Periventricular gradient pathology is linked to ependymal reactivity and cell adhesion disruption in multiple sclerosis.

Cerebrospinal fluid (CSF)-adjacent brain areas are especially vulnerable to diffuse degeneration in multiple sclerosis (MS). Surface-in gradients arising from CSF-borne cytotoxic factors have been proposed to predict disease relapses independent of white matter lesions. Yet, whether such factors disrupt ependymal cells to penetrate the ventricular border in MS remains unknown. Here, using ultra-high-field magnetic resonance imaging-guided histology, electron microscopy and single-nucleus multiomics, we found that ependymal pathology correlates with periventricular gradients and involves an immune-reactive state marked by transporter and junctional protein dysregulation. We further defined the gene regulatory networks underpinning the MS ependymal state and predicted ligands known to be enriched in MS CSF that could drive the emergence of this state. One of the candidates, IFNγ, increased murine ependymal permeability in vivo, indicating that CSF ligands can modulate ependymal function and regional inflammation. These findings identify CSF-driven ependymal dysfunction as a contributor to periventricular pathology in MS.