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Deep gray matter atrophy mediates the associations between glymphatic dysfunction and clinical disability in
Hao Zhang1, Ruisi Gong1, Hefei Fu2
1Department of Radiology, The First Hospital of China Medical University, Shenyang, Liaoning, 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.
