Background

As disease progression remains poorly understood in multiple sclerosis (MS), we aim to investigate the sequence in which different disease milestones occur using a novel data-driven approach.

Methods

We analysed a cohort of 295 relapse-onset MS patients and 96 healthy controls, and considered 28 features, capturing information on T2-lesion load, regional brain and spinal cord volumes, resting-state functional centrality (“hubness”), microstructural tissue integrity of major white matter (WM) tracts and performance on multiple cognitive tests. We used a discriminative event-based model to estimate the sequence of biomarker abnormality in MS progression in general, as well as specific models for worsening physical disability and cognitive impairment.

Results

We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events. The models for disability and cognition show early functional changes of the default-mode network and earlier changes in spinal cord volume compared to the general MS population. Overall, GM atrophy seems crucial due to its early involvement in the disease course, whereas WM tract integrity appears to be affected relatively late despite the early onset of WM lesions.

Conclusion

Data-driven modelling revealed the relative occurrence of both imaging and non-imaging events as MS progresses, providing insights into disease propagation mechanisms, and allowing fine-grained staging of patients for monitoring purposes

中文翻译：

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多发性硬化症的结构，功能和认知变化顺序

背景

由于在多发性硬化症（MS）中疾病进展仍知之甚少，我们旨在研究使用新型数据驱动方法发生不同疾病里程碑的顺序。

方法

我们分析了295名复发性MS患者和96名健康对照的队列，并考虑了28种特征，捕获了有关T2病变负荷，区域性大脑和脊髓体积，静息状态功能中心（“枢纽”），微结构组织完整性的信息多种认知测验对主要白质（WM）谱和表现的影响。我们使用基于事件的判别模型来估计总体上MS进展中生物标志物异常的序列，以及用于使身体残疾和认知障碍恶化的特定模型。

结果

我们证明了小脑，丘脑的灰质（GM）萎缩和皮质脊髓束的改变是MS病理学的早期事件，而其他WM束以及工作记忆，注意力和执行功能的认知范围始终是晚期事件。与一般的MS人群相比，残疾和认知模型显示了默认模式网络的早期功能变化以及脊髓体积的早期变化。总体而言，由于GM萎缩早期参与了病程，因此GM萎缩似乎至关重要，尽管WM病变较早发作，但WM道完整性似乎相对较晚受到了影响。

结论

数据驱动的建模揭示了随着MS的发展，成像和非成像事件的相对发生率，提供了对疾病传播机制的洞察力，并允许对患者进行细粒度分期以进行监测