Glymphatic Dysfunction in Neuromyelitis Optica Spectrum Disorder

Ying Zhang^1,2Hong-xi Chen¹Ziyan Shi¹Rui Wang^1,2Xiaofei Wang¹Qin Du¹Yuntao Mo³Shixiang Chen⁴Hongyu Zhou^5*

• ¹Sichuan University West China Hospital Department of Neurology, Chengdu, China
• ²General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, chnegdu, China
• ³West China School of Medicine, Sichuan University, chengdu, China
• ⁴West China School of Medicine, Sichuan University, cheng du, China
• ⁵West China Hospital, Sichuan University, Chengdu, China

Background: Neuromyelitis optica spectrum disorder (NMOSD) involves aquaporin-4-mediated astrocyte injury, potentially impairing the glymphatic system. We assessed glymphatic function using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, choroid plexus (CP) volume, and perivascular space (PVS) metrics, and explored associations with disability and brain structure. Methods: Thirty-nine aquaporin-4 immunoglobulin G (AQP4-IgG)-positive NMOSD patients without overt intracranial lesions and twenty-one age-and sex-matched healthy controls underwent 3T MRI using three-dimensional fast spoiled gradient-echo (3D-FSPGR) and diffusion tensor imaging (DTI). Manual segmentation of CP was performed in ITK-SNAP, and an automated pipeline derived DTI-ALPS and normalized PVS. Clinical assessments included the Expanded Disability Status Scale (EDSS), Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD), Fatigue Impact Scale (FIS), and Pittsburgh Sleep Quality Index (PSQI). Statistical analyses comprised group comparisons, partial correlations (age/sex– adjusted), Firth penalized logistic regression and multivariable linear regression model, with false discovery rate (FDR) correction. Results: Among 39 NMOSD patients and 21 matched healthy controls, NMOSD patients showed trends toward higher DTI-ALPS (1.47 ± 0.10 vs. 1.45 ± 0.17, p = 0.20), larger CP volume (1,616 ± 408 mm3 vs. 1,600 ± 371 mm3, p = 0.80), and altered PVS (0.46 ± 0.06% vs. 0.45 ± 0.05%, p = 0.20). Within NMOSD, CP volume positively correlated with EDSS (r = 0.44, p = 0.002, FDR-corrected) and lateral ventricle volume (r = 0.46, p = 0.008, FDR-corrected). Baseline EDSS showed positive correlations with anxiety (HAMA; r = 0.36, p = 0.029) and depression (HAMD; r = 0.56, p < 0.001). In multivariable models, older age predicted lower odds of disability improvement (Coefficient = -0.024; 95% CI, -0.046 - 0.003; p = 0.029). 3 Conclusions: In NMOSD, subtle CP volume enlargement is associated with disability status and ventricular enlargement, suggesting the presence of glymphatic dysfunction. CP alterations may represent a potential imaging biomarker of disease burden.