Parkinson’s disease (PD) is a chronic and progressive neurological disorder affecting movements, muscles control, balance, cognitive functions, depression and thus affecting overall quality of life. These symptoms appear to have gender specific directions in PD patients^1,2,3 however, specific factors that contribute to gender disparities are not well known. Examining these differences in various domains may be useful toward gender specific diagnosis and treatment of PD patients. Magnetic resonance imaging (MRI) has been widely used to detect brain’s structural and functional changes both in animal models of PD and clinically in human PD subjects^4,5,6. MRI detected brain atrophy in multiple sites including cortical and subcortical structures in PD patients^7,8. Knowing the fact that males and females PD patients have different disease symptoms, progration and treatment outcomes^1,2,3,7,8, hence, characterization of brain tissue changes and structural networks connectivity in males and females PD patients during the disease progression is crucial for the effective treatment of PD. So far no study is available that characterizes the gender based changes in cortical thickness and structural networks connectivity in PD patients.In the current study, we aim to investigate the gender-based differences on cortical thickness and structural networks connectivity in PD patients.64 PD patients (43-male; female-21), and 46 controls (12-male; female-34) were included in this study. With informed consent all these subjects underwent standardized clinical assessment and whole brain MRI. Accurate diagnoses of PD were made using UK Parkinson’s Disease Society Brain Bank criteria for Parkinson’s disease. Whole brain MRI was performed on a 1.5-Tesla Siemens Sonata clinical-scanner (Siemens Medical Systems, Malvern, PA, USA) using a vendor-supplied head coil. T1-weighted 3D images were acquired using magnetization prepared rapid acquisition gradient-echo pulse sequence covering whole brain with TR/TE=3000ms/3.5ms, slice thickness=1.2mm, FOV of 240×240mm² and 192 phase encode steps, with flip angle=8°. High-resolution T1-weighted 3D brain images were used to quantify the cortical thicknesses in all subjects using well established FreeSurfer pipeline (v 5.3.0), as described in detail elsewhere⁹. For the structural networks construction we used graph theory based analysis using GAT software¹⁰ that used the freesurfer derived metrix. For the quality assessment we manually evaluated all processed data and make sure that no brain areas were excluded from analyses. Similarly, gray, white, and pial boundaries were also visually assessed, and if needed, edits were made to correct misidentified brain sites. In most subjects, only minor edits were required to remove non-brain areas after automatically detected skull strip procedures.All the statistical computations were performed using the Statistical Package for Social Sciences version 16.0. After final processing, gray matter surface maps were smoothed using a Gaussian kernel (FWHM, 15mm). Cortical thickness changes among different groups were examined using a vertex-by-vertex general linear model, with regional cortical thickness modeled as a function of groups, and age included as covariate in the analysis (p<0.05, FDR). The statistical parametric maps and structural networks were generated individually for both left and right hemispheres. For the structural identification of various brain sites, clusters with significant difference between groups were overlaid onto averaged inflated cortical surface maps. A p-value of less than 0.05 was considered to be statistically significant.Male PD patients showed significantly reduced cortical thickness in various brain regions compared to both female PD patients and female controls (figure 1 A, and figure 2 B). No significant change in cortical thickness was observed between control females and PD females, between control males and PD males, and between control males and PD females. Structural connectivity analysis showed disrupted structural networks connectivity in PD males compared to both PD females and control females (figure 1 B, C; 2B).Gender differences on cortical thickness and structural networks connectivity appeared in PD patients. Males are significantly affected than females, which is suggestive of more brain tissue damage in PD males than PD females. Estrogen is an important female hormone that regulates multiple functions including neuroprotection and neurtrophic action in the brain¹¹, and this may be the one of the reason for no obvious changes in cortical thickness as well as brain connectivity in female PD patients. The brain structural network efficiency has been shown to associated with cognitive index and psychomotor speed¹². Presence of altered structural networks in PD males than PD females and control females suggestive of more diminished cognitive, visual, sensory and motor dysfunctions in PD males. These male-specific cortical thickness changes and disrupted structural networks connectivity may contribute to or derive from physiological and genetically differences between males and females and may have significant implications in diagnosing and treating PD among the gender.