163 General Discussion 8 a different disease stage or process of ageing compared to the bigger confluent WMH.4 In more progressed small vessel disease (SVD) cases, not only periventricular/ confluent WMH will have merged to one big lesion, but also periventricular/confluent WMH and deep WMH can form confluent WMHs. This will result in a higher volume of confluent WMH and also in a relatively lower volume of periventricular and deep WMH. In more severe SVD cases it is, therefore, difficult to investigate different WMH types and their shape separately. In this thesis, WMH shape was investigated at baseline. It would also be interesting to investigate how WMH shapes evolve over time. However, it is very challenging to model WMH shape changes over time because of the way WMH naturally progress. Smaller irregular lesions might over time blend with bigger WMH, leading to large shape changes caused by a potentially minor size increase. Such an event of WMH progression might engulf irregular edges of smaller lesions that were identifiable at earlier timepoints. Bigger lesions might therefore look more regular in shape, even if they used to be smaller and more irregular at earlier timepoints. WMH shape irregularity is likely to reflect a progression-prone type of SVD, as Chapter 3 suggests. This limitation suggests that WMH shape can be best utilized as a marker in the earlier disease stages. This does not diminish the clinical importance of WMH shape assessment, since lifestyle changes and treatments that can be used to modify SVD progression are also more effective at earlier disease stages.5 Based on the growing body of literature, the question to be raised is not if WMH shape is a marker with added value over WMH volume, but how WMH shape should be considered and interpreted, and if and how they are related to aging or possibly different disease stages. 8.3 FUTURE DIRECTIONS Dementia research is a dynamic field where interdisciplinary work is becoming increasingly important. The fact that a big part of dementia cases are later confirmed to be mixed pathologies, makes it important to investigate neurodegenerative and neurovascular pathologies together and not only as separate disease entities.6 There may be links between the different pathologies and it remains unclear if one disease enhances the other or how much shared disease processes are part of the reason for mixed pathologies.6 Moreover, SVD is a highly heterogenous whole-brain disease in itself and its subtypes are currently mostly ill-defined. Not only are new biomarkers needed, but we also need to better understand how existing biomarkers relate to different types of SVD pathology.
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