2 23 Cardiovascular risk factors are related to distinct white matter hyperintensity MRI phenotypes ‘tissue volumes’. The lesion prediction algorithm of the lesion segmentation toolbox version 2.0.1513 (https://www.sta tistical-modeling.de/lst.html) for SPM12 was used for WMH segmentation. The quality of the WMH segmentations was visually checked by a trained researcher (IK) under supervision of a neuroradiologist experienced in brain segmentation (JB). Cortical brain infarcts were manually delineated and removed from the WMH probability maps. The lateral ventricles were segmented on the T1-weighted images using the automated lateral ventricle delineation toolbox14 (ALVIN; https://www.nitrc. org/projects/alvin_lv/ in SPM8. A threshold of 0.10 was applied on the probabilistic WMH segmentations. Periventricular WMH were defined as WMH contiguous with the lateral ventricles and extending ≤ 10 mm into the deep white matter. Confluent WMH were defined as WMH contiguous with the lateral ventricles and extending > 10 mm into the deep white matter. Deep WMH were defined as being located > 3 mm from the lateral ventricles and > 5 voxels (3.45 × 10−3 ml). Based on the binary WMH segmentation data, WMH shape markers were calculated.7 For periventricular/confluent WMH, solidity was calculated by dividing lesion volume by the volume of its convex hull. Dividing the convex hull sur- face area by the lesion surface area provides the convexity of the WMH. A lower solidity and a lower convexity indicates a more complex shape.7 The concavity index is a measure of roughness and was calculated from solidity and convexity.7 A higher concavity index indicates a more irregular shape.15 Eccentricity of deep WMH was calculated by dividing the minor axis of the WMH by its major axis. Fractal dimension was calculated as a measure for irregularity of deep, and periventricular/confluent WMH using the box-counting method. Higher fractal dimension and eccentricity values suggest a more complex WMH shape.7 These WMH shape markers were selected because of their ability to capture the expected shape variations of different types of WMH accurately (see Supplementary Table S.2.8.1 for an overview).7 Mean values per WMH shape marker were calculated per patient and used for further analyses. The accuracy of the WMH shape marker calculation is dependent on WMH size. Periventricular/confluent lesions vary in size and especially in earlier stages the lesions are not only smaller, but are in a different range of shape markers. The shape parameters used in our study are more accurate in capturing the WMH shape of bigger periventricular/confluent lesions. Therefore a minimum WMH volume of 4 ml was applied as a threshold for the analyses of periventricular/confluent WMH shape markers to assure our method is robust and accurate.
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