BackgroundOrthostatic hypotension (OH) is a common symptom of multiple system atrophy (MSA), however, its role in cognitive impairment and the mechanism in these patients remains unclear. This study aims to assess the role of OH on cognitive impairment in MSA patients, as well as to explore the potential association of cerebral autoregulation (CA) and white matter hyperintensities (WMHs) on cognitive impairment.MethodsThis observational study was conducted in three general hospitals in China from January 2018 to October 2023, with patients at one center followed up for 6 months after enrollment. The primary outcomes included cognitive function assessed using the Mini-Mental State Examination (MMSE) and Montreal cognitive assessment (MoCA). Secondary outcomes included the results of the Head-up tilt test, scores for CA and the extent of WMHs.ResultsThe 132 MSA patients included 72 men (54.54%) with a mean age of 61.16 (7.80) years. Among them, 80 patients (60.61%) had orthostatic hypotension, and 48 patients (36.36%) had cognitive impairment. OH plays an important role in cognitive impairment in MSA patients (OR = 0.328,95% CI 0.135-0.797, P = 0.014). Cognitive impairment was associated with impaired CA (OR = 0.088,95% CI 0.012-0.657, P = 0.018) and severe WMHs (OR = 0.030,95% CI 0.002-0.423, P = 0.009), particularly in the presence of OH.ConclusionOH is associated with cognitive impairment in MSA patients, and cognitive decline is linked to impaired CA and increased WMHs. Future studies are needed to explore the mechanisms underlying cognitive impairment in MSA patients.