Brain structural abnormalities are often observed on magnetic resonance imaging (MRI) scans of Cushing's syndrome patients, but the pathogenesis is not fully understood. To understand the relationship between brain structural abnormalities and potential risk factors in active Cushing's disease (CD) patients, a total of 101 treatment-naïve CD patients and 95 sex-, age-and education matched controls with non-functioning adenomas (NFA) underwent clinical evaluation and MRI investigation, and the relative risk factors were analyzed. 14 patients in sustained remission after transsphenoidal surgery were followed. Compared with the NFA subjects, the patients with CD had more cortical (P < 0.01) and subcortical atrophy (P < 0.01) and a higher prevalence of white matter hyperintensity (WMH) (P < 0.01). WMH severity in CD patients positively correlated with age (r = 0.532, P = 0.000), disease course (r = 0.257, P = 0.009), postprandial glucose (r = 0.278, P = 0.005), frequency of left ventricular hypertrophy (r = 0.398, P = 0.001) and hypothyroidism (r = 0.246, P = 0.014). The markers of cortical and subcortical atrophy (sylvian fissure ratio, bifrontal ratio, bicaudate ratio and third ventricle width) were positively associated with the progression of WMH in the CD patients. In the follow-up of 14 patients with CD, brain atrophy and WMH was partially reversible after correction of hypercortisolism. In conclusions, brain atrophy and WMH were more likely to appear in CD patients and were possibly partially reversible following correction of hypercortisolism. Cushing's syndrome results directly from chronic exposure to excess glucocorticoids. Alongside various physical symptoms, patients with Cushing's syndrome, whether endogenous or exogenous, display a wide variety of neuropsychiatric and cognitive symptoms, which are indicative of the involvement of the central nervous system 1,2. Brain structural abnormalities related to Cushing's syndrome have been repeatedly found, including smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy 3. Brain imaging studies and neuropsychological studies have indicated that hypercortisolism or supraphysiological levels of exogenous glucocorticoids are especially deleterious to the hippocampus and frontal lobes, and there were specific correlations between hippocampal volume and verbal learning, recall and memory function scores 4,5. Although some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning and brain volume are partly reversible after correction of hypercortisolism 6,7 , it remains unclear what pathophysiological processes are causing these reductions and reversibility, and we cannot draw conclusions concerning the underlying microstructural changes that are involved. Patients with Cushing's syndrome has persistent cardiovascular risk factors 8 , which is closely related to cerebrovascular injury including white matter hyperintensities (WMH) 9. Several recent studies examined white matter structural changes in Cushing's syndrome patient...