Determinants of cerebral infarction and intracerebral hemorrhage: the Rotterdam Study

Stroke is a frequent disorder in elderly people. Despite improvements in primary prevention, the burden of stroke remains high and is predicted to even increase in the near future due to aging of the population. Therefore, additional targets for primary prevention are urgently needed. Most previous epidemiological studies have not specifically studied the two main subtypes of stroke, i.e., cerebral infarction and intracerebral hemorrhage, whereas differences in etiology between these subtypes suggest that they may have different risk profiles. Therefore, primary prevention may benefit from the identification of subtype-specific determinants. The aims of this thesis were to study trends in stroke incidence rates and stroke risk factors in the past twenty years, and to identify new determinants for any stroke, cerebral infarction, and intracerebral hemorrhage. The studies described in this thesis were part of the Rotterdam Study, a large population-based cohort study among elderly people who were followed from 1990 up to the present day for the occurrence of stroke and other diseases that are frequent in the elderly. Changes in stroke incidence rates and stroke risk factors in Rotterdam in the Netherlands between 1990 and 2008 were described in chapter 2. The major finding was a 34% decrease in stroke incidence rates in men, but no change in women. The prevalence of risk factors, such as hypertension and obesity had increased, although cigarette smoking had decreased in men. Other risk factors, such as atrial fibrillation, low high-density lipoprotein cholesterol and diabetes mellitus were unchanged. However, the proportion of men and women taking preventive medication had increased enormously. The divergent trends in stroke incidence rates in men and women stress the need for adequate recognition and treatment of stroke risk factors in women. In chapter 3, I reported my findings regarding the association of the plasma protein von Willebrand factor, which plays an important role in hemostasis but also marks the presence of endothelial dysfunction, with stroke and its subtype cerebral infarction. Higher von Willebrand factor levels were associated with an increased risk of stroke and cerebral infarction (chapter 3.1). However, genetic determinants of von Willebrand factor levels were not associated with stroke risk, either individually or joint in a weighted sum score (chapter 3.2). These findings suggest that von Willebrand factor is a marker for stroke risk, but probably not an important causal factor. Chapter 4 includes three studies concerning the association between retinal characteristics and risk of any stroke, cerebral infarction and intracerebral hemorrhage. The first study showed that wider retinal venular calibers were not only associated with an increased risk of cerebral infarction, but also with an increased risk of intracerebral hemorrhage (chapter 4.1). Furthermore, these associations were stronger for lobar than deep intracerebral hemorrhages. Both narrower arteriolar calibers and wider venular calibers were strongly associated with risk of anticoagulation-related intracerebral hemorrhage. The second study showed that the presence of retinopathy signs was associated with an increased risk of any stroke, but that this association was due to an increased risk of unspecified stroke and not due to an increased risk of either cerebral infarction or intracerebral hemorrhage (chapter 4.2). The third study addressed the association between age-related macular degeneration and risk of stroke and showed that late stage age-related macular degeneration was associated with an increased risk of intracerebral hemorrhage, but not with risk of cerebral infarction (chapter 4.3). Altogether, these three studies suggest that several retinal characteristics may be used as markers for future or present cerebrovascular pathology. Chapter 5 contains three studies on metabolic determinants of stroke. In chapter 5.1 I described the association between serum lipid fractions and risk of intracerebral hemorrhage and presence of cerebral microbleeds, and showed that low triglyceride levels are associated with an increased risk of intracerebral hemorrhage, and with the presence of deep or infratentorial microbleeds, but not with lobar microbleeds. Because deep and infratentorial microbleeds are considered markers of arteriolosclerosis, whereas lobar microbleeds more likely reflect amyloid angiopathy, these findings suggest that low triglyceride levels may play a role in the development of arteriolosclerotic microangiopathy. Chapter 5.2 addressed the association between liver enzyme levels and risk of intracerebral hemorrhage, and the role of alcohol in this association. Alkaline phosphatase and lactate dehydrogenase were associated with an increased risk of intracerebral hemorrhage independently of alcohol intake. However, aspartate transaminase, alanine transaminase and gamma-glutamyltranspeptidase were associated with intracerebral hemorrhage only in people who drink excessive amounts of alcohol. In chapter 5.3, I described the associations between insulin resistance markers and risk of any stroke, cerebral infarction and intracerebral hemorrhage in nondiabetic elderly. Insulin resistance markers were not associated with risk of any stroke or its subtypes. Although diabetes mellitus is a strong risk factor for stroke, these findings suggest that below the diabetes threshold, the degree of insulin resistance is not associated with risk of any stroke, cerebral infarction or intracerebral hemorrhage. Chapter 6 is a general discussion of the main findings, methodological issues concerning the classification of stroke subtypes, potential clinical implications of the main findings and future perspectives. To conclude, in this thesis I reported on several new determinants of cerebral infarction and intracerebral hemorrhage. Future research should further unravel the pathophysiologic mechanisms and investigate the potential of these determinants as risk predictors or as targets for preventive intervention.

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