Cerebrospinal fluid-linked periventricular gradient pathology in multiple sclerosis associates with ependymal cell reactivity and cell adhesion disruption

So-called surface-in gradients, which predict disease relapses independent of white matter lesions, are thought to arise from CSF-borne cytotoxic factors and represent a distinct therapeutic target. Yet, how such factors access the brain, particularly at the ventricular border, remains unclear.

While ependymal injury in MS has been suggested, a comprehensive assessment of cell health in the disease is lacking. Using ultra-high-field MRI-guided histology, electron microscopy, and single-nucleus multiomics, we deeply profiled human ependymal cells in MS. We found that ependymal pathology correlates with periventricular gradients and involves an immune-reactive state marked by transporter and junctional protein dysregulation.