Abstract
OBJECTIVE: Anxiety is a prevalent non-motor symptom in Parkinson's disease (PD) with observed sex differences. This study aimed to investigate sex-specific gray matter volume (GMV) associations with anxiety and preliminarily explore the potential mediating role of these regional GMV alterations in the relationship between depressive and anxiety symptoms in de novo PD patients. METHODS: A total of 108 de novo PD patients were enrolled. Anxiety and depressive symptoms were assessed using the Hamilton Anxiety Rating Scale (HAMA) and the 24-item Hamilton Depression Rating Scale (HAMD-24), respectively. Whole-brain GMV was analyzed using voxel-based morphometry (VBM) on T1-weighted MRI data. A 2 × 2 analysis of variance (sex × anxiety status) was conducted to examine main and interaction effects, controlling for age, education, HAMD-24 total score, and total intracranial volume. Sex-stratified, cross-sectional mediation analyses were subsequently performed. RESULTS: Whole-brain analysis revealed a significant sex-by-anxiety interaction in the right precuneus (p = 0.015). Post-hoc correlation analyses indicated that anxiety severity was negatively associated with GMV in the right precuneus in male patients (r = -0.387, p = 0.010) and with GMV in the left insula in female patients (r = -0.437, p = 0.004). Mediation analyses suggested that right precuneus GMV partially mediated the association between HAMD-24 and HAMA scores in males (mediation proportion: 17.1%). Similarly, left insular GMV partially mediated this association in females (mediation proportion: 15.4%). CONCLUSION: This study identified sex-specific GMV correlates of anxiety in de novo PD, primarily involving the precuneus in males and the insula in females. These structural differences may partially underlie the co-occurrence of depressive and anxiety symptoms, highlighting sexually dimorphic neuroanatomical substrates for affective disturbances in PD.