"Ependymal-in" Gradient of Thalamic Damage in Progressive Multiple Sclerosis

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Leptomeningeal and perivenular inflammation contribute to cortical damage in multiple sclerosis (MS).
• A "surface-in" gradient of damage is observed in cortical lesions, but its presence in deep grey matter nuclei was unknown.

Purpose of the Study:

• To investigate if a similar gradient of neuronal and axonal damage occurs in the deep grey matter (thalamus) of progressive MS.
• To correlate this gradient with inflammatory markers in the thalamus and cerebrospinal fluid (CSF).

Main Methods:

• Examined postmortem dorsomedial thalamic nuclei from 41 secondary progressive MS cases and controls.
• Assessed neuron (NeuN+) and axon (SMI31+) density, and microglia (MHC-II+) activation.
• Analyzed CSF samples for inflammatory and neurodegeneration factors.

Main Results:

• A "subependymal-in" gradient of neuro-axonal loss and increased microglia activation was found in MS thalamic lesions.
• This gradient was greatest near the ependyma/CSF boundary and correlated inversely with neuronal/axonal density.
• Gradients were associated with rapid MS progression, leptomeningeal inflammation, and elevated CSF inflammatory/neurodegeneration biomarkers.

Conclusions:

• A distinct "ependymal-in" gradient of pathological changes exists in the thalamus in progressive MS.
• Intrathecal inflammation, compartmentalized in subependymal infiltrates or CSF, plays a key role in MS progression.
• CSF biomarkers and advanced imaging may aid in diagnosing MS subtypes and personalizing treatment.