Part 1 | Vascular risk factors for depression and apathy 47 3 Introduction Late-life depression is not only a common and disabling condition in later life, it also predicts the onset of major medical illnesses, such as stroke 1 2 3 4. Depression is driven by multiple etiologic factors, including personality (such as neuroticism) 5 and vascular factors 2 6 7. Especially among older people, both of these pathways may act to a certain degree in individual patients. Therefore, the degree to which depression is a predictor of incident stroke might be conditional on the relative weight of vascular disease (vascular depression) and of neuroticism (neurotic depression) as the underlying pathways to depression. Meta-analyses show that late-life depression is prospectively associated with stroke 3 8. Nonetheless, the same meta-analyses point to significant heterogeneity across studies 8, that has not been explained properly 8. Recently, it was found that depression in the oldest-old does not increase stroke risk, but is a risk factor for all-cause mortality 9. The effects of depression on stroke risk may be due to residual confounding by severity of subclinical vascular disease 10. Many older persons without a history of ischemic heart disease or stroke have a significant level of vascular pathology in presence of generalized atherosclerosis. Recently, we have shown that the intima-media thickness of the carotid artery, a marker for generalized atherosclerosis, is associated with depressive symptoms, even in the absence of a history of vascular events 11 . This association, however, was confined to the somatic-affective symptoms domain of depression, which may indeed point to overlap between subclinical vascular disease and depression 11. Interestingly, incident depression after a myocardial infarction also predicted a poorer prognosis of heart disease, whereas recurrent depression as well as depression associated with a high level of neuroticism did not 12 13 14. These findings fit with the hypothesis that the risk of depression on future vascular events is conditional upon depressive symptoms related to underlying vascular disease and not upon neuroticism-associated depression. In the Longitudinal Aging Study Amsterdam (LASA), we have shown that depression only predicted incident stroke in older persons with preexisting cardiac disease 4. A logical explanation would be that in noncardiac patients the contribution of vascular disease burden to depression is minimal and other pathways like high levels of neuroticism may be more important. Nonetheless, this explanation does not fully fit with abovementioned findings that depression is also associated with subclinical vascular disease 11. The present study, therefore, is an extension of our previous findings in LASA 4 . We assume that the association between depression and vascular events is confounded by underlying vascular disease in later life and that this may differ for different subtypes of depression (vascular vs neurotic-associated depression). The aim of this study was to examine whether a lower level of neuroticism in older persons with depression without preexisting cardiac disease would be associated with increased risk of stroke in LASA. We a priori hypothesize that vascular depression, defined theoretically by a high etiologic contribution of vascular disease, increases the risk on future strokes, whereas neuroticism-associated depression does not.
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