Thalamic atrophy in multiple sclerosis is associated with tract disconnection and altered microglia

Area of Science:

• Neuroscience
• Immunology
• Neuropathology

Background:

• Thalamic atrophy is an early and progressive feature of multiple sclerosis (MS).
• Thalamic demyelination in MS does not consistently correlate with observed atrophy.
• Investigating the pathological drivers of thalamic atrophy is crucial for understanding MS progression.

Purpose of the Study:

• To identify the pathological contributors to thalamic atrophy in multiple sclerosis (MS).
• To correlate microstructural integrity, myelination, inflammation, and microglial activation with thalamic atrophy in MS.
• To explore the relationship between thalamic subnuclear volume changes and associated white matter tracts and cellular pathology.

Main Methods:

• Combined post-mortem magnetic resonance imaging (MRI) and immunohistochemistry on thalamic tissue from MS and control donors.
• Assessed volumes of four thalamic nuclei groups and microstructural integrity of connecting white matter tracts using diffusion-weighted imaging.
• Quantified myelination, inflammation, neurodegeneration, and microglial activation via immunohistochemistry.

Main Results:

• Medial and posterior thalamic nuclei showed greater atrophy than anterior and lateral nuclei in MS.
• Reduced fractional anisotropy in white matter tracts connected to posterior, medial, and anterior thalamic nuclei was observed.
• Increased density and complexity of microglial cells in the mediodorsal nuclei correlated with reduced medial thalamic volume, indicating phagocytosis of pre-synapses without overall synaptic loss.

Conclusions:

• Thalamic subnuclear atrophy in MS is associated with structural network disconnection and intrathalamic microglial alterations.
• Thalamic atrophy in MS is not driven by demyelination.
• Findings suggest novel therapeutic targets for thalamic neuroprotection in multiple sclerosis.