Brain atrophy and lesion dynamics in multiple sclerosis

In this thesis, research was performed to provide more insight in the relationship between the development of white matter (WM) lesions and the development of atrophy in the brain of patients with multiple sclerosis (MS) through the use of structural MRI. By broadening our understanding of the dynamics between these two pathological hallmarks during different phases of MS, ultimately the goal was to contribute to future effective targeting of the disease. The REFLEX/REFLEXION (NCT00404352/NCT00813709) datasets have played a major role in this thesis. This multi-center data from patients with clinically isolated syndrome (with a high risk of converting to a diagnosis of MS) provides a unique opportunity to study the relationship between lesion changes and atrophy in the earliest stages of the disease over a prolonged period. However, in order to gain insight in the relationship between WM lesions and atrophy, methods are needed to quantify these pathologies. Therefore the purpose of Section 1 was to develop and validate methods to quantify (changes in) WM lesions in MS. In Chapter 1.1 a semi-automated method to quantify WM lesion volume changes was developed and validated and in Chapter 1.2 we presented a semi-automated method to segment “black hole” lesions in MS. Section 2, is about the relationship between the development of WM lesions and that of atrophy in MS. In Chapter 2.1 we performed a systematic review about the relationship between WM lesions and gray matter (GM) atrophy. In Chapter 2.2 we investigated the concurrent (within the same study year) spatio-temporal relationship between WM lesion changes and whole-brain atrophy and in Chapter 2.3 we investigated this relationship between consecutive study years. Finally, in Section 3, our investigations of the prediction of clinical and radiological disease progression based on early imaging features are described in Chapter 3.1. Overall, there seems to be a complex interplay between the timing of treatment, treatment phase, and disease type, which has important clinical implications as this might alter the interaction between the development of WM lesions and atrophy. Moreover, the effectiveness of different types of disease-modifying treatments and their different mechanisms of action may also modulate not only the observed association between WM lesions and atrophy but also the main pathologic substrate of the neurodegenerative process. Future studies should further investigate both hypothesized causal relationships between lesions and atrophy, as well as the possibility of correlated but not causally linked changes to further our understanding of brain atrophy and lesion dynamics.