2 29 Cardiovascular risk factors are related to distinct white matter hyperintensity MRI phenotypes similar study populations failed to show such an association.21,22 A recent systematic review addressing a possible association between type 2 diabetes and total WMH volume shows an association.23 The review did not only focus on cross-sectional or cohort studies, but also included case-control, and Mendelian randomization studies. Furthermore, a previous case-control study focused on patients with type 2 diabetes showed a higher eccentricity of deep WMH and a larger number of periventricular/ confluent WMH in diabetic patients compared to controls, but no differences in WMH volume.6 In our study in non-demented older adults, we did not find an association of diabetes with WMH shape markers, but found an association of diabetes with deep WMH volume. No previous studies have explored WMH shape in non-demented older adults, therefore our results cannot be directly compared to other studies. Based on these findings, WMH shape may be more sensitive than WMH volume for hypertensioninduced brain changes, but not for diabetes-induced brain changes. The association between hyperlipidemia and WMH remains ambiguous. In a previous study, an association between high cholesterol levels and a larger WMH burden was found in the general population above 65 years of age.24 Participants in this previous study are quite comparable to our study regarding age and cardiovascular risk factor profile. A previous case-control study focusing on stroke patients has shown a potential protective role of hyperlipidemia, as hyperlipidemia was associated with lower WMH volumes in two independent cohorts.25 However, it is unclear if this protective effect is (partially) mediated through the pharmacological treatment of hyperlipidemia with statins.25 This previous study has assessed a specific patient population (stroke patients) with a lower mean age in one of the cohorts compared to our study. No previous study has examined the association between hyper- lipidemia and WMH shape. In our study we did not find an association between hyperlipidemia and WMH volume, nor shape markers. Previous studies conducted using UK-biobank data, with a cross-sectional26, as well as an observational cohort study design27, showed an association of BMI with WMH volume. This effect may be mediated via low-grade systemic inflammation.28 However, no previous study has examined the association between BMI and WMH shape markers. In our study, we found no associations between BMI and WMH volume or shape markers. It should be noted that mean BMI in the UK-biobank study was similar to our study, while mean age was lower compared to our study.26 Little is known about the exact histopathological mechanisms underlying the formation of WMH, mainly due to the small number of pathology studies that have been conducted.29 Interestingly, in a histopathological study, structural markers of vascular dysfunction were found to be associated with WMH.30 More specifically, vascular integrity was shown to be reduced in areas where WMH were present compared to normal appearing white matter.30 Periventricular, and deep WMH were associated with different underlying neuropathological findings in a study
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