2 21 Cardiovascular risk factors are related to distinct white matter hyperintensity MRI phenotypes 2.2 INTRODUCTION Cerebral small vessel disease (SVD) is associated with the occurrence of dementia and stroke.1 In SVD, different underlying pathological mechanisms (such as small or large vessel atheromas or embolisms) lead to the phenotype of MRI-visible brain changes, namely white matter hyperintensities (WMH), lacunes and microbleeds.2,3 Individual cardiovascular risk factors play an important role in the etiology of SVD as they impact the small vessels via different pathological pathways and hence lead to distinct patterns of SVD related brain changes that may be differentiated.4 An example of this principle is the association between hypertension and deep cerebral microbleeds versus cerebral amyloid angiopathy and lobar microbleeds.5 Although WMH are the key MRI marker of idiopathic SVD, little is known about the association of individual cardiovascular risk factors and distinct patterns of WMH. WMH volume is typically used to study WMH, but this marker fails to fully quantify the complex brain changes related to underlying pathological changes of SVD.4 Moreover, WMH volume alone is insufficient for differentiation of underlying disease mechanisms leading to WMH. Aiming to overcome the limitations of conventional WMH volume markers, in recent studies WMH type and shape were introduced as more advanced WMH markers.6,7 For example, different WMH type (periventricular, deep and confluent) and also different WMH shape is associated with different underlying pathological changes.4,8,9 Furthermore, previous studies on WMH shape show potential diagnostic and prognostic value related to an increased mortality and stroke risk.6,7,10 The investigation of WMH type and shape markers may therefore help in the postulation of potential mechanisms of WMH development. Our hypothesis is that in older adults specific cardiovascular risk factors relate to distinct patterns of WMH, which can be quantified using advanced WMH MRI markers. Studying this hypothesis may aid in the understanding of WMH development and could in the future be used for earlier detection of individuals at risk for stroke or dementia. Therefore, we aimed to investigate the association between cardiovascular risk factors and advanced WMH markers (shape, type, and volume) in non-demented older adults. 2.3 METHODS 2.3.1 Participants We included data from the BioCog consortium study, collected from the University Medical Center Utrecht site.11 Inclusion criteria for the BioCog study were: minimal age of 65 years, a mini-mental state exam (MMSE) score of 24 or higher, and major surgery scheduled of at least 60 min (cardiothoracic (n = 35), gastroenterological (n = 22), gynecologic (n = 6), jaw (n = 11), ear nose throat (13), orthopedic (43), urological
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