Vascular risk factors for depression and apathy | Part II 122 Abstract The vascular apathy hypothesis states that cerebral small vessel disease (CSVD) can cause apathy, even when no other symptoms of CSVD are present. In order to examine this hypothesis, the objectives of this narrative review are to evaluate the evidence for a pathophysiological mechanism linking CSVD to apathy and to examine whether CSVD can be a sole cause of apathy. The nature of the CSVD-apathy relationship was evaluated using the Bradford Hill criteria as a method for research on the distinction between association and causation. Pathological, neuroimaging, and behavioral studies show that CSVD can cause lesions in the reward network, which causes an apathy syndrome. Studies in healthy older individuals, stroke patients and cognitively impaired persons consistently show an association between CSVD markers and apathy, although studies in older persons suffering from depression are inconclusive. A biological gradient is confirmed, as well as a temporal relationship, although the evidence for the latter is still weak. The specificity of this causal relationship is low given there often are other contributing factors in CSVD patients with apathy, particularly depression and cognitive deterioration. Differentiating between vascular apathy and other apathy syndromes on the basis of clinical features is not yet possible, while in-depth knowledge about differences in the prognosis and efficacy of treatment options for apathy caused by CSVD and other apathy syndromes is lacking. Since we cannot differentiate between etiologically different apathy syndromes as yet, it is premature to use the term vascular apathy which would suggest a distinct clinical apathy syndrome. Introduction As a clinical syndrome, apathy is characterized by diminished motivation, leading to a reduction in emotions, thoughts and initiative to perform activities 1 . Cerebral small vessel disease (CSVD), an atherosclerotic disease of the brain causing ischemic changes in the surrounding brain tissue, is suspected to be a cause of this frequent and disabling syndrome 2 3. Neuroimaging markers of CSVD include white matter hyperintensities (WMH), cerebral microbleeds, lacunar infarcts and visible perivascular spaces. Clinically, CVSD is associated with several symptoms and consequences, in particular cognitive impairment, problems with gait and balance and a higher incidence of depression, stroke, dementia, disability and death 4. The vascular apathy hypothesis states that CSVD can be a sole cause of apathy, even in the absence of other symptoms of CSVD 5 6 7. Apathy is seen in 2-6% of the general population, with its prevalence increasing with age 8. Also the prevalence of CSVD increases with age, from 5% in people aged 50 years to almost 100% in those older than 90 years 9. In CSVD populations 52% had severe apathy (based on the Apathy Scale and a median cut-off of 3) 10. Given these high prevalence rates, the vascular apathy hypothesis is particularly relevant for older populations, even more so considering the often more profound consequences of apathy such as aggravated functional impairment 11, reduced quality of life 3, high caregiver burden 12 13, and a raised risk of incident cardiovascular disease, stroke and mortality 14 and dementia 15.
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