Vascular risk factors for depression and apathy | Part II 124 Table 1. Bradford-Hill criteria for causation Criterion Description Plausibility There is a rational, logical basis for an association. Strength The association is strong. Temporality The cause precedes the effect. Biological gradient There is a dose-response relationship. Consistency The association is established in multiple observations in different populations under different circumstances. Specificity The outcome is best predicted by one primary factor. Coherence The association is coherent with other knowledge. Experimental evidence The association is confirmed in experimental designs. Analogy An analogue phenomenon in another area is already accepted. For the plausibility-criterion we looked into the pathophysiological mechanisms that would link CSVD to apathy, thus supporting a causal relationship. To establish the strength of the association we looked into the odds ratios (OR), standard mean differences (SMD) and (clinical) significance of associations between CSVD biomarkers and apathy measures. A biological gradient was established if the level of CSVD was associated with the level of apathy. The temporality-criterion was fulfilled if the CSVD-apathy association was established in prospective studies. The consistency was based on the diversity of populations and circumstances in which the association was established and on the validity of the methods used to asses CSVD and apathy. Moreover, we established if these findings were coherent with results from other areas of research. In our context specificity is established when the outcome (apathy) is best predicted by this one primary factor (CSVD). Hence, we looked at other important risk-factors for apathy and to what extent these could have influenced the results of studies assessing the CSVD-apathy association. The criterion of experimental evidence cannot be evaluated since no cure for CSVD is yet established. Bradford-Hill stated that the criterion of analogy can provide some circumstantial additional support 16, but it is not a core criterion for causation and we chose not to use it as evidence in this narrative review. Results Plausibility What pathophysiological mechanisms would link CSVD to apathy? In CSVD the small perforating arterioles, the capillaries and probably the venules of the brain are dysfunctioning, causing lesions. WMH, cerebral microbleeds, lacunar infarcts and perivascular spaces are biomarkers of CSVD, visible on neuroimaging 18. It concerns a
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