Part II | Vascular risk factors for depression and apathy 109 6 Discussion Main findings The results of our review indeed support the hypothesis that SSVD is related with apathy. More specifically, as peripheral proxies for SSVD, hypertension and cardiovascular disease were consistently found to be associated with apathy 9 29 30 43. With the only study examining ABI finding a significant association with apathy while another single study focusing on arterial stiffness did not 43 44, the results with respect to other peripheral measures of atherosclerosis were inconclusive. Apathy was, however, also linked to cerebral microbleeds 51 and WMH load 30 48. SSVD was related to white matter diffusivity; however a direct association between white matter diffusivity and apathy has not been established yet 45 50. The evidence on the relationship between cortical thickness and apathy is inconclusive 31 32 47. Hypertension, cardiovascular disease, white matter hyperintensities and apathy Both systolic and diastolic blood pressure were associated with apathy 9 30 43, while associations between white matter hyperintensities and apathy (and cerebral microbleeds and apathy) were found in large-scale and high-quality studies 30 48 51. Although Delrieu et al.49 did not find any such evidence, their study may have been underpowered. Finally, cardiovascular disease was firmly associated with apathy, not only cross-sectionally but also longitudinally 9 29. Although its aetiology is not fully understood, WMH reflects ischaemic arteriolosclerosis in the brain 27 and is related to congenital heart disease, hypertension, carotid blood flow, diabetes and cardiovascular health 52. WMH may then be seen as consequence of chronic hypoperfusion as well as impaired cerebrovascular reactivity. Nonetheless, bloodbrain-barrier leakage and myelin-remodeling problems could play a role 53. The relation between hypertension, cardiovascular disease and WMH could be limited blood flow to the brain and/or arterial stiffness 52 53 54. How SSVD can lead to apathy is not yet fully understood. Destruction of limbic or reward pathways are considered as a potential cause. Indeed, apathy was found to be associated with impaired connectivity of limbic association tracts in patients with clinical SVD 55. The results of the DTI studies of white matter connectivity and apathy in SSVD, however, were not conclusive 45 50. Cortical thinning, SSVD and apathy The contradictory findings regarding the relationship between cortical thickness and apathy might be due to other mechanisms than SSVD leading to cortical thinning. Cortical thickness and WMH are associated, but they are not interchangeable 56 57. Cortical thinning in the parietal lobes, anterior insula and caudate nuclei bilateral is related to WMH, but widespread cortical thinning is related to normal aging as well as early
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