Part II | Vascular risk factors for depression and apathy 129 7 Hence, we conclude a causal relationship between CSVD and apathy is coherent with knowledge from other areas of research. Specificity To evaluate the specificity of the CSVD-apathy association we will look at other relevant risk-factors for apathy and if these could have confounded the results. Particularly in older populations, physical and motor disabilities, a diminished level of consciousness (as seen in delirium), substance use (for instance use of antipsychotics or benzodiazepines) or major changes in the patients environment are well-established and highly relevant risk-factors for apathetic behavior 69 70 71 72 73. These are ruled out in the diagnostic criteria for apathy 1, but most epidemiological research, especially in the general population, uses apathy rating scales rather than a broader clinical assessment 7. Of the 27 studies on the CSVD-apathy association which we assessed for this narrative review only 9 controlled for the use of sedatives34 35 44 45 48 49 31 32 40, the other studies did not or to a limited extent (i.e. only antidepressants), and only 8 controlled for physical impairment 37 36 35 40 47 58 56 49. In the brain, motivation, initiative and execution, -which are diminished in the apathy syndrome-, involve generating and weighing options, reaching a decision, generating arousal and acting, where the ability to anticipate, desire and like the outcome acts as a reward system and self-stimulating feedback loop 74. Besides the various brain areas forming the reward network 75 also multiple neurotransmitter systems that can be affected by neurodegeneration, such as the dopamine and serotonin systems, play a role in these processes 74 22. And not only the reward network, but also the salience network,-a network that processes emotional information and activates other networks to respond-, is associated with apathy and particularly in depression this network might be functionally affected 76 23 77. Depressive disorder is a frequent and relevant risk-factor for apathy, with apathy in latelife depression posing a risk for treatment resistance and often persevering, particularly in those with residual depressive symptoms 32 72. Except for a few studies of the CSVD-apathy relationship which only partially corrected for the presence of a depressive disorder 52 26, all studies considered in this narrative review acknowledged, assessed and corrected for this possible confounder. There is yet another highly relevant pathway causing apathy in late-life: cognitive impairment 72 69. Apathy in late-life, particularly in those with depression as well, is associated with cognitive impairment and dementia 78 15 79. In all studies on the CSVD-apathy relationship evaluated here, cognitive impairment was assessed and corrected for, although in some studies only to a limited extent (i.e. exclusion of participants with severe cognitive dysfunction) 26 39.
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