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

Thalamic atrophy already occurs in the early stages of multiple sclerosis (MS) and continues progressively throughout the disease. Demyelination is one of the main pathological hallmarks of MS and yet, thalamic demyelination does not correlate well with thalamic atrophy. By combining post-mortem magnetic resonance imaging with immunohistochemistry of thalami from 13 control and 13 MS donors, we investigated the underlying pathological contributors of thalamic atrophy and pathology. We first assessed the volumes of four thalamic nuclei groups (anterior, lateral, medial and posterior). Then, diffusion weighted imaging was used to assess the microstructural integrity of white matter tracts connecting each thalamic nuclei group. In addition, we studied myelination, inflammation, neurodegeneration and microglial activation by immunohistochemistry. We uncovered that medial and posterior thalamic nuclei were more atrophic compared to the anterior and lateral nuclei. Bilateral posterior nuclei and the right medial and anterior nuclei showed reduced fractional anisotropy in connected white matter tracks. We further show that microglial cells in the mediodorsal nuclei have an increased density and morphological complexity in MS compared to control donors. Microglia show signs of phagocytosis of pre-synapses, although we did not observe an overall synaptic loss in the thalamus of MS donors. These microglial changes within mediodorsal nuclei correlated with lower medial thalamic volume. Taken together, this study provides evidence that thalamic (subnuclear) atrophy relates tostructural thalamic network disconnection and within-thalamic microglial changes, but not thalamic demyelination. These findings could impact future treatment strategies aimed at thalamic neuroprotection.