Vascular risk factors for depression and apathy | Part II 130 Furthermore, not only CSVD but also large vessel ischemic or hemorrhagic stroke has been shown to be associated with apathy 38. Could large vessel stroke act as a confounder the studies under review? This is not very likely, since only 2 studies did not report on the presence of stroke 24 42, 4 studies included stroke patients only 41 37 39 36, while all the other studies excluded participants with a history of stroke 45 51 46 31 32 33 40 or with signs of large vessel stroke on neuroimaging 26 52 43 34 50 35 44 47 54 53 58 48 49 10. In conclusion, the majority of the studies on the CSVD-apathy association might be confounded by the use of (sedative) medication or physical impairment, which is a weakness in the body of evidence supporting this relationship. While the presence of depressive disorder, cognitive impairment and stroke are well controlled for in most studies, particularly in old-age these risk-factors often co-occur with CSVD and might still contribute in causing an apathy syndrome in the individual. And indeed, in individuals with apathetic behavior showing CSVD on neuroimaging there was not seldom an interplay between cognitive impairment, depressive disorder and apathy 72 79 48. Hence, the specificity of the causal relationship between CSVD and apathy is low. Discussion CSVD and apathy: a causal relationship? In conclusion, there is evidence that not only shows an association between WMH as a biomarker of CSVD and apathy but also supports a causal relationship between CSVD and apathy. Nevertheless, the evidence of a temporal and dose-response relationship is still weak and would benefit from prospective studies investigating the relationship between total CSVD burden (or WMH) change and change in apathy severity, most preferably in or comparing different, well-characterized populations. Better still would be if imaging techniques were applied, -such as DTI-, that provide information on the disruption of networks, in prospective studies on apathy and apathy severity, since not only the volume of WMH or total CSVD burden, but also the location of the damage due to WMH or CSVD might be a determining factor in the extent of network destruction in the brain. Vascular apathy: a distinct clinical syndrome? Although there is evidence to support that CSVD can be a cause and possibly a sole cause of an apathy syndrome, this does not mean that use of the term ´vascular apathy´ as a subcategory of the more generic term ´apathy syndrome´ is applicable to clinical practice. One of the objectives of this narrative review was to establish if we can say that vascular apathy is a clinical syndrome in its own right, i.e., a combination of symptoms resulting from a single cause or so commonly occurring together as to constitute a distinct clinical picture?
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