Exploring neuropsychological alterations in VEXAS syndrome

Abstract VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an adult-onset “hemato-autoinflammatory” disease provoked by somatic mutations in the UBA1 gene within hematopoietic progenitor cells. While dermatologic, rheumatologic and hematologic manifestations are well-documented, its neurological and cognitive implications remain poorly characterized. Given the chronic inflammatory burden of VEXAS, this study aimed to explore cognitive functioning in affected individuals. In this retrospective pilot study, we performed a neuropsychological assessment in patients with genetically confirmed VEXAS, VEXAS-like individuals (VEXAS-compatible symptoms without UBA1 variations), patients with mild cognitive impairment (MCI), and healthy controls (HC). Participants underwent computerized attention testing (Cognitrone) and multidomain cognitive evaluation (ENB-2), with analyses adjusted for age and education. Thirty-four participants were included: 7 patients with genetically confirmed VEXAS syndrome, 5 VEXAS-like patients, 11 individuals with mild cognitive impairment (MCI), and 11 healthy controls (HC). Mean age ranged from 63.3 ± 10.3 years in the VEXAS-like group to 75.7 ± 6.9 years in the VEXAS group. After adjustment for age and education, VEXAS-like patients showed cognitive performances broadly comparable to those of healthy controls. Patients with VEXAS demonstrated lower performance on selected measures of attentional control and response monitoring, whereas individuals with MCI showed broader cognitive impairment. Measures related to memory interference and complex attention displayed limited differences across groups. This pilot study represents the first standardized neuropsychological evaluation of patients with VEXAS syndrome. The findings suggest the presence of subtle differences in selected cognitive domains, warranting confirmation in larger longitudinal studies integrating inflammatory biomarkers and neuroimaging measures.