Cerebral small vessel disease (SVD) is a cerebrovascular pathology that affects the small vessels of the brain, resulting in heterogeneous brain tissue changes. These can lead to neuropsychiatric symptoms such as apathy, a loss of motivation, and depression, which is characterised by low mood and a loss of pleasure. Apathy and depression are both prevalent symptoms in SVD, but an understanding of the relationship between underlying disease processes and the expression of these neuropsychiatric symptoms remains poor.

This thesis uses magnetic resonance imaging techniques to examine the neurobiological basis of apathy and depression in SVD. We show that apathy is related to focal grey matter damage and distributed white matter microstructural change. These microstructural changes underlie large-scale white matter network disruption, which is related to apathy, but not depression. We then show that depression, as a construct, can be dissociated into distinct symptoms which are associated with overlapping and distinct areas of cortical atrophy over time. This suggests that depression as a general syndrome may be characterised by atrophy in core structures, while different symptoms are associated with atrophy in more specialised areas. Consistent with these patterns of overarching tissue damage, we find that apathy, but not depression, predicts conversion to dementia in patients with SVD.

Our findings suggest that different types of SVD-related pathology lead to apathy and depression. Diffuse white matter damage may lead to widespread network disruption, resulting in apathy and cognitive impairment. In contrast, depressive symptoms are associated with focal patterns of grey matter atrophy over time. This highlights the importance of differentiating neuropsychiatric symptoms, and paves the way for targeted treatment approaches.