Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T₁/T₂-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T₂*-weighted imaging for cortical lesion segmentation and 3 T T₁/T₂-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

中文翻译：

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早期多发性硬化症的皮质和白质神经轴突病理学的体内表征

神经轴突病理学是多发性硬化症疾病进展的主要决定因素。然而，其潜在的病理生理机制，包括其与炎性脱髓鞘的联系以及在病程中的暂时发生仍是未知的。我们使用超高场（7 T），超高梯度强度扩散和T ₁ / T ₂加权髓鞘敏感性磁共振成像来表征早期多发性皮层和白质中髓鞘的微结构变化和神经轴突完整性。硬化，它们在病变组织和正常出现组织中的分布及其与神经功能障碍的相关性。26名早期多发性硬化症受试者（病程≤5年）和24名年龄匹配的健康对照者接受了7 TT ₂*皮层病变分割的加权成像和3 TT ₁ / T ₂加权髓鞘敏感的成像以及神经突取向分散和密度成像，以评估皮层和白色的病变和正常出现组织中的微结构髓鞘，轴突和树突完整性事情。还评估了常规平均扩散率和分数各向异性度量以进行比较。在92％的早期多发性硬化症患者中发现了皮层病变，其特征是细胞内体积分数降低（配对t检验P = 0.015 ），髓鞘敏感性对比降低（相关样本Wilcoxon符号秩检验P = 0.030） ）和较高的平均扩散率（P相对于对侧正常外观的皮层，相关样本的Wilcoxon秩和检验= 0.022）。相对于正常出现的白质，在白质病变中观察到了相似的发现（所有P <0.001），同时取向分散性增加（配对t检验，P <0.001 ）和较低的分数各向异性（相关样品，P <0.001） Wilcoxon符号秩检验）表明底层纤维取向不太连贯。此外，多发性硬化症患者中正常出现的白质比对照组中的白质具有更低的细胞内体积分数（P = 0.029，不成对t-测试）。多发性硬化症受试者和对照组之间的皮质厚度没有显着差异。在基于表面的一般线性建模中，左初级运动体感觉皮层的较高方向分散度与扩展的残疾状态量表得分的增加相关（P<0.05）。微结构病理学在多发性硬化症的早期很常见，主要集中在皮层病变中，而在白质中则更为弥散。这些结果表明在皮质和白质病变中早期脱髓鞘伴随细胞和/或细胞体积的损失，在白质病变中具有额外的轴突分散。在皮层中，局灶性病变的改变可能先于弥漫性萎缩和皮质变薄。正常出现的白质中的发现揭示了炎性脱髓鞘病变之外的早期轴突病理。