97 White matter hyperintensity shape is associated with long-term dementia risk 5 5.5 DISCUSSION We showed that a more irregular shape of periventricular/confluent WMHs was associated with an increased long-term dementia risk in community-dwelling older adults. No associations were found between the shape of deep WMHs and long-term dementia risk. Higher total, periventricular/confluent, and deep WMH volume was associated with an increased long-term dementia risk. This is the first study investigating the association between WMH shape and longterm dementia risk. Previous studies already suggested that WMH shape could facilitate a more detailed characterization of WMHs,13, 22, 18 as it can help to more accurately quantify the heterogeneity of WMH related to underlying pathological changes. Distinct WMH shape patterns were previously shown to be associated with increased long-term risk of stroke and mortality.13 Moreover, a more complex WMH shape was related to physical frailty in a previous study25 and may also indicate a predisposition for postoperative delirium.26 In the current study, we showed that distinct WMH shape patterns are related to long-term dementia risk. The current findings strengthen the hypothesis that differences in long-term disease outcome can be predicted by MRI-based WMH shape markers. WMH shape may be a suitable additional marker next to WMH volume to describe WMH changes, as the heterogeneous nature of WMH that has been demonstrated in histopathological studies cannot be fully described by WMH volume alone.7, 10 Variations in WMH shape patterns are likely to reflect the heterogeneous nature of the pathologies underlying WMHs. As SVD affects the vasculature of the brain, hypoperfusion is a key pathological contributor to white matter damage.27 Periventricular/confluent WMHs are located centrally in the brain within a deep watershed area that is vulnerable to hypoperfusion, as this area is supplied by long perforating arterial branches.7 Disruption of the complex structure of the microvascular network surrounding the lateral ventricles may be reflected in distinct WMH shape patterns. In previous studies where periventricular WMH and deep WMH burden and volume were analyzed in community-dwelling older adults, periventricular WMH volumes and burden were frequently associated with long-term dementia risk and cognitive decline,28-30 but not with deep WMH.28-30 In our study, we indeed showed an association between periventricular WMH volume and long-term dementia occurrence, and additionally showed an association with deep WMH volume. Furthermore, as WMH volume increases, periventricular WMHs can merge with deep WMHs to form confluent WMHs. This will result in a relatively lower deep WMH volume and may
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