Jasmin Annica Kuhn-Keller

30 Chapter 2 including Alzheimer’s patients, subjects at risk for cerebrovascular disease and healthy controls.31 The study found periventricular WMH volume to be correlated with severity of arteriolosclerosis and breakdown of the ventricular lining.31 Deep WMH volume, however, was correlated with cerebral hemorrhages and microinfarcts, as well as demyelination.31 Depending on the affected cell type (e.g. vascular or parenchymal), the type of pathophysiology and the anatomical structure of the affected areas, WMH shape may be influenced. These differences in WMH etiology may become evident as different WMH shape patterns and locations (for example punctuate versus elongated deep WMH). Some previous studies have also shown a link between WMH shape and underlying histological findings.8,9 Overall, pathological studies confirm the hypothesis that WMH have a heterogenous etiology18—with a strong vascular component. Vascular pathologies may lead to parenchymal changes, subsequently leading to distinct WMH phenotypes on MRI. How different WMH lesion and shape patterns develop related to a certain underlying pathology remains to be investigated in future studies, as in our study it is impossible to link WMH shape patterns to specific underlying mechanisms. Novel advanced MRI markers (such as WMH shape) that are more specific than WMH volume, may help in elucidating the link between histopathology and MRI findings. The strengths of our study are the relatively large sample size, and the application of novel advanced MRI image processing methods. A limitation of our study could be that participants were all scheduled for major elective surgery, and therefore this sample might not be an equivalent of a general population-based group. This could limit the generalizability of our findings to the general population, as this could have led to an underestimation of the associations. Another limitation of our study could be that the cardiovascular risk factors were based on medical records and self-reported rather than objective measurements (e.g. blood pressure, glucose levels and cholesterol/triglyceride levels). Although these risk factors were scored by qualified physicians (anesthesiologists (in training)), we cannot exclude the possibility that some patients may have undiagnosed hypertension, diabetes or hypercholesterolemia. This may partially account for the lack of significant associations between these cardiovascular risk factors and the WMH markers. An additional limitation could be that although most participants had a relatively high MMSE score (median: 29, (IQR: 27,30)), there may have been participants included in this study with mild cognitive impairment. A technical limitation of our method could be that when total WMH volume increases, usually the deep WMH count decreases, as bigger WMH lesions start to overlap with each other. For instance, deep WMH may become part of confluent WMH and only shape markers for periventricular/confluent WMH can be determined. This can partially explain why we found fewer associations with deep WMH shape markers.

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