48 Chapter 3 3.5 DISCUSSION We found that a more irregular shape of periventricular/confluent WMH at baseline was associated with a larger increase in WMH volume, and with occurrence of new subcortical infarcts, new microbleeds, new enlarged perivascular spaces, and new cerebellar infarcts at the 5.2 year follow-up. Furthermore, less elongated and more irregularly shaped deep WMHs were associated with a larger increase in WMH volume, and new cortical infarcts at follow-up. A rounder shape of deep WMH was associated with new microbleeds at follow-up. It has been previously shown that a more irregular WMH shape is associated with an increased long-term risk for dementia in community-dwelling older adults,4 but how this effect is mediated remained unclear. The current study showed that specific WMH shape patterns are indicative of specific markers of cerebrovascular disease progression. The aetiology of WMH of presumed vascular origin in older adults is heterogenous and the exact pathophysiology remains poorly understood. Based upon our findings, we can speculate that a more irregular shape of WMH may reflect a more severe underlying aetiology of cerebrovascular disease, and as such is subsequently followed by increased progression of cerebrovascular disease-related brain changes. Histopathological studies have previously suggested that a more irregular WMH shape is associated with more severe parenchymal damage.5,15 Areas of smooth periventricular WMH showed demyelination and tortuous venules, as well as damage to the ventricular lining.5 On the other hand, previous histopathological investigations showed that irregular periventricular/confluent WMH showed gliosis, fiber loss, and reduced myelin.5 Moreover, the vessel walls in the areas of irregular WMH were thickened due to fibrohyalinosis and lipohyalinosis.5 A more complex and irregular shape of WMH may, therefore, be related to underlying pathologies that accelerate cerebrovascular disease progression. WMH are a hallmark imaging marker of cerebral small vessel disease (SVD). In SVD changes in the normal functioning of especially the arterioles, and capillaries (such as small or large vessel atheromas or emboli) subsequently lead to WMH through hypoperfusion. MRI markers that are typically associated with SVD are WMHs, microbleeds, enlarged perivascular spaces and subcortical infarcts.16 Large vessel disease (LVD), on the other hand, is mostly caused by atherosclerosis and atheroma depositions in the wall of larger upstream arteries, such as the carotid arteries. A typical brain MRI marker of LVD is a cortical infarct.16 LVD can also lead to lacunelike infarcts via atheromas in the larger parent arteries,16,17 which is also where SVD and LVD pathology may be linked.16
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