This study aimed to evaluate cerebral oxygen extraction fraction (OEF) changes in patients with systemic lupus erythematosus (SLE), particularly those with neuropsychiatric SLE (NPSLE), using an MRI-based OEF mapping technique. The study also sought to investigate the relationship between regional OEF alterations and cognitive function, exploring the potential of OEF as a non-invasive imaging biomarker for diagnosing NPSLE and monitoring cognitive impairment in SLE.

A total of 43 SLE patients were enrolled, including 18 with NPSLE and 25 without NPSLE, along with 26 healthy controls (HC) recruited via social media. All participants met the 2019 EULAR/ACR classification criteria for SLE, and NPSLE was classified according to the 1999 American College of Rheumatology case definitions. Exclusion criteria included prior neurological diseases, central nervous system-acting medications, image artifacts, and major stroke or hemorrhage.

All participants underwent MRI on a 3.0T scanner using a standardized protocol that included three-dimensional T1-weighted imaging and a multi-echo gradient-echo sequence. OEF maps were generated using the quantitative susceptibility mapping plus quantitative blood oxygen level-dependent (QSM+QBOLD, or QQ) model, which integrates phase and magnitude information to provide reliable whole-brain and regional OEF estimation. Whole-brain voxel-wise analysis was performed using SPM12, with age, sex, and education as covariates. Region-of-interest analysis focused on subcortical gray matter structures, including subregions of the amygdala, hippocampus, and caudate nucleus, which were delineated using the BNA246 atlas. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) within one week of MRI. Statistical analyses included ANOVA, ANCOVA with progressive adjustment for confounders (age, sex, education, brain volume, medications, and vascular risk factors), and partial Spearman correlation.

Whole-brain voxel-wise analysis revealed significant OEF differences among HC, non-NPSLE, and NPSLE groups, primarily located in the limbic system, including the orbitofrontal cortex and bilateral insular lobes (voxel-level p < 0.001 uncorrected, cluster-level family-wise error corrected p < 0.05).

Region-of-interest analysis showed that non-NPSLE patients had significantly lower OEF values than HC in the bilateral medial amygdala, bilateral rostral hippocampus, and bilateral dorsal caudate nucleus. A general decreasing trend in OEF was observed across all selected subcortical gray matter regions in non-NPSLE patients. In contrast, NPSLE patients exhibited significantly higher OEF values in the right rostral and caudal hippocampus compared with non-NPSLE patients. These differences remained significant after adjusting for age, sex, education, total brain volume, medication use (corticosteroids, immunosuppressants, antimalarials), and vascular risk factors (systolic and diastolic blood pressure, triglycerides, HDL, LDL, fasting blood glucose), demonstrating robustness.

Across all participants, OEF values in the bilateral medial amygdala, right lateral amygdala, left rostral hippocampus, and right dorsal caudate nucleus were positively correlated with MoCA scores after adjusting for age, sex, and education (r ranging from 0.251 to 0.335, all p < 0.05), indicating an association between higher OEF and better cognitive performance.

This study demonstrates that MRI-based OEF mapping using the QQ method is a non-invasive and accessible technique capable of detecting cerebral oxygen metabolic alterations in SLE patients. The observed OEF changes predominantly involved the limbic system and subcortical gray matter structures, regions known to be vulnerable in SLE. Reduced OEF in non-NPSLE patients may reflect early metabolic impairment or tissue degradation occurring before the onset of overt neuropsychiatric symptoms. Elevated OEF in hippocampal subregions of NPSLE patients may represent compensatory responses to neuroinflammation or ischemic injury secondary to microvascular damage. The positive correlation between regional OEF and cognitive performance suggests that OEF may serve as a potential functional biomarker for cognitive impairment and an adjunctive tool for diagnosing and managing NPSLE. Future multicenter studies with larger sample sizes and longitudinal designs are needed to validate these findings and further elucidate the biological mechanisms underlying OEF alterations in SLE.