Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). While perivenular inflammation induces vasculocentric lesions, leptomeningeal involvement follows a subpial 'surface-in' gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and CSF samples from 41 post-mortem secondary progressive MS cases compared to 5 non-neurological controls and 12 controls with other neurological diseases. CSF/ependyma-oriented gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing distance (12% at 10mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest (38%) at 2mm from the ependyma/CSF boundary and least at 10mm (13%). Conversely, gradient of MHC-II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by 15% at 10mm and this gradient inversely correlated with the neuronal (R=-0.91,p<0.0001) and axonal (R=-0.79,p<0.0001) thalamic changes. Observed gradients were also detected in normal-appearing thalamus and were associated with: rapid/severe disease progression; presence of leptomeningeal tertiary lymphoid-like structures; large subependymal infiltrates, enriched in CD20+ B cells and occasionally containing CXCL13+CD35+ follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase-3-like-1, TNFR-1, parvalbumin, neurofilament-light-chains and TNF. Substantial "ependymal-in" gradient of pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized either in sub-ependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS progression. This article is protected by copyright. All rights reserved.
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