Deep Gray Matter Atrophy Mediates the Associations Between Glymphatic Dysfunction and Clinical Disability in Relapsing-Remitting Multiple Sclerosis: A Neuroimaging Subgroup Study

Lingling Cui^1*Hao Zhang¹JIbin Cao^1*Ruisi Gong¹Jinlin Jiao¹Mengyao Li¹Zixuan Song¹Ziying Zhang¹Yueluan Jiang²Ye Han³Feng Shi³

• ¹Department of Radiology, First Hospital of China Medical University, Shenyang, China
• ²Siemens Healthineers China, Shanghai, China
• ³United Imaging Intelligence Co Ltd, Shanghai, China

Background: Impaired glymphatic function is linked to cerebral atrophy and contributes to clinical disability in patients with relapsing-remitting multiple sclerosis (RRMS). Deep gray matter volume (DGMV) loss is associated with disability; however, its mediating effect in MS-related disability and glymphatic function changes remains underexplored. Methods: One hundred and thirty-one RRMS patients and 50 healthy controls (HC) underwent MRI scans. The DTI-ALPS index was used to evaluate glymphatic function. Z-scores of cortical and deep gray matter volumes (CGMV and DGMV) and WM-FA in RRMS patients were determined based on the mean and standard deviation of HC. RRMS patients were divided into two subgroups: the "MS-DGM-preserved" subgroup (z-scores of both CGMV, DGMV, and WM-FA > -2) and the "MS-DGM-atrophied" subgroup (z-scores of DGMV < -2) according to combinations of z-scores compared to HC. The mediating effect of DGMV in the relationship between the DTI-ALPS index and the clinical disability was further explored. Patients were followed up and had longitudinal outcomes. Results: Among all participants, 79 cases (60.3%) were classified as the MS-DGM-preserved subgroup, and 52 cases (39.7%) as the MS-DGM-atrophied subgroup. The MS-DGM-atrophied subgroup exhibited lower DTI-ALPS index (d=1.42, p-FDR< 0.001), higher T2-hyperintense white matter lesion volume (d=0.98, p-FDR< 0.001) and EDSS scores (d=0.49, p-FDR< 0.001), and longer disease duration (d=0.33, p-FDR=0.005) compared to the MS-DGM-preserved subgroup. Additionally, in the MS-DGM-atrophied subgroup, the DTI-ALPS index was significantly positively correlated with DGMV (r=0.59, p-FDR<0.001), and negatively correlated with EDSS scores and disease duration (r=-0.59, r=-0.56, p-FDR<0.001). Mediation analysis revealed that DGMV partially mediated the relationship between the DTI-ALPS index and clinical disability (EDSS and disease duration). In the longitudinal cohort, 18 MS patients were followed for a median time of 14 months (12.75, 14.00 months; range: 8-18 months). Compared to baseline, the DTI-ALPS index significantly decreased during follow-up (d=0.92, p-FDR=0.009). Conclusion: The RRMS subgroups based on the gradient classification of DGMV using structural MRI effectively distinguishes differences in glymphatic function and clinical disability. When DGM atrophy reaches a certain threshold, it partially mediates the relationship between glymphatic function and clinical disability.