85 White matter hyperintensity shape is associated with long-term dementia risk 5 5.2 BACKGROUND Cerebral small vessel disease (SVD) contributes to the development of dementia and cognitive decline.1, 2 SVD usually starts with only minor brain abnormalities that show slow progression over many decades. At an early stage individuals with SVD may benefit from available lifestyle interventions and future drug trials aimed at prevention of dementia, as previous studies showed that early lifestyle interventions in populations at risk could slow the pathophysiological processes in cerebral SVD.3-5 However, it is currently impossible to accurately identify those individuals with SVD who have an increased risk of dementia at an early stage. Novel, more sensitive, and specific biomarkers are therefore needed. WMHs are a common finding in older adults and may be caused by acquired diseases over the lifecourse.6 A major cause of WMHs is cerebral SVD. Although WMHs are associated with the occurrence of dementia and cognitive decline,7, 8 not everyone with WMHs will develop cognitive decline or dementia.7 The challenge is to identify individuals with specific WMH patterns who are at risk to develop cognitive decline or dementia. WMH volume is a much used, but crude, marker that does not allow such a distinction. Other WMH markers, such as WMH type and shape, have therefore been introduced in recent studies as promising novel markers that may offer a more detailed characterization of WMHs than volume alone. Neuroimaging studies in community-dwelling older adults previously analyzed the burden or volumes of periventricular and deep WMH, suggesting that periventricular WMHs have a stronger association with cognitive decline than deep WMHs.9 These findings are probably mostly driven by the usually larger volume of periventricular WMH compared to deep WMH. To date, WMH shape has received little attention. Some previous post mortem histopathological studies showed that WMH shape was associated with a difference in underlying pathologies.7, 10 In these studies, a more irregular shape of confluent WMH was associated with more severe parenchymal changes than mild and smooth periventricular WMH.11, 12 We hypothesized that different underlying SVD pathologies result in a different WMH shape that can be quantified by MRI-based WMH shape markers. Indeed, our previous study showed that WMH shape was associated with long-term risk for stroke and increased mortality in patients with an increased vascular risk.13 However, the association of WMH shape markers and long-term dementia risk remains unknown. We therefore aimed to investigate the association between WMH shape and volume and long-term dementia risk in community-dwelling older adults.
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