Pathogenesis of Leukoaraiosis: A Review

Leukoaraiosis (LA) represents the most common phenotype of cerebral small vessel disease. It is of undoubted significance regarding its vast prevalence and neuropsychi‐ atric consequences, such as cognitive impairment, higher risk for ischaemic stroke and death. It has been associated with increasing age and conventional vascular risk factors (VRF). Despite huge efforts, LA pathogenesis is still incompletely understood. The hypotheses of ischaemia and malfunctioning blood‐brain barrier seem to oppose each other. Hence, the focus has turned to endothelial dysfunction, through which both aforementioned mechanisms could be coupled. The VRF, which are almost universally present in patients with LA, have a detrimental impact on endothelium on their own. However, in LA there may be an additional or even primary endothelial dysfunction at play. This seems to be at the core of LA pathogenesis, leading to chronic ischaemia in cerebral white matter and blood‐brain barrier dysfunction culminating in LA. The genetic susceptibility to harmful effects of VRF on endothelial function seems to play an important role. Regarding the burden of LA, interventional approaches should be aimed at decelerating or even halting the progression of the disease. These should focus on strict management of VRF and strategies to enhance endothelial function.