Part II | Vascular risk factors for depression and apathy 149 8 In Chapter 7, the vascular apathy hypothesis was evaluated from a broader perspective. We evaluated the evidence for a pathophysiological mechanism in CSVD that could cause apathy and the evidence for the hypothesis that CSVD can be a sole cause of apathy by the Bradford-Hill criteria to distinguish between association and causation. Pathological, neuroimaging and behavioral studies plausibly and coherently showed that pathophysiologically CSVD can cause lesions in the reward network, which can clinically cause an apathy syndrome. Although observational studies in elderly individuals with depression were inconclusive, studies in healthy older adults, stroke patients and people with cognitive impairment consistently showed an association between CSVD (or WMH as a marker of CSVD) and apathy; a biological gradient was confirmed, as well as a temporal relationship, although the evidence for the latter was still weak. The specificity of this causal relation was low and there were often other contributing factors at play in CSVD patients showing symptoms of apathy, particularly depression and cognitive deterioration. Differentiating between vascular apathy and other apathy syndromes on clinical features was not (yet) possible, and in-depth knowledge about differences in the prognosis and efficacy of treatment options for apathy caused by CSVD and other apathy syndromes was lacking. In conclusion, although a causal relationship between CSVD and apathy was established, CSVD was often not the sole cause of apathy, and we recommend looking for other contributing factors in CSVD patients with apathetic symptoms. We also concluded that it is premature to use the term “vascular apathy” since it refers to a distinct clinical apathy syndrome, where we cannot yet differentiate apathy syndromes. Methodological and research considerations Of course, there are limitations to the findings of the research reported in this thesis, research considerations to be made and lessons to be learned for future designs. First, in the three studies presented in Part I, we focused on the relationship between cerebrovascular disease and late-life depression, without considering apathy, where apathy might have been a (residual) confounder. When planning longitudinal aetiological or efficacy studies of late-life depression, we recommend researchers to take apathy into account. When we specifically took care to distinguish between mood and apathy symptoms (Chapter 5), this yielded unexpected results. We could not establish a CSVD-apathy association in remitted depression as previous studies had done in other populations. Since loss-of-interest, anhedonia and psychomotor retardations are also part of a depressive syndrome, we suggested that apathy in remitted depression might more often than has thus far been recognized be a residual symptom of the depression patients have recovered from. This hypothesis warrants further looking into since depression affects so many people, also in later life, and apathy in depression and remaining apathy in remitted depression are also highly prevalent, with all its serious clinical and societal consequences. “Positive” symptoms of depression, such as a diminished mood, ruminating, negative thinking and suicidal thoughts and behavior have, understandably, been receiving much
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