Rodriguez-Mogeda Carla, Koubiyr Ismail, Prouskas Stefanos E, Georgallidou Margarita, van der Pol Susanne M A, Fernandez Rosalia Franco, de Graaf Yvon Galis, van der Werf Ysbrand D, Jonkman Laura E, Schenk Geert J, Barkhof Frederik, Hulst Hanneke E, Witte Maarten E, Schoonheim Menno M, de Vries Helga E
Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
MS Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Acta Neuropathol. 2025 May 28;149(1):52. doi: 10.1007/s00401-025-02893-4.
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.
丘脑萎缩在多发性硬化症（MS）的早期阶段就已出现，并在整个疾病过程中持续进展。脱髓鞘是MS的主要病理特征之一，然而，丘脑脱髓鞘与丘脑萎缩的相关性并不显著。通过将尸检磁共振成像与来自13名对照者和13名MS患者的丘脑免疫组织化学相结合，我们研究了丘脑萎缩和病理的潜在病理因素。我们首先评估了四个丘脑核团（前核、外侧核、内侧核和后核）的体积。然后，使用扩散加权成像来评估连接每个丘脑核团的白质束的微观结构完整性。此外，我们通过免疫组织化学研究了髓鞘形成、炎症、神经退行性变和小胶质细胞活化。我们发现，与前核和外侧核相比，内侧和后丘脑核萎缩更明显。双侧后核以及右侧内侧和前核在相连的白质束中表现出分数各向异性降低。我们进一步表明，与对照者相比，MS患者中背内侧核中小胶质细胞的密度和形态复杂性增加。小胶质细胞显示出对突触前成分的吞噬迹象，尽管我们在MS患者的丘脑中未观察到总体突触丢失。背内侧核内的这些小胶质细胞变化与内侧丘脑体积减小相关。综上所述。本研究提供了证据表明丘脑（亚核）萎缩与丘脑结构网络断开和丘脑内小胶质细胞变化有关，但与丘脑脱髓鞘无关。这些发现可能会影响未来旨在保护丘脑神经的治疗策略。
