49 White matter hyperintensity shape and long-term progression of cerebrovascular disease 3 There are several possible mechanisms to explain the association of WMH shape and progression of different SVD and LVD markers. For example, subcortical infarcts and WMHs may share (part of) the same SVD-related pathological pathways.18,19 WMHs might be related to subcortical infarcts via secondary hypoperfusion and the resulting ischemia in the parenchyma surrounding the WMHs.20 We found that a more irregular shape of periventricular/confluent WMHs was related to, among others, new subcortical infarcts, new microbleeds, and new enlarged perivascular spaces. In a previous population-based study, pre-existing and incident microbleeds were associated with incident lacunes and progression of WMH volume.21 The authors propose that this association can be explained by shared pathways of haemorrhagic and ischemic pathologies in the preclinical phase of cerebrovascular disease.21 While some previous studies report an association between WMH burden and enlarged perivascular spaces, a previous meta-analysis has concluded that there is no clear association.22 In the current study, baseline periventricular/confluent WMH shape was associated with new enlarged perivascular spaces at follow-up, but we did not find an association between baseline WMH volume and new enlarged perivascular spaces at follow-up. This result was found despite the relatively limited progression of enlarged perivascular spaces at follow-up. This suggests that WMH shape might contain additionally relevant information regarding SVD compared to WMH volume alone. Furthermore, enlarged perivascular spaces are a relatively new marker of SVD23 and the current findings strengthen their presumed connection to SVD pathology. Combined, these findings illustrate that WMH shape may help to differentiate between different further subtypes of SVD, which is reflected in the association of different WMH shape patterns to different cerebrovascular markers. For example previous research has already shown that different more rare subtypes of SVD lead to different patterns of MRI changes (e.g. in cerebral amyloid angiopathy (CAA) or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)24,25), but much is still unknown in this heterogenous disease. WMH shape may help to further differentiate subtypes of SVD by providing a more detailed characterization of WMHs on MRI. In the current study, less elongated and more irregularly shaped deep WMHs were associated, among others, with new cortical infarcts at follow-up. Since cortical infarcts are a marker of LVD, the related WMH shape patterns of deep WMH may be indicative of a pathophysiological involvement of LVD. Periventricular/confluent WMH shape, on the other hand, was not related to new cortical infarcts at followup. Cerebellar infarcts can represent both SVD and LVD and are presumed to be of embolic origin. In the current study, cerebellar infarcts were associated with periventricular/confluent WMH shape, but not with deep WMH shape markers.
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