Accumulating evidence has demonstrated multi-dimensional dysfunction in amyotrophic lateral sclerosis (ALS), including motor, cognitive and behavioral impairments. Widespread cortical and subcortical dysfunction in ALS has been established to understand the underlying pathological changes in vivo. However, genetic and clinical heterogeneity contaminated the consistence of these findings and limited the clinical application for patients management. Evidence from Bede et al has found widespread basal ganglia impairment in ALS, which was more pronounced in patients carrying C9orf72 hexnucleotide repeat. Their study indicated that frontolstriatal loop dysfunction can deepen our understanding of neuropsychological profile of ALS^[1]. In addition, disease onset, progression pattern, as well as gender dimorphism also contribute to ALS heterogeneous^[2]. Some studies have hypothesis that female and male ALS patients may add the heterogeneity in this complex disease. Therefore, we focus on gender differences in ALS through analyzing subcortical structures and cognitive profiles, especially the subregions of the striatum.Forty- one ALS patients (26 men) and 41 age matched healthy controls (19 men) were included in this study. Male and female patients showed reduced education level compared with respective normal controls (F=14.022, P<0.000). GE 3.0T HDxt was used to acquire 3D-T1 images. We used FIRST (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FIRST) to segment the subcortical structures automatically. Normalized subcortical volume was calculated by multiplying the scaling factor determined by SIENAX. In order to limit the number of variables, the mean normalized subcortical volume was estimated by dividing the bilateral total volume. We used revised-ALSFRS, disease duration, disease progression rate and upper motor neuron score to evaluate the clinical motor deficits in ALS patients, which showed no group difference between male and female patients. Global cognitive status was assessed by MMSE. Because of the sensitivity for executive impairment and heavy load on the integrity of fronto-striatal circuits, we used digit span (forward and backward) and semantic fluency (naming animal, fruits and vegetables in 1 minutes, separately) to estimate executive function^[3]. For statistical analysis, multivariate general linear model was used to analyze volumetric and cognitive data separately. Group was set as a fixed factor (including male patients, female patients, male controls and female controls), controlling for age and education level. Post hoc pairwise comparisons were conducted among these 4 levels. Linear regression model was only applied in ALS patients with cognitive score as dependent variable, age, education level and the nucleus with significant group difference were included as predictors.Multi-variate GLM analyses demonstrated reduced volume in three subregions of striatum and hippocampus. We did not found any group differences between amygdala, thalamus and globus pallidus. Post hoc pairwise comparison showed atrophy of the caudate and hippocampus in male patients compared with female controls. While female patients showed significant reduced volume in accumben nucleus, in contrast with both male and female controls (Fig. 1). The cognitive performance of MMSE, semantic fluency and digit span were poorer in both patients than normal controls. In female patients, atrophy in accumben nucleus and lower education level predict poorer performance in global cognition (Fig. 2). Lower education level and older age contributed to poorer cognitive test in male patients.All the subregions of striatum and hippocampus atrophy can be found in ALS patients, indicating that subcortical structure, especially striatum should be taking into account in searching for effective biomarker in ALS. The difference of specific involvement of subcortical structure between male and female patients, as well as the predictors for executive function demonstrated gender imparity in the underlying pathology. Although the caudate nucleus was functional connected with associative network, which is important in maintain normal cognition[4]. Aging and lower education level may be more important in deteriorating the executive function in male patients. Additionally, it is well know that accumben nucleus was involved in limbic system for emotional processing[4]. Thus, despite atrophy in accumben nucleus can predict cognitive decline in female patients, we cannot rule out the influence from emotional disorder, such as depression and anxiety. Because evidence from depression found that female gender was important risk factor for depression[5].Specific atrophy in striatum and hippocampus between male and female ALS patients, in combination with their cognitive profile, indicated that we should take into consideration gender dimorphism for further study. And emotional evaluation should gain our attention when assessing for cognitive function in female patients, because of the possibility of exacerbation effect from emotional status.