73 White matter hyperintensity shape and cognitive decline over 5 years 4 Previously, we found that a more irregular shape of periventricular/confluent WMHs was associated with an increased long-term dementia risk over 10 years in the same dataset.6 However, which cognitive functions mediate this association at a more short-term (5 years) remained unclear. A recent cross-sectional study in patients with manifest arterial disease using the same WMH shape markers showed that a more irregular shape of periventricular/confluent WMH was related to decreased executive functioning and memory performance.18 Moreover, another cross-sectional study in cognitively impaired individuals showed that mental speed and fluid abilities showed a stronger association to a more irregular shape of WMH (based on a confluency sum score) than WMH volume.19 To the best of our knowledge, our study is the first to investigate WMH shape and cognitive decline over time in domain scores in community-dwelling older adults. Our study showed that WMH shape markers are associated with decline in individual cognitive domains over time. As these associations were largely independent of WMH volume, this suggests that WMH shape conveys additional information about WMHs, which is not captured by WMH volume alone. In previous studies periventricular/confluent WMH burden or volume showed a stronger association with cognitive functioning and cognitive decline compared to deep WMH burden or volume.20,21 In a longitudinal study in the general population (n=563), with a similar age and comparable population to our study, periventricular WMH burden was associated with cognitive decline over nearly 10 years, but deep WMH burden was not.20 While deep WMH are often found in regions of short-looped U-fibers connecting different cortical regions, periventricular WMH largely involve regions of long associating fibers with subcortical nuclei and other more distant brain regions.22,23 Therefore, changes in a long fiber region may have more severe consequences, and also cognitive reserve mechanisms may suffer more from changes in periventricular regions compared to deep white matter regions. Another explanation could be that periventricular/confluent WMH are typically larger in volume compared to deep WMH and therefore involve a larger area of the brain. In our study, we found that both periventricular/confluent WMH volume and deep WMH volume are related to cognitive decline in all three domains (memory, executive function, and processing speed), most pronounced in the memory and processing speed domains. In a previous meta-analysis in relatively healthy older adults without cognitive impairment from 60 years of age, WMH volume and burden were also related to cognitive decline in three cognitive domains (memory, attention and executive function), slightly more pronounced for the domain attention and executive function.3
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