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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.<\/jats:p>","DOI":"10.1007\/s00401-025-02893-4","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T12:20:30Z","timestamp":1748434830000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Thalamic atrophy in multiple sclerosis is associated with tract disconnection and altered microglia"],"prefix":"10.1007","volume":"149","author":[{"given":"Carla","family":"Rodriguez-Mogeda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail","family":"Koubiyr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanos E.","family":"Prouskas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Georgallidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne M. 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MS serves on the editorial boards of Neurology, Multiple Sclerosis Journal and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene\/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. FB is supported by the NIHR biomedical research centre at UCLH, and is in the steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai and Prothena. FB is advisory board member for Combinostics, Scottish Brain Sciences, Alzheimer Europe and is consultant for Roche, Celltrion, Rewind Therapeutics, Merck, Bracco. FB is also in research agreements with ADDI, Merck, Biogen, GE Healthcare, Roche and co-founder and shareholder of Queen Square Analytics LTD. LJ receives active funding from the Alzheimer Association (AARG-22\u2013974381), The Dutch Top Sector Life Sciences and Health (S-000438), The Netherlands Organization for Health Research and Development (09120012110015), and Imeka.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"52"}}