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Small vessel disease is a stroke subtype characterized by pathology of the small perforating arteries, which supply the sub-cortical structures of the brain. Small vessel disease is associated with high rates of apathy and depression, thought to be caused by a disruption of white matter cortical-subcortical pathways important for emotion regulation. It provides an important biological model to investigate mechanisms underlying these key neuropsychiatric disorders. This study investigated whether apathy and depression can be distinguished in small vessel disease both in terms of their relative relationship with white matter microstructure, and secondly whether they can independently predict functional outcomes. Participants with small vessel disease (n = 118; mean age = 68.9 years; 65% male) defined as a clinical and magnetic resonance imaging confirmed lacunar stroke with radiological leukoaraiosis were recruited and completed cognitive testing, measures of apathy, depression, quality of life and diffusion tensor imaging. Healthy controls (n = 398; mean age = 64.3 years; 52% male) were also studied in order to interpret the degree of apathy and depression found within the small vessel disease group. Firstly, a multilevel structural equation modelling approach was used to identify: (i) the relationships between median fractional anisotropy and apathy, depression and cognitive impairment; and (ii) if apathy and depression make independent contributions to quality of life in patients with small vessel disease. Secondly, we applied a whole-brain voxel-based analysis to investigate which regions of white matter were associated with apathy and depression, controlling for age, gender and cognitive functioning. Structural equation modelling results indicated both apathy (r = -0.23, P ≤ 0.001) and depression (r = -0.41, P ≤ 0.001) were independent predictors of quality of life. A reduced median fractional anisotropy was significantly associated with apathy (r = -0.38, P ≤ 0.001), but not depression (r = -0.16, P = 0.09). On voxel-based analysis, apathy was associated with widespread reduction in white matter integrity, with the strongest effects in limbic association tracts such as the anterior cingulum, fornix and uncinate fasciculus. In contrast, when controlling for apathy, we found no significant relationship between our white matter parameters and symptoms of depression. In conclusion, white matter microstructural changes in small vessel disease are associated with apathy but not directly with depressive symptoms. These results suggest that apathy, but not depression, in small vessel disease is related to damage to cortical-subcortical networks associated with emotion regulation, reward and goal-directed behaviour. [ABSTRACT FROM AUTHOR]