Glymphatic system dysfunction in multiple sclerosis: A systematic review and meta-analysis

The glymphatic system (GS) facilitates cerebral waste elimination through the exchange of cerebrospinal and interstitial fluid along perivascular pathways, serving a crucial role in neural homeostasis. GS dysfunction has been implicated in various neurological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This review aimed to assess glymphatic dysfunction in people with MS (PwMS), NMOSD, and MOGAD using diffusion tensor imaging-based analysis along the perivascular space (DTI-ALPS).

PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched up to March 10, 2025. We reviewed studies comparing ALPS index values between patient groups and healthy controls (HC). We further analyzed the relationships between glymphatic function and clinical characteristics, as well as MRI indices.

The meta-analysis revealed significantly lower ALPS index values in PwMS compared to HC (SMD = -0.91, p < 0.01), suggesting impaired glymphatic function. A significant inverse correlation was found between the ALPS index and disease duration (r = -0.26, p < 0.01), Expanded Disability Status Scale (EDSS) (r = -0.32, p < 0.01), and white matter lesion volume (r = -0.42, p < 0.01). Lower ALPS values, or reduced glymphatic function, were associated with more advanced disease, greater disability, and a higher lesion burden in MS. Preliminary findings for NMOSD and MOGAD also showed reduced glymphatic function; however, due to the limited and heterogeneous data available, these conditions were not included in the meta-analytic synthesis. Their results are discussed narratively and should be interpreted cautiously.

Evidence for glymphatic dysfunction in PwMS is supported by a small body of research, correlating with disease activity measures. DTI-ALPS offers a non-invasive technique to evaluate glymphatic activity and holds promise as a potential biomarker for monitoring disease progression. Further studies with larger sample sizes and standardized protocols are needed to confirm these findings.