=0.009/0.003], substantia nigra pars compacta (SNc; L/R: P=0.001/0.037), and right substantia nigra pars reticulata (SNr; P=0.002) in non-smokers compared with smokers, with no marked interaction effect between PD and smoking status observed when applying the Bonferroni adjustment for multiple comparisons. Using cigarette smoking status and the SI as separate moderator variables, the moderation was shown up by a significant interaction effect in a disordinal and double-edged form. In our results, smoking-moderated protection for PD movement deficits emerged when PD was progressed. Among the affected deep brain nuclei, the nuclei most moderated by the impact of cigarette smoking on the interaction between brain iron and PD symptoms were the thalamus [smoking status associated with the Unified Parkinson's Disease Rating Scale (UPDRS) total score, P=0.04 (L); rigidity, P=0.03 (L); SI associated with UPDRS-III, P (L/R) =0.049/0.0497; rigidity, P (L/R) =0.01/0.02; bradykinesia, P (L/R) =0.048/0.04], the right red nucleus (SI associated with rigidity, P=0.04; bradykinesia, P=0.02), and the left SNc [smoking status associated with the Hoehn and Yahr (H&Y) stage, P=0.01]. Conclusions: This was the first study investigating the impacts of current cigarette smoking on PD using quantified iron deposition. Our study confirmed the protective role of cigarette smoking against PD, consistent with the findings of previous studies. Furthermore, neuroprotection was present only when the PD pathology had progressed to a certain extent. In the interaction between iron deposition and clinical PD symptoms, our findings suggest that the thalamus, red nucleus, and SNc are likely to be the most affected nuclei moderated by cigarette smoking.