Part II | Vascular risk factors for depression and apathy 123 7 Although attractive as a hypothesis, many questions remain unanswered. Questions that remain are whether CSVD is a true causal factor for apathy and whether it can be a sole cause of apathy. Furthermore, the term ‘vascular apathy’ suggests a distinguishable clinical syndrome, but is that claim truly supported by the evidence? This information is not only relevant for researchers, but also for clinicians. Researchers need a clear overview on what we do and what we do not know to help devise relevant research designs to fill in the gaps in our knowledge. Clinicians need this information to decide on how to interpret symptoms of patients presenting with apathy and signs of CSVD on imaging and to decide on what information and advice to give to these patients and their relatives and/or caregivers. Objectives The objective of the present narrative review article is twofold. We sought to gather and evaluate the evidence suggesting a pathophysiological mechanism linking CSVD and apathy and to examine whether the hypothesis that CSVD can be a sole cause of apathy has been substantiated. Methods In order to be able to distinguish between association and causation, we tested the evidence using the Bradford Hill criteria 16 17, which are summarized in Table 1. No single criterion can prove causation, but each criterion adds to the credibility of causation. In order to establish whether CSVD can cause apathy, we searched the literature for evidence on the plausibility and the strength of associations. In addition, we assessed whether there is a biological gradient, we evaluated data on the temporality of associations and the consistency and coherence of the findings. Our second objective, to determine if CSVD can be a sole cause of apathy, was evaluated using the specificity-criterion. We performed various searches to identify relevant research work (see supplementary material for each specific research question). ´White matter hyperintensities´, ´lacunar infarcts´, ´cerebral microbleeds´, ´cortical thickness´ and ´perivascular spaces´ were included in the search criteria for ´cerebral small vessel disease´. When we searched for a combination of cerebral small vessel disease and apathy, we also included ´vascular apathy´ as a search term. Searches were performed in PUBMED, English language, on December the 9th, 2021. Abstracts of all articles were checked for relevance by the first author (LW). For some of the research questions recent (structured) reviews and metaanalyses were available. Information on other more recent research work which was not included in these (structured) reviews or meta-analyses was added when relevant to the argumentation.
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