Objectives <p>This study aims to assess the activity of the glymphatic system in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) and non-NPSLE using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) and explore the potential correlation between the DTI-ALPS index and clinical indicators.</p> Materials and methods <p>A total of 33 non-NPSLE patients, 13 NPSLE patients, and 33 age-matched healthy controls (HC) were enrolled in this study. Clinical indicators of patients were recorded, and DTI images were obtained to determine diffusivity along the <i>x</i>-, <i>y</i>-, and <i>z</i>-axes at the level of the lateral ventricle body. The DTI-ALPS index was calculated, and one-way ANOVA analysis with Bonferroni post hoc tests was used to assess differences among HC, non-NPSLE, and NPSLE. Pearson or Spearman correlation analysis was applied to investigate the correlation between DTI-ALPS index and clinical indicators. According to the SLEDAI scores, 44 SLE patients (non-NPSLE, <i>n</i> = 31; NPSLE, <i>n</i> = 13) were categorized into four groups, and one-way ANOVA analysis with Bonferroni post hoc tests was used to compare the ALPS index among the four groups.</p> Results <p>Compared to the healthy control (HC) group (1.705 ± 0.167), the ALPS index in the total SLE group (1.507 ± 0.138) was significantly lower [<i>t</i> (77) = 3.921, <i>P</i> &lt; 0.001]. Both the NPSLE group (1.550 ± 0.113, <i>n</i> = 33) and non-NPSLE group (1.578 ± 0.148, <i>n</i> = 13) exhibited significantly reduced ALPS index in comparison with the HC group. One-way ANOVA showed a significant group effect on the ALPS index [<i>F</i> (2,76) = 7.775, <i>P</i> &lt; 0.001]. Bonferroni-corrected post hoc tests indicated that the HC group had a higher ALPS index than the non-NPSLE group [mean difference = 0.127, 95% confidence interval (CI) (0.036, 0.219), <i>P_adj</i> = 0.003], and higher than the NPSLE group [mean difference = 0.155, 95% CI (0.033, 0.277), <i>P_adj</i> = 0.008]. The NPSLE was lower than that of the non-NPSLE, but this difference was not statistically significant (<i>P_adj</i> = 1.000), which may be partly due to the small NPSLE sample size. And we classified total SLE patients into four grades based on their SLEDAI scores. One-way ANOVA demonstrated a significant difference in ALPS index among the four SLEDAI grades [<i>F</i> (3, 40) = 3.210, <i>P</i> = 0.033]. After Bonferroni correction, only the difference between Grade 1 and Grade 3 remained significant (<i>P_adj</i> = 0.029); all other comparisons were not significant. Addition, no significant correlations were found between DTI-ALPS index and various clinical indicators, including serum C3, C4, CH50, anti-Smith antibodies, and SLEDAI scores.</p> Conclusion <p>The DTI-ALPS index can serve as a noninvasive imaging biomarker for assessing glymphatic system function in non-NPSLE and NPSLE patients. These findings contribute to a better understanding of the pathophysiological mechanisms of SLE.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>•<i> The pathological mechanism of SLE may be related to functional impairment of the glymphatic system</i>.</p> <p>• <i>DTI-ALPS index may serve as an MR biomarker for SLE patients</i>.</p> </entry> </row> </tbody> </tgroup> </Table></p>